Abstract
Background:
The consequences of COVID-19, such as respiratory failure and mortality, require the search for fast and effective solutions. The aim of this retrospective study is to determine the effect of extracorporeal hemadsorption on mortality in severe COVID-19 cases hospitalized in the intensive care unit (ICU).
Methods:
Our study is retrospective, single-center, and observational. The study included ICU patients diagnosed with COVID-19 who received extracorporeal hemadsorption treatment between March 2020 and December 2020. Effects on mortality were examined by comparing pre- and post-hemadsorption values.
Results:
Seventeen patients were included in the study. The mortality rate in the study was 64.7%. After hemadsorption, an increase was observed in the lymphocyte numbers, APACHE-II, and SOFA values of the patients (p = 0.026, 0.043, and 0.033; respectively). A significant decrease was observed in CRP and fibrinogen levels (p = 0.003 and 0.005; respectively). In the non-surviving patient group, APACHE-II, SOFA, and procalcitonin values were found to be high before and after the procedure (p = 0.002, 0.048, and 0.06; respectively).
Conclusion:
In COVID-19 patients, APACHE-II and SOFA scores may be useful in predicting the effectiveness of extracorporeal hemadsorption. Our study found that patients with higher APACHE-II and SOFA scores at baseline had a higher mortality rate after hemadsorption. These findings show that the use of intensive care scoring systems may be useful in determining which patients should receive extracorporeal hemadsorption and that hemadsorption should be performed in the early stages of the disease.
Background
Coronavirus disease-19 (Covid-19) caused by the novel coronavirus, severe acute respiratory syndrome coronarvirus-2 (SARS-CoV-2), has a spectrum of clinical manifestations from mild to severe. 1 The majority of patients experience minor viral symptoms; however, 15% of patients develop severe pneumonia, and in certain instances, this progresses to acute respiratory distress syndrome (ARDS).2,3 Acute hypoxic respiratory failure was frequently observed in up to 60%–70% of patients admitted to intensive care (ICU), shock in 30%, myocardial dysfunction in 20%–30%, and acute renal failure in 10%–30%. 4
During SARS-CoV-2 infection, the levels of interleukin (IL)-1β, IL-7, IL-8, IL-10, interferon-gamma (IFN-ɣ), monocyte chemoattractant peptide (MCP)-1, macrophage inflammatory protein (MIP) 1A-1B, granulocyte-colony stimulating factor (G-CSF), and tumor necrosis factor-alpha (TNF-α) are elevated. 5
Cytokine storm syndrome (CSS) has a significant impact on severe COVID-19 development and mortality. Therefore, immunomodulation therapies are considered part of standard practice in the management of patients with severe COVID-19. One of the immunomodulation treatment methods is specific treatments such as Tocilizumab, Anakinra, and Baricitinib for IL-6, IL-1, and Janus kinase (JAK) inhibition. 6 One of the immunomodulation treatment methods is extracorporeal cytokine hemadsorption systems. Hemadsorption treatments aim to retain target pathogens by adsorption technique by developing special membranes, superficial coating, and functionalization of the matrix. Many studies in the literature show hemadsorption to be beneficial in sepsis, septic shock, and acute lung injury.7–9 Use of hemoperfusion among critical COVID-19 patients may reduce mortality and improve SPO2 and PaCO2. 10 Hemadsorption has been pointed out as a potential treatment for severe COVID-19 and CSS. 11
The aim of this study was to determine the changes in laboratory, multiple organ dysfunction scores and inflammatory markers in COVID-19 patients as a result of the removal of cytokines from the environment. We hypothesized that these values would decrease as a result and that the disease clinic would improve accordingly.
Materials and methods
Ethical approval and study population
Patients receiving hemadsorption treatment who were admitted to the Antalya Training and Research Hospital Adult in ICU with a diagnosis of COVID-19 between March 2020 and December 2020 were included in this study. The study is retrospective, single-center, and observational. The study was conducted in accordance with the principles stated in the Declaration of Helsinki. Ethics committee approval and necessary permissions were obtained from the Ministry of Health and provincial health directorates for the study (Ethics committee number: 15/8-2020). Patients and their relatives were informed in detail before the procedure, and additional consent was obtained for hemadsorption.
Inclusion and exclusion criteria
Patients admitted to the adult ICU who tested positive for COVID-19 by polymerase chain reaction (PCR) or were diagnosed by computed tomography and then underwent hemadsorption treatment were included in this study. We excluded patients with severe coagulation problems, individuals under the age of 18 years, data could not reach and patients whose treatment period could not be completed (72 h), and pregnant women.
