ĐIỀU HÒA MIỄN DỊCH Ở BN COVID 19

1. ĐIỀU TRỊ ĐIỀU HÒA MIỄN DỊCH
TRONG COVID-19
BS. Dư Quốc Minh Quân1
PGS.TS.BS Phạm Thị Ngọc Thảo2
T6 - 2021
ĐẠI HỌC Y DƯỢC TP. HỒ CHÍ MINH
BỘ MÔN HỒI SỨC CẤP CỨU CHỐNG ĐỘC
CHƯƠNG TRÌNH ĐÀO TẠO LIÊN TỤC TRỰC TUYẾN
COVID-19 TỪ CHẨN ĐOÁN, ĐIỀU TRỊ ĐẾN PHÒNG NGỪA
1 Khoa Hồi sức cấp cứu, Bệnh viện Chợ Rẫy
2 Phó giám đốc Bệnh viện Chợ Rẫy, Chủ nhiệm Bộ môn Hồi sức cấp cứu chống độc, Đại học Y Dược
TP. Hồ Chí Minh

2. NỘI DUNG
• Bão cytokine ở bệnh nhân COVID-19
• Các hướng tiếp cận trong điều trị
• Các thuốc được khuyến cáo sử dụng hiện nay
• Lọc máu và thay huyết tương ở bệnh nhân COVID-19

3. BÃO CYTOKINE
VÀ VAI TRÒ CỦA ĐIỀU HÒA MIỄN DỊCH
Ở BỆNH NHÂN COVID-19

4. • Cytokine:
• Xuất phát từ tiếng Hy Lạp: Tế bào
(cyto) và di chuyển (kinos)
• Phân tử protein nhỏ
• Được giải phóng từ nhiều tế bào
khác nhau trong cơ thể, gồm cả
hệ miễn dịch
• Có liên quan tới phản ứng của cơ
thể chống lại nhiễm khuẩn và gây
ra viêm
CYTOKINE VÀ CHỨC NĂNG
Type Actions
Interferons Regulation of innate immunity, activation of
antiviral properties, antiproliferative effects
Interleukins Growth and differentiation of leukocytes; many
are proinflammatory
Chemokines Control of chemotaxis, leukocyte recruitment;
many are proinflammatory
Colony-
stimulating
factors
Stimulation of hematopoietic progenitor cell
proliferation and differentiation
Tumor necrosis
factor
Proinflammatory, activates cytotoxic T
lymphocytes

5. • Mô tả chung: “Bão cytokine là tình
trạng viêm quá mức và đe dọa tính
mạng gây ra bởi các cytokine viêm”
• Cytokine storm syndrome (CSS) ;
Cytokine release syndrome (CRS)
• Biểu hiện trên nhiều cơ quan khác
nhau
HỘI CHỨNG BÃO CYTOKINE

6. XÂM NHẬP CỦA VIRUS SARS-COV-2
Gupta, A., et al. Nature Medicine 26(7): 1017-1032.

7. CƠ CHẾ BỆNH SINH CỦA BÃO CYTOKINE
• Số lượng lớn tế bào Bạch cầu (Tế bào T, B, BC đơn nhân,…) được
kích hoạt và giải phóng cytokine viêm → Tiếp tục kích hoạt TB Bạch
cầu → Chu trình bệnh sinh
• Tế bào miễn dịch được kích hoạt theo cơ chế tương tác thụ thể
• Có thể đe dọa tính mạng do: viêm hệ thống quá mức, sốc hạ áp, suy
đa tạng

8. nd ribavirin modestly ameliorated dis-
ot affect mortality [115, 121, 117, 122].
antiviral gene in epithelial cells without over-stimulating the
immune system, use of IFN-λ may be an ideal therapeutic
ntation
genic
o
ns
17) 39:529–539 535
• Đáp ứng với sự xâm nhập của
virus gây bệnh
• Đáp ứng viêm bị rối loạn/bệnh lý:
gây nên các tổn thương cơ quan
tiến triển
• Đáp ứng viêm bảo vệ/được điều
hòa sẽ giúp giảm các tác động có
hại và tăng cường sự phục hồi các
thương tổn
CƠ CHẾ BỆNH SINH CỦA BÃO CYTOKINE
Channappanavar, R. and S. Perlman (2017). "Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology."
Semin Immunopathol 39(5): 529-539.

9. Granzymes and perforin are the two main types of cytotoxic molecules. Granzymes
are proteases that induce apoptosis by activating caspases that damage the membrane
permeability of mitochondria leading to cell death. Granzymes also directly cause
oxidative damage to intracellular pathogens [4]. Perforin is a protein that creates pores
on the target cell cytoplasmic membrane leading to lethal osmotic instability and the
delivery of granzyme B to trigger apoptosis of the target cell [5–8]. When this
sequence of events is successful, macrophages phagocytize the cellular debris, the
Table 1 Pathogenesis of cytokine storm syndromes
Disease Mutation Potential mechanism Phenotype
Familial HLH
FHL1 Unknown Potential locus on
chromosome 9q23
FHL2 PRF1 Deficiency of perforin HLH in childhood
FHL3 UNC13-D Impaired exocytosis
FHL4 STX11 Impaired exocytosis
FHL5 STXBP2 Impaired exocytosis
Primary immunodeficiency HLH
Chediak–Higashi LYST Dysregulation lysosome
trafficking
Oculocutaneous albinism,
immunodeficiency, HLH,
neurologic symptoms
Griscelli
Syndrome Type 2
RAB27A Dysregulation lysosome
trafficking
Skin/hair hypopigmentation,
immunodeficiency, HLH
XLP1 SH2D1A
(SAP)
Activation of T/NK cells Immunodeficiency, HLH
XLP2 (Duncan
Disease)
XIAP Antiapoptotic protein Susceptibility to EBV, EBV-HLH
Secondary HLH
Infections T-cell function
suppression
EBV, Herpes,
CMV
Malignancy T/NK cell dysfunction?
T/NK cell
lymphoma
Macrophage
activation
syndrome
Deficient secretion of
perforin/inhibition of
SAP gene
XLP X-linked lymphoproliferative disorder, HLH hemophagocytic lymphohistiocytosis
a LRR domain (like the TLRs). The two most studied NLRs
are NOD1 and NOD2, which bind bacterial peptidoglycan.
Activation of the NLR pathway is under the control of the
RICK kinase and induces NFκB and AP-1. Other NLRs
There are three RLRs discovered to date
MDA5, and LGP2), and they bind double-stran
RNA (dsRNA) [32].
As said earlier, PRRs are activated not only by e
Fig. 1 Cytokine cascade during sepsis
Semin Immunopathol
CƠ CHẾ BỆNH SINH CỦA BÃO CYTOKINE
Randy Q. Cron, Edward M. Behrens. Cytokine Storm Syndrome. ISBN 978-3-030-
22093-8 ISBN 978-3-030-22094-5
Chousterman, B. G., et al. (2017). "Cytokine storm and sepsis disease pathogenesis."
Seminars in Immunopathology 39(5): 517-528
Nhiều cơ chế khác nhau đóng góp vào bão cytokine
ở các bệnh lý khác nhau

