Cytokine Hemoadsorption as Rescue Therapy for Critically Ill Patients With SARS-CoV-2 Pneumonia With Severe Respiratory Failure and Hypercytokinemia

Introduction: A dysregulated inflammatory response, known as “cytokine storm”, plays an important role in the pathophysiology of coronavirus 2019 disease (COVID-19). Identifying patients with a dysregulated inflammatory response and at high risk for severe respiratory failure, organ dysfunction, and death is clinically relevant, as they could benefit from the specific therapies, such as cytokine removal by hemoadsorption. This study aimed to evaluate cytokine hemoadsorption as rescue therapy in critically ill patients with SARS-CoV-2 pneumonia, severe respiratory failure refractory to prone positioning, and hypercytokinemia.Methods: In this single center, observational and retrospective study, critically ill patients with SARS-CoV-2 pneumonia, severe acute respiratory failure, and hypercytokinemia were analyzed. All the patients underwent cytokine hemoadsorption using CytoSorb® (Cytosorbents Europe, Berlin, Germany). The indication for treatment was acute respiratory failure, inadequate clinical response to the prone position, and hypercytokinemia.Results: Among a total of 343 patients who were admitted to the intensive care unit (ICU) due to SARS-CoV-2 infection between March 3, 2020 and June 22, 2020, six patients received rescue therapy with cytokine hemoadsorption. All the patients needed invasive mechanical ventilation and prone positioning. A significant difference was found in the pre- and post-treatment D-dimer (17,868 mcg/ml [4,196–45,287] vs. 4,488 mcg/ml [3,166–17,076], p = 0.046), C-reactive protein (12.9 mg/dl [10.6] vs. 3.5 mg/dl [2.8], p = 0.028), ferritin (1,539 mcg/L [764–27,414] vs. 1,197 ng/ml [524–3,857], p = 0.04) and interleukin-6 (17,367 pg/ml [4,539–22,532] vs. 2,403 pg/ml [917–3,724], p = 0.043) levels. No significant differences in the pre- and post-treatment interleukin-10 levels (22.3 pg/ml [19.2–191] vs. 5.6 pg/ml [5.2–36.6], p = 0.068) were observed. Improvements in oxygenation (prehemoadsorption PaO2/FIO2 ratio 103 [18.4] vs. posthemoadsorption PaO2/FIO2 ratio 222 [20.9], p = 0.029) and in the organ dysfunction (prehemoadsorption SOFA score 9 [4.75] vs. posthemoadsorption SOFA score 7.7 [5.4], p = 0.046) were observed. ICU and in-hospital mortality was 33.7%.Conclusions: In this case series, critically ill patients with COVID-19 with severe acute respiratory failure refractory to prone positioning and hypercytokinemia who received adjuvant treatment with cytokine hemoadsorption showed a significant reduction in IL-6 plasma levels and other inflammatory biomarkers. Improvements in oxygenation and SOFA score were also observed.

Risk factor analysis and nomogram for predicting in-hospital mortality in ICU patients with sepsis and lung infection

Background Lung infection is a common cause of sepsis, and patients with sepsis and lung infection are more ill and have a higher mortality rate than sepsis patients without lung infection. We constructed a nomogram prediction model to accurately evaluate the prognosis of and provide treatment advice for patients with sepsis and lung infection. Methods Data were retrospectively extracted from the Medical Information Mart for Intensive Care (MIMIC-III) open-source clinical database. The definition of Sepsis 3.0 [10] was used, which includes patients with life-threatening organ dysfunction caused by an uncontrolled host response to infection, and SOFA score ≥ 2. The nomogram prediction model was constructed from the training set using logistic regression analysis, and was then internally validated and underwent sensitivity analysis. Results The risk factors of age, lactate, temperature, oxygenation index, BUN, lactate, Glasgow Coma Score (GCS), liver disease, cancer, organ transplantation, Troponin T(TnT), neutrophil-to-lymphocyte ratio (NLR), and CRRT, MV, and vasopressor use were included in the nomogram. We compared our nomogram with the Sequential Organ Failure Assessment (SOFA) score and Simplified Acute Physiology Score II (SAPSII), the nomogram had better discrimination ability, with areas under the receiver operating characteristic curve (AUROC) of 0.743 (95% C.I.: 0.713–0.773) and 0.746 (95% C.I.: 0.699–0.790) in the training and validation sets, respectively. The calibration plot indicated that the nomogram was adequate for predicting the in-hospital mortality risk in both sets. The decision-curve analysis (DCA) of the nomogram revealed that it provided net benefits for clinical use over using the SOFA score and SAPSII in both sets. Conclusion Our new nomogram is a convenient tool for accurate predictions of in-hospital mortality among ICU patients with sepsis and lung infection. Treatment strategies that improve the factors considered relevant in the model could increase in-hospital survival for these ICU patients.

