Petar UgurovI; Dijana PopevskiI; Tanja GramosliI; Dashurie NeziriI; Dragica VuckovaI; Marko GjorgonI; Emil StoicovskiI; Sanja MarinkovicI; Lidija Veljanovska-KiridjievskaI; Katerina IgnevskaI; Sanja MehandziskaI; Elena AmbarkovaI; Zan MitrevI; Rodney Alexander RosaliaI
ABSTRACTIntroduction: Severe coronavirus disease 2019 (COVID-19) is characterised by hyperinflammatory state, systemic coagulopathies, and multiorgan involvement, especially acute respiratory distress syndrome (ARDS). We here describe our preliminary clinical experience with COVID-19 patients treated via an early initiation of extracorporeal blood purification combined with systemic heparinisation and respiratory support.
ACT = Activation clotting time
AKI = Acute kidney injury
ALT = Alanine aminotransferase
ARDS = Acute respiratory distress syndrome
AST = Aspartate aminotransferase
BMI = Body mass index
BSA = Body surface area
CI = Confidence interval
COVID-19 = Coronavirus disease 2019
CPAP = Continuous positive airway pressure
CRP = C-reactive protein
CT = Computed tomography
CXCL-8 = Chemokine (C-X-C motif) ligand 8
ECOS = Extracorporeal organ support
EO = Eosinophil
FIB = Fibrinogen
HCT = Hematocrit
HGB = Hemoglobin
ICU = Intensive care unit
IL = Interleukin
INR = International normalised ratio
IQR = Interquartile range
IU = International units
LDH = Lactate dehydrogenase
LYM = Lymphocyte
MONO = Monocyte
NEU = Neutrophil
NEU/LYM = Neutrophil-to-lymphocyte
NLR = Neutrophil-to-lymphocyte ratio
NMK = Republic of North Macedonia
PLT = Thrombocyte
RT-PCR = Reverse transcription polymerase chain reaction
SARSCoV-2 = Severe Acute Respiratory Syndrome Coronavirus 2
SII = Systemic immune-inflammation index, thrombocyte* (neutrophil-to-lymphocyte)
SpO2 = Oxygen saturation
STROBE = STrengthening the Reporting of OBservational studies in Epidemiology
TNF-α = Tumour necrosis factor alpha
WBC = White blood cell
The current coronavirus disease 2019 (COVID-19) pandemic is manifesting itself as an unprecedented threat to the global population. The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) started in Wuhan, Hubei Province, People's Republic of China. Since then, it has spread in a rapid, deadly pace throughout the world instigating the World Health Organization to classify COVID-19 as a global epidemic on February 28, 2020.
Severe COVID-19 is characterised by (infectious) pneumonia; complications typically include acute respiratory distress syndrome (ARDS). COVID-19 has also been linked with acute cardiac injury[4,5], kidney malfunction, and secondary infections.
COVID-19 progression is associated with dysregulated immunity, commonly referred to as cytokine storm, in particular, aberrant interleukin (IL)-6 levels[9-11] that promote numerous pathological downstream effects. Hyperinflammation is a well-established trigger of multiorgan failure, e.g., acute kidney injury (AKI). Moreover, recent reports point to a link between hyperinflammation and COVID-19-induced coagulopathy[12,13] as a result of increased production of clotting factors by the liver.
Despite several lines of evidence pointing to a potential clinical benefit of controlling hyperinflammation triggered by COVID-19, management of COVID-19 remains mostly supportive built around continuous respiratory support[15-18].
To this end, considering the underlying immunological character of COVID-19 and the high risk of SARS-CoV-2 hyperinflammation to trigger ARDS, hypercoagulability, and AKI, we have established a treatment protocol for COVID-19. We follow selected biochemical, immunological, and coagulation risk factors to tailor therapy; our approach centres around the 1) early initiation of blood purification using the oXiris® (AN69ST) filter[19,20], 2) systemic heparinisation, and 3) respiratory support, continuous positive airway pressure (CPAP), and physical therapy.
With this initial report, we present a preliminary overview of biochemical, immunological, inflammatory, and coagulation biomarkers assessed, and offer insights into their correlations with clinical status. Finally, we report the early results in regards to treatment outcome.
This single-centre case series included 15 consecutive patients with confirmed COVID-19 treated in June 2020. The study designed is presented in the STrengthening the Reporting of OBservational studies in Epidemiology, or STROBE, diagram (Figure 1).
