Literature Review of Hemadsorption Therapy in Severe COVID-19 Cases: a Narrative Review

Abstract

Background:
A novel therapy for reducing the cytokines in the circulatory system used for severe COVID-19 cases was hemoperfusion or hemadsorption method. Although the hemoperfusion methods have been shown to be beneficial in the cytokine storm during influenza infection, it is not known to what extent it is successful for COVID-19 patients. Therefore, the purpose of this study is to review the studies on severe COVID-19 treated with the hemoperfusion methods.

Methods:
A literature search was conducted using the databases PubMed, Science Direct, and Springer databases. Since the included articles consisted of case reports, case series, and one controlled trial, only the mean of the analyzed data could be calculated.

Results:
Sixteen studies were included in the narrative review, including 86 patients with severe COVID-19. All the patients had hemoperfusion therapy with following cartridges: CytoSorb®, oXiris®, Biosky filter, SeaStar® CLR filter, HA280, HA330 Jafron©, and resin directed hemadsorption cartridges. Mortality rate, the mean of intubation time, duration in intensive care unit and hospital were 29%, 14.93 days, 17.21 days, and 31.7 days, respectively. The mean values of C-reactive protein and interleukin-6 decreased after hemoperfusion sessions (131.7 to 66.0, 527.5 to 334.7, respectively).

Conclusions:
In this narrative review, it is demonstrated that hemadsorption therapy is an alternative salvage treatment method in critically ill COVID-19 patients, but the data must be supported by strong evidence.

Full text

Clin. Lab. 2/2022
401
Clin. Lab. 2022;68:401-409
©Copyright ORIGINAL ARTICLE
Literature Review of Hemadsorption Therapy in
Severe COVID-19 Cases: a Narrative Review
Suna Koc 1 and Harun Uysal 2
1 Department of Anesthesiology and Reanimation, Biruni University, Istanbul, Turkey
2 Department of Anesthesiology and Reanimation, Bezmialem University, Istanbul, Turkey
SUMMARY
Background: A novel therapy for reducing the cytokines in the circulatory system used for severe COVID-19 cases
was hemoperfusion or hemadsorption method. Although the hemoperfusion methods have been shown to be bene-
ficial in the cytokine storm during influenza infection, it is not known to what extent it is successful for COVID-19
patients. Therefore, the purpose of this study is to review the studies on severe COVID-19 treated with the hemo-
perfusion methods.
Methods: A literature search was conducted using the databases PubMed, Science Direct, and Springer databases.
Since the included articles consisted of case reports, case series, and one controlled trial, only the mean of the ana-
lyzed data could be calculated.
Results: Sixteen studies were included in the narrative review, including 86 patients with severe COVID-19. All
the patients had hemoperfusion therapy with following cartridges: CytoSorb®, oXiris®, Biosky filter, SeaStar®
CLR filter, HA280, HA330 Jafron©, and resin directed hemadsorption cartridges. Mortality rate, the mean of in-
tubation time, duration in intensive care unit and hospital were 29%, 14.93 days, 17.21 days, and 31.7 days, re-
spectively. The mean values of C-reactive protein and interleukin-6 decreased after hemoperfusion sessions (131.7
to 66.0, 527.5 to 334.7, respectively).
Conclusions: In this narrative review, it is demonstrated that hemadsorption therapy is an alternative salvage
treatment method in critically ill COVID-19 patients, but the data must be supported by strong evidence.
(Clin. Lab. 2022;68:401-409. DOI: 10.7754/Clin.Lab.2021.210839)
Correspondence:
Harun Uysal, MD
Department of Anesthesiology and Reanimation
Bezmialem Vakif University Medical School
Topkapi
Adnan Menderes Blv
34093 Fatih
Istanbul
Turkey
Phone: +90 5063433494
Email: drharunuysal@hotmail.com
____________________________________________
Manuscript accepted September 27, 2021
KEY WORDS
COVID-19, severe coronavirus infection, hemoperfu-
sion, hemadsorption, CytoSorb, cytokine storm,
cytokine release syndrome
INTRODUCTION
The novel coronavirus disease (COVID-19) is a disease
which can present severe acute respiratory syndrome
with multiple organ dysfunction and sepsis [1]. Up-to-
date, there have been 68,845,368 cases of COVID-19
globally, including 1,570,304 deaths, reported to the
World Health Organization (WHO) (https://covid19.
who.int/).
According to the published studies, 67% of severe
COVID-19 patients develop an excessive immune re-