Correlation of SOFA Score and Hormone Value for Predicting 28-days Mortality for Septic Patients

Introduction. Sepsis is a group of symptoms of organ dysfunction that can be life-threatening because of dysregulation of body response toward ongoing infection. Organ dysfunction in sepsis can be measured by Sequential Organ Failure Assessment (SOFA) and T3 hormone. The study was aimed to identify the correlation of T3 in predicting mortality of 28 days patients in Intensive Care Unit RSMH Palembang. Method. This study design is cohort prospective. The inclusion criteria consist of a patient diagnosed with sepsis and septic shock in the Intensive Care Unit, 18-64 years old. Patients with a history of thyroid disease, pregnant or post-pregnancy, the patient admitted in referral from other hospitals, and patients with a history of psychiatry medication and thyroid medication were excluded. Data collected is the patient whose stay in Intensive Care Unit RSMH followed in 28 days from January 2021 until the sample was fulfilled (39 samples). Analyzing data was SPSS version 23 with chi-square analysis and Fisher's Exact to identify the relationship. Pearson correlation to identify correlation coefficient, and Medical application to measure AUC, cutoff value, sensitivity, and specificity. Result. The result showed that age (p=0,445). gender (p=1,00), need of ICU (p=0,228), isolation-nonisolation ward (p=0,437) didn't have any significant relationship toward mortality. SOFA score correlate statistically with positive correlation and medium strength (0,633) toward mortality of sepsis patient (p=0,000). T3 hormon correlate positively with medium strength (0,514) toward mortality of sepsis patient (p=0,001). T3 hormone toward SOFA correlate negatively (-0,365) with significant correlation (p=0,22). T3 hormone has AUC 0,291 with sensitivity 3,3% and specificity 67,7%. Conclusion. T3 hormone has a significant negative correlation to mortality in sepsis patients but cannot be used to predict mortality with a low AUC value (0,291).

Veno-Arterial Extracorporeal Membrane Oxygenation in Adults with Septic Shock

Survivors and non-survivors were compared for 20 adults supported with veno-arterial extracorporeal membrane oxygenation (VA ECMO) for refractory septic shock from 2012-2018. The primary outcome was hospital survival. Secondary outcomes were ECMO associated complications and survival to decannulation. Median age was 53.5 (IQR 42.0-61.3). At ≤ 24 hours prior to cannulation, median SOFA score was 17.5 (IQR 15 - 19) and 17 patients (85%) had new cardiac dysfunction. Median left ventricular ejection fraction (LVEF) was 20% (IQR 10-38). Thirteen patients had a mixed (cardiogenic and distributive) or cardiogenic shock profile (65%), 7 had a distributive shock profile (35%), and 17 (85%) survived to decannulation. Fourteen (70%) survived to hospital discharge and median cerebral performance category score was 1 (IQR 1-2). No differences were found in age, comorbid conditions, time from shock onset to cannulation, peak flow rate on ECMO, ECMO complications, shock profile, LVEF, or vasoactive-inotrope score (VIS). More patients in the distributive shock profile experienced limb ischemia complications (n=3, 42.9%) compared to the cardiogenic and mixed shock profiles (n=1, 7.7%). Survivors to hospital discharge had a lower SOFA score. VA ECMO support may be a beneficial therapy for refractory septic shock and could be considered in select adult patients.

