What Is the Place of Intermediate Care Unit in Patients with COVID-19? A Single Center Experience

Introduction COVID-19 pandemic has led to an increased rate of intensive care unit (ICU) stays. Intermediate care units (IMCUs) are a useful resource for the management of patients with severe COVID-19 that do not require ICU admission. In this research, we aimed to determine survival outcomes and parameters predicting mortality in patients who have been admitted to IMCU. Materials and Methods Patients who were admitted to IMCU between April 2019 and January 2021 were analyzed retrospectively. Sociodemographics, clinical characteristics, and blood parameters on admission were compared between the patients who died in IMCU and the others. Blood parameters at discharge were compared between survived and deceased individuals. Survival analysis was performed via Kaplan–Meier analysis. Blood parameters predicting mortality were determined by univariate and multivariate Cox regression analysis. Results A total of 140 patients were included within the scope of this study. The median age was 72.5 years, and 77 (55%) of them were male and 63 (45%) of them were female. A total of 37 (26.4%) patients deceased in IMCU, and 40 patients (28.5%) were transferred to ICU. Higher platelet count (HR 3.454; 95% CI 1.383–8.625; p=0.008), procalcitonin levels (HR 3.083; 95% CI 1.158–8.206; p=0.024), and lower oxygen saturation (HR 4.121; 95% CI 2.018–8.414; p < 0.001) were associated with an increased risk of mortality in IMCU. At discharge from IMCU, higher procalcitonin levels (HR 2.809; 95% CI 1.216–6.487; p=0.016), lower platelet count (HR 2.269; 95% CI 1.012–5.085; p=0.047), and noninvasive mechanic ventilation requirement (HR 2.363; 95% CI 1.201–4.651; p=0.013) were associated with an increased risk of mortality. Median OS was found as 41 days. The overall survival rate was found 40% while the IMCU survival rate was 73.6%. Conclusions IMCU seems to have a positive effect on survival in patients with severe COVID-19 infection. Close monitoring of these parameters and early intervention may improve survival rates and outcomes.


Introduction
Te consequences of coronavirus disease 2019 (COVID- 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which has occurred in the Wuhan region of China and spread all over the world and have infuenced all stages of health services [1]. Te severity of patients infected with COVID-19 could be elaborated as follows: 15% severe illness and 5% have critical illness. Overall mortality ranged from 0.25% to 3.0%. Case fatality rates are much higher for vulnerable populations, such as patients over the age of 80 years (>14%) and those with comorbid conditions (10% for those with cardiovascular disease and 7% for those with diabetes) [2,3]. Many countries do not have sufcient ICU bed capacity and prolonged hospitalization of patients who require invasive mechanic ventilation [4,5]. Intermediate care units (IMCUs) are logistically located between the hospital ward and the ICU. Tese units provide continuous monitoring, noninvasive respiratory support, and vasopressors and are increasingly utilized for their potential to optimise hospital productivity and reduce pressure on ICU beds and ICU mortality [6,7]. Up to date, some indicators such as hypersensitive C-reactive protein (h-CRP), procalcitonin (PCT), creatinine, LDH, aspartate aminotransferase (AST), hypersensitive cardiac troponin-I, prothrombin time, D-dimer, and lymphocyte count have provided supportive information to assess the severity of the disease and predict the prognosis of COVID-19 [8][9][10]. In this research, we aimed to determine survival outcomes and parameters predicting mortality in patients who have been admitted to IMCU.

Patients.
All patients underwent chest CT and RT-PCR tests before admission to IMCU. Individuals who were >18 years old, with a positive RT-PCR result that was hospitalized in the IMCU patients were included in this study. Patients <18 years of age, having pregnancy, missing baseline, or outcome data, and with negative RT-PCR results were excluded. In the frst step, the patients were divided into two groups of individuals who were deceased in IMCU and others. Patients who were discharged from IMCU were allocated to two groups survived and deceased subjects.

Method.
Following the approval of the study protocol by the Ministry of Health (2020-06-05T19_28_13. Xxml), ethics committee approval of the study from Tepecik Training and Research Hospital was obtained (Date 25.01.2021 No: 2021/01-22). Te study was performed in the IMCU Department of Tepecik Training and Research Hospital. Patients, who were admitted to IMCU between April 2019 and January 2021, were analyzed retrospectively. Te data of 140 individuals were collected from the hospital database. Chest computer tomography severity score (CT-SS) was used to evaluate the parenchymal involvement. Patients were classifed into 2 groups those with mild/moderate parenchymal involvement and those with severe parenchymal involvement. Only laboratoryconfrmed cases that were hospitalized in IMCU were included in the analysis. On admission and at discharge, blood parameters including complete blood count (CBC), albumin, C-reactive protein (CRP), procalcitonin, fbrinogen, troponin, and D-dimer values were analyzed. Blood parameters at the time of admission were compared between the patients who died in the IMCU and the others. Age, gender, comorbid disease, the severity of lung involvement, and noninvasive ventilation requirement were analyzed in these two groups. Blood parameters at the time of discharge were compared between survived and deceased patients. Te fowchart of the study is shown in Figure 1. Patients who were discharged from IMCU were followed up until November 2021. Postdischarge survival (PDS) was defned as the length of time from discharge to death from any cause. Overall survival (OS) was defned as the time from diagnosis of COVID-19 until death from any cause.