S. Koc and H. Uysal
Clin. Lab. 2/2022
402
sponse characterized by sepsis [2]. The hyperinflamma-
tion response observed in these patients is often referred
to as "cytokine storm" or "cytokine release syndrome
(CRS)". Cytokine storm or CRS is associated with in-
creased levels of cytokines such as circulating IL-6, IL-
1β, and tumor necrosis factor and worsening of acute
respiratory symptoms. In addition, the release of pro-in-
flammatory cytokines is associated with the degree of
lung injury, CRS-associated multi-organ damage such
as kidney, heart dysfunction, and micro or macro-vascu-
lar thrombosis [3].
Once infected with COVID-19, the disease manifests it-
self in 3 stages. Stage 1 is the asymptomatic incubation
period. Stage 2 is the non-severe symptomatic stage of
the disease. At this stage, the patient can recover or
progress. The illness of 80 percent of patients ends at
this stage. Finally, stage 3 is the stage in which severe
respiratory symptoms worsen. At the end of the stage,
the patient may die with respiratory failure as a result of
diffuse alveolar damage or recover. This last stage is
characterized by excessive inflammation of the lungs,
cytokine storm in the circulatory system, and extrapul-
monary involvement [4].
Steroids, declared by the Food and Drug Administration
(FDA) as the first drug to reduce mortality in severe
COVID-19, were used to suppress inflammation during
the cytokine storm known as CRS. In a meta-analysis
by the rapid evidence appraisal for COVID-19 therapies
working group of WHO, administration of systemic
corticosteroids, compared with usual care or placebo,
was associated with lower 28-day all-cause mortality in
patients critically infected with COVID-19 [5]. Another
method used to suppress the excessive inflammatory re-
sponse in COVID-19 patients is the removal of pro-in-
flammatory cytokines from the circulatory system by
hemoperfusion or hemadsorption methods. With this
method, the patient's blood is extracorporeally passed
through a sorbent-containing cartridge and larger en-
dogenous or exogenous molecules, cytokines, patho-
gens, endotoxins are removed depending on the types of
sorbent used in the devices. The FDA has approved four
hemadsorption devices for emergency use authorization
to prevent CRS in critical COVID-19 patients [3].
Theoretically, with hemadsorption or hemoperfusion
methods the aim is to reduce deaths by suppressing the
excessive inflammatory response in COVID-19. How-
ever, the effectiveness of hemadsorption treatments
used in severely ill COVID-19 patients has not yet been
studied by large randomized controlled studies or meta-
analysis studies. The FDA, on the other hand, granted
an emergency use authorization based on clinical ex-
perience and the results of studies on acute respiratory
distress syndrome with infections such as influenza oth-
er than COVID-19. So far, there have been no large-
scale randomized controlled studies published on this
subject in the literature. The aim of this study is to re-
view the results of studies published in the literature as
case reports, case series or randomized controlled trials.
MATERIALS AND METHODS
Search strategy and selection criteria
A systematic search was conducted on studies published
in Pubmed, ScienceDirect, and Springer databases. Ac-
cording to the indexes, the search terms "COVID-19
and 2019 novel coronavirus" and "hemadsorption, he-
moperfusion, cytosorb" were used without any language
restrictions. Eligible were those that were case reports,
case series, and controlled trials about hemoperfusion in
severe COVID-19 patients. Studies that were duplicate
publications, reviews, editorials, clinical practice expe-
rience, views and comments, advice, research letters,
comments, and articles in which the desired variables
were not described were excluded. The steps of the lit-
erature search were shown in Figure 1.
Data extraction and analysis
Records were managed by EndNote X6.0 software to
exclude duplicates and to edit references. The following
variables were extracted from the studies: number of
participants, age, gender, type and duration of treat-
ment, number of hemoperfusion sessions, mortality rate,
C-reactive protein (CRP), and interleukin-6 (IL-6) val-
ues. The data were collected and analyzed using SPSS
software (23.0 Version). Since the included studies con-
sisted of case reports, case series, and one controlled
trial, statistical variables such as heterogeneity, odds ra-
tio, and p-value could not be estimated.
RESULTS
Among a total of 16 articles, 86 patients who had severe
COVID-19 and received hemadsorption therapy were
included in the study. Twelve of the articles included in
the study were case reports, three were case series, and
one was a randomized controlled trial. The average age
of the patients was 51.31 years. Sixty-four (74.4%) of
86 patients included in the study were male and 22 were
female (25.6%). CytoSorb® in 7 of 16 studies, HA380
cartridge in 2 studies, resin-directed hemoadsorption
cartridges in one study, oXiris® hemofilter in one study,
Biosky filter and CytoSorb® in one study, SeaStar®
CLR filter in one study, HA280 cartridge in one study,
and HA330 Jafron© cartridge in two studies were used
for hemadsorption therapy. In the studies, an average of
3.07 sessions of hemoperfusion were applied. Mortality
rate was calculated as 29% in all patients. The mean in-
tubation time in the calculated cases was found to be
14.93 days. The average length of stay in the intensive
care unit was 17.21 days. The average period of dis-
charge from the hospital was calculated as 31.7 days.
Specific features of the cases in the studies were given
in Table 1.
The laboratory data before and after the hemoperfusion
procedure were given in Table 2. While the mean of
CRP value was 131.7 before the procedure, it decreased
to 66 after hemadsorption. The mean of IL-6 value,