Non-linear and Interaction Analyses of Biomarkers for Organ Dysfunctions as Predictive Markers for Sepsis: A Nationwide Retrospective Study

The Sequential Organ Failure Assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction in sepsis. However, differences in prognostic value between SOFA subscores have not been sufficiently evaluated. This retrospective observational study used a large-scale database containing about 30 million patients. Among them, we included 38,869 adult patients with sepsis from 2006 to 2019. The cardiovascular and neurological subscores were calculated by a modified method. Associations between the biomarkers of the SOFA components and mortality were examined using restricted cubic spline analyses, which showed that an increase in the total modified SOFA score was linearly associated with increased mortality. However, the prognostic association of subscores varied widely: platelet count showed a J-shaped association, creatinine showed an inverted J-shaped association, and bilirubin showed only a weak association. We also evaluated interaction effects on mortality between an increase of one subscore and another. The joint odds ratios on mortality of two modified SOFA subscores were synergistically increased compared to the sum of the single odds ratios, especially in cardiovascular-neurological, coagulation-hepatic, and renal-hepatic combinations. In conclusion, total modified SOFA score was associated with increased mortality despite the varied prognostic associations of the subscores, possibly because interactions between subscores synergistically enhanced prognostic accuracy.

Circulating Long Noncoding RNAs Positively Correlate with the Increased Risk, Elevated Severity and Unfavorable Prognosis in the Sepsis Patients

Objective This study aimed to evaluate the correlation of circulating long noncoding RNAs (lncRNAs) expression with disease risk, severity, inflammatory cytokines levels and prognosis in patients with sepsis. Methods Differential expression profiles of lncRNA in the serum of sepsis rats were screened by high-throughput transcriptome sequencing. Homologous lncRNAs in the upregulation group were identified by homology analysis in rats and humans. The expression differences of these homologous lncRNAs in the serum of 176 sepsis patients and 176 healthy controls (HCs) were detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). And inflammatory cytokines levels were detected by enzyme-linked immunosorbent assay (ELISA). A receiver operating characteristic (ROC) curve was used to verify the diagnostic and prognosis values. Spearman correlation coefficient was used to analyze the correlation between the variables. Follow-up was performed to observe the 28-day mortality. Results Among the screened differentially up-regulated lncRNAs, only two lncRNAs were homologous in rats and humans, which in human named PKN2-antisense RNA 1 (PKN2-AS1) and AC068888.1, respectively. Those two lncRNAs were significantly increased in patients with sepsis compared with those in HCs (P < 0.001), in patients with septic shock compared with those no septic shock (P < 0.001), and in non-survivors compared with survivors (P < 0.001). And those two lncRNAs were positively correlated with sepsis-related organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHE) II score, lactate (Lac), c-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in sepsis patients. Likelihood ratio forward stepwise multivariate logistic regression analysis revealed that high lncRNA AC068888.1 expression was an independent risk factor for septic shock (P < 0.001) and unfavorable prognosis (P = 0.006), but high lncRNA PKN2-AS1 expression was only for unfavorable prognosis (P = 0.019). The ROC curve exhibited a significant predictive value for sepsis risk with area under the curve (AUC) values of 0.879 and 0.842, respectively. For predicting septic shock risk, combining lncRNA AC068888.1 with SOFA score and Lac level, the ROC curve analysis significantly improved the predictability (AUC = 0.882). For predicting 28-day death risk, combining those two lncRNAs with SOFA and APACHE II scores, the ROC curve analysis also significantly improved the predictability (AUC = 0.860). The Kaplan–Meier curves indicated that the survival probability was much worse with those two lncRNAs high expression compared to low expression in patients with sepsis (P < 0.001). Conclusion The circulating absolute expression levels of lncRNA PKN2-AS1 and AC068888.1 in the serum may be used for the early diagnosis, clinical severity evaluation and prognosis of sepsis.