10. PHÓNG THÍCH CÁC CYTOKINE VÀ CHEMOKINE
Fig. 1. Schematic representation of the
“Cytokine storm” development after SARS-
CoV-2 infection. The presence of SARS-CoV-2
in the lung induces an uncontrolled generalized
immune response. Several immune cells (like
T-lymphocytes, macrophages and dendritic
cells) sustain the impressive secretion of cyto-
kines and chemokines ultimately leading to
acute respiratory distress syndrome.
F. Coperchini, et al.
Nhiều tế bào miễn dịch
khác nhau như tế bào
T, đại thực bào, tế bào
có chân...tham gia vào
quá trình phóng thích
kéo dài các cytokines
và các chemokines, dẫn
đến tổn thương cơ
quan tiến triển
Coperchini F. et al.. The cytokine storm in COVID-19: An overview of the involvement of the
chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020;53:25-32.

11. • Mỗi triệu chứng là
tương tác của
nhiều loại cytokine
khác nha
• Biểu hiện của bão
cytokine đa dạng
trên nhiều hệ cơ
quan khác nhau
fever, general malaise, and fatigue, but can also cause vascular leakage,
cardiomyopathy, lung injury, and acute-phase protein synthesis [4]. IL-
6, which is an important target in CRS induced by adoptive cell therapy,
can lead to vascular leakage, activation of complement and the coa-
gulation cascade, leading to the characteristic symptoms of severe CRS,
such as diffuse intravascular coagulation (DIC) [5,6]. It is noteworthy
that IL-6 is likely to cause cardiomyopathy by promoting myocardial
dysfunction, which is often observed in patients with CRS [7]. In ad-
dition, activation of endothelial cells may also be one of the hallmarks
of the severe group was 76 % higher than that of the mild group (30 %)
[15]. Furthermore, histological examination and biopsy samples ob-
tained from a patient who died from severe SARS-CoV-2 infection
showed an increased concentration of highly proinflammatory
CCR4+CCR6+ Th17+ CD4 T cells, suggesting that T cell hyper-
activation contributed in part to the severe immune injury in this pa-
tient [16]. Pulmonary examination in other patients with early phase
SARS-COV-2 pneumonia also revealed patchy inflammatory cell in-
filtration; however, the pathological results in early stage of SARS-
Fig. 1. Schematic representation of clinical features versus pathogenic inflammatory cytokine response in SARS-CoV-2 infections.
BIỂU HIỆN LÂM SÀNG DO BÃO CYTOKINE
Sun, X., et al. (2020). "Cytokine storm intervention in the early stages of COVID-19 pneumonia." Cytokine Growth Factor Rev 53: 38-42.

12. HẬU QUẢ BÃO CYTOKINE Ở BN COVID-19

13. Gabarre, P., et al. (2020). "Acute kidney injury in critically ill patients with COVID-19." Intensive Care Med 46(7): 1339-1348.
• Tổn thương do
đáp ứng viêm
gây ra bởi
cytokine là một
trong các cơ
chế gây tổn
thương thận
cấp
CSS VÀ TỔN THƯƠNG ĐA CƠ QUAN
Fig. 3 Mechanisms of acute kidney injury (AKI) during severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection. SARS-CoV-2 can pen-
etrate proximal tubule cells by linking with ACE2 and CD147, as well as in the podocytes, by linking with ACE2. Virus entry may be responsible for
podocyte dysfunction, leading to glomerular diseases such as focal segmental glomerulosclerosis (FSGS), and acute proximal tubular injury leading

14. CSS VÀ TỔN THƯƠNG ĐA CƠ QUAN
L. Téllez, R.M. Martín Ma
COVID-19 and liver damage
Other:
Liver with stasis due to myocardial injury
Hypoxia
Ischaemic damage due to hypoperfusion
Direct cytotoxic effect of the virus
• Invasion, assembly and release of viral particles
Pharmacological toxicity
• Increased transaminase levels
• Drug-induced liver injury (DILI)
Immune-mediated liver injury
• Immune hyperactivation
Pathophysiology of liver injury: various mechanisms related to SARS-CoV2 infection may induce liver abnormalities,
ctly to the cytopathic effect of the virus and due to the indirect effect of immune hyperactivation and drug toxicity.

15. Fig. 1 In patients infected with SARS-CoV-2, coinfection of viruses,
bacteria, and fungi is an important factor that cannot be ignored.
Coinfection of SARS-CoV-2 with viruses, bacteria, and fungi will in-
crease the difficulty of diagnosis, treatment, and prognosis of COVID-
19, and even increase the symptoms and mortality of the disease. At the
same time, coinfected microorganisms may also become a new strategy
for the development of new treatments for SARS-CoV-2 infection
Appl Microbiol Biotechnol
• Đồng nhiễm (1-3%)
và nhiễm khuẩn thứ
phát (14-20%) ở
bệnh nhân COVID-
19
• Tăng nguy cơ và
mức độ nghiêm
trọng của CSS
ĐỒNG NHIỄM VÀ NHIỄM KHUẨN THỨ PHÁT
Langford BJ, So M, Raybardhan S, et al. Bacterial co-infection and secondary infection in patients with COVID-19: a
living rapid review and meta-analysis. Clin Microbiol Infect. 2020;26(12):1622-1629.

16. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405-407.
DIỄN TIẾN CỦA TỔN THƯƠNG ĐA CƠ QUAN
406 The Journal of Heart and Lung Transplantation, Vol 39, No 5, May 2020

17. CHẨN ĐOÁN BÃO CYTOKINE
Ở BỆNH NHÂN COVID-19

18. CÁC DẤU HIỆU TRÊN LÂM SÀNG
Biểu hiện lâm sàng đa dạng trên nhiều cơ quan và thường không đặc hiệu

19. CÁC DẤU HIỆU TRÊN XÉT NGHIỆM
• Chỉ số sinh hóa (Biomarker)
• Tỉ lệ thay đổi nồng độ cytokine hơn là giá trị tuyệt đối
• Chỉ số:
• TNFα, IL-6,...
• CRP, PCT
• Đánh giá chức năng các cơ quan (gan, thận, tim…)
• Chỉ số đông máu (D-Dimer, thời gian đông máu,…)
• Tại một số cơ sở y tế lớn có thể định lượng được panel nhiều loại IL

20. syndrome additional cytokines such as IL-18, IL8, IP10,
MCP1, MIG, and MIP1β are also elevated [62]. These
cytokines also have been reported to be elevated in clas-
sical HLH and MAS. Why some patients develop HLH/
MAS and others do not is poorly understood. Some pa-
tients may harbor genetic variants that predispose them
to developing HLH/MAS. In addition, IL-6 may also
promote the development of HLH/MAS in the setting of
many unanswered questions regarding the optimal clinical
management of CRS. The recommendations for the man-
agement of CRS are thus still evolving constantly. Current
treatment algorithms for CRS are based on expert opinion
and represent the experience of the pioneers in the field of
T cell-engaging immunotherapies [28, 29]. The most widely
used grading scheme for the severity of CRS was developed
by the National Cancer Institute (NCI) (Fig. 3) [29].
Fig. 3 Proposed pathomechanism of CRS. Activation of manly T cells or lysis of immune cells induces a release of interferon gamma (IFN-γ) or
tumor necrosis factor alpha (TNF-α). This leads to the activation of macrophages, dendritic cells, other immune cells and endothelial cells. These
• Grade 1
• Fever
• Constitutional symptoms
• Grade 2
• Hypotension responding to fluids/low dose
vasopressors
• Grade 2 organ toxicities
• Grade 3
• Shock requiring high dose/multiple vasopressors
• Hypoxia requiring >= 40% FiO2
• Grade 3 organ toxicities, grade 4 transaminases
• Grade 4
• Mechanical ventilation
• Grade 4 organ toxicities (exclude transaminases)
PHÂN ĐỘ HỘI CHỨNG

