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  Table of Contents 
Year : 2021  |  Volume : 22  |  Issue : 2  |  Page : 149-156

Liver fibrosis-4 score predicts mortality in critically ill patients with coronavirus disease 2019

1 Department of Anesthesia and Intensive Care, Faculty of Medicine, Tanta University, Tanta, Egypt; Department of Intensive Care, Security Forces Hospital, Riyadh, KSA
2 Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
3 Department of Statistics, Federal University of Parana, Curitiba, Brazil
4 Department of Neuroscience, Biomedicine and Movement, Section of Clinical Biochemistry, University of Verona, Verona, Italy
5 Department of Intensive Care, Security Forces Hospital, Riyadh, KSA
6 Drug and Poison Information Center, Security Forces Hospital, Riyadh, KSA
7 Department of Rheumatology, Security Forces Hospital, Riyadh, KSA
8 Cardiac Intensive Care Unit, Cincinnati Children's Hospital Medical Center, The Heart Institute, Cincinnati, Ohio, USA

Date of Submission03-Apr-2021
Date of Decision22-Apr-2021
Date of Acceptance22-Apr-2021
Date of Web Publication29-Sep-2021

Correspondence Address:
Dr. Mohammed Fawzi Abosamak
Department of Anesthesia and Intensive Care, Faculty of Medicine, Tanta University, Tanta, Post Code 31511

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/TheIAForum.TheIAForum_49_21

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Background: Emerging evidence suggests that liver dysfunction in the course of coronavirus disease 2019 (COVID-19) illness is a critical prognostic factor for mortality in COVID-19 patients, and the Fibrosis-4 (FIB-4) score, developed to reflect level of hepatic fibrosis, has been associated with adverse outcomes in hospitalized COVID-19 patients. This study aimed to investigate intensive care unit (ICU) admitted patients, a high-risk subpopulation, research on which is lacking.
Materials and Methods: This retrospective cohort study examined FIB-4 scores and clinical endpoints including death, acute cardiac injury (ACI), acute kidney injury, and need for mechanical ventilation in critically ill COVID-19 patients, without prior hepatic disease, throughout ICU stay.
Results: Of 60 patients enrolled, 35% had ICU admission FIB-4 >2.67. Among nonsurvivors, FIB-4 was significantly higher at admission (median 3.19 vs. 1.44; P < 0.001) and only a minority normalized <1.45 (36.0%). Each one-unit increment in admission FIB-4 was associated with 67.4% increased odds of death (95% confidence interval [CI], 9.8%–162.6%; P = 0.017). FIB-4 >2.67 was associated with a median survival time of 18 days from ICU admission versus 40 days with FIB-4 <2.67 (P = 0.016). Admission FIB-4 was also higher in patients developing ACI (median 4.99 vs. 1.76; P < 0.001). FIB-4 correlated with age (r = 0.449; P < 0.001), and aspartate transaminase with alanine transaminase (r = 0.674; P < 0.001) and lactate dehydrogenase (r = 0.618; P < 0.001).
Conclusion: High ICU admission FIB-4 is associated with mortality in critically ill COVID-19 patients, with failure to normalize at time of death, however, the high score is likely a result of generalized cytotoxicity rather than advanced hepatic fibrosis.

Keywords: Coronavirus disease 2019, fibrosis-4, intensive care unit, liver fibrosis, mortality

How to cite this article:
Abosamak MF, Szergyuk I, Santos De Oliveira MH, Lippi G, Al-Jabbary AS, Al-Najjar AH, Albadi MA, Henry BM. Liver fibrosis-4 score predicts mortality in critically ill patients with coronavirus disease 2019. Indian Anaesth Forum 2021;22:149-56

How to cite this URL:
Abosamak MF, Szergyuk I, Santos De Oliveira MH, Lippi G, Al-Jabbary AS, Al-Najjar AH, Albadi MA, Henry BM. Liver fibrosis-4 score predicts mortality in critically ill patients with coronavirus disease 2019. Indian Anaesth Forum [serial online] 2021 [cited 2022 May 23];22:149-56. Available from: http://www.theiaforum.org/text.asp?2021/22/2/149/326981

