The coronavirus diseases 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and it is commonly referred to as the novel coronavirus (2019-nCov) that first appeared in 2019, is a novel pandemic rapidly spreading virus that belongs to the Coronaviridae family of enveloped, positive-sense single-stranded RNA group of viruses[1-3]. Since COVID-19 was originated in December 2019 in Wuhan, China, and was declared by WHO as pandemic on March 2020, it is primarily responsible for approximately 2.52 M deaths as of February 28, 2021, in COVID-19 infected patients that were commonly have comorbidities, including but not excluded to, diabetes, chronic lung diseases, kidney and cardiovascular diseases, and cancer [4-5].

Although in most case scenarios the clinical presentations of COVID-19 infected patients vary from asymptomatic or mild-moderate respiratory symptoms, the vulnerable COVID-19 infected patients may rapidly progress into severe acute respiratory distress syndrome (ARDS), cardiopulmonary collapse accompanied with hemodynamics instability and severe metabolic acidosis, disseminated intravascular coagulation (DIC), cardiovascular injuries (ischemia, pulmonary thromboembolism, and deep venous thrombosis),  cerebral infarctions (embolism), and multi-organ failure [6-7]. The pathogenesis of SARS-COV-2 is distinctive and has huge attention due to its novel special feature in attacking not only the respiratory system but also other many known and unknown systems in the body [8]. In addition to the highly variable incubation period of 2-14 days, hugely pervasive tendencies, and their ability to modernize themselves, making COVID-19 a global crisis that requires the combined efforts of all humans to combat it [9].

Several theories are explaining the involvement of different systems in the body, the first being "Cytokine Storm" and the second being "Radical Storm" These two theories show clear evidence of the involvement of the immune system in eradicating the virus or worsening disease. [10] A cytokine storm is a dysfunctional reaction in immunopathogenic cascades resulting in hyper-inflammatory cytokines production, including but not excluded to, interleukins 2, 6, 8, and 12 (IL-2, IL-6, IL-8, and IL-12, respectively), and TNF-α during uncontrolled immuno-reaction progression, primarily ending with ARDS and other aforementioned COVID-19 associated complications [11-14].

Largely, elevated biochemical levels that contributing to COVID-19 associated complications are lactate dehydrogenase (LDH), c-reactive protein (CRP), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), serum Ferritin, IL-6, neutrophils to lymphocytes ratio (NLR), monocytes to lymphocytes ratio (MLR), creatinine (SCr), alkaline phosphatase (ALP), D-Dimer, and Troponin-I [15-16]. In particular, the blood levels of CRP and Ferritin levels are the most correlated positive phase reactant that are commonly used in clinical practices for theirs diagnostic and prognostic values. Notably, elevated levels of Ferritin and CRP are highly correlated to diseases prognosticating and both have a high-performance utility in early prediction for COVID-19 trending even before radiological CT findings [17]. However, growing evidence shows that Ferritin level is uniquely elevated in an overestimated manner which may give a superiority prognostic value over CRP [18-20].

Generally, Serum Ferritin level is primarily affected by iron status and it is proportionately elevated secondary to hemophagocytic-compensatory hyperimmune status in the excessive inflammation due to COVID-19 pathogenesis as a well-known biomarker in other variety of infectious and non-infectious conditions. [21-22] Additionally, Hyperferritinemia is a common feature that is frequently observed in mechanically ventilated critically ill patients with severe ARDS and it is closely related to poor recovery from COVID-19 and high mortality probability. [23-24] Theoretically, while both Ferritin and CRP are considered as a positive acute phase reactant and serum albumin is considered as a negative phase reactant, the prediction capacity of dual ratios of Ferritin to Albumin (FER: ALB) and CRP to Albumin (CRP: ALB) are expected to be higher in COVID-19 infection patients [25-26].

However, serum Ferritin and CRP levels are particularly interesting due to their dual potential diagnostic and prognostic roles, and when both levels are integrated with other biochemical parameters, clinical and radiological findings, valid tools, and multi-disciplinary clinical judgments, rapid and more efficient risk stratification and assessment are anticipated to optimally guide clinicians for these high mortality risk cohort. [27] For this reason, our main goal was to assess the complications and mortality prognostic value for the two aforementioned tested prognosticators in mechanically Ventilated Critically I'll COVID-19 Infected Patients. 

