Review for 10.1186/s12876-025-04141-1 (2025)

Title: Correlation between systemic inflammatory response syndrome and prognosis of patients
with cirrhosis and hepatic encephalopathy
Version: 2 Date: 07 May 2025
Reviewer's report:
The authors conducted a retrospective cohort study to examine the clinical significance of
systemic inflammatory response syndrome (SIRS) in patients with liver cirrhosis (LC) who
were hospitalized for hepatic encephalopathy (HE). The study included 161 patients who
met inclusion criteria and excluded 238 patients with malignancies, neurological diseases,
or incomplete data. Of the included patients, 60 were diagnosed with SIRS and 40 died
during hospitalization. The authors reported that SIRS and MELD score >18 were independent
predictors of in-hospital mortality and that increasing SIRS score was associated with a stepwise
increase in 28-day mortality. They also noted that patients with both SIRS and MELD >18
had the worst prognosis. Furthermore, infection was common and was disproportionately
observed in SIRS patients, who had worse outcomes. The manuscript highlights a clinically
important issue in hepatology and critical care, particularly the interaction between systemic
inflammation and neurological deterioration in decompensated cirrhosis. The findings are
statistically supported and the authors present a thorough analysis of multiple risk factors,
including SIRS criteria, MELD score, infection status, and laboratory markers. However, the
study suffers from several critical methodological flaws, conceptual limitations, incomplete
reporting of key clinical data, and major concerns related to the use of outdated diagnostic
frameworks and unadjusted confounding. The manuscript is also affected by imprecise language,
inconsistent terminology, and a lack of clarity in figure presentation and reference use. These
issues must be addressed before the study can be considered for publication.
Major Concerns
A primary concern is the sole reliance on the 2001 SIRS criteria to define systemic inflammation.
While historically relevant, SIRS has been largely superseded by Sepsis-3 definitions and other
scoring systems such as SOFA and qSOFA. These updated criteria offer more specificity in
critical illness, particularly in cirrhotic patients where baseline inflammatory markers may be
misleading due to hypersplenism, bacterial translocation, and chronic immune dysfunction.
The manuscript does not mention or compare these updated criteria, nor does it discuss their
limitations or why SIRS was chosen as the sole definition. The lack of alternative benchmarks
undermines the interpretability of the findings in current clinical practice. This concern is
compounded by the fact that SIRS and its components—white blood cell count, neutrophil count,
C-reactive protein, and NLR—are simultaneously included as separate variables in multivariate
regression analyses. These variables are pathophysiologically linked and mathematically
correlated, which introduces collinearity and inflates the statistical significance of the findings.
The authors do not report any variance inflation factor (VIF) or statistical method to address this
problem. As such, the independence of SIRS as a prognostic variable is questionable.
Another significant problem is the use of a MELD score >18 as a dichotomous threshold to
stratify patients. This cutoff appears arbitrary and is not substantiated with reference to previous
studies or guidelines. The MELD score is a continuous variable that reflects liver function
and mortality risk in a graded manner. A dichotomous cutoff imposes artificial categorization
and may obscure more nuanced relationships. Furthermore, the manuscript does not provide
sensitivity analyses to show whether alternative cutoffs would yield similar results. In addition, it
is unclear whether the MELD score was calculated at a single time point or tracked dynamically
during hospitalization. This is important because MELD can vary in acutely decompensated
patients and could reflect either baseline severity or acute changes. Similarly, the classification
of infection is vague and lacks critical clinical detail. The manuscript states that infection was
present in 84 patients but does not specify the diagnostic criteria used, the site of infection, or the
microbiological confirmation methods. It is also unclear whether these infections were present
on admission or acquired during hospitalization. The sequence of events—whether infection
led to SIRS, which then precipitated HE, or vice versa—is not defined, making causality
assumptions speculative. Moreover, no information is provided about how infections were
managed, whether patients received antibiotics, and how this may have influenced outcomes.
Given the central role of infection in cirrhosis-related decompensation and the known overlap
between sepsis and HE, the omission of this detail severely limits interpretive value.
The study design also raises concerns about sampling bias. From the original 399 patients
screened, 238 were excluded, amounting to nearly 60% of the cohort. While the authors provide
some categories for exclusion—malignancy, neurological comorbidities, and missing data—
they do not stratify these reasons further or analyze the characteristics of excluded patients.