  Introduction Top

Among extrapulmonary manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, acute liver injury has garnered substantial attention during the coronavirus disease 2019 (COVID-19) pandemic for its association with worse outcomes in infected patients.[1],[2],[3],[4] A large multicenter study involving 2273 patients has recently reported a prevalence of 45% for mild liver injury and ~28% for moderate to severe liver injury in COVID-19 patients.[4] Elevations in liver function tests, namely aspartate transaminase (AST) and alanine transaminase (ALT), have been associated with disease severity, intensive care unit (ICU) admission, and mortality in COVID-19.[4],[5],[6] Liver injury in patients with SARS-Cov-2 infection may be attributed to a number of possible mechanisms, including direct viral hepatocyte/cholangiocyte injury, cytokine storm, acute respiratory distress syndrome-associated hypoxia, as well as iatrogenic damage induced by hepatotoxic antiviral medications.[1],[3] Moreover, liver dysfunction may predispose patients to develop the more aggressive disease by impairing innate and adaptive host immunity,[7] as well as augmenting the release of pro-inflammatory cytokines, thus ultimately exacerbating COVID-19-associated immune dysfunction.[8] Therefore, timely identification of patients at higher risk for hepatic dysregulation should be a priority.

Several studies have reported an association between poor clinical outcomes in hospitalized COVID-19 patients and the Fibrosis-4 (FIB-4) score, an index combining AST and ALT levels, with age and platelet count,[9],[10],[11],[12] which was primarily developed as a noninvasive marker to track the degree of cirrhosis in hepatitis C infected patients,[13] as well as nonalcoholic fatty liver disease,[14] with the aim of avoiding liver biopsy. Its utility in COVID-19 patients is particularly promising given that both advanced age and thrombocytopenia have also been linked to adverse outcomes in SARS-CoV-2 infected patients.[15],[16] Among hospitalized patients, a higher FIB-4 score has been associated with severe COVID-19 illness,[8] mechanical ventilation,[10] mortality,[9],[12] as well as shorter time to ICU admission.[10] In this study, inclusive of only those with normal baseline liver function, we aimed to examine the association between FIB-4 score and various clinical endpoints in critically ill COVID-19 ICU patients, a subpopulation at the highest risk of mortality.[17]

  Materials and Methods Top

COVID-19 patients admitted to the ICU of the Security Forces Hospital, Riyadh, Saudi Arabia between May 2020 and August 2020 were enrolled in this retrospective cohort study. Inclusion criteria were SARS-CoV-2 infection confirmed with reverse transcriptase-polymerase chain reaction via nasopharyngeal swab and COVID-19 severe enough to require ICU admission for a minimum period of >24 h. Exclusion criteria were abnormal baseline (pre-COVID-19) liver function tests, any history of chronic liver disease, or use of chemotherapy within 1 month of the date of hospitalization due to the potential to bias FIB-4 score.

This study was approved by the Institutional Review Board of the Security Forces Hospital and received a waiver of informed consent due to no greater than minimal risk to participants. This study was conducted in accordance with the Declaration of Helsinki, under the terms of relevant local and national legislation.

Data were extracted by physicians from patients' electronic medical records into an electronic data collection form, with select records checked for accuracy by a second physician. Serum levels of AST (U/L), ALT (U/L), and platelet count (PLT, 109/L) were recorded at ICU admission and daily over course of ICU stay. FIB-4 scores were computed on three occasions: Upon admission to ICU, at peak for each patient, and their last day of ICU stay marked by either discharge or death. The following formula was used to obtain FIB-4 scores:[13]

FIB-4 <1.45 represented a normal score, based on an established negative predictive value of 90% for excluding hepatic fibrosis,[13] while FIB-4 >2.67 was considered highly reflective of advanced hepatic fibrosis, with an associated positive predictive value of 80%.[14]

Data on variables including age, sex, body mass index (BMI), and comorbidities such as obesity, hypertension (HTN), coronary artery disease, heart failure (HF), hyperlipidemia, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and history of stroke were recorded. Data on laboratory biomarkers, including white blood cells (WBC, 109/L), absolute neutrophil count (109/L), absolute lymphocyte count (109/L), neutrophil to lymphocyte ratio (NLR), platelets (109/L), C-reactive protein (CRP, mg/L), ferritin (ng/mL), procalcitonin (ng/mL), lactate (mmol/L), lactate dehydrogenase (LDH, U/L), creatine kinase (CK, U/L), cardiac troponin T (cTnT) ng/mL), D-dimer (DDU μg/mL), total bilirubin (μmol/L), and creatinine (μmol/L) were captured over course of entire hospital stay.