Hemadsorption Therapy in Severe COVID-19
Clin. Lab. 2/2022
403
Table 1. The summary of clinical data of the included articles.
Specialities of cases
Presented with acute abdomen
and pulmonary embolism and
experienced septic shock, acute
renal failure, and ARDS.
All patients experienced acute
renal failure, ARDS, septic
shock and cytokine storm.
One patient had malignancy
(leukemia), two patients had
cardiovascular disorders and
hypertension, three patients had
chronic kidney disease and
diabetes mellitus, one patient
had pneumoconiosis.
Received tocilizumab
Pregnant woman had a
caesarean.
The cases were presented in a
letter to the editor.
Hypertension and diabetes
mellitus.
Asthma and obesity
Duration
of
discharge
32
20
21
90
Duration
of ICU
stay
20.7
10
10
22
25.5
25
Duration
of
intubation
17.38
10
10
22
18.5
26
Mor-
tality
0
0
15
0
4
0
1
1
0
0
Number
of
sessions
2
2
6
3
3
3
3
2
7
4
Treatment
type
CRRT with
CytoSorb®
CRRT with
CytoSorb®
CRRT with
resin directed
hemoadsorption
cartridges
CRRT with
CytoSorb®
CRRT with
CytoSorb®
CRRT with
oXiris®
hemofilter
RRT plus
CytoSorb®
CRRT with
CytoSorb® and
ECMO with
Biosky filter
Gender
Female
0
11
3
2
0
1
0
0
0
Male
1
39
3
2
1
0
2
1
1
Age
45
49.64
57.3
40
22
60.5
71
56
Number
of
patients
1
35
15
6
4
1
1
2
7
1
s.
ns.
s.
ns.
Type
of
article
case
report
case
series
con-
trolled
trial
case
report
case
report
case
report
case
report
case
report
Alharthy
et al. [6]
Alharthy
et al. [7]
Asgharpour
et al. [8]
Berlot
et al. [9]
Keklik
et al. [10]
Ma
et al. [11]
Melegari
et al. [12]
Mezger
et al. [13]