Statistical Analysis.
Statistical analysis was performed using the IBM SPSS (Statistical Package for the Social Sciences) Statistics 25.0 Program. Data were expressed in mean ± standard deviation (SD) or median (min-max) for continuous variables and in number n (%) for categorical variables. Normality was assessed using the Shapiro-Wilk (n < 50) and Kolmogorov-Smirnov tests. Te Mann-Whitney test was utilized if the normal distribution was not appropriate. In case normal distribution was appropriate, independent-sample t-test was used for the comparison of numerical variables. Categorical variables were assessed using the chi-square test. Survival analysis was performed using the Kaplan-Meier analysis and Cox regression analysis. Numerical variables predicting mortality and noninvasive mechanical ventilation requirement were determined by univariate and multivariate Cox regression analysis. A p value of <0.05 was considered statistically signifcant. Te data that support the fndings of this study are available from the corresponding author (B.H.) upon reasonable request.

Sociodemographic and Clinical Characteristics.
A total of 140 patients were included within the scope of this study. Te median age was 72.5 years, and 77 (55%) of them were male and 63 (45%) of them were female. A total of 37 (26.4%) patients deceased in IMCU, and 40 patients (28.5%) were transferred to ICU. Te majority of the patients (n � 117, 83.5%) had lung involvement at admission. Te severity of lung involvement was as follows: 40.7% (n � 57) was mild to moderate and 42.8% (n � 60) was severe. Hypertension (HT) (n � 84, 60%) was the most common comorbid disease in patients followed by coronary artery disease (CAD) (  Data are shown as number (percentage (n (%)) and median (minimum-maximum). COPD, chronic obstructive pulmonary disease; WBC, white blood cells; CRP, C-reactive protein; PCT, procalcitonin.
Te overall survival rate was found as 40% while the IMCU survival rate was 73.6%. Te median overall survival was 41 days (Figure 2). Median OS was 29 days in patients (n � 12) who required NIVM and had deceased in IMCU ( Figure 3). Median OS was 19 days in patients (n � 41) who required NIVM while 144 days in others (n � 99) who did not (p � 0.008) ( Table 2 and Figure 4).