The primary endpoint assessed was survival until hospital discharge, while the secondary endpoints were acute cardiac injury (ACI), acute kidney injury (AKI), and need for mechanical ventilation. ACI was defined as serum level of high-sensitive cTnT >100 ng/L at any point during the hospital stay,[18] while AKI was defined as increase in serum creatinine by ≥26.5 μmol/L within 48 h after ICU admission.[19]

Categorical variables were described by absolute and relative frequencies, and differences between groups were analyzed using Fisher's exact test. Quantitative variables were represented by the median and interquartile range (IQR), and differences between groups were evaluated using Mann–Whitney's U-test. Prevalence of comorbidities, levels of various hematologic and inflammatory biomarkers, and FIB-4 scores on admission, at peak, and discharge/death, were assessed for the difference between survivors and nonsurvivors. FIB-4 values were also compared with regard to the presence or absence of secondary endpoints. Comparisons of FIB-4 scores between different time points within survival and nonsurvival groups, as well as secondary endpoint groups, were performed using Wilcoxon signed-rank test. The association between categorical FIB-4 score and death was estimated using Kaplan-Meier to produce median survival times and survival curves for FIB-4 categories based on the aforementioned cutoff of FIB-4 >2.67, with an associated high probability of hepatic fibrosis.[14] The difference between survival curves was assessed using the Log-rank test.

Correlation between AST, ALT, and lactate, LDH, cTnT, creatinine, CPK, as well as between FIB-4 and ferritin, CRP, procalcitonin, WBC count, NLR, CK, and age was performed using Spearman's correlation coefficient. Logistic regression was also performed to identify baseline characteristics, comorbidities, and laboratory values at ICU admission independently associated with patient death, with calculation of 95% confidence intervals (95% CI), and after adjusting for confounders. Statistical analysis was performed using R software (version 4.0.2, R Foundation for Statistical Computing, Vienna, Austria), with a threshold of significance being P < 0.05.

  Results Top

A total of 60 patients with confirmed SARS-CoV-2 infection and admitted to the ICU were enrolled. Males accounted for 73% (n = 44) of the cohort. The median age was 57 (IQR, 49–67) years. All patients had elevated BMI ranging from overweight to extremely obese (median 31 [IQR, 27.7–36.5] m/kg2), with 38% (n = 17) classified as obese. HTN (n = 31, 52%), diabetes (n = 34, 57%), and hyperlipidemia (n = 18, 30%) were the most frequently observed co-morbidities. Full patient baseline data are presented in [Table 1].
Table 1: Baseline characteristics, comorbidities, fibrosis -4 scores, and circulating biomarkers in intensive care unit admitted coronavirus disease 2019 patients, as well as according to survival

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Most patients had significantly elevated AST (median 48 [IQR, 37–71] U/L) and an AST/ALT ratio >1 was observed in 46 (76.7%) patients (median 1.43 [IQR, 1.05–1.95]) on ICU admission. Platelets (median 213 [IQR, 156–285] ×109/L) and total bilirubin (median 7.6 [IQR, 5.5–10.8] μmol/L) were within normal range in all patients at ICU admission, while ALT was normal in most (median 33 [IQR, 24–47] U/L) [Table 1]d. Notably, NLR was significantly elevated in most patients (median 5.78 [IQR, 2.91–9.89]).

The median FIB-4 score at ICU admission was 1.87 (IQR, 1.35–3.36), with 35% (n = 21) having a normal score (i.e., <1.45), reflecting low likelihood of hepatic fibrosis. A score above normal cut-off was observed in 65% (n = 39), with 30% (n = 18) between the 1.45 and 2.67 cutoffs, and 35% (n = 21) with a score above 2.67, in the range representing high probability of hepatic fibrosis[14] [Table 1]c. FIB-4 scores were not correlated with any hematologic or inflammatory biomarkers [all P > 0.05; [Supplemental Digital Content 1]].

