Clinical and technical evidence
A literature search was carried out for this briefing in accordance with the interim process and methods statement. This briefing includes the most relevant or best available published evidence relating to the clinical effectiveness of the technology. Further information about how the evidence for this briefing was selected is available on request by contacting email@example.com.
The evidence includes a collection of case reports and cohort studies including 56 patients with COVID‑19 and respiratory failure. Most of the studies in this briefing were reported through webinars on the company websites.
Each of the technologies described in this briefing have been used for alternative indications, primarily sepsis and including pneumonia, acute respiratory distress syndrome (ARDS) and flu. There is a significant amount of published evidence reporting the use of adsorbent technologies, as well as other blood purifying devices, for treating sepsis. A recent systematic review and meta-analysis (Putzu et al. 2019) summarises the evidence for blood purifying devices for sepsis. This indicates that current evidence is of low quality and further evidence is needed before recommending the devices. An unpublished report summarising background evidence for the use of the D2000 adsorption cartridge in 9 people with respiratory infections, flu and sepsis was submitted to NICE. The report found there were no adverse events related to using the device. There is an ongoing study using the D2000 adsorption cartridge in people with COVID‑19 but currently there are no reported cases.
This briefing summarises the early clinical data reported after using cytokine adsorbent devices in people with COVID‑19. Because of the recent emergence of COVID‑19 in early 2020, the evidence in this summary has not been peer reviewed and is of low methodological quality, but there are ongoing higher-quality studies. The evidence primarily reports the effect of adsorption devices on blood levels of cytokines and lung function but there are limited data about the effect of the treatment on rates of patient recovery and mortality. Well-designed comparative studies are needed to establish whether adsorption devices decrease mortality rates. The evidence summarised is from outside of the UK and critical care treatment and procedures may be different between countries. This limits the generalisability of findings.
These are summarised below:
Single arm observational study including 10 patients with COVID-19 and severe ARDS in China.
Levels of IL-6 and lactate were reduced after CytoSorb therapy compared with pre-treatment levels. Lung function, defined as ratio of arterial oxygen partial pressure to fractional inspired oxygen (paO2/FiO2 ratio), improved after treatment and blood pressure stabilised (defined by a reduction in the norepinephrine/mean arterial pressure ratio). The intensive care mortality rate in this population was 50%, 1 patient died after being moved off the intensive care unit. This resulted in an overall hospital mortality rate of 60%.
This was a small observational study that reported adsorbent technology use in an older (mean age 68 years) and predominantly male (n=8) population with severe COVID‑19 complications. The findings may not be generalisable to the wider population. CytoSorb was combined with renal replacement therapy in 8 of the 10 patients which may confound the findings, the remaining 2 had CytoSorb without additional extracorporeal therapies. No statistical analyses were reported.
A cohort study including 21 patients with COVID‑19 comparing CytoSorb therapy and standard care with standard care alone.
CytoSorb with continuous renal replacement therapy (CRRT) alongside standard care (n=11) compared with CRRT alongside standard care (n=10).
The CytoSorb group had a lower mortality rate 30 days after treatment compared with the control group (18% and 30%, respectively). Both groups had an initial reduction in the inflammatory biomarker, C‑reactive protein (CRP), but a larger reduction was seen in the CytoSorb group 30 days after treatment. The CytoSorb group had improved lung function (paO2/FiO2 ratio) 30 days after treatment, whereas lung function in the control group had decreased after 30 days.
The demographics between the cohorts were well matched and baseline ventilatory parameters were similar. The CytoSorb group had increased comorbidities and poorer lung function at baseline, but these differences were not statistically significant. Cohort allocation was not randomised which increased the risk of selection bias. The sample size was small, power calculations were not reported, and no statistical analysis was presented. Two patients had CytoSorb treatment for only 1 day before being moved to a different hospital, which may confound the findings.
Four case reports of patients with COVID-19 treated with CytoSorb. (Italy, n=2; Germany, n=2).
Three of the 4 cases describe IL-6 levels reducing after treatment with CytoSorb, 2 cases were combined with extracorporeal membrane oxygenation (ECMO), the third case combined CytoSorb with tocilizumab. The fourth case describes a patient that received 3 sessions of treatment with CytoSorb but because of excessive clotting the treatment was unsuccessful and was stopped.
This evidence summarises 4 specific clinical experiences of using CytoSorb as well as either extracorporeal therapy or drug therapy. Reporting of demographic information and clinical findings is inconsistent between studies. This evidence is anecdotal and of low quality and is not generalisable to the wider population.