Patients were classified according to their clinical presentation in four severity degrees:
1. Mild cases The clinical symptoms are mild, with no apparent sign of pneumonia on imaging. 2. Moderate cases Showing fever and respiratory symptoms with radiological findings of pneumonia. 3. Severe cases A. Respiratory distress (30 breaths/min). B. Oxygen saturation (SpO2) < 90% at rest.
C. Arterial partial pressure of oxygen (or PaO2)/fraction of inspired oxygen (or FiO2): 300 mmHg (1 mmHg = 0.133 kPa).
Cases with chest imaging that show lesion > 50% progression within 24 hours shall
be managed as severe cases. 4. Critical cases A. Respiratory failure requiring mechanical ventilation. B. Shock. C. Organ failure that requires intensive care unit (ICU) care. Inclusion Criteria Written or temporary verbal informed consent. Adults > 18 years. Confirmed COVID-19 pneumonia using reverse transcription-polymerase chain reaction
(RT-PCR), X-ray, and/or computed tomography.
1. Mild cases
The clinical symptoms are mild, with no apparent sign of pneumonia on imaging.
2. Moderate cases
Showing fever and respiratory symptoms with radiological findings of pneumonia.
3. Severe cases
A. Respiratory distress (30 breaths/min).
B. Oxygen saturation (SpO2) < 90% at rest.
C. Arterial partial pressure of oxygen (or PaO2)/fraction of inspired oxygen (or FiO2): 300 mmHg (1 mmHg = 0.133 kPa).
Cases with chest imaging that show lesion > 50% progression within 24 hours shall be managed as severe cases.
4. Critical cases
A. Respiratory failure requiring mechanical ventilation.
C. Organ failure that requires intensive care unit (ICU) care.
Written or temporary verbal informed consent.
Adults > 18 years.
Confirmed COVID-19 pneumonia using reverse transcription-polymerase chain reaction (RT-PCR), X-ray, and/or computed tomography.
Ethics Approval and Consent to Participate
The local ethical committee of the Zan Mitrev Clinic reviewed and approved the clinical practice, treatment procedures described, and the results reported in this manuscript and approved the submission (#EBPZ.357). Trial registration: ClinicalTrials.gov, NCT04478539. Registered 14th of July 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04478539
Consent for Publication
Written or temporary verbal informed consent was obtained from all patients for publication of this manuscript and any accompanying images; the use of all health and medical information for scientific research and manuscript preparation was approved. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of Data and Material
All original data described in this case report can be submitted for evaluation upon reasonable request.
Blood samples were collected from each patient at ≥ 1 x every 24 hours for routine blood analysis and to assess the treatment effects: white blood cell (WBC) count, lymphocyte count, neutrophil count, thrombocyte (PLT) count, monocyte count, and eosinophil count were determined as well as the neutrophil-to-lymphocyte (NEU/LYM) ratio (NLR) and the systemic immune-inflammation index PLT*(NEU/LYM). Moreover, blood biochemistry parameters such as Na+, K+, aspartate aminotransferase, alanine aminotransferase, bilirubin, urea, C-reactive protein (CRP), as well as procalcitonin and lactate dehydrogenase (LDH) were assessed using Siemens ADVIA Centaur XP Immunoassay System.
Data on coagulation parameters were obtained from all patients; coagulation tests included D-dimers, fibrinogen (FIB), and international normalised ratio. Tests were performed using a Sysmex CA-600 automatic coagulation analyser.
Analyses of human cytokines IL-6, IL-8/chemokine (C-X-C motif) ligand 8 (CXCL-8), and tumour necrosis factor alpha (TNF-α) in serum samples were performed using the Human Magnetic Luminex® assay (R&D Systems, United States of America), according to the manufacturer's instructions. The measurements were performed in triplicates using a Luminex® 100/200 System.
Categorical parameters were summarised as absolute numbers and percentages. Continuous data are shown as mean ± standard deviation; alternatively, non-parametric data are presented as median + interquartile range (IQR). Continuous variables were evaluated using the D'Agostino-Pearson normality test. The data were analysed with the statistical program GraphPad Prism, version 7.03.
The treatment protocol is shown in Figure 2 and follows practice safety recommendations, treatment strategies, and up-to-date sepsis management guidelines[22-25].
The multidisciplinary care and therapeutic approach consist of the early initiation of blood purification using the AN69ST (oXiris®) hemofilter, initiated within 4-12 hours of admission and high-dose heparinisation. We opt for an aggressive non-invasive respiratory therapy, including CPAP on-mask and physical therapy in an attempt to avoid mechanical ventilation. In the case of secondary infections, we administer targeted antibiotic therapy.