A single-center, observational, retrospective study was conducted on all mechanically ventilated critically I'll COVID-19 infected patients that were admitted into the intensive care units (ICUs) of our Royal Medical Services (RMS) institutions, Jordan between April 2020 and Dec 2020. Owing to our study’s retrospective design, a signed consent form was waived. This study was approved by our institutional ethical review board (IRB). All eligible mechanically ventilated critically ill COVID-19 infected patients for this study, were admitted from other COVID-19 isolation wards and all had moderate-severe ARDS as explained numerically by persistent average Pa02 / FiO2 <200 and radiologically confirmed. Analytical variables were firstly evaluated for normality of distribution by using Kolmogorov-Smirnov Test. Normally distributed continuous variables were expressed as Mean±SD by using independent T-Test while non-parametric categorical/ordinal variables were expressed as either Number (Percentages) by Chi Square Test or as Median (IQR) by using the Mann-Whitney U Test, respectively. All demographical, co-morbidities, biochemical, clinical, radiological, and pharmacological data were extracted from the institutional electronic system (Hakeem). Comparative variables were compared across Cohort I (Survivors) and Cohort II (Non-Survivors). A receiver operating characteristic (ROC) curve followed by sensitivity analysis was used to determine the area under the ROC curves (AUROCs), predictive performances, and the optimal cut-off values for the two tested prognosticators (CRP and Ferritin). Youden’s indices, sensitivities, specificities, positive and negative predictive values, and accuracy indices were also calculated. Statistical analyses were performed using IBM SPSS ver. 25 (IBM Corp., Armonk, NY, USA) and P-values ≤0.05 were considered statistically significant. Other secondary endpoints, including but not excluded to, intensive Care Unit (ICU) and overall hospital length of stay (LOS).

From three hundred and seventy-four (N = 374) adult and elderly admitted mechanically ventilated critically ill 

Table 1: Mechanically ventilated critically ill COVID-19 infected patients’ comparative variables and analyze outcome data between Cohort I (Survivors) and Cohort II (Non-Survivors)

Data results of the comparative variables between the Survivors and Non-Survivors groups are statistically analyzed by independent T, Whitney-U, and Chi Square Tests Data (at p-value< 0.05). Data results of the comparative variables between the Survivors and Non-Survivors groups are expressed as Mean±SD, Mean (Range), Number (Percentage). Cohort I: Survivors. Cohort II: Non-Survivors. Yrs: Years.Kg: Kilogram. m: Meter. BW: Actual body weight at admission. BMI: Body mass index at admission.ICU: Intensive care unit. S: Significant (p-Value <0.05).NS: Non-significant (p-Value >0.05). N: Number of study’s critically ill patients

Table 2: Mechanically ventilated critically ill COVID-19 infected patients’ comparative variables and analyze outcome data between Cohort I (Survivors) and Cohort II (Non-Survivors)

Data results of the comparative variables between the Survivors and Non-Survivors groups are statistically analyzed by independent T, Whitney-U, and Chi Square Tests Data (at p-value< 0.05). Data results of the comparative variables between the Survivors and Non-Survivors groups are expressed as Mean±SD, Mean (Range), Number (Percentage). Cohort I: Survivors. Cohort II: Non-Survivors. N: Number of study’s critically ill patients. bpm: beat per minute. mcg: microgram. min: minute. NE: Norepinephrine. SI: Shock index. S: Significant (p-Value <0.05). NS: Non-significant (p-Value >0.05). H.ALB: Human Albumin 20%. GCS: Glasgow coma scale. ALB: Albumin level. CRP: C-reactive protein. FER: Ferritin. LDH: Lactate dehydrogenase. CRP: ALB: CRP to ALB ratio. FER: ALB: FER to ALB ratio

Table 3: The optimal cut-off point, sensitivity, specificity, positive and negative predictive values, Youden, and accuracy indices for the two tested mortality prognosticators of CRP and FER

CRP: C-reactive protein. FER: Plasma ferritin level. TPR: True positive rate (sensitivity) FPR: False positive rate. YI: Youden index. PPV: Positive 

predictive value. NPV: Negative predictive value. AI: Accuracy index. TNR: True negative ratio (specificity)

COVID-19 infected patients in our COVID-19 isolation ICU department at Queen Alia Military Hospital, Royal Medical Services, Amman, Jordan between May 2020 and Dec 2020, one hundred and ninety-three (N = 193) were finally included in this study with forty-six (N = 46), and one-hundred and thirty-five (N = 135) cases were excluded from the study due to either not developing moderate-severe ARDS (persistent Pa02: FiO2<200 and radiologically confirmed), incompleted recruited baseline data or follow-up data, respectively.

The mean age of the whole study cohort was 58.37±9.96 years, and the Survivors Cohort were insignificantly older than the Non-Survivors Cohort (58.55±9.95 years versus 58.09±10.05 years, respectively, p>0.05). Significantly, males were distributed in the study in approximately 2: 1 ratio compared to female (127 (65.8%) versus 66 (34.2%), respectively, p<0.05) in which 67.68% (67 COVID-19 critically ill men) and 32.32% (32 COVID-19 critically ill women) were belonged to the Survivors Cohort compared to 63.83% (60 COVID-19 critically ill men) and 36.17% (34 critically ill women) were belonged to the Non-Survivors Cohort.