FIB-4 scores were significantly correlated with age [r = 0.449; P < 0.001; [Supplemental Digital Content 1]], and among comorbidities, significantly elevated only in patients with HF [P = 0.027 with Mann–Whitney's U-test; [Supplemental Digital Content 2]].

Twenty-five (42%) patients died, while the secondary endpoints of ACI developed in 9 (15%) patients, AKI in 22 (37%), and mechanical ventilation was required in 34 (57%). The median age was significantly higher in nonsurvivors compared to survivors (67 vs. 50 years; P = 0.002). No significant differences were found with respect to sex (P = 0.921) and BMI (P = 1.00) in nonsurvivors versus survivors, whilst HF was significantly more prevalent in nonsurvivors (P = 0.026) [Table 1].

At ICU admission, serum creatinine (P = 0.044), serum lactate (P = 0.045), D-dimer (P = 0.004), and cTnT (P = 0.045) were significantly elevated in nonsurvivors opposed to those who survived. Despite many being elevated overall, no differences were observed in any inflammatory or hematologic biomarker at ICU admission between survivors and nonsurvivors [Table 1]d.

A significant elevation in median ICU admission AST (median difference: +18 U/L, P = 0.004) and median AST/ALT value (1.92 vs. 1.25; P = 0.008) was observed in nonsurvivors as opposed to survivors, while no significant differences were found in ICU admission ALT (P = 0.359) or total bilirubin (P = 0.929) [Table 1]. To probe alternative sources of AST (skeletal muscle or heart), we correlated AST with ALT, cTnT, CK, creatinine, lactate, and LDH. Overall, AST was highly correlated with ALT (r = 0.674; P < 0.001) and moderately correlated with LDH (r = 0.618; P < 0.001). No correlation was observed with cTnT (r = 0.317; P = 0.151), CK (r = 0.010; P = 0.970), creatinine (r = 0.162; P = 0.228), nor lactate (r = 0.247; P = 0.173).

Nonsurvivors were more frequently observed than survivors to have a FIB-4 score >2.67 measured at ICU admission (71.4% vs. 28.6%; P = 0.001), at peak (68.6% vs. 31.4%, P < 0.001), and at discharge/death (93.75% vs. 6.25%, P < 0.001) [Table 1]c. Nonsurvivors also had overall higher ICU admission FIB-4 score (median 3.19 vs. 1.44; P < 0.001); the score then peaked at a level significantly higher than the survival group (median 7.25 vs. 2.03; P < 0.001); and finally failed to normalize <1.45 at discharge/death in nonsurvivors (median 3.55 vs. 1.10; P < 0.001), with only 36.0% normalized compared to 68.6% in the survival group [Figure 1]a.
Figure 1: Fibrosis-4 scores by survival (a), acute cardiac injury (b), acute kidney injury (c), and need for mechanical ventilation (d), measured at intensive care unit admission, peak during intensive care unit stay, and intensive care unit discharge or death in critically ill coronavirus disease 2019 patients

Click here to view

Logistic regression analysis results are shown in [Table 2]. Each one-unit increment in FIB-4 score at ICU admission was found to be associated with 67.4% increased odds of death (95% CI, 9.8%–162.6%; P = 0.017), after controlling for all covariates displaying a statistically significant difference between the groups in bivariate analysis (excluding AST and ALT to prevent collinearity).
Table 2: Logistic regression for death

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In survival analysis, an ICU admission FIB-4 score above 2.67 was associated with a median survival time of 18 days from ICU admission, while a score <2.67 was associated with a median survival time of 40 days [P = 0.016; [Figure 2]]. Using receiver operator characteristic curve to determine an optimal cutoff point for predicting death, a FIB-4 score >2.95 was associated with sensitivity of 0.60, specificity of 0.84, and area under the curve of 0.787, but yielded the same median survival times as the 2.67 cutoff [Supplemental Digital Content 3].
Figure 2: Survival curves for Fibrosis-4 score categories <2.67 and >2.67 in intensive care unit admitted coronavirus disease 2019 patients