Extracorporeal Organ Support (ECOS) and Blood Purification
The Prismaflex® oXiris® system was mounted in the ICU and connected 4-12 hours after admission upon establishing control of the haemostasis, activation clotting time (ACT) of 180 secs. The patient is connected to the Prismaflex® oXiris® system via a double-lumen catheter placed in the femoral vein or vena subclavia.
Flow rates were maintained as follows: effluent dose 35 mL/Kg/h, dialysate 14-16 mL/Kg/h, blood 150 mL/min, replacement fluid 16-18 mL/Kg/h; patient fluid removal is tailored to the individual's volume status ≈ 100-250 mL/h. Blood purification is initiated within 4-12 hours of admission, and the oXiris® ECOS modality was chosen according to the patient's kidney function: continuous venovenous hemofiltration, continuous venovenous hemodiafiltration, or slow continuous ultrafiltration.
An initial 25000 international units (IU) bolus injection (≈ 300 IU/kg) followed by continuous infusion of 300 IU/kg dissolved in physiological buffer (0.9% sodium chloride) administered at 6-8 mL/h flow rate; target ACT ≥ 180 s during hospitalisation.
Oxygen therapy: Patients with severe symptoms should receive nasal cannulas or oxygen masks and timely assessment of respiratory distress and/or hypoxemia should be performed.
Non-invasive ventilation: CPAP on mask for patients with SpO2 86-90%; prone position.
Invasive mechanical ventilation: Lung protective ventilation strategy, namely low tidal volume (4-6 ml/kg of ideal body weight) and low level of airway platform pressure (< 30 cmH2O) should be used to perform mechanical ventilation to reduce ventilator-related lung injury.
While the airway platform pressure is maintained at 30 cmH2O, high positive end-expiratory pressure can be used to keep the airway warm and moist. Sedation and muscle relaxants were used according to the clinical condition and preferably in a prone position. Furthermore, anaesthesia regimens are tailored to promote early weaning from mechanical ventilation.
Empiric administration of Azithromycin in the first 48 hours; antibiotic therapy is discontinued, switched to targeted according to the antimicrobial susceptibility testing[26,27].
Individual medical therapy was continued according to the patient's pre-existing conditions and comorbidities.
A total of 15 patients with confirmed SARS-CoV-2 infection manifesting as COVID-19 were treated at our clinic in June 2020. Table 1 shows the basic patient characteristics. Of the 15 cases, two were females - the mean age of the cohort was 60.2 years (range 27-83). The patients were referred to us from peripheral hospitals across the country.
|Female gender (%)||2 (13%)|
|Obesity (BMI > 35 Kg/m2)||2|
|Glucose (mmol/L)||6.6 (5.7-12.8)|
|Urea (mmol/L)||4.5 (3.1-6.2)|
|Aspartate transaminase (U/L)||58.9±23.2|
|Alanine transaminase (U/L)||75.1±40.4|
|Lactate dehydrogenase (U/L)||330.5 (258.8-453.5)|
|Hemoglobulin (g/dL)||13.2 (12.3-14.0)|
|Hematocrit (%)||37.90 (36.30-40.40)|
|C-reactive protein (mg/mL)||74.1 (55.1-127.8)|
|White blood cell counts (*103 counts/µL)||6.3 (2.9-10.1)|
|Platelets (*103 counts/µL)||140 (108 to 208)|
|NEU (%)||83.11 (64.3-89.2)|
|LYM (%)||9.8 (7.3-21.5)|
|MONO (%)||3.3 (2.6-6.9)|
|EO (%)||0.1 (0.04-0.44)|
|NLR (*103 counts/µL)||8.3 (3.5-12.2)|
|Systemic immune-inflammation index||1311 (406.2-2791)|
|D-dimers (ng/mL)||790.0 (395.0-1980)|
|Fibrinogen (g/L)||7 (3.6-8)|
Primary symptoms reported were dyspnea, fever, and low peripheral saturation; 10 cases presented with severe disease; all patients had advanced COVID-19 pneumonia (Figure 3).
Patients presented with elevated levels of CRP (74.1 mg/L; IQR 55.10-127.8), mild thrombocytopenia (140*103 counts/µL; IQR 108-208), and increased values of D-dimers (790.0 ng/mL; IQR 395-1980) and FIB (5.8±2.4 g/L). LDH and NLR were high at admission with values of 330.5 IU (IQR 258.8-453.5) and 8.3 (IQR3.5-12.2), respectively (Table 1). Two patients were intubated within 24 hours of admission; both patients did not recover and died on the 5th and 26th hospitalisation day, respectively; both cases developed severe ARDS and multiorgan failure.