Sequential Organ Failure Assessment Outperforms Quantitative Chest CT Imaging Parameters for Mortality Prediction in COVID-19 ARDS

(1) Background: Respiratory insufficiency with acute respiratory distress syndrome (ARDS) and multi-organ dysfunction leads to high mortality in COVID-19 patients. In times of limited intensive care unit (ICU) resources, chest CTs became an important tool for the assessment of lung involvement and for patient triage despite uncertainties about the predictive diagnostic value. This study evaluated chest CT-based imaging parameters for their potential to predict in-hospital mortality compared to clinical scores. (2) Methods: 89 COVID-19 ICU ARDS patients requiring mechanical ventilation or continuous positive airway pressure mask ventilation were included in this single center retrospective study. AI-based lung injury assessment and measurements indicating pulmonary hypertension (PA-to-AA ratio) on admission CT, oxygenation indices, lung compliance and sequential organ failure assessment (SOFA) scores on ICU admission were assessed for their diagnostic performance to predict in-hospital mortality. (3) Results: CT severity scores and PA-to-AA ratios were not significantly associated with in-hospital mortality, whereas the SOFA score showed a significant association (p < 0.001). In ROC analysis, the SOFA score resulted in an area under the curve (AUC) for in-hospital mortality of 0.74 (95%-CI 0.63–0.85), whereas CT severity scores (0.53, 95%-CI 0.40–0.67) and PA-to-AA ratios (0.46, 95%-CI 0.34–0.58) did not yield sufficient AUCs. These results were consistent for the subgroup of more critically ill patients with moderate and severe ARDS on admission (oxygenation index <200, n = 53) with an AUC for SOFA score of 0.77 (95%-CI 0.64–0.89), compared to 0.55 (95%-CI 0.39–0.72) for CT severity scores and 0.51 (95%-CI 0.35–0.67) for PA-to-AA ratios. (4) Conclusions: Severe COVID-19 disease is not limited to lung (vessel) injury but leads to a multi-organ involvement. The findings of this study suggest that risk stratification should not solely be based on chest CT parameters but needs to include multi-organ failure assessment for COVID-19 ICU ARDS patients for optimized future patient management and resource allocation.

Assessment of Metabolic Dysfunction in Sepsis in a Retrospective Single-Centre Cohort

Objective. Our primary aim was to assess selected metabolic dysfunction parameters, both independently and as a complement to the SOFA score, as predictors of short-term mortality in patients with infection admitted to the intensive care unit (ICU). Methods. We retrospectively enrolled all consecutive adult patients admitted to the eight ICUs of Lille University Hospital, between January 2015 and September 2016, with suspected or confirmed infection. We selected seven routinely measured biological and clinical parameters of metabolic dysfunction (maximal arterial lactatemia, minimal and maximal temperature, minimal and maximal glycaemia, cholesterolemia, and triglyceridemia), in addition to age and the Charlson’s comorbidity score. All parameters and SOFA scores were recorded within 24 h of admission. Results. We included 956 patients with infection, among which 295 (30.9%) died within 90 days. Among the seven metabolic parameters investigated, only maximal lactatemia was associated with higher risk of 90-day hospital mortality in SOFA-adjusted analyses (SOFA-adjusted OR, 1.17; 95%CI, 1.10 to 1.25; p < 0.001 ). Age and the Charlson’s comorbidity score were also statistically associated with a poor prognosis in SOFA-adjusted analyses. We were thus able to develop a metabolic failure, age, and comorbidity assessment (MACA) score based on scales of lactatemia, age, and the Charlson’s score, intended for use in combination with the SOFA score. Conclusions. The maximal lactatemia level within 24 h of ICU admission is the best predictor of short-term mortality among seven measures of metabolic dysfunction. Our combined “SOFA + MACA” score could facilitate early detection of patients likely to develop severe infections. Its accuracy requires further evaluation.

