3.4 Assessment of the predictive performance of Flu-IV scores
The AUROC value for the Flu-IV score model developed based upon the
above multivariate analysis was 0.927 in our overall patient cohort
(95% CI 0.906 - 0.944), and was higher than that of the ROX
index (AUROC = 0.688, 95% CI 0.654 - 0.721, p <
0.001 ), modified ROX index (AUROC = 0.747, 95% CI 0.715 -
0.778, p < 0.001), or HACOR scale (AUROC = 0.524,95% CI 0.488 - 0.560, p < 0.001) (Supplementary
Material 6 and Figure 3). Similar findings were also independently made
in both our derivation cohort (Supplementary Material 7 and
Supplementary Figure 1) and validation cohort (Supplementary Material 8
and Supplementary Figure 2).
Table 2 compiles the mortality rates, sensitivity, and specificity
values associated with our Flu-IV score model in the overall patient
cohort. Patients were stratified into high- and low-risk cohorts based
upon whether they had Flu-IV scores that were above or below the optimal
cutoff score of 6 points. Subsequent Kaplan-Meier curves confirmed that
high-risk patients were significantly more likely to require IMV
relative to low-risk patients (49.5% vs 1.8%, log-rank test, p< 0.001) (Figure 4).
Discussion
This was a multicenter retrospective study designed to develop a novel
model capable of predicting the odds of IMV within 14 days of admission
for Flu-p patients. Our resultant Flu-IV risk score model was more
accurate and exhibited better predictive performance relative to the
ROX, modified ROX, and HACOR scales when evaluating these patients.
We found that 10.6% of the patients in the present study necessitated
IMV within 14 days of admission, in line with prior reports regarding
severe influenza patient outcomes [15-16]. The 14-day mortality of
patients that did require IMV was significantly greater than that of
patients that did not. As 92.1% of Flu-p patients that undergo IMV do
so within 14 days of admission, predicting 14-day IMV rates is critical
to appropriate patient management.
We identified multiple variables that are known to be associated with
more severe influenza and that were also associated with a higher risk
of IMV in Flu-p patients [17], including age > 65
years, a lymphocyte count < 0.8×109/L, and
systemic corticosteroid use. Cellular immunity is a key mediator of
antiviral responses [18], and advanced age is associated with a
decline in overall patient immune status [19]. Severe influenza is
also often characterized by lymphocytopenia in 50-100% of cases
[20-21], although the mechanistic basis for this finding remains
poorly understood. There is some evidence that CD4+ and CD8+ T cells may
undergo higher rates of apoptotic death in individuals with severe
disease owing to higher circulating levels of soluble Fas ligand and
caspase-1 [22], thereby contributing to an overall decline in
lymphocyte counts. Such virus-induced lymphocytopenia can delay viral
clearance. Alternatively, these lymphocytes may be recruited to the
respiratory tract and other organs, resulting in their apparent
depletion from circulation [23]. Lymphocyte accumulation within the
lungs can drive more severe localized inflammation and tissue damage.
Systemic corticosteroid use can suppress overall immune functionality
and increase the odds of developing severe nosocomial pneumonia
necessitating IMV [24-25].
Severe Flu-p is characterized by impaired pulmonary function and diffuse
alveolar damage [26], with tachypnea and decreased
PaO2/FiO2 serving as direct
manifestations of such pulmonary damage. Pneumonia patients also often
exhibit metabolic acidosis that is linked to hyper-inflammation and
impaired tissue perfusion [27], thereby exacerbating pulmonary
damage. Impaired pulmonary function and the retention of carbon dioxide
in the lungs can further drive respiratory acidosis, leading to higher
rates of NIMV failure and an increased risk of requiring IMV [28].
Inhibiting viral replication at early time points can reduce
virus-induced inflammation and tissue damage, thereby decreasing overall
influenza-related mortality rates [29]. This has been proven by
abundant clinical studies [30-31]. Our data also suggest that early
NAI treatment was associated with a lower risk of Flu-p patient
intubation.
The ROX, modified ROX, and HACOR scales have been designed to predict
the odds of IIMV failure in patients suffering from hypoxemia. Just 49%
of patients in the present study cohort exhibited hypoxemia upon
admission. Importantly, these scoring systems were not designed for the
analysis of Flu-p patients. While some of the variables included in our
Flu-IV model were the same as those included in the ROX, modified ROX,
and HACOR scales, these tools were not able to reliably predict IMV
rates among Flu-p patients. We found that our Flu-IV tool was able to
predict IMV rates significantly more reliably than these three scales as
determined based upon AUROC values. A Flu-IV cutoff score of 6 was able
to effectively stratify Flu-p patients into low- and high-risk
categories. Considering its good negative prediction value, the Flu-IV
score could be used particularly as a rule-out approach to early
discharge patient with a low score. Importantly, our Flu-IV scoring
model is simple, allowing clinicians to predict the odds of a given
patient requiring IMV within 14 days of admission based upon eight
parameters that can be readily measured even in small or primary
hospitals. This model can be used to evaluate patients at an early time
point prior to the onset of respiratory failure, and as such, we believe
it represents a valuable tool for the management of Flu-p patients in a
variety of clinical settings.