S. Koc and H. Uysal
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404
Table 1. The summary of clinical data of the included articles (continued).
Specialities of cases
Had a myocardial
infarction and a stent
was placed.
Received 500 mg
tocilizumab every 12
hours for 3 doses.
Received tocilizumab
and plasma
immunoglobulin G
antibodies.
Two of the cases had
hypertension and one of
the cases had
cardiovascular disease.
Four patients who did not
receive hemoperfusion
were included in the
control group in the study.
All patients in the control
group died after
intubation. CRP decreased
significantly in the HP
group. Lymphocytopenia
worsened in the control
group. Procalcitonin
increased in two of the
cases not receiving HP.
Respiratory functions did
not improve or worsen in
the HP group.
Duration
of
discharge
13
12
Duration
of ICU
stay
13
12
Duration
of
intubation
2
Mor-
tality
0
0
0
0
1
Number
of
sessions
2
3
4
2
2
Treatment type
Hemoperfusion
with HA230
cartridge, Jafron©
CRRT with HA
380 cartridge
CRRT with HA
330 Jafron©
cartridge
hemoperfusion
Hemofiltration
with SeaStar®
CLR filter
Hemoperfusion
with CytoSorb®
Gender
Female
0
0
0
1
0
0
Male
1
1
1
4
1
Age
73
54
75
53
57.8
Number
of
patients
1
1
1
1
4
1
s.
ns.
Type of
article
case
report
case
report
case
report
case
report
case
series
Moradi
et al. [14]
Dastan
et al. [15]
Fernando
et al. *
Al-Qudsi
et al. [16]
Rampino
et al. [17]

Hemadsorption Therapy in Severe COVID-19
Clin. Lab. 2/2022
405
Table 1. The summary of clinical data of the included articles (continued).
Specialities of
cases
Diabetes
mellitus,
received one
dose of
tocilizumab
and plasma.
Two patients
had diabetes
mellitus, three
had
cardiovascular
disease, one
had kidney
dysfunction,
one had hyper-
lipidemia, two
had smoking
and one had
neurologic
dysfunction.
Hypertension
and diabetes
mellitus
Duration
of
discharge
60
7
31.7
Duration
of ICU
stay
15.4
5
17.21
Duration
of
intubation
12.5
14.93
Mor-
tality
0
3
0
25
Number
of
sessions
2
3
4
3.07
Treatment type
CRRT with
Cytosorbents®
HP with HA380
cartridge or
CRRT and HP
with HA380
CRRT and
Hemoperfusion
with HA280
cartridge
Gender
Female
4
22
Male
1
4
1
64
Age
51
44.25
54
51.31
Number
of
patients
1
8
1
86
Total or average
Type of
article
case
report
case
series
case
report
Rizvi
et al. [18]
Shadvar
et al. [19]
Vardanjani
et al. [20]
s. - survivors, ns. - non-survivors, CRRT - continuous renal replacement therapy, RRT - renal replacement therapy, HP - hemoperfusion,
ECMO - extracorporeal membrane oxygenation, ARDS - acute respiratory distress syndrome, ICU - intensive care unit, CRP - C-reactive
protein,* Fernando J, et al., HA330 hemoperfusion combined with CRRT for a 75-year old man with Covid-19 and Acute Kidney Injury, case
from Ecuador. Jafron Oversea Clin Cases. 2020;21.