Effect of Remdesivir on mortality and length of stay in hospitalized COVID-19 patients: A single center study

Objectives: To see the difference in mortality among hospitalized COVID-19 patients given Remdesivir (RDV) with those who were not given RDV. Methods: A prospective cohort study was conducted on patients who were admitted to the COVID-19 isolation unit at The Indus Hospital, Korangi Campus Karachi between March and June 2020. Results: Groups were similar in age and gender distribution. RDV group was more hypoxic, had severe ARDS and needed higher Oxygen support compared to non-RDV group (p=0.000). Median SOFA score was 2 in RDV vs 5 in non-RDV (p=0.000). More than moderate COVID pneumonia was found in 92% of the RDV group while 89% of non-RDV group (p value=0.001). Median day of illness to administer Remdesivir was 10. There was no difference in mortality (45.5% in RDV vs 40.4% in non-RDV; p=0.4) between the two groups. Median length of hospital stay was 12 days (IQR=7.5-14.5) in RDV group compared to 10 days (IQR=6-14) in non-RDV group (p=0.009). Conclusion: RDV did not show any difference in in-hospital mortality in our patients. More patients had severe ARDS in the RDV group while patients in the non-RDV group had higher SOFA score and multi-organ failure. Length of stay was longer in patients receiving Remdesivir. doi: https://doi.org/10.12669/pjms.38.ICON-2022.5779 How to cite this:Shaikh Q, Sarfaraz S, Rahim A, Hussain M, Shah R, Soomro S. Effect of Remdesivir on mortality and length of stay in hospitalized COVID-19 patients: A single center study. Pak J Med Sci. 2022;38(2):405-410. doi: https://doi.org/10.12669/pjms.38.ICON-2022.5779 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Increase in the Complement Activation Product C4d and the Terminal Complement Complex sC5b-9 Is Associated with Disease Severity and a Fatal Outcome in Necrotizing Soft-Tissue Infection

The hyperinflammatory burden is immense in necrotizing soft-tissue infection (NSTI). The complement system is a key during the innate immune response and may be a promising target to reduce the inflammatory response, potentially improving the clinical outcome. However, complement activation and its association to disease severity and survival remain unknown in NSTI. Therefore, we prospectively enrolled patients with NSTI and sampled blood at admission and once daily for the following 3 days. Plasma C4c, C4d, C3bc, and C3dg and the terminal complement complex (TCC) were evaluated using ELISA techniques. In total, 242 patients were included with a median age of 62 years, with a 60% male predominance. All-cause 30-day mortality was 17% (95% confidence interval [CI] 13–23) with a follow-up of &#x3e;98%. C4c and C3dg were negatively correlated with Simplified Acute Physiology Score II (<i>Rho</i> −0.22, <i>p</i> &#x3c; 0.001 and <i>Rho</i> −0.17, <i>p</i> = 0.01). Patients with septic shock (<i>n</i> = 114, 47%) had higher levels of baseline TCC than those in non-shock patients (18 vs. 14, <i>p</i> &#x3c; 0.001). TCC correlated with the Sequential Organ Failure Assessment (SOFA) score (<i>Rho</i> 0.19, <i>p</i> = 0.004). In multivariate Cox regression analysis (adjusted for age, sex, comorbidity, and SOFA score), high baseline C4d (&#x3e;20 ng/mL) and the combination of high C4d and TCC (&#x3e;31 arbitrary units/mL) were associated with increased 30-day mortality (hazard ratio [HR] 3.26, 95% CI 1.56–6.81 and HR 5.12, 95% CI 2.15–12.23, respectively). High levels of both C4d and TCC demonstrated a negative predictive value of 0.87. In conclusion, we found that in patients with NSTI, complement activation correlated with the severity of the disease. High baseline C4d and combination of high C4d and TCC are associated with increased 30-day mortality. Low baseline C4d or TCC indicates a higher probability of survival.