21. Criteria
Preliminary predictive criteria for COVID-19
cytokine storm
Roberto Caricchio ,1
Marcello Gallucci ,2
Chandra Dass,3
Xinyan Zhang,1
Stefania Gallucci ,4
David Fleece,5
Michael Bromberg,6
Gerard J Criner,7
Temple
University COVID-19 Research Group
editor Josef S
al material is
nline only.To view,
the journal online
oi.org/10.1136/
s-2020-218323).
heumatology, Lewis
of Medicine at
versity, Philadelphia,
a, USA
t of Psychology,
f Milano-Bicocca,
Lewis Katz School of
Temple University,
a, Pennsylvania, USA
gy and Immunology,
School of Medicine
niversity,
a, Pennsylvania, USA
Lewis Katz School of
Temple University,
a, Pennsylvania, USA
Hematology, Lewis
of Medicine at
versity, Philadelphia,
a, USA
edicine and
wis Katz School of
ABSTRACT
Objectives To develop predictive criteria for
COVID-19-associated cytokine storm (CS), a severe
hyperimmune response that results in organ damage
in some patients infected with COVID-19. We
hypothesised that criteria for inflammation and cell
death would predict this type of CS.
Methods We analysed 513 hospitalised patients who
were positive for COVID-19 reverse transcriptase PCR
and for ground-glass opacity by chest high-resolution
CT. To achieve an early diagnosis, we analysed the
laboratory results of the first 7 days of hospitalisation.
We implemented logistic regression and principal
component analysis to determine the predictive
criteria. We used a ’genetic algorithm’ to derive the
cut-offs for each laboratory result. We validated the
criteria with a second cohort of 258 patients.
Results We found that the criteria for
macrophage activation syndrome, haemophagocytic
lymphohistiocytosis and the HScore did not identify
the COVID-19 cytokine storm (COVID-CS). We
developed new predictive criteria, with sensitivity
and specificity of 0.85 and 0.80, respectively,
comprising three clusters of laboratory results that
involve (1) inflammation, (2) cell death and tissue
damage, and (3) prerenal electrolyte imbalance. The
lymphohistiocytosis (HLH) and macrophage acti-
vation syndrome (MAS), rely on well-established
criteria to identify their occurrence.4 5
Results
from recent reports suggest that COVID-19-
associated CS is a unique form of a hyperinflam-
matory response, which needs further clinical
and laboratory characterisation as well as classi-
fication criteria.6
It has been suggested that the
2016 MAS classification criteria are not appli-
cable to patients with COVID-19,7–9
while it
remains to be determined whether the 2004 HLH
criteria and the HScore may be more helpful.10–12
Reports from COVID-19 cohorts and autopsies
highlight significant diffuse inflammation and
widespread tissue damage, such as renal, cardiac
and muscular damage, in addition to pulmonary
impairment.13–17
These findings underscore the
need for criteria that should include not only the
respiratory status but also markers of inflamma-
tion and tissue damage. The latter were recently
reported to be associated with higher mortality
in COVID-19.18
We therefore designed a novel
statistical strategy based on our clinical experience
at Temple University Hospital19
and developed
preliminary criteria that can be used to identify
the CS during COVID-19 infection.
copyright.
Ann
Rheum
Dis:
first
published
as
10.1136/annrheumdis-2020-218323
on
25
September
2020.
Download
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Table 4 Predictive criteria for COVID-19 cytokine storm
Entry criteria (must be all met) Cut-off values
+Signs/symptoms of COVID-19
±RT-PCR positive for COVID-19
+GGO by HRCT (or chest X-ray)
Ferritin >250ng/mL
C reactive protein >4.6mg/dL
AND (one variable from each cluster)
Cluster I
Albumin <2.8g/dL
Lymphocytes (%) <10.2
Neutrophil Abs >11.4K/mm3
Cluster II
ALT >60U/L
AST >87U/L
D-dimers >4,930ng/mL
LDH >416U/L
Troponin I >1.09ng/mL
Cluster III
Anion gap <6.8mmol/L
Chloride >106mmol/L
Potassium >4.9mmol/L
BUN:creatinine ratio >29 ratio
Criteria are met when patients fulfil all the entry criteria and at least one criterion
per each cluster. Cut-off values were calculated using a genetic algorithm.
Abs, absolute numbers;ALT, alanine aminotransferase;AST, aspartate
aminotransferase; BUN, blood urea nitrogen; GGO, ground-glass opacity; HTCT,
high-resolution CT; LDH, lactate dehydrogenase; RT-PCR, reverse transcriptase PCR.
THANG ĐIỂM COVID-CS
days of hospitalisation or up to the 24hours within reaching
the clinical consensus of CS. Using the logistic regression, we
found that 12 laboratory parameters predict development of
CS and by PCA, we determined that these 12 variables could
be included in three coherent clusters (table 4). Based on factor
analysis, we considered the parameters belonging to the same
cluster as alternative indicators (OR rule), with the rationale
that parameters of the same cluster highly correlate and may
be indicators of the same condition or mechanism. We consid-
ered parameters belonging to the different clusters instead as
necessary indicators (AND rule) because they represent condi-
tions or mechanisms that should be met. Our analyses high-
lighted three clusters of laboratory results, and the alteration
of one parameter for each cluster predicts the development of
COVID-CS (table 4).
The first cluster included decreased levels of albumin and
percentage of lymphocytes, along with increased absolute
numbers of neutrophils in patients in storm compared with
patients who did not develop a storm (tables 3 and 4). The abso-
lute number of lymphocytes formed a separated component and
correlated with the first cluster, and we excluded it from the
criteria because of its close correlation and redundancy with
the percentage of lymphocytes. The second cluster included the
increased levels of alanine aminotransaminase (ALT), aspartate
aminotransferase (AST), D-dimers, LDH and troponin I. The
third cluster included the decreased anion gap and increased
levels of chloride, potassium and blood urea nitrogen (BUN):cre-
atinine ratio (tables 3 and 4). These results highlight an important
component of tissue damage occurring during the COVID-CS.
In order to develop cut-offs that can be used in clinical prac-
tice, we used daily laboratory parameters and estimated the
cut-off for each individual laboratory parameter using a genetic
reference.
Abs, absolute numbers;ALT, alanine aminotransferase;AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C reactive protein; CS, cytokine storm; LDH, lactate
dehydrogenase.
Table 4 Predictive criteria for COVID-19 cytokine storm
Entry criteria (must be all met) Cut-off values
+Signs/symptoms of COVID-19
±RT-PCR positive for COVID-19
+GGO by HRCT (or chest X-ray)
Ferritin >250ng/mL
C reactive protein >4.6mg/dL
AND (one variable from each cluster)
Cluster I
Albumin <2.8g/dL
Lymphocytes (%) <10.2
Neutrophil Abs >11.4K/mm3
Cluster II
• Caricchio đề xuất thang điểm tiêu chuẩn để chẩn đoán bão cytokine ở bn COVID-19
• Tiêu chuẩn chính + tối thiểu 1 trong mỗi nhóm tiêu chuẩn phụ
• Kiểm chứng lại một đoàn hệ 258 bệnh nhân với kết quả rất tương đồng, có độ nhạy 73-79% và
độ đặc hiệu 84%.

22. ĐIỀU TRỊ BÃO CYTOKINE
Ở BỆNH NHÂN COVID-19

23. CHIẾN LƯỢC ĐIỀU TRỊ
• Chiến lược điều trị nhắm đến điều hoà đáp ứng miễn dịch và/hoặc loại
bỏ các cytokine ra khỏi cơ thể bằng các biện pháp lọc máu
Immunomodulatory therapies Lọc máu thay huyết tương
Fig. 2. A summary of the process of onset SARS-CoV2 pathogenesis with potential treatment options against the virus-induced cytokine storm.
X. Sun, et al.