S. Koc and H. Uysal
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406
Table 2. The summary of laboratory data of the included articles.
CRP
IL-6
b.
a.
b.
a.
Alharthy et al. [6]
99
Alharthy et al. [7]
s.
145.4
43.6
612.85
170.11
ns.
128.4
144.3
721.87
1,252.6
Asgharpour et al. [8]
s.
165.3
75.6
122.8
49
ns.
127
101.3
165
113.6
Berlot et al. [9]
229
59
1,040
415
Keklik et al. [10]
141
42
Ma et al. [11]
278.9
107
430.35
83.85
Melegari et al. [12]
123.53
18.51
Mezger et al. [13]
319
800
51.9
Moradi et al. [14]
115
46
Dastan et al. [15]
226.35
210.18
Fernando et al. [16]
5,000
109
Al-Qudsi et al. [17]
2,242
1,681
Rampino et al. [18]
s.
30
13
250
110
ns.
130
190
Rizvi et al. [19]
Shadvar et al. [20]
137.3
86.1
Vardanjani et al. [21]
103
12
265
10
Average
131,7
66,0
527,5
334,7
s. - survivors, ns. - non-survivors, b. - before hemoperfusion, a. - after hemoperfusion, CRP - C-reactive protein, IL-6 - interleukin 6.
which was calculated in almost all articles included in
the study, decreased from 527.5 to 334.7 after hemoper-
fusion.
DISCUSSION
While the mortality rate in severe COVID-19 patients
ranged from 62% [21] to 77% [22], this narrative re-
view demonstrated that hemoperfusion and cytokine ad-
sorption decreased the mortality rate to 29%, improved
the clinical conditions, and decreased cytokine levels
during the period of cytokine storm. It was also revealed
that the laboratory data including the mean values of
CRP and IL-6 decreased compared to pre-therapy.
However, this potential benefit of hemadsorption ther-
apy was not supported by statistically significant data.
The cytokine storm seen during severe COVID-19 in-
fection is associated with the development and progres-
sion of acute respiratory distress syndrome (ARDS),
septic shock, and multiple organ failure. Therefore, it
suggests that clearance of cytokines from serum may
have an important role in preventing related complica-
tions [23,24]. Hemoperfusion or hemadsorption is a
treatment technique which is based on the process of re-
moving toxic materials from the blood by passing the
patient's blood through an adsorber. Hemoperfusion car-
tridges adsorb cytokines and prevent them from adher-
ing to alveoli and blood vessel endothelium. Hemoper-
fusion cartridges were designed for use in septic shock
secondary to H1N1 influenza. Since successful results
were obtained with the hemoperfusion method in ARDS
patients induced by H1N1, it is thought to be helpful in
the treatment of COVID-19 patients [2, 25,26]. Blood
purification systems were also used in patients with se-
vere H7N9 influenza infection with cytokine storm, and
it was observed that their clinical conditions improve
rapidly [28,29]. In addition, hemoperfusion has proven
to be successful in preventing severe CRS, multiple or-
gan failure, pneumonia, and chimeric antigen receptor T
cell associated hydrosarca [29,30].
Since COVID-19 is an emerging and rapidly evolving
situation, hemoperfusion has been used in critically ill
patients, although there is insufficient data. In our re-
view, in the only controlled study by Asgharpour et al.
[8] ten critically ill COVID-19 patients were enrolled,

Hemadsorption Therapy in Severe COVID-19
Clin. Lab. 2/2022
407
Figure 1. Flowchart of the included and excluded articles.
and six of them improved, but four of them expired. In
this study, the hemoperfusion treatment was started in
4.7 days with resin directed hemadsorption cartridges.
The mean of peripheral capillary oxygen saturations
was 89.60 ± 3.94% before the three sessions of hemo-
perfusion and increased to 92.13 ± 3.28% after the he-
moperfusion (p < 0.001). Mean CRP level before and
after the sessions was 136.25 ± 84.39 and 78.25
± 38.67 mg/L, respectively (p = 0.016). Mean serum
level of IL-6 was 139.70 ± 105.62 pg/mL and decreased
to 72.06 ± 65.87 after the intervention (p = 0.073).
Therewithal, these data did not show a significant dif-
ference between survivor and non-survivor groups.
Among the groups, only the plasma lymphocyte count
was significantly lower in the improved group (p =
0.038). The most important limitations of this study
were absence of a control group and small number of
participants. Rampino et al. [17] reported a case series
showing potential positive results of 9 COVID patients
admitted to their intensive care unit. Five of them re-
ceiving hemoperfusion with CytoSorb survived, where-
as all untreated patients died. In a retrospective case se-
ries by Alharthy et al. [6] including 50 COVID-19 pa-
tients with acute kidney injury, 70% of the cases sur-
vived but 30% expired. This mortality rate was lower
than previous studies on COVID-19 and acute kidney
injury was reported up to 52% [6]. Although the results
of the studies included in this review are promising in
critically ill COVID-19 cases, they have not been sup-
ported by strong evidence. Due to the retrospective na-
ture of the studies, it is controversial whether the pa-
tients will improve or not with other empiric therapies
without hemoperfusion. Meanwhile, the removal of cir-
culating antibiotics and antiviral agents by hemoadsorp-
tion therapy prevents the advantages of hemoperfusion.
Even if circulating cytokine levels are removed with he-
moadsorption, its effects on the patient are controver-
sial. Although this increased inflammation begins to
Records identified through
database searching
n = 117
Additional records identified
through other sources
n = 0
Records after duplicates removed
n = 43
Articles excluded for the following reasons (n = 27)
Reviews, n = 9
Editorials, n = 2
Could not reach the full-text, n = 3
Clinical practice experience, n = 1
Views & comments, n = 1
Advice, n = 1
Research letters, n = 4
Comments, n = 2
Desired variables not described, n = 3
Full-text articles included in the study
n = 16