The evidence reported in this briefing is in addition to the evidence reported in the Health Technology Wales topic exploration report on the Jafron cytokine adsorber. The new evidence for this technology includes 21 patients with COVID‑19 across 5 sites. One case report has been published, 8 were described on the webinar and 6 cases were compared with 6 cases of COVID‑19 treated with standard care and submitted as unpublished evidence. The cases have been summarised below.
The patient had 3 sessions of treatment with the HA380 adsorption therapy. Before treatment the patient's peripheral oxygen saturation was 82%, after treatment peripheral oxygen saturation increased to 95%. IL‑6 levels decreased from 226.36 picograms per millilitre (pg/ml) to 210.18 pg/ml, IL‑1 reduced from 523.3 pg/ml to 38.25 pg/ml, IL‑8 reduced from 886.5 pg/ml to 482.4 pg/ml and tumour necrosis factor alpha level decreased from 49.5 pg/ml to 47.3 pg/ml. The patient was discharged from intensive care.
HA380 haemoperfusion cartridge with ECMO, no comparator (3 cases, China).
HA330 haemoperfusion cartridge, no comparator (5 cases from 2 sites in Thailand).
Inflammatory biomarker, CRP, cytokines IL‑6, IL‑8 and IL‑10 were reduced in all patients after HA380 haemoperfusion cartridge with ECMO therapy. Biomarkers reflecting lung function and oxygenation also improved. Of the 3 patients treated HA380 haemoperfusion cartridge with ECMO therapy, 1 died, 1 remains on ECMO treatment and 1 is being weaned off ECMO and ventilation. Five patients were treated with HA330 haemoperfusion cartridge at 2 sites in Thailand. Of the 5 cases, 4 showed lung function improvements and 1 did not. CRP levels were reported for 2 of the cases, both showed reduced levels of CRP after treatment.
These cases reports describe the clinical experience of using HA380 or HA330 haemoperfusion therapy to treat COVID‑19. The treatment protocol varied between sites, 5 cases had additional extracorporeal therapy including ECMO or renal replacement therapy. These cases report that HA380 and HA330 hemadsorption devices can be used safely as an adjunctive therapy for COVID‑19. The anecdotal evidence is of low quality, reporting is inconsistent between cases and the results are not generalisable to the wider population.
The study reports that all 6 patients that had treatment with HA380 haemoperfusion cartridge survived and showed reductions in inflammatory parameters and improvements in haemodynamic conditions, all patients survived. Patients that did not have treatment with the HA380 haemoperfusion cartridge developed AKI, 1 patient died.
The reporting of this study is limited. The unpublished summary provided by the company does not report patient demographics, or study methodology including inclusion criteria, treatment protocol or outcome measures. Because of the limitations of the reporting in this summary it is difficult to draw conclusions from the data.
Effect of CytoSorb adsorber on hemodynamic and immunological parameters in critical ill patients with COVID-19 (CYTOCOV-19). ClinicalTrials.gov identifier: NCT04344080. Status: recruiting. Indication: COVID-19. Devices: CytoSorb, CytoSorbents. Date: December 2020. Country: Germany.
Cytokine adsorption in severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV). ClinicalTrials.gov identifier: NCT04324528. Status: recruiting. Indication: severe COVID-19 pneumonia. Devices: CytoSorb, CytoSorbents. Date: 26 September 2020. Country: Germany.
Plasma adsorption in patients with confirmed COVID-19. ClinicalTrials.gov identifier: NCT04358003. Status: recruiting. Indication: COVID-19 respiratory failure. Devices: D2000 Plasma Adsorption Cartridge, Marker Therapeutics. Date: 1 August 2020. Country: No location given.
Treatment of COVID-19-induced cytokine storm with filter haemoperfusion HA330. Trials identifier: IRCT20200317046797N5. Status: recruiting. Indication: COVID-19 severe cytokine storm and respiratory symptoms (ARDS). Devices: HA330. Date: none given. Country: Iran.
Efficacy of HA330 haemoperfusion in critically ill patients with severe COVID-19 (HA-COVID19). Trials identifier: TCTR20200409006. Status: pending (not yet recruiting). Indication: COVID-19, ARDS. Devices: HA330 haemoperfusion. Date: 1 May 2021. Country: Thailand.
CytoSorb in treating critically ill hospitalized adult patients with novel coronavirus pneumonia (COVID-19). Trials identifier: ChiCTR2000030475. Status: prospective registration. Indication: novel coronavirus pneumonia (COVID-19). Devices: CytoSorb. Date: 25 June 2020. Country: China.
Evaluating the use of polymyxin B cartridge haemoperfusion for patients with septic shock and COVID-19. ClinicalTrials.gov identifier: NCT04352985. Status: available. Indication: septic shock and COVID-19. Devices: Toraymyxin PMX-20R (PMX Cartridge). Date: none given. Country: none given.