Discussion
IMCU may contribute to a decrease in mortality by providing closer follow-up and better patient care for patients who need more care than compared to standard clinical treatment but do not require ICU admission [6,7]. Studies on IMCU in COVID-19 patients have been conducted previously; however, our study was the frst article from Turkey. Te diference between this research compared to other studies in terms of evaluating hospitalization and discharge parameters separately, long-term follow-up after discharge from IMCU, and evaluation of survival. Advanced age was found to be associated with increased mortality [11][12][13][14]. In a recent IMCU study of 253 patients,   Tese parameters were defned as independent risk factors for mortality [15]. In our study, age and comorbid diseases were not statistically signifcant in survival. Tis situation might be due to the fact that a signifcant proportion of our cohort was at an advanced age and had the comorbid disease. In our study, the median length of stay in IMCU was found to be 6 days (ranging between 1 and 80), and this result was similar to the Intermediate Respiratory Intensive Care Unit (RICU) study with an average length of stay of 3.3 ± 2.8 days in the deceased and 6.4 ± 3.3 days in the survivors [16]. In previous literature, it was stated that some indicators such as highly sensitive CRP, PCT, creatinine, LDH, AST, hypersensitive cardiac troponin I, prothrombin time, Ddimer, and lymphocyte count are helpful in evaluating the severity of the disease and can predict the prognosis of COVID-19 [4][5][6]. CRP is usually elevated in some diseases with chronic infammation such as many cancers. Furthermore, PCT appears to provide better sensitivity and specifcity than CRP (respectively, 89% and 94% vs. 71% and 78% for CRP) [17]. In a study examining the risk factors of COVID-19 infection in diabetic patients, PCT elevation was found to be associated with the severity of the infection. In our study cohort, elevated PCT was shown to increase the risks of systemic infection and sepsis in diabetic patients with COVID-19 infection [18]. In our study, diabetes patients constituted a signifcant portion of approximately one-third (32.9%) of the cohort. More than 25% of COVID-19 patients were diagnosed with Euthyroid sick syndrome (ESS) in another study. COVID-19 patients with ESS had a signifcantly higher prevalence of severe events and had stronger infammatory responses, with higher levels of CRP and erythrocyte sedimentation rate as well as a higher positive rate of procalcitonin. Nonetheless, no signifcant efects of ESS were found on the rates of mortality [19]. In another study, particularly interleukin-6 and procalcitonin were robustly associated with an increased risk of death during hospitalization and reduced hospital discharge [20].
However, PCT may be falsely increased in some neoplastic situations. Tus, some solid tumors (medullar carcinoma of the thyroid and small-cell lung cancer) as well as some hematological malignancies are thought to be associated with PCT positivity [21][22][23][24]. In our study cohort, 22.1% of the patients had cancer. Tere was no diference in mortality between those with and without cancer. Terefore, the cause of high procalcitonin levels, which we found to be associated with increased mortality, was not thought to be related to cancer. In light of the studies mentioned above, although PCT has variable results on mortality in COVID-19 infection, it was shown to increase mortality in our study. Te most important reason for this is that the patients are critical intensive care patients and may be considered as being at risk for secondary infections and associated sepsis.
In a national multicenter retrospective study in China, the incidence of thrombocytopenia (<150 × 10 9 /L) was found to be 36.2% in COVID-19, and it was shown that thrombocytopenia was associated with disease severity and mortality [25]. Trombocytopenia can be explained by 3 diferent mechanisms. First, systemic infammation or high IL-6 levels can cause a cytokine storm and suppress the hematopoietic microenvironment and hematopoiesis [26,27]. Second, SARS-CoV-2 can directly infect hematopoietic stem cells and megakaryocytes through angiotensinconverting enzyme 2 (ACE2), CD13, or CD66a [28]. Te third can be evaluated as the presence of antiviral antibodies that crossreact with hematopoietic cells and (or) platelets.   [29]. Trombotic microangiopathy and disseminated intravascular coagulation were demonstrated in autopsies of patients who developed thrombocytopenia and died [30]. In our study, the presence of thrombocytopenia at the time of discharge from IMCU was associated with increased mortality. Tis may be a component of disseminated intravascular coagulation or a part of bone marrow depression secondary to infection. Tromboembolic events might lead to sudden death in COVID-19 patients [31]. Platelets play a very important role in thrombogenesis. Recently, it has been shown that high platelet activation, including platelet adhesion and aggregation, α granule secretion, and intense granule release, was closely linked to thrombosis in COVID-19. In addition, Zhang et al. showed that the spike protein of SARS-CoV-2 directly stimulates platelets, inducing the release of clotting factors, and thrombosis by increasing infammatory cytokines and leukocyte-platelet aggregates [32]. In our study, thrombocytosis was found to be associated with increased mortality in IMCU. Based on these data, early thrombocytosis and late thrombocytopenia can be explained as important indicators of increased mortality.
In our study, while the need for noninvasive mechanical ventilation in the critically IMCU had no efect on mortality, postdischarge mortality was found to be higher in patients who required longer mechanical ventilation. On the other hand, noninvasive mechanical ventilation, a mask with a reservoir, and a high-fow nasal cannula can reduce the rate of endotracheal intubation in critical IMCU. In an IMCU study of COVID-19 patients with severe respiratory failure, the endotracheal intubation rate was found to be 37.1% [33]. Among COVID-19 patients hospitalized in critical intensive care units in China, the percentage of those who required ICU ranged from 5% to 32% [1]. In our study, 40 patients were transferred to ICU, and the endotracheal intubation rate was found to be 28.5%. Te reason for low intubation rate was thought to be due to the fact that the rate of patients with SpO2 ≤90% was 30%, and early intervention has been performed in hypoxia. In a study conducted in Wuhan, mortality rates were reported between 81% and 97% in patients requiring invasive mechanical ventilation [34]. Similarly, in our study, 35 of 40 patients who required invasive mechanical ventilation and were transferred to the ICU had deceased, and the mortality rate was 87.5%. Te reason for higher mortality rate could be explained as the risk of widespread ICU death, intubation, and antibioticresistant bacterial superinfections. In the study that included 253 patients mentioned above, 80 patients died during hospitalization, and the mortality rate was 31.6%. Te IMCU mortality rate was found to be 24.2% [15]. Similarly, in our study, while the IMCU mortality rate was 26.4%, the mortality rate during hospitalization was found to be 51.4%, which was higher than the aforementioned study.