Management procedure
For this study, we collected demographic data (sex, age, comorbidity, body mass index (BMI), mortality), laboratory data (C-reactive protein (CRP), procalcitonin, D-dimer, fibrinogen, ferritin, lymphocyte, neutrophil, platelet, creatinine, lactate dehydrogenase (LDH), and IL-6) and immediate monitor values via patient bedside observation forms and the Miamed computer system. The laboratory data, vital parameters, Acute Physiology and Chronic Health Evaluation-II (APACHE-II), and Sequential Organ Failure Assessment (SOFA) scores of the patients were assessed both prior to and following hemadsorption. Hemodynamic data (mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP)) as well as clinical findings were also included.
Cytokine adsorption was planned according to our national guidelines published and updated by the Ministry of Health. The diagnosis of CSS was made by assessing both clinical and laboratory data. CSS diagnosis relied on the presence of fever, leukocytosis, lymphopenia, thrombocytopenia, and hypofibrinogenemia, as well as elevated levels of ferritin, CRP, and D-dimer.
Cytokine adsorption was performed using Jafron-HA330 (Jafron, Zhuhai, China) hemadsorption cartridges for disposable resin at a blood flow rate of 250–300 mL/min via femoral or jugular venous catheters in accordance with our local ICU protocol. Cytokine adsorption was performed for at least 3 h each time and the duration was determined by the attending physician. Clinical and laboratory evaluation was performed on the morning of cytokine adsorption and the morning after the last dose of cytokine adsorption. All patients in this study received therapeutic drugs (antimicrobials, anti-thrombotic agents, and immunomodulators), mechanical ventilation, organ support therapies (vasopressors and renal replacement therapy) in accordance with the clinical decision of the hospital.
Statistical analysis
The data were analyzed using IBM SPSS Statistics 25.0 (IBM Corp.; 2017 IBM SPSS Statistics for Windows, Version 25.0; Armonk, New York, USA). Numerical variables were presented as mean and standard deviation (SD) or median (interquartile range; IQR), and categorical variables were presented as number (n) and percentage (%). The normal distribution of numerical variables was examined using the Shapiro-Wilk test. Numerical variables were analyzed using the Student’s T test or Mann-Whitney U test. The Pearson Chi-square or Fisher exact test was used for the analysis of categorical variables. The Paired-T Test was employed to analyze the continuous parametric variables of two dependent groups, while the Wilcoxon Signed Rank Test was utilized for non-parametric variables. p < 0.05 was selected for the statistical significance of the alpha.
Results
Initially, 20 patients were included in the study; however, 3 patients who were unable to complete the treatment period (72 h) were subsequently excluded. The demographic characteristics of the patients are summarized in Table 1.
Demographic data.
Data are presented as median (IQR) or n (%).
In our study, there were 14 (82.4%) male and 3 (17.6%) female patients. The mean age was 55.0 (49.0 –65.0) years. Eight patients (47%) had comorbidities. Out of the seventeen patients, eleven individuals experienced mortality, accounting for 64.7% of the cases.
After hemadsorption, there was a notable increase in APACHE-II and SOFA values, along with lymphocyte counts, according to an analysis of all patient data. In contrast, there was a significant decrease in CRP and fibrinogen levels (p < 0.05; Table 2).
Comparison of patients’ values before and after hemadsorption.
Data are presented as median (IQR). p < 0.05 is statistically significant.
APACHE-II: acute physiology and chronic health evaluation II; SOFA: sequential organ failure assessment; CRP: C-reactive protein; LDH: lactate dehydrogenase; IL-6: Interleukin-6.
After doing a subgroup analysis, it was shown that after hemadsorption, the APACHE-II, SOFA, and lymphocyte counts of the non-surviving patients exhibited an increase, whereas the CRP and fibrinogen levels decreased in these patients (p < 0.05). Upon comparing the data from surviving patients, it was seen that the APACHE II and SOFA values remained unchanged after the process. However, there was a substantial decrease in CRP and ferritin levels (p < 0.05), while no significant changes were observed in fibrinogen and lymphocyte counts. There was no significant change in IL-6 levels before and after hemadsorption in the group of non-surviving and surviving patients (Tables 3 and 4).
Comparison of non-surviving patients’ values before and after hemadsorption.
Data are presented as median (IQR). p < 0.05 is statistically significant.
APACHE-II: acute physiology and chronic health evaluation-II; SOFA: sequential organ failure assessment; CRP: C-reactive protein; LDH: lactate dehydrogenase; IL-6: interleukin-6.
Comparison of surviving patients’ values before and after hemadsorption.