Without a comparison to included patients, the risk of selection bias is high. For example, it
is possible that excluded patients had milder or more severe disease or different inflammatory
profiles. Furthermore, patients with neurological diseases were excluded, yet the criteria for
defining these conditions are not specified, despite their relevance in patients with HE. Another
concern is that treatment-related data are entirely missing. No information is provided on
whether patients received rifaximin, lactulose, mannitol, intravenous antibiotics, vasopressors,
or were transferred to ICU care. These interventions have substantial effects on survival and are
necessary variables in prognostic modeling. Without adjustment for treatment modalities, the
associations between SIRS, MELD, and mortality risk may be confounded by differences in care
received. Moreover, the analysis of SIRS score stratification is limited by small subgroup sizes.
For example, only 16 patients had a SIRS score of 3 and only 8 had a score of 4. These small
numbers reduce statistical power and generate wide confidence intervals, making the reported
hazard ratios unstable. The authors report that patients with a score of 4 had a hazard ratio of
31.5 for mortality, but the confidence interval spans from 3.8 to over 250, indicating a lack of
precision.
Minor Concerns
Several aspects of the manuscript’s presentation require improvement. The term “massive
diuresis” is used in the list of HE precipitants but is not defined clinically or supported by any
reference. The authors should use standard terminology and clarify whether this refers to overuse
of diuretics, dehydration, or electrolyte shifts. The manuscript frequently uses non-standard
phrasing such as “patients suffering liver cirrhosis,” which should be revised to “patients with
liver cirrhosis.” Laboratory and clinical variables are reported redundantly in both the text
and tables, which detracts from the flow of the results section. The figures, particularly the
Kaplan-Meier survival plots, lack full explanatory legends. For example, the reader is not told
how censored observations were handled or what statistical test was used to compare survival
curves. Some abbreviations such as NEU, NLR, and INR are used before being defined. The
ethics statement in the manuscript is minimal and should be expanded to include the protocol
approval number and institutional review board. The supplementary materials are mentioned
inconsistently and not always referenced when their data are used in the main text.
Limitations
The manuscript omits discussion of several important limitations. The authors do not
acknowledge the absence of treatment data, which could substantially affect survival and
inflammatory response. Nor do they discuss the subjectivity of HE grading, which relies on
clinical interpretation and could vary among physicians. No effort was made to account for inter-
rater variability in HE staging. The lack of cause-specific mortality data is also problematic. The
authors report all-cause in-hospital death but do not determine whether deaths were due to liver
failure, infection, variceal bleeding, or other causes. This prevents more refined analysis of SIRS
impact. The study is based on data from a single center in China and lacks external validation,
so the generalizability of findings is limited. Moreover, the manuscript does not describe how
missing data were handled, whether any imputation was performed, or how the authors ensured
data completeness for key variables. These issues limit the internal and external validity of the
study.
Language and Grammar
The manuscript contains numerous grammatical errors and requires careful language editing
to improve clarity. There is inconsistent use of past and present tense throughout the methods
and results. Sentences are often overly long and contain redundant phrases. For example,
the sentence “These findings suggest that the presence of SIRS as well as SIRS score were
significantly associated with 28-day mortality” is ungrammatical and should read, “These
findings suggest that both the presence and score of SIRS were significantly associated with 28-
day mortality.” Other phrases such as “patients who suffered infection” should be rewritten as
“patients with infection.” The discussion section is repetitive and often rephrases results without
adding interpretive insight. Overall, the manuscript would benefit from thorough editing by a
native English speaker with experience in academic writing.
Reference Use and Style
The references are relevant but are not well integrated into the text. Citations are often
placed at the end of sentences without being woven into the discussion. This weakens the
argumentative flow and suggests superficial engagement with the literature. More recent
references on Sepsis-3, SOFA, and qSOFA scoring in cirrhotic patients should be included,
as well as contemporary studies on HE management and the role of systemic inflammation.
Several references are outdated and some journal names are not consistently abbreviated. All
citations should be checked for completeness, and the reference list should be revised to meet the
formatting requirements of the target journal. In-text citation placement should be improved by
embedding references naturally into analytical statements rather than appending them passively
to conclusions.