24. SARS: Systematic Review of Treatment Effects
Lauren J. Stockman1,2*
, Richard Bellamy3
, Paul Garner4
1 Centers for Disease Control and Prevention, Respiratory and Enteric Viruses Branch, Atlanta, Georgia, United States of America, 2 Department of Veterans’ Affairs, Atlanta
Research and Education Foundation, Decatur, Georgia, United States of America, 3 James Cook University Hospital, Middlesbrough, United Kingdom, 4 Liverpool School of
Tropical Medicine, Liverpool, United Kingdom
Funding: This document is an
output from a project funded by the
UK Department for International
Development (DFID) for the benefit
of developing countries. The views
expressed are not necessarily those
of DFID. The funders had no role in
study design, data collection and
analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors
have declared that no competing
interests exist.
Academic Editor: Donald Low,
Mount Sinai Hospital, Canada
Citation: Stockman LJ, Bellamy R,
Garner P (2006) SARS: Systematic
review of treatment effects. PLoS
Med 3(9): e343. DOI: 10.1371/journal.
pmed.0030343
A B S T R A C T
Background
The SARS outbreak of 2002–2003 presented clinicians with a new, life-threatening disease for
which they had no experience in treating and no research on the effectiveness of treatment
options. The World Health Organization (WHO) expert panel on SARS treatment requested a
systematic review and comprehensive summary of treatments used for SARS-infected patients
in order to guide future treatment and identify priorities for research.
Methods and Findings
In response to the WHO request we conducted a systematic review of the published
literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN),
intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies
and in SARS patients. We also searched for clinical trial evidence of treatment for acute
respiratory distress syndrome. Sources of data were the literature databases MEDLINE, EMBASE,
PLoSMEDICINE
Impo
Most of
natural
reliably
charact
have be
treatme
not vali
was init
logical
patient
infectio
any tru
The v
range i
istration
to a cl
Table 1. Summary of the Evidence for Benefit or Harm of Drugs
Used to Treat SARS
Treatment Inconclusivea
Possible Harma
Total Studies
with Evidence
(English and
Chinese)b
Ribavirin 26 4 30
Corticosteroid 25 4 29
LPV/r 2 0 2
IFN-a 3 0 3
Convalescent plasma
or Immunoglobulin
7 0 7
a
Studies were classified into six categories, but there were four categories without any
studies: ‘‘possible benefit,’’ ‘‘possible harm,’’ ‘‘definite benefit,’’ ‘‘definite harm’’ (see Box 1).
b
Studies totalled 54; some reported on more than one drug.
• Ribavirin, corticosteroids, lopinavir,
ritonavir, IFN, IVIG và huyết thanh
của bn SARS
• 54 nghiên cứu trên BN SARS, 15
nghiên cứu in-vitro, 3 nghiên cứu
ARDS
• Hầu hết các nghiên cứu đều không
kết luận được lợi ích
• Một số nghiên cứu cho thấy
corticosteroid và ribavirin có thể
có hại
Stockman, L. J., et al. (2006). "SARS: systematic review of treatment effects." PLoS medicine 3(9): e343-e343.
Systematic Review of Treatment Effects
n1,2*
, Richard Bellamy3
, Paul Garner4
trol and Prevention, Respiratory and Enteric Viruses Branch, Atlanta, Georgia, United States of America, 2 Department of Veterans’ Affairs, Atlanta
oundation, Decatur, Georgia, United States of America, 3 James Cook University Hospital, Middlesbrough, United Kingdom, 4 Liverpool School of
ol, United Kingdom
s an
ded by the
ational
he benefit
he views
rily those
no role in
on and
A B S T R A C T
Background
The SARS outbreak of 2002–2003 presented clinicians with a new, life-threatening disease for
which they had no experience in treating and no research on the effectiveness of treatment
PLoSMEDICINE
NGHIÊN CỨU TRONG DỊCH SARS TRƯỚC ĐÂY

25. ĐÍCH NHẮM TRONG ĐIỀU HÒA MIỄN DỊCH
3. Therapeutic agents with the potential of interfering with
COVID-19 associated cytokine storm
3.1. IL-6 inhibitors
patients recruited with either severe or critical cases of COVID-19.
Patients were treated with either a single dose or two doses 12 h apart
of tocilizumab along with standard therapy. Following the adminis-
tration of tocilizumab, fever was resolved in all patients on the first day.
Within five days of treatment, 84.2% of patients experienced a re-
Fig. 1. Schematic diagram depicting the potential target pathways to counteract the cytokine storm. Once the SARS-CoV-2 invades the pulmonary epithelial
cells, immune cells, such as mast cells recognize the viral RNA by their receptors, such as Toll-like receptors (TLR). This interaction activates transcription factors,
such as NF-kB and STAT to ignite an inflammatory program harboring the cytokine storm. Among the different inflammatory products are the interleukins IL-1β, IL-6
that can promote further inflammation by interacting with corresponding receptors. Both the interleukins and their receptors can be targeted by the mentioned
agents. JAK/STAT and mast cells can also be blocked to attenuate the constitutive inflammatory activation.
S.M. Abdin, et al.
2
4. Dexamethasone; a breakthrough in Covid-19 therapy
A ground-breaking development in the fight against COVID-19 came
from the Randomized Evaluation of COVID-19 therapy Trial on June 16,
2020. This randomized trial was started in March 2020 as a randomized
Fig. 2. Cytokine storm in COVID-19 associated ARDS and mechanism of action
of dexamethasone.
Noreen S, et al. Dexamethasone: Therapeutic potential, risks, and future projection during COVID-19 pandemic. Eur J Pharmacol. 2021;894:173854
Dựa trên hiểu biết trước đây về các con đường của đáp ứng viêm, nhiều tác nhân đã
được nghiên cứu thử nghiệm trên lâm sàng

26. GLUCOCORTICOID VÀ ĐIỀU HÒA ĐÁP ỨNG VIÊM

27. DEXAMETHASONE Ở BN COVID-19
The new engl and jour nal o f medicine
The members of the writing committee
(Peter Horby, F.R.C.P., Wei Shen Lim,
F.R.C.P., Jonathan R. Emberson, Ph.D.,
Marion Mafham, M.D., Jennifer L. Bell,
M.Sc., Louise Linsell, D.Phil., Natalie Sta-
plin, Ph.D., Christopher Brightling, F.Med.
Sci., Andrew Ustianowski, Ph.D., Einas
Elmahi,M.Phil.,BenjaminPrudon,F.R.C.P.,
Christopher Green, D.Phil., Timothy Fel-
ton, Ph.D., David Chadwick, Ph.D., Kan-
chan Rege, F.R.C.Path., Christopher Fe-
gan, M.D., Lucy C. Chappell, Ph.D.,
Saul N. Faust, F.R.C.P.C.H., Thomas Jaki,
Ph.D., Katie Jeffery, Ph.D., Alan Mont-
gomery, Ph.D., Kathryn Rowan, Ph.D.,
Edmund Juszczak, M.Sc., J. Kenneth Bail-
lie, M.D., Ph.D., Richard Haynes, D.M.,
BACKGROUND
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Gluco-
corticoids may modulate inflammation-mediated lung injury and thereby reduce
progression to respiratory failure and death.
METHODS
In this controlled, open-label trial comparing a range of possible treatments in
patients who were hospitalized with Covid-19, we randomly assigned patients to
receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to
10 days or to receive usual care alone. The primary outcome was 28-day mortality.
Here, we report the preliminary results of this comparison.
RESULTS
A total of 2104 patients were assigned to receive dexamethasone and 4321 to re-
ABSTR ACT
Dexamethasone in Hospitalized Patients
with Covid-19 — Preliminary Report
The RECOVERY Collaborative Group*
Original Article
Dexamethasone in Hospitalized Patients with Covid-19
Mortality
(%)
50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Invasive Mechanical Ventilation (N=1007)
A All Participants (N=6425)
Rate ratio, 0.83 (95% CI, 0.75–0.93)
P<0.001
No. at Risk
Usual care
Dexamethasone
4321
2104
3754
1903
3427
1725
3271
1659
3205
1621
Usual care
Dexamethasone
B
Mortality
(%)
50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Rate ratio, 0.64 (95% CI, 0.51–0.81)
No. at Risk
Usual care
Dexamethasone
683
324
572
290
481
248
424
232
400
228
Usual care
Dexamethasone
Dexamethasone in Hospitalized Patients with Covid-19
Mortality
(%)
50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Invasive Mechanical Ventilation (N=1007)
A All Participants (N=6425)
Rate ratio, 0.83 (95% CI, 0.75–0.93)
P<0.001
No. at Risk
Usual care
Dexamethasone
4321
2104
3754
1903
3427
1725
3271
1659
3205
1621
Usual care
Dexamethasone
B
Mortality
(%)
50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Rate ratio, 0.64 (95% CI, 0.51–0.81)
No. at Risk
Usual care
Dexamethasone
683
324
572
290
481
248
424
232
400
228
Usual care
Dexamethasone
NGHIÊN CỨU RECOVERY
• RCT, nhãn mở; 2104 can thiệp vs 4321 chứng
• Can thiệp: Dexamethasone uống/TM 6mg/ngày trong
tối đa 10 ngày