Data are presented as median (IQR). p < 0.05 is statistically significant.
APACHE-II: acute physiology and chronic health evaluation-II; SOFA: sequential organ failure assessment; CRP: C-reactive protein; LDH: lactate dehydrogenase; IL-6: Interleukin-6.
The group of non-surviving patients showed higher values for APACHE II, SOFA, and procalcitonin both before and after the process (p < 0.05; Table 5).
Comparison of values before and after hemadsorption between non-surviving and surviving patients.
Data are presented as median (IQR). p < 0.05 is statistically significant.
APACHE-II: acute physiology and chronic health evaluation-II; SOFA: sequential organ failure assessment; CRP: C-reactive protein; LDH: lactate dehydrogenase; IL-6: interleukin-6.
Comparing vital signs revealed that surviving patients showed an increase in diastolic blood pressure following hemadsorption, while non-surviving patients showed a decline (Table 6).
Comparison of patients’ vital signs before and after hemadsorption.
Discussion
In this study, we hypothesized that HA treatments would change the laboratory, multiple organ dysfunction scores and inflammatory markers of patients with COVID-19 as a result of the removal of cytokines from the environment, and accordingly, the disease clinic may improve.
When all patients were considered, APACHEI-I and SOFA values before HA were significantly increased after HA treatment, while CRP and fibrinogen were significantly decreased. Again, when this patient group was divided into living and deceased patients, APACHE II and SOFA values increased and CRP and fibrinogen decreased in the deceased group, similar to the total patient group. In the living group, APACHEII and CRP levels increased after HA, although not significantly.
When the deceased and survivors were compared within themselves, the most important difference between the groups before and after HA treatment was that APACHE II, SOFA score and procalcitonin levels were higher in the deceased group.
When we interpret the data obtained from our study, since APACHE-II and SOFA scores were higher in non-surviving patients, it is advisable to consider intensive care scoring systems when making decisions about administering hemadsorption treatment. Treating patients with high APACHE-II and SOFA scores is believed to be more challenging; hence, treatment should be initiated as soon as possible.
Similar to previous studies, 12 in our study, hemadsorption treatment led to a decrease in CRP and fibrinogen levels, as well as an increase in the number of lymphocytes, when considering the total patient group. However, there was no notable disparity between the fibrinogen levels and lymphocyte counts before and after the procedure in the group of patients who survived. This could potentially be attributed to the limited number of surviving patients in our study. Due to its retrospective design, our study did not allow for an evaluation of this aspect. However, we believe that looking at the numbers and ratios of CD4+ and CD8+ lymphocytes along with the lymphocyte count could provide more information in future studies, particularly when considering the pathophysiology of COVID-19.
In our study, in non-surviving patients, there was no notable alteration in ferritin levels after the treatment. However, in the group of surviving patients, there was a substantial fall in ferritin levels following the procedure. Uysal et al. 13 conducted a study to assess the impact of hemadsorption treatment on laboratory parameters in severe COVID-19. The findings revealed that ferritin levels decreased or remained unchanged with hemadsorption, which aligns with our study’s results. However, it is worth noting that ferritin levels decreased specifically in surviving patients. In our study, the higher pre- and post-procedure procalcitonin values in the deceased patients compared to the living patient group may indicate the contribution of secondary bacterial infections to mortality.
A study conducted by Premužić et al., 14 which included fifteen serious cases of COVID-19 undergoing hemadsorption, showed a significant decrease in IL-6 levels, improved respiratory parameters, improvement in pulmonary X-ray graphs, and a decline in SOFA scores after hemadsorption. They discovered that hemadsorption before the onset of organ failure contributed to reducing mortality. They have identified mortality at about 50%. The mortality rate in our study is 64%. In the literature, the mortality rate was lower than in our study and there were studies with high results. Alavi Darazam et al. 10 found the mortality rate to be 70% in a study with 55 patients.Metin girmek için buraya tıklayın veya dokunun. Uysal et al. 13 showed that the mortality rate was 86% in their study.Metin girmek için buraya tıklayın veya dokunun. We think that the main reason for this is patient-related, as can be inferred from other results. In our study, poor patients were treated and mortality rates may have been found to be high because it was used as a kind of rescue treatment.
Prior research has demonstrated a reduction in IL-6 levels among individuals with severe instances of COVID-19 who underwent hemadsorption. In particular, extracorporeal hemadsorption was applied to the cases for 24–48 h, and it was emphasized that if the IL-6 level persists, extending the duration of the procedure may be beneficial in controlling the hyperinflammatory state. 15 Nevertheless, our analysis revealed that there was no notable disparity in IL-6 levels before and after hemadsorption among both non-surviving and surviving patients. The outcome of our investigation leads us to consider the determinants of the reduction in IL-6 levels associated with hemadsorption. This highlights the need for further research on the parameters on the decrease in IL-6 levels and mortality rates.