The primary outcome of this study (An overall 28-day ICU mortality) was detected in ninety-four (N = 94) with an overall incidence of 48.70% during an average of 

Figure 1: ROC Curve Analysis of Plasma Ferritin for Prediction of 28-Day ICU Mortality in Critically Ill COVID-19 Patients

Figure 2: Roc Curve Analysis of CRP for Prediction of 28-Day ICU Mortality in Critically Ill COVID-19 Patients

12.40±4.79 days and   16.67±6.81 days of the ICU and overall hospital admission days, respectively, in which both were also significantly higher in the Non-Survivors Cohort compared to the Survivors Cohort (17.30±4.14 days and 24.72±1.98 days vs 9.23±1.06 days and 11.46±2.12 days, respectively, p<0.005). Also, the Non-Survivors Cohort was further sub-divided into two 2 phases, The Early Phase (≤14 days) and the Late Phase (>14 days), in which the incidence of mortality for our eligible studied mechanically ventilated critically ill COVID-19 infected patients, was lower in the Early Phase compared to the Late Phase (31 (16.06%) vs 63 (32.64%), respectively, p<0.05).

Hemodynamically, the shock index (SI) is significantly lower in the Survivors Cohort compared with Non-Survivors Cohort (1.12±0.03 bpm/mmHg vs 1.29±0.17 bpm/mmHg, respectively, p<0.05) even though there was a statistically insignificant difference regarding Norepinephrine (NE) rate in both aforementioned cohorts (9.27±1.68 mcg/min vs 9.94±1.89 mcg/min, respectively, p>0.05). Biochemically, the c-reactive protein (CRP) and ferritin (FER), the two widely used diagnostic and prognostic indicators which both belong to the positive acute phase reactants, were significantly higher in the Non-Survivors Cohort than in the Survivors Cohort (143.09±59.28 mg/dl and 891.51±377.82 ng/ml vs 88.38±34.38 mg/dl and 465.76±154.07 ng/ml, respectively, p<0.05). Other mortality prognosticators, including but not excluded to, lactate dehydrogenase (LDH) and D-Dimer levels were also significantly higher in the Non-Survivors Cohort than in the Survivors Cohort (383.56±54.11 IU/l and 0.79±0.41 mg/l vs 234.55±34.22 IU/l and 0.58±0.21 mg/l, respectively, p<0.05). 

There were insignificant differences between the two mortality cohorts (Survivors vs Non-Survivors) regarding Glasgow Coma Scale (GSC), Child-Pugh Score, and the anthropometrics comparative variables of body weight (BW) and body mass index (BMI) (12 (12-13), 6 (6-8), 74.63±10.06 kg, and 26.19±3.85 kg/m2 vs 12 (12-13), 6 (6-7), 73.45±10.56 kg, 25.50±4.22 kg/m2, retrospectively, p>0.05). The mechanically ventilated critically ill COVID-19 infected patients’ comparative variables and analytical outcomes data between Cohort I and Cohort II. are fully summarized in Tables 1-2.

Table 3 shows the optimal cut-off point, sensitivity (TPR), specificity (TNR), Youden index (YI), positive and negative predictive values (PPV and NPV), and the accuracy index (AI), for the tested prognosticators. According to our study, the best cut-off values for CRP and FER in predicting the overall 28-day ICU mortality in mechanically ventilated critically ill COVID-19 infected patients were 97.12 mg/dl and 716.50 ng. ml, respectively. While the area under the curve (AUC) of the receiver operating characteristic (ROC) for our tested mortality predictor indicators were significantly greater for FER prognosticator than for CRP prognosticator (0.893 (95% CI, 0.836-0.960) vs 0.834 (95% CI, 0.767-0.900), respectively, p<0.05).

The present study includes two studied outcome cohorts, the Survivors Cohort and the Non-Survivors Cohort, of admitted mechanically ventilated critically ill COVID-19 infected patients with moderate-severe ARDS. To the best of our knowledge, the uniqueness of this study is primarily involved in its direct prognostic performance comparison between two commonly used prognosticators in a specified COVID-19 infected cohort. Mechanically ventilated critically ill patients have the highest probability of mortality in case of being on the storm of cytokines and radicals. In the context of our ever-shrinking resources, there is an urgent need for early risk stratification with rapid, affordable, valid, reliable, and discriminative predictive tools in this high-risk and high uncertainty critically COVID-19 infected cohort to avoid any potential or even possible delay on targeted life-saving interventions.