Click here to view

FIB-4 scores by the presence of ACI, AKI, and need for mechanical ventilation, measured over the course of ICU stay are presented in [Figure 1]b, [Figure 1]c, [Figure 1]d. Overall, admission FIB-4 scores were significantly higher in patients that developed ACI (median 4.99 vs. 1.76; P = 0.015), but not in those who developed AKI (median 2.62 vs. 1.69; P = 0.052) or needing mechanical ventilation (median 1.98 vs. 1.65; P = 0.394) [Supplemental Digital Content 4]. FIB-4 normalized <1.45 in 33.3% (n = 3) of patients who developed ACI, in 72.7% (n = 16) with AKI, and in 52.9% (n = 18) of those needing mechanical ventilation. When analyzed categorically, the prevalence of FIB-4 >2.67 was not significantly different between patients that did or did not develop ACI (P = 0.054), AKI (P = 0.263), nor needed mechanical ventilation (P = 0.287), and FIB-4 >2.67 was not significantly more prevalent than FIB-4 ≤2.67 with regard to each secondary endpoint either [Supplemental Digital Content 5].

  Discussion Top

Our findings demonstrate that high FIB-4 score at ICU admission is predictive of survival in critically ill COVID-19 patients. Higher admission FIB-4 score increased the odds of mortality by 67.4% for every one-unit increment, and survival time of patients with an admission score reflecting a higher risk of hepatic fibrosis was 22 days shorter than in patients with low FIB-4. The accuracy of predicting COVID-19-related mortality in our cohort was most optimal past the cutoff of 2.95. Moreover, patients who died had consistently elevated FIB-4 scores throughout the entire course of ICU stay and notably, with failure to normalize over course of illness when compared to the survival group.

Together with findings of a strong correlation between FIB-4 and age, the differences in baseline characteristics and laboratory values observed between survival and death group seem to suggest that older age and higher AST, primarily contribute to findings of elevated FIB-4 in nonsurvivors, while platelet count, with only a statistically insignificant trend toward lower levels in patients that died, may contribute to a lesser extent.

In search of the source(s) of AST elevation, we only observed a moderate correlation between AST and LDH, a nonspecific marker of tissue damage, suggesting that AST causing elevated FIB-4 may be derived from generalized cellular injury (including hepatic) caused by multiple ongoing mechanisms in the setting of COVID-19 illness. In a case series by Schattenberg et al., a questionably high rate of advanced hepatic fibrosis was identified using FIB-4 in a cohort of 44 hospitalized COVID-19 patients, with findings of elevated LDH and CK in the absence of severe liver dysfunction attributed to cytotoxicity.[20] Nonetheless, this correlation holds up in light of research reporting LDH as a particularly useful tool for identifying COVID-19 patients at the highest risk for severe illness and death,[21] much alike to FIB-4, as we have demonstrated. All things considered, despite the fact that the FIB-4 cutoffs used have been validated in many conditions resulting in hepatic fibrosis,[13],[14] an elevated FIB-4 in COVID-19 may actually not be reflective of liver disease and be over-diagnosing hepatic fibrosis. Hence, its utility in COVID-19 may be limited to evaluating the risk of adverse outcomes. Nonetheless, without confirmation from biopsy, elastography, or ultrasound of the liver, these deductions are inconclusive.

Admission FIB-4 was also higher in patients that went on to develop ACI, however, AST was not correlated with cTnT. Therefore, the cardiac injury did not appear as a clinically significant source of AST causing increased FIB-4 either. Instead, this effect may be an indirect result of increased hepatic pressures following impaired cardiac function. Such an explanation, however, cannot be generalized to all 15 nonsurvival cases with FIB-4 >2.67, as only 6 (40%) of them presented with ACI. Likewise, Li et al. arrived at a similar conclusion though, unlike in our study, they found a correlation with CK, suggesting skeletal muscle as a source of AST.[12] Furthermore, high fibrosis risk did not seem to reflect the development of ACI, given that FIB-4 >2.67 among these patients was not significantly more prevalent than FIB-4 ≤2.67.

ICU admission FIB-4 was not significantly higher in patients that developed AKI, and AST was not correlated with creatinine, excluding renal injury as a significant source of AST in our cohort.