In our study, when vital signs were compared, it was noted that non-surviving patients saw a decline in diastolic blood pressure following hemadsorption, whereas surviving patients exhibited an increase. However, there is no significant difference in systolic blood pressure and mean arterial pressure. Various factors, including the equilibrium between pro-inflammatory and anti-inflammatory cytokines, have an impact on blood pressure. Hence, elucidating the reasons behind the unaltered systolic blood pressure and mean arterial pressure, despite the impact on diastolic blood pressure, proves to be challenging. It is important to highlight that studies have demonstrated a correlation between the aforementioned SNP in the TNF-alpha gene and elevated systolic blood pressure. 16
Experts 17 and some guidelines 18 have recommended extracorporeal hemadsorption for the eliminating of inflammatory mediators, providing organ support and reducing mortality in COVID-19 patients with multiple organ failure. Ama unutulmamalıdır ki bu sonuçlar zamanla kendini yenilemiş ve güncel kılavuzlarla desteklenmemiştir. However, further studies and detailed evidence are needed to evaluate the efficacy of hemadsorption techniques in managing CSS in COVID-19 patients.
It is critical to remember that cytokines are essential for the immune response’s proper functioning. The intricacy of the immune response and the variations particular to each patient are significant. 19 A single nucleotide polymorphism can completely change the structure of TNF-α in individuals, for example, the replacement of alanine with guanine in the 308th row in the TNF-α sequence can completely change its structure and create a more lethal form, the current risk of death increases 3.7 times. 20
Other effects of the HA systems we use for treatment should be kept in mind. Studies have shown that HA methods also affect drug levels. After 2 h of post-treatment, pre- and post-transition antibiotics (including vancomycin, amikacin, tobramycin, and gentamicin), digoxin, theophylline, phenobarbital, phenytoin, carbamazepine and valproic acid were effectively removed. 21 Therefore, patients undergoing adsorption therapy should be carefully monitored with drug levels (where possible) and should be supplemented with additional doses as necessary. 22
Although SNPs have the potential to significantly alter the structure of cytokines like TNF-α in individuals, leading to the development of more lethal variants, 23 the present comprehension of therapy alternatives and the ideal moment to discontinue treatment remain ambiguous. With so many independent factors, it is not yet clear how we should treat, where we are in the treatment and where we should stop. Removal of pro- and anti-inflammatory cytokines from the environment may gradually impair the body’s ability to eliminate infections and restore physiological homeostasis. The physiological roles of cytokines in the health and disease process should be recognized. They are absolutely essential for the proper functioning of the localized and systemic host immune response. Removal of IL-6 and TNF-α, for example, can alter cell signaling and attenuate the innate immune response to PAMPs and DAMPs. 24
Our study has limitations. As it is a retrospective study, the power to establish causal relationships is limited and the risk of selection bias is increased. Prospective, randomized controlled trials are more suitable for providing strong evidence in clinical research. Being single-center can create site-specific biases. A multicenter approach would be more appropriate to increase the reliability and applicability of your results. and small sample size limits the generalizability of your findings and reduces the statistical power of your analysis. Including a control group in your study design would allow for a clearer assessment of the effectiveness of the intervention. In our study, we only looked at IL-6 as part of the cytokine storm; however, it would be more accurate to look at all cytokines and IL together. A larger sample size is important to increase the reliability and impact of your results.
Conclusion
Multiple factors can affect the impact of hemadsorption on mortality in patients with COVID-19. APACHE-II and SOFA scores can be valuable in forecasting the effectiveness of hemadsorption. In COVID-19, this can act as a guide for determining the ideal disease stage at which to apply hemadsorption therapy. Our study initially discovered a positive relationship between high APACHE-II and SOFA scores and an increased mortality rate following hemadsorption. These findings suggest that utilizing intensive care scoring systems can be advantageous in identifying the individuals who should undergo hemadsorption. Furthermore, it is recommended to administer hemadsorption in the first phases of the disease, wherever feasible, for critically ill patients. The results highlight the significance of reductions in ferritin levels as a prognostic marker in COVID-19 patients who are undergoing hemadsorption. In our study, there were higher pre- and postprocedure procalcitonin levels in the non-surviving patients, compared to the surviving patients. This may indicate the contribution of secondary bacterial infections to mortality.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