S. Koc and H. Uysal
Clin. Lab. 2/2022
408
damage other organs during the cytokine storm, exces-
sive reduction of these inflammatory molecules and cy-
tokines in the circulation can also cause immunosup-
pression, leading to increased viral damage and second-
ary infections [3]. In future studies, the results on hem-
adsorption therapy should be presented with strong evi-
dence from randomized controlled trials comparing
them with other treatment modalities such as steroids,
and taking into account the influencing factors such as
dose, duration, and timing of hemoperfusion.
Cartridges used during hemoperfusion are divided into
selective and non-selective. The Jafron resin directed
hemoperfusion cartridges, CytoSorb® and oXiris®, are
classified as non-selective. Since they have various
sizes of pore widths, they can adsorb various sized ma-
terials, resulting in various clinical consequences [8].
For example, the HA130 cartridge is used for the pre-
vention of uremic symptoms in chronic hemodialysis
patients and HA330 is effective in modulation of the in-
flammatory process [30]. The HA330 cartridge was
shown to increase oxygenation, reduce pulmonary ede-
ma, and alveolar and circulating cytokine levels in
ARDS cases [31]. The device called CytoSorb® has a
porous polymer material and enables molecules such as
IL-6, TNF-a, IL-10, and IL-1b in the range of 5 to
60 kDa to be adsorbed irreversibly [32]. In a study by
Friesecke et al. [33], patients with sepsis in the intensive
care unit showed significant decreases in IL-6 levels af-
ter hemoperfusion with CytoSorb®. Another cartridge is
oXiris, originating from the AN69ST membrane. Stud-
ies on oXiris showed hemodynamic improvement, a de-
crease in serum lactate, and reduction in mortality in pa-
tients with sepsis or septic shock [34-36]. In the litera-
ture, a wide variety of cartridges have been used in
studies on COVID-19. Among these studies, there is not
enough data to show which cartridge is superior to the
other. It is necessary to conduct randomized controlled
studies in which the effects of different cartridges are
studied.
The most important limitation of this review is that the
articles included in the study were not randomized con-
trolled studies and the results did not contain a statisti-
cally significant level. The studies in the review also in-
clude methodological differences such as sample size,
type of the cartridges used for hemoperfusion, laborato-
ry data, duration, doses, and timing of the sessions. In
the future, randomized prospective controlled studies
that compare effective treatment methods, comparing
the effectiveness of different cartridges and determining
the optimal dose, duration, and timing of hemoperfusion
will provide a high level of evidence.
CONCLUSION
Due to the reduced mortality rates in our review for crit-
ically ill COVID-19 patients treated with hemadsorp-
tion therapy, we consider that hemoperfusion is an alter-
native salvage treatment for the critically ill patients
who do not respond to empirical treatment for COVID-
19. Theoretically, we can suggest that hemoperfusion
therapy is beneficial only in reducing circulating cyto-
kines such as CRP and IL-6 during cytokine storm.
Large multicenter prospective studies in selected pa-
tients are needed to fully elucidate the effectiveness of
hemoadsorption in critically ill COVID-19 patients.
Statement of Ethics:
All authors declare that the study was conducted in ac-
cordance with the World Medical Association Helsinki
“Ethical Principles for Medical Research Containing
Human Subjects”. This study did not have to be ap-
proved by an ethics committee because it did bibliomet-
ric and submetric analyses of currently published stud-
ies.
Source of Funds:
The authors declared that this study has received no fi-
nancial support or funding.
Declaration of Interest:
The authors did not report any conflicts of interest.
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