Our findings are in line with several recent studies associating FIB-4 with adverse outcomes in COVID-19. In a cohort of 202 hospitalized COVID-19 patients, Li et al. found 79% increased odds of death per 1-unit rise in FIB-4,[12] slightly higher than in our study (67.4%), but such difference may be attributed to the inclusion of only critically ill patients in our study. Another study, first to investigate FIB-4 scores in COVID-19 patients with confirmed nonalcoholic fatty liver disease, demonstrated increased prevalence of severe COVID-19 illness from 13.6% in patients with FIB-4 ≤1.3%–42.9% with FIB-4 >2.67.[8] Similar to our survival estimates, Park et al. discovered that higher FIB-4 groups have shorter survival time (28.8 days) than lower FIB-4 groups (44 days).[9] Moreover, in a retrospective multicenter study, Ibáñez-Samaniego et al. observed that time to ICU admission was significantly shorter in patients with FIB-4 ≥2.67 compared to those with low risk of hepatic fibrosis (5 vs. 10 days; P = 0.05).[10] In addition, we observed older age, elevated D-dimer, and higher cTnT among several other laboratory values measured in nonsurvivors, which is consistent with reports identifying these variables as risk factors for mortality in COVID-19.[12]

Nonetheless, some of our other findings are discordant with prior research. In the aforementioned study by Ibáñez-Samaniego et al., the researchers reported 3.41-fold increased odds of mechanical ventilation in hospitalized COVID-19 patients with an FIB-4 score ≥2.67 on admission.[10] In our study, on the other hand, we found no significant difference in FIB-4 between patients needing and not needing mechanical ventilation, as well as comparable frequency of FIB-4 ≤2.67 and >2.67 among them. The difference in findings may be explained by the fact that our cohort comprised of critically ill patients, of whom a large proportion developed need for mechanical ventilation (56.7%), as opposed to the hospitalized patients in the study by Ibáñez-Samaniego et al. (22.5%).[10] Our critically ill patients were likely much sicker at baseline and more likely to develop respiratory failure, making need for mechanical ventilation a more nonspecific finding. Furthermore, Li et al. suggested that the association between FIB-4 and mortality is driven in part by hyperinflammatory state.[12] Whilst in our study, we identified no significant correlations between FIB-4 and inflammatory biomarkers, including CRP, NLR, and ferritin. Recent evidence determined NLR to be a particularly useful marker for predicting COVID-19 prognosis,[22] however, despite being elevated overall in our cohort of critically ill patients, this ratio was comparable among survivors and nonsurvivors. Thus, elevated FIB-4 might not be synergistic with the dysregulated immune state of COVID-19 in contributing to mortality.

The main strength of this study is that we followed FIB-4 scores over the course of ICU stay, thus we were not only able to explore associations of ICU admission FIB-4 levels with mortality, but also observe how FIB-4 scores changed based on endpoints over time. Further, the inclusion of only patients with normal (pre-COVID-19) baseline liver function and exclusion of chronic liver disease in this cohort precludes any effect modification that this condition would have on FIB-4, allowing us to demonstrate that FIB-4 is a useful index in predicting mortality in ICU COVID-19 patients, independent of underlying liver disease. However, without any confirmation with biopsy or imaging it is not certain whether FIB-4 actually reflects the degree of liver fibrosis, and the potential for liver fibrosis and post-COVID-19 related hepatic sequelae requires further study. The secondary endpoints of ACI and AKI were solely based on surrogate laboratory measurements of circulating biomarkers rather than a clinical diagnosis. Finally, the ethnicity of our cohort limits the external validity of our findings, and these observations may not be as generalizable to patients infected by the newer COVID-19 variants, which may be associated with increased virulence and higher mortality.

In conclusion, a significant proportion of ICU COVID-19 patients with no preexisting liver disease have FIB-4 score highly suggestive of advanced hepatic fibrosis. This is likely the result of generalized COVID-19 related cytotoxicity. Given that elevated FIB-4 score on admission was found to have a high prognostic value for mortality, we recommend regularly checking FIB-4 scores, derivative parameters of which are simple, cost-effective, and routinely measured, to identify particularly vulnerable patients.

Ethical approval

This study was reviewed and approved by the Institutional Review Board (IRB) of the Security Forces Hospital.

Informed consent

This study received a waiver of informed consent due to no greater than minimal risk to participants.

Data availability

Data available on reasonable request from the authors.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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