The other patients were discharged after, on average, 9.3 days (IQR 5.3-10.1) of intensive care in our COVID-19 center.
Treatment led to a gradual normalisation of biochemical parameters (Figure 4); in particular, we observed a linear trend (r=0.40, 95% confidence interval [CI] 0.21 to 0.57; P<0.0001) between platelet numbers, WBC (r=0.37, 95% CI 0.18 to 0.54; P=0.0003), and the clinical picture during hospitalisation suggesting that an increase of PLT was associated with recovery. A similar trend was observed for the WBC. In contrast, clinical recovery was associated with a decrease in FIB levels (r=-0.45, 95% CI -0.63 to -0.21; P=0.0004) and CRP (r=0.39 95% CI -0.57 to -0.20) (Figure 5A).
IL-6 is the primary cytokine leading to hepatic CRP production; we observed that early initiation of oXiris® blood purification was associated with stable or decreasing levels of IL-6, IL-8, and TNF-α which in turn led to a gradual reduction of systemic CRP levels across the whole cohort (Figures 4 and 6).
The treatment approach led to an improvement in SpO2, a decrease of inflammatory mediators, and an increase in the number of PLT.
In one particular case, a 50-year-old male admitted with a SpO2 of 92% on 2L of oxygen (Figure 2I and J) with previous episodes of high body temperature received, in addition to the two cycles of oXiris® blood purification, 8 mg/kg of Tocilizumab given over 120 minutes via intravenous infusion (Figure 6B). The latter was administered on the explicit, consented request of his family. Administration of IL-6r blocking antibody led to a transient spike of IL-6 levels as reported before. He was also treated with Azithromycin, which was adapted to Ciprofloxacin after multiplex RT-PCR identified Methylin-resistant Staphylococcus aureus and Klebsiella pneumoniae; he was discharged after 15 days.
In some cases, the clinical course was complicated because of bacterial co-infections; a case of a 56-year-old male with dyspnea, SpO2 of 90% on room air, and a body temperature of 38 °C at admission was challenging due to a Klebsiella pneumoniae infection.
The same pathogen was detected in a 70-year-old female. We also confirmed Streptococcus beta haemolyticus in her respiratory samples and vancomycin-resistant Enterococcus in urine samples taken within 24 hours after admission. We successfully treated her with two cycles of blood purification and antibiotics consisting of Azithromycin and Ampicillin/Sulbactam.
Another male presenting with high fever (38.8 °C), dry cough, dyspnea, and SpO2 of 85% had a co-infection of Streptococcus pneumoniae in his throat swabs detected using RT-PCR. We treated him with two cycles of oXiris® blood purification and Azithromycin. He was discharged after eight days with markedly recovered symptoms: CRP level was 6.4 mg/L, WBC count of 4.5x10^3/µL, and normalised platelet count was 186*103/µL.
The first mortality case involved an 83-year-old male with dyspnoea, tachypnoea, and extremely low SpO2 (65%) despite 6L oxygen, suggesting ARDS. Biochemical analysis revealed significant abnormalities; CRP was 279.9 mg/L, and LDH was 671 U/L. He was immediately placed on extracorporeal blood purification; we also discovered Streptococcus beta haemolyticus in his throat, and nasal swab detected it. Targeted therapy with Ampicillin/Sulbactam was initiated. However, despite intensive treatment including mechanical ventilation and a total of three cycles of oXiris® hemofiltration, the patient's condition deteriorated over the next days as he developed multiorgan failure; he passed away five days after his admission (Figure 6H).
The 2nd mortality case pertained to a 73-year-old male admitted with dyspnoea, tachypnoea, severely reduced SpO2 (< 70%) on room air and elevated LDH at 527 U/L. Despite two cycles of oXiris® blood purification, SpO2 levels were not improving. We were able to stabilise his condition with mechanical respiratory support. His condition was sensitive due to the discovery of Klebsiella pneumoniae in his bronchial secretion. For this reason, we switched antibiotherapy to include Ampicillin/Sulbactam. Still, despite systemic heparinisation, the levels of D-dimers (Figure 5B, purple coloured symbols) were increased to 31400 ng/mL on the 9th hospitalisation day. Towards the end of his 4th oXiris® cycle, we observed notable improvements, and we were able to extubate him in the next 48 hours (Figure 6O). However, within 48 hours his condition suddenly worsened necessitating re-intubation. Additional cycles of blood purification were unsuccessful in rescuing his clinical situation, and he succumbed to complications related to ARDS on the 26th day on the ICU.