28. DEXAMETHASONE Ở BN COVID-19
Figure 2. Mortality at 28 Days in All Patients and According to Respiratory Support at Randomization.
Shown are Kaplan–Meier survival curves for 28-day mortality among all the patients in the trial (primary outcome)
(Panel A) and in three respiratory-support subgroups according to whether the patients were undergoing invasive
mechanical ventilation (Panel B), receiving oxygen only without mechanical ventilation (Panel C), or receiving no
supplemental oxygen (Panel D) at the time of randomization. The Kaplan–Meier curves have not been adjusted for
age. The rate ratios have been adjusted for the age of the patients in three categories (<70 years, 70 to 79 years, and
0
0 7 14 21 28
Days since Randomization
C Oxygen Only (N=3883) D
No. at Risk
Usual care
Dexamethasone
4321
2104
3754
1903
3427
1725
3271
1659
3205
1621
No Oxygen Received (N=1535)
Mortality
(%) 50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Rate ratio, 0.82 (95% CI, 0.72–0.94)
No. at Risk
Usual care
Dexamethasone
2604
1279
2195
1135
2018
1036
1950
1006
1916
981
Usual care
Dexamethasone
Mortality
(%)
50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Rate ratio, 1.19 (95% CI, 0.91–1.55)
No. at Risk
Usual care
Dexamethasone
Usual care
Dexamethasone
0
1034
501
987
478
928
441
897
421
889
412
0 7 14 21 28
Days since Randomization
No. at Risk
Usual care
Dexamethasone
683
324
572
290
481
248
424
232
400
228
Figure 2. Mortality at 28 Days in All Patients and According to Respiratory Support at Randomization.
Shown are Kaplan–Meier survival curves for 28-day mortality among all the patients in the trial (primary outcome)
(Panel A) and in three respiratory-support subgroups according to whether the patients were undergoing invasive
mechanical ventilation (Panel B), receiving oxygen only without mechanical ventilation (Panel C), or receiving no
supplemental oxygen (Panel D) at the time of randomization. The Kaplan–Meier curves have not been adjusted for
age. The rate ratios have been adjusted for the age of the patients in three categories (<70 years, 70 to 79 years, and
0
0 7 14 21 28
Days since Randomization
C Oxygen Only (N=3883) D
No. at Risk
Usual care
Dexamethasone
4321
2104
3754
1903
3427
1725
3271
1659
3205
1621
No Oxygen Received (N=1535)
Mortality
(%)
50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Rate ratio, 0.82 (95% CI, 0.72–0.94)
No. at Risk
Usual care
Dexamethasone
2604
1279
2195
1135
2018
1036
1950
1006
1916
981
Usual care
Dexamethasone
Mortality
(%)
50
40
30
10
20
0
0 7 14 21 28
Days since Randomization
Rate ratio, 1.19 (95% CI, 0.91–1.55)
No. at Risk
Usual care
Dexamethasone
Usual care
Dexamethasone
0
1034
501
987
478
928
441
897
421
889
412
0 7 14 21 28
Days since Randomization
No. at Risk
Usual care
Dexamethasone
683
324
572
290
481
248
424
232
400
228
• Giảm tỉ lệ tử vong thay đổi theo nhu cầu hỗ trợ HH
• Thở máy: RR = 29.3% vs 41.4%
• Hỗ trợ oxy (không TM): 23.3% vs 26.2%