Although most of the COVID-19 infectious cases have belonged to mild-moderate severity status even though the patients are admitted into the isolated COVID-19 departments, a significant proportion of COVID-19 infected patients rapidly progresses into a more advanced critical situation with potential life-threatening outcomes or even faces death. In this study, we primarily investigated the mortality predictive value of FER and CRP prognosticators in addition to addressed other major clinical outcomes of ICU and overall hospital LOS. Our study revealed a significant role of the aforementioned tested prognosticators in indicating more severe disease outcomes, including 28-day mortality risk, especially in COVID-19 infected critically ill patients with higher baseline pre-ICU admission days and co-morbidities.  Moreover, many studies demonstrated that COVID-19 patients with higher baseline co-morbidities had a significantly higher level of CRP and FER compared with comparable infected patients with lower co-morbidities status [27-34]. The analytical comparative variables revealed a significantly higher baseline pre-ICU admission days and co-morbidity levels in the Non-Survivors Cohort compared with the Survivors Cohort (7.42±4.57 days vs 2.23±1.06 days) and (57 (60.64%) vs 47 (47.47%) for co-morbidities count >2), respectively, p<0.05. 

The prognostic value of our tested positive acute phase reactants, CRP and FER, have been demonstrated significant performances in many studies and on different diseases and syndromes, including COVID-19 infectious, with variable sensitivities, specificities, accuracies, positive and negative predictive values, and youden’s indices which allow us for early identification, stratification, diagnosis in some circumstances, and morbidities and mortalities prognosis, therefore contributing to overall positive impacts [35-37]. Circulated CRP and FER levels increases during viral infections, including COVID-19, due to cytokine storm and many inflammatory cytokines, including for example; IL-6, IL-12, and IFN-γ, are rapidly released to stimulate hepatocytes, macrophages, and others to cause hyper-CRP levels and hyperferritinemia 38-40). The resulting complex interrelated cytokine storms, exaggerated positive acute phase reactants, and uncontrolled hyper-immunity responses participate in the progression of ARDS which its severity is strongly correlated with both CRP and FER levels [41-43]. Generally, the uncontrolled and dysfunctional immune reaction, exaggerated CRP levels, hyperferritinemia, hyperinflammatory associated cytokine storm, oxidative stress associated radical storm, and the thrombotic storm finally result in multiple organ failure including ARDS [44-46].

Other commonly used prognosticators in COVID-19 infected critically ill patients, including but not excluded to, CRP to ALB ratio (CRP: ALB), FER to ALB ratio (FER: ALB), D-Dimer, lactate dehydrogenase (LDH), and shock index (SI) in septic COVID-19 infected patients. As previously mentioned in the result section, the SI, LDH, and D-Dimer prognosticators had a significantly higher level in the Non-Survivors Cohort compared with the Survivors Cohort with an overall average level of 1.19±0.14 bpm/mmHg, 308.88±44.90 IU/L, and 0.69±0.35 mg/L, respectively. The ratios of our tested prognosticators to serum albumin (ALB) levels, CRP: ALB and FER: ALB, were also significantly higher in the Non-Survivors Cohort compared with the Survivors Cohort [58.71±24.91:1 vs 31.92±19.06: 1 and 346.11±112.85: 1 vs 176.33±76.62: 1, respectively, p<0.05]. ALB is considered the primary negative acute-phase protein that is synthesized in the liver and can be significantly and negatively affected in COVID-19 infectious by many complex and interrelated mechanisms rather than nutritional factors, including but not excluded to, CRP associated albumin synthesis downregulation, cytokines associated exaggerated albumin transcapillary escaping rate, stress associated albumin hypercatabolic status [47-50]. Our study revealed that the Survivors Cohort had a higher insignificant ALB level compared with the Non-Survivors Cohort (2.64±0.12 g/dl vs 2.57±0.13 g/dl, respectively, p>0.05) although the average amount of human albumin (H.ALB) administered in the Survivors Cohort was significantly higher compared with the Non-Survivors Cohort [18.89±3.16 g/day vs 14.06±6.09 g/day, respectively, p<0.05) which may indicate a possible mortality benefit of H.ALB administration for mechanically ventilated critically ill COVID-19 infected patients not related to ALB level.

The exaggerated elevation of serum levels of c-reactive protein and ferritin in COVID-19 infected patients, especially the mechanically ventilated critically ill cohort, can be potentially used for their reasonable performances and prediction utility in early identification and stratification of COVID-19 infected patients severities despite global ever-shrinking in medical teams and facilities, especially in critical care units to make sure optimum resource provision and implement swift management protocols. This study is limited by its retrospective design. A larger, multisite, and prospective study is needed to control for multiple confounders and to clarify the causation between the tested prognosticators and mortality. Despite these limitations, our conclusions may have an added value to the current excessively evolving controversial pieces of evidence, especially in the mechanically ventilated critically ill cohorts.

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