In summary, a treatment approach based on early initiation of blood purification using the AN69ST (oXiris®) hemofilter, systemic heparinisation, and respiratory support may support clinical recovery in moderate to severe cases of COVID-19.
We present with this work our initial case series of 15 COVID-19 patients treated with early initiation of extracorporeal blood purification using the oXiris® (AN69ST) hemofilter, systemic heparinisation, and respiratory support; we monitored several biochemical, immunological, inflammatory, and coagulation biomarkers to tailor therapy to the individual requirements.
The first cases of COVID-19 in the Republic of North Macedonia (NMK) were confirmed in early March 2020. The country has seen a sudden rise in the confirmed cases since restrictions were lifted in May 2020; the number of cases is slowly outnumbering the national ICU-bed capacity.
As of July 28th, the current COVID-19 pandemic has resulted in 466 deaths over a population of roughly 2.0 million. These numbers echo the global statistics, with 16.5 million confirmed cases of COVID-19 worldwide and an estimated mortality rate of 3.7%. About 5% of the infected population will develop advanced disease requiring intensive care, often necessitating ECOS therapies. Of this critically ill subgroup, the mortality rate is high 40-50%.
We report here our initial case series; it is a relatively small cohort compared to global numbers. The reason being that our clinic was initially designated a "clean" hospital and allowed only to perform cardiovascular emergency procedures. Confirmed COVID-19 patients between March and June were referred to the public clinic of infectious diseases. During the first months of the outbreak in NMK, we operated on two COVID-19 patients with ruptured abdominal aorta aneurysms; the first case presented an extremely critical condition and succumbed to his condition on the 2nd postoperative day. The second case was successfully treated with a protocol resembling approach described in this report (Supplementary Figure 1). He was discharged after six days. Follow-up at 30 days pointed to a gradual normalisation of several inflammatory biomarkers; for instance, CRP was reduced to 29.9 mg/L from the initial 175.6 mg/L at admission.
The role of lung injury in COVID-19 is well-established; however, recent observations point to a high risk for AKI in COVID-19 patients, but also hypercoagulability. Several lines of evidence have implicated a role for pro-inflammatory cytokines in the pathology of COVID-19, especially in severe cases. Ruan et al. described that the critically-ill patients had higher systemic levels of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor, interferon-gamma-inducible protein-10, monocyte chemotactic protein 1, macrophage inflammatory protein-1A, TNF-α, and IL-6. Aberrant IL-6 levels were indicative of an adverse outcome. Another marker associated with disease severity and adverse outcomes is the NLR[29,30]. In addition, hypercoagulability is now considered as one of the hallmarks of COVID-19 progression with both D-dimers and FIB levels suggested having predictive power in establishing disease severity.
The intensive monitoring of the aforementioned parameters (Figures 4, 5, and 6) guides our clinical practice and allows us to tailor our treatment to the acute needs of the patient. Treatment focuses on limiting lung injury and on promoting physiological breathing using daily intermittent physical therapy regimens combined with CPAP-ventilation and prone position. Secondly, hypercoagulability and possibility of thromboembolism were countered through systemic administration of high dosages of heparin to maintain ACT > 180 seconds. It is noteworthy to mention that even bolus dosages of 25000 IU were not sufficient to reach ACT values of > 200 seconds, pointing to severe dysregulation of the coagulation cascade in COVID-19 patients. Thirdly, hyperinflammation was controlled using oXiris® hemofilter based extracorporeal blood purification.
Control of systemic levels of cytokines (IL-6, IL-8/CXCL-8/TNF-α) (Figure 6) was achieved using the Prismaflex® system (Baxter International Inc. Deerfield, Illinois) mounted with the oXiris® hemofilter. The oXiris® filter is a hollow fibre acrylonitrile and methanesulfonate (AN69ST) membrane that removes larger molecular weight molecules. Approved first in Europe in 2009, its initial CE-marked indication was extended in 2017 for patients who require blood purification, including those requiring continuous renal replacement therapy, and in conditions with excessive endotoxin and inflammatory mediator levels. The system also received emergency Food and Drug Administration authorisation for COVID-19 treatment in April.