29. pro-inflammatory cytokines and chemokines are elevated in infected
patients (Huang, C. et al., 2020). Storm of pro-inflammatory cytokines
and chemokines leads to the activation of T-helper-1(Th1) immune cells.
Th1cell activation causes recruitment of IL-4 and IL-10, whose primary
function is to reduce inflammation. This idea was initiated from the
endothelial cells, thus preventing the release of l
prevent chemotaxis at the site of inflammatio
Chapman, K.E., 2011). They also inhibit macroph
the significant perpetrators of cytokine storm in
dividuals (Youssef, J. et al., 2016) (Fig. 2).
4. Dexamethasone; a breakthrough in Covid
A ground-breaking development in the fight a
from the Randomized Evaluation of COVID-19 th
2020. This randomized trial was started in March
Fig. 1. %Age reduction in mortality rate with use of corticosteroids in COVID-
19 associated ARDS (Villar, J. et al., 2020, Wu, C. et al., 2020, Ye, Zha et al., Fig. 2. Cytokine storm in COVID-19 associated ARDS
3
Risks
The WHO declared corticosteroids an effective medication hailed
amethasone trial results in treating COVID-19 patients (News,
20b). Although dexamethasone proved an effective remedy against
VID-19, some severe side effects are associated with CS use. Hor-
nal imbalance, fluid retention, weight gain, anxiety, and disturbed
ep pattern considered as the most commonly linked risks of dexa-
thasone. While hemorrhage, blurred vision, and eye disorders rarely
ur as a risk of dexamethasone. Conversely, a low dose of dexa-
thasone is needed for coronavirus patients that limited ARDS chances
ahase, E., 2020b). Most of the risks associated with CS use for an
ended period may change the regular hormonal balance (Curtis, J.R.
l., 2007). However, if CS therapy is halted or diminished too quickly,
hdrawal symptoms, including headache, vomiting, arthralgia,
algia, bone pain, and weight reduction, possibly will also arise
elds, T., 2009). In a recent research publication, Marinella explained
t the immunosuppression could be augmented by dexamethasone in
cerous patients. Dexamethasone is generally recommended as an
colleagues (Shang, L. et al., 2020), patients shoul
the following principles when administering cort
benefit ratio should be calculated before use of c
Table 1
Risks associated with dexamethasone use.
Dexamethasone Risks Re
Short term use
(≤1 month)
Prolonged viremia, bacterial
super infections, autoimmune
and cardiovascular events,
resistance to neuromuscular
blocking agents
(M
Wa
Bro
Ma
Long term use
(≥1–3 months)
Hyperglycemia, glaucoma,
cataracts, fluid retention,
hypertension, psychological
effects including mood
swings, confusion and
behavior changes,
Osteoporosis, Menstrual
disorder, Abnormal hair
growth
(H
Ma
Ze
et
HIỆU QUẢ VÀ CÁC TÁC DỤNG CẦN LƯU Ý
Noreen S, et al. Dexamethasone: Therapeutic potential, risks, and future projection during COVID-19 pandemic. Eur J Pharmacol. 2021;894:173854

30. THUỐC ỨC CHẾ IL-6: TOCILIZUMAB
For the primary outcome of 28-day mortality, the
nk observed minus expected statistic and its
ce were used to test the null hypothesis of equal
al curves (ie, the log-rank test) and to calculate the
ep estimate of the average mortality rate ratio. We
er at risk
ilizumab
0
2022
7
1736
14
1547
21
1445
28
1398
0
10
20
30
40
50
60
100
A
Mortality
(%)
Rate ratio 0·85 (0·76–0·94)
Log-rank p=0·0028
Tocilizumab group
Usual care group
time of randomisation: age, sex, ethnicity, amount of
respiratory support, days since symptom onset, and use
of systemic corticosteroids (including dexamethasone).
Observed effects within subgroup categories were
compared by means of a χ² test for heterogeneity or
trend, in accordance with the prespecified analysis plan.
Estimates of rate and risk ratios are shown with
95% CIs. All p values are two-sided and are shown
without adjustment for multiple testing. The full
database is held by the study team which collected the
data from study sites and did the analyses at the Nuffield
Department of Population Health, University of Oxford
(Oxford, UK).
Before commencement of the randomisation to
tocilizumab versus usual care, the trial steering
committee determined that if 28-day mortality in the
usual care group was above 25% then recruitment of
around 4000 patients to this comparison would provide
90% power at two-sided p=0·01 to detect a proportional
reduction in 28-day mortality of one-fifth. Consequently,
Roche Products provided sufficient treatment for
2000 patients to receive tocilizumab. The trial steering
committee, masked to the results, closed recruitment to
the tocilizumab comparison at the end of Jan 24, 2021, as
over 4000 patients had been randomly assigned.
For the primary outcome of 28-day mortality, the
results from RECOVERY were subsequently included in
a meta-analysis of results from all previous randomised
trials of tocilizumb versus usual care in patients with
COVID-19. For each trial, we compared the observed
number of deaths among patients allocated tocilizumab
21550 patients enrolled into the RECOVERY trial at one
of the 131 sites in the UK participating in the tocilizumab
comparison were eligible for random assignment.
2022 patients were randomly allocated to tocilizumab and
2094 were randomly allocated to usual care. The mean
age of these participants was 63·6 years (SD 13·6). At
randomisation, 562 (14%) of 4116 patients were receiving
invasive mechanical ventilation, 1686 (41%) of 4116 were
receiving non-invasive respiratory support (including
high-flow nasal oxygen, continuous positive airway
pressure, and non-invasive ventilation), and 1868 (45%) of
Treatment allocation RR (95% CI) p value
Tocilizumab group
(n=2022)
Usual care group
(n=2094)
Primary outcome
28-day mortality 621 (31%) 729 (35%) 0·85 (0·76–0·94) 0·0028
Secondary outcomes
Median time to being
discharged, days
19 >28 ·· ··
Discharged from hospital
within 28 days
1150 (57%) 1044 (50%) 1·22 (1·12–1·33) <0·0001
Receipt of invasive mechanical
ventilation or death*
619/1754 (35%) 754/1800 (42%) 0·84 (0·77–0·92) <0·0001
Invasive mechanical
ventilation
265/1754 (15%) 343/1800 (19%) 0·79 (0·69–0·92) 0·0019
Death 490/1754 (28%) 580/1800 (32%) 0·87 (0·78–0·96) 0·0055
Subsidiary clinical outcomes
Receipt of ventilation† 290/935 (31%) 323/933 (35%) 0·90 (0·79–1·02) 0·10
Non-invasive ventilation 281/935 (30%) 309/933 (33%) 0·91 (0·79–1·04) 0·15
Invasive mechanical
ventilation
67/935 (7%) 86/933 (9%) 0·78 (0·57–1·06) 0·11
• BN COVID-19 có hạ oxy máu và CRP ≥ 75 mg/L
• 2022 BN can thiệp với Tocilizumab 400-800mg ± liều 2 sau 12-24h so với 2094 nhóm chứng
Kết quả tương tự cũng quan sát thấy ở các phân nhóm nhỏ, kể cả ở bệnh nhân đang được dùng
corticosteroid toàn thân.
NGHIÊN CỨU RECOVERY

