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.