The oXiris® filter uses a modified AN69ST membrane and has an affinity for both endotoxins and cytokines. The modified oXiris® membrane has three-fold more polyethyleneimine for optimal endotoxin adsorption. Additional (10-fold) higher amount of immobilised heparin efficiently reduces thrombogenicity. It has shown a superb capacity to adsorb cytokines and endotoxins control abnormal levels of systemic cytokines and improve haemodynamic parameters[37,38]. To this end, our COVID-19 treatment bundle is based on the use of oXiris® blood purification to counter the multidimensional inflammatory attack on the body triggered by the SARS-CoV-2.
Our treatment approach is built on our previous experience and our ongoing partnerships with European experts on the treatment of sepsis and related infections diseases.
Blood purification has been evaluated in mechanically ventilated COVID-19 cases and patients on extracorporeal membrane oxygenation. Both groups reported promising results, an effective reduction in pro-inflammatory cytokines and recovery in most of the treated patients.
Our results further provide empiric evidence for the effectiveness of blood purification to prevent, control and reduce hyperinflammation in COVID-19. However, our treatment approach differs on three key points: 1) the blood purification device, oXiris® vs. CytoSorb® ; the latter is a CE-marked device containing polymer beads to adsorb cytokines used in blood pump circuits vs. the modified AN69ST membrane; 2) we performed blood purification in moderate to severe cases within 4-12 hours of admission, intending to prevent disease progression and the need of mechanical ventilation; and 3) we use repetitive cycles whenever the inflammation markers were increasing.
Collectively, the work here presents a promising outlook on the treatment possibilities using a standardised procedure based on 1) control of excessive pro-inflammatory cytokines through early initiation of blood purification (Figure 6), 2) prevention of hypercoagulability through systemic heparinisation (Figure 5), and intensive physical therapy combined with CPAP-respiratory support (Figure 2).
In summary, we observed that clinical recovery was associated with an increase in PLT and WBC, whereas a decrease in CRP and FIB was observed in patients with improving clinical conditions.
Blood purification to control excessive inflammation has gained acceptance as a treatment modality for COVID-19[20,43] and was successfully used in one case.
Our findings propose a base for further evaluation but should be appraised with caution due to the limitations of single-centre observational studies and the small cohort. We provide several lines of evidence that a fully integrated digital monitoring system to guide timing, and intensity of blood purification may support clinical recovery; however, clinical trials are required to assess our findings and determine the clinical effectiveness and safety of blood purification in critically ill COVID-19 patients.
Finally, a long-term assessment is warranted to determine complete recovery, especially the resolution of COVID-19 pneumonia and recuperation of normal lung function.
An early initiation of blood purification using the oXiris® hemofilter was effective in preventing aberrant pro-inflammatory levels of COVID-19 patients. Furthermore, we observed no cases of thromboembolism which might be linked to the systemic heparinisation regimen.
Collectively, we show that real-time digital monitoring of vital signs, biochemical, immunological, and coagulation markers, and X-ray imaging in COVID-19 patients offer the opportunity to track disease severity and tailor therapy based on cytokine-hemofiltration, heparin anticoagulation, and respiratory support.
Finally, a multi-centre randomised study is warranted to adequately scrutinise the clinical effectiveness of extracorporeal blood purification in the treatment of COVID-19.
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Authors' roles & responsibilities
PU Responsible for diagnostics and patient care; drafting the work; final approval of the version to be published
DP Responsible for diagnostics and patient care; drafting the work; final approval of the version to be published
TG Responsible for diagnostics and patient care; final approval of the version to be published
DN Responsible for diagnostics and patient care; drafting the work; final approval of the version to be published
DV Responsible for diagnostics and patient care; final approval of the version to be published
MG Responsible for diagnostics and patient care; final approval of the version to be published
ES Responsible for diagnostics and patient care; final approval of the version to be published
SM Responsible for diagnostics and patient care; final approval of the version to be published
LV-K Performed the radiological examinations; final approval of the version to be published
KI Final approval of the version to be published
SM Responsible for cytokine analysis; final approval of the version to be published
EA Responsible for the medical policies; and critical review of the work; final approval of the version to be published
RAR Responsible for cytokine analysis; academic assistance; coordination of acquisition of data; analysis of data; drafting the work; final approval of the version to be published
ZM Study director; Responsible for diagnostics and patient care; final approval of the version to be published
Article receive on Tuesday, July 28, 2020
Article accepted on Thursday, August 6, 2020