31. THUỐC ỨC CHẾ IL-6: TOCILIZUMAB
The new engl and jour nal o f medicine
Table 2. Primary and Secondary Outcomes.*
Outcome or Analysis
Tocilizumab
(N=353)
Sarilumab
(N=48)
Control
(N=402)
Primary outcome
Organ support–free days
Median (IQR) 10 (−1 to 16) 11 (0 to 16) 0 (−1 to 15)
Adjusted odds ratio
Mean 1.65±0.23 1.83±0.44 1
Median (95% credible interval) 1.64 (1.25 to 2.14) 1.76 (1.17 to 2.91) 1
Probability of superiority to control — % >99.9 99.5 —
Subcomponents of organ support–free days
In-hospital death — no./total no. (%) 98/350 (28) 10/45 (22) 142/397 (36)
Concurrent with tocilizumab randomization — — 127/355 (36)†
Concurrent with sarilumab randomization — — 19/63 (30)†
Median no. of days free of organ support in survi-
vors (IQR)
14 (7 to 17) 15 (6 to 17) 13 (4 to 17)
Primary in-hospital survival
Adjusted odds ratio
Mean 1.66±0.31 2.25±0.96 1
Median (95% credible interval) 1.64 (1.14 to 2.35) 2.01 (1.18 to 4.71) 1
Probability of superiority to control — % 99.6 99.5 —
Secondary analysis of primary outcome
Adjusted odds ratio
Mean 1.68±0.24 1.84±0.44 1
• BN COVID-19 nặng nhập ICU, cần hỗ trợ
hô hấp (HFNC trở lên) và/hoặc hỗ trợ tuần
hoàn
• 2 nhóm can thiệp với đối vận thụ thể IL-6
và nhóm chứng
• Tocilizumab (8mg/kg)
• Sarilumab (400mg
• Cải thiện tử vong ở nhóm được sử dụng
chất ức chế IL-6 so với nhóm chứng, HR ở
nhóm chứng là 1,61 (95% 1,25 – 2,08).
Phân tích các hiệu quả thứ phát cũng cho
thấy hiệu quả của ức chế IL-6.
NGHIÊN CỨU REMAP-CAP

32. THUỐC ỨC CHẾ JANUS KINASE: BARICITINIB
The new engl and journal of medicine
The authors’ full names, academic de-
grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
Kalil at the University of Nebraska Medi-
cal Center, 985400 Nebraska Medicine,
Omaha, NE 68198-5400, or at akalil@
unmc.edu.
A complete list of members of the ACTT-2
Study Group is provided in the Supple-
BACKGROUND
Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflam-
mation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor,
plus remdesivir are not known.
METHODS
We conducted a double-blind, randomized, placebo-controlled trial evaluating
baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients
received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control).
ABSTR ACT
Baricitinib plus Remdesivir for Hospitalized
Adults with Covid-19
A.C. Kalil, T.F. Patterson, A.K. Mehta, K.M. Tomashek, C.R. Wolfe, V. Ghazaryan,
V.C. Marconi, G.M. Ruiz-Palacios, L. Hsieh, S. Kline, V. Tapson, N.M. Iovine,
M.K. Jain, D.A. Sweeney, H.M. El Sahly, A.R. Branche, J. Regalado Pineda,
D.C. Lye, U. Sandkovsky, A.F. Luetkemeyer, S.H. Cohen, R.W. Finberg,
P.E.H. Jackson, B. Taiwo, C.I. Paules, H. Arguinchona, P. Goepfert, N. Ahuja,
M. Frank, M. Oh, E.S. Kim, S.Y. Tan, R.A. Mularski, H. Nielsen, P.O. Ponce,
B.S. Taylor, L.A. Larson, N.G. Rouphael, Y. Saklawi, V.D. Cantos, E.R. Ko,
J.J. Engemann, A.N. Amin, M. Watanabe, J. Billings, M.-C. Elie, R.T. Davey,
T.H. Burgess, J. Ferreira, M. Green, M. Makowski, A. Cardoso, S. de Bono, T. Bonnett,
M. Proschan, G.A. Deye, W. Dempsey, S.U. Nayak, L.E. Dodd, and J.H. Beigel
Original Article
The new engl and jour nal o f medicine
Proportion
Recovered
1.00
0.50
0.75
0.25
0.00
0 4 10 16 22 28
Days
Overall
P=0.03
6 12 18 24
2 8 14 20 26
Placebo+RDV
Baricitinib+RDV
No. at Risk Proportion
Recovered
1.00
0.50
0.75
0.25
0.00
0 4 10 16 22 28
Days
B Baseline Ordinal Score of 4
6 12 18 24
2 8 14 20 26
Placebo+RDV
Baricitinib+RDV
No. at Risk
Bệnh nhân COVID-19 cần nhập viện
515 baricitinib và remdesivir vs 518 bệnh
remdesivir và placebo
Ở nhóm có sử dụng baricitinib:
• Thời gian hồi phục ngắn hơn (7 vs 8, RR=1,16)
• Hồi phục lâm sàng ở ngày 15 OR = 1,3
• Tỉ lệ tử vong 28 ngày thấp hơn (5,1% vs 7,8%)
Biến cố bất lợi nghiêm trọng xảy ra nhiều hơn ở
nhóm can thiệp (21% so với 16%, p = 0,03) cũng
như biến cố nhiễm khuẩn mới (5,9% so với 11,2%,
p = 0,003).

33. KHUYẾN CÁO TRONG ĐIỀU TRỊ: NIH 2021
Dùng Remdesivir hoặc
Dexamethasone hoặc phối hợp
Dùng Dexamethasone kèm hoặc
không kèm remdesivir
Thêm tocilizumab
Sử dụng dexamethasone
Thêm tocilizumab nếu trong vòng
24 giờ đầu nhập ICU

34. KHUYẾN CÁO TRONG ĐIỀU TRỊ: NIH 2021
recommendations on the use of the following:
• Baricitinib in combination with remdesivir when corticosteroids cannot be used,
• Dexamethasone (or other corticosteroids) with or without remdesivir, and
• Tocilizumab with dexamethasone (with or without remdesivir).
See additional recommendations on the use of baricitinib and tocilizumab below.
Other Immunomodulators
There are insufficient data for the Panel to recommend either for or against the use of the following immunomodulators
for the treatment of COVID-19:
• Baricitinib in combination with a corticosteroid; because both agents are potent immunosuppressants, there is a
potential additive risk