In our study, low oxygen levels were associated with a high mortality on admission to IMCU. In previous studies, it has been shown that dyspnea during hospitalization and the persistence of hypoxia despite oxygen support are independent predictors of mortality in COVID-19 [35,36]. Tere are several mechanisms that elaborate the relationship between hypoxia and mortality in COVID-19 as hypoxia increases viral replication and infammation. In this way, edema and tissue hypoxia occur at the alveolar level, and mortality increases in COVID-19 [37]. Hypoxia may also be associated with pulmonary vasoconstriction in COVID-19 pneumonia [38]. Under experimental conditions, hypoxia leads to partial protein S defciency, leading to coagulation [39]. In summary, although hypoxia is a result of viralinduced pulmonary infltration and pneumonic consolidation, it is thought to increase mortality by causing viral proliferation, lung infammation, cytokine release, pulmonary vasoconstriction, and intravascular thrombosis in the setting of COVID-19 infection [37].
To access host cells, SARS-CoV-2 uses a surface glycoprotein (peplomer) known as spike; ACE2 has been shown International Journal of Clinical Practice to be a coreceptor for coronavirus entry [40]. ACE2 is also expressed by endothelial cells [41], and other major clinical events usually observed in COVID-19 patients (e.g., high blood pressure [42], thrombosis [43] kidney disease [44], pulmonary embolism [45], cerebrovascular, and neurologic disorders) [46] indicate that the virus is targeting the endothelium, one of the largest organs in the human body [47]. In addition to this, evidence is emerging that the multiorgan injury observed in COVID-19 is a consequence of cytokineinduced endothelial dysfunction (endothelium) [48]. IL-6 causes endothelial activation and neutrophil infltration, which results in NO (nitric oxide)-mediated changes to vascular permeability and loss of vascular tone [49]. Tis is refected clinically by the development of septic shock [43]. Endothelial dysfunction is aggravated by hypoxia, which augments thrombosis by both increasing blood viscosity and hypoxia-inducible transcription factor-dependent signaling pathway [50]. In our study, one of the efects of hypoxia on mortality can be considered as the induction of endothelial damage due to SARS-CoV-2. During the median follow-up of 462 days (ranging between 316 and 590) after discharge from IMCU, 47 of the 103 patients had deceased. Twelve of 63 discharged individuals had died. In a recent study, it was shown that COVID-19 patients developed endothelial dysfunction, which was signifcantly impaired compared to the healthy control group at 6-month follow-up [51]. Terefore, endothelial dysfunction may be the cause of increased mortality in long-term follow-up after COVID-19, as well as in acute COVID-19 infection. In COVID-19, patients with severe symptoms, as myeloid-derived suppressed cells (MDSCs) increase, so does the activity of arginase, the enzyme responsible for metabolizing L-Arginine into ornithine and urea, and consequently L-Arginine level decreases [52]. Previous research has shown that reduced L-Arginine levels increase the production of reactive oxygen species (ROS) and exacerbate infammation in the endothelium [53]. Arginine is an amino acid that acts as a substrate for endothelial nitric oxide (NO) synthase (eNOS). It has been previously shown to signifcantly improve endothelial function, providing a strong rationale for its use in COVID-19 patients [54]. Several investigators have suggested that endotheliitis may be the critical mechanism underlying the impaired systemic microcirculatory function observed in various vascular beds in patients experiencing prolonged COVID-19 symptoms. Consistent with this, the Lincoln survey indicates that the supplementation with l-Arginine + Vitamin C has benefcial efects on Long-COVID, in terms of attenuating its typical symptoms and improving efort perception [55]. Based on these data, L-Arginine, which has been shown to improve endothelial functions and reduce prolonged COVID-19 symptoms, may improve survival in long-term follow-up after COVID-19 infection. On the other hand, the advanced age and comorbidity of the patients admitted to IMCU should also be considered, regardless of the COVID-19 infection, as mortality is already high in this group of patients. Te limitation of our study could be elaborated as a single-center retrospective study and the exact causes of death after hospital discharge could not be determined.

. Conclusions
IMCU can contribute to the multidisciplinary management of the disease by providing noninvasive respiratory support and close monitoring to COVID-19 patients and can reduce ICU occupancy rates. Based on the risk factors demonstrated in previous studies and our fndings, a risk scoring system should be developed for COVID-19 patients admitted to IMCU. In addition, early transfer to the ICU in patients with high-risk factors may improve survival outcomes. Multicenter prospective studies are needed to confrm this proposition. IMCU units are important in terms of contributing to reducing ICU bed occupancy rates and reducing mortality in COVID-19 patients.
In light of the results of our study, high platelet count and procalcitonin levels, hypoxia was associated with an increased risk of mortality in IMCU. At discharge from IMCU low platelet count, high procalcitonin levels and the requirement for noninvasive mechanical ventilation were found to be associated with increased overall mortality. It could be stated that monitoring of these parameters in the follow-up of COVID-19 patients might enhance treatment outcomes via reducing mortality and morbidity.

Data Availability
Necessary data can be obtained from the corresponding author.

Conflicts of Interest
Te authors declare that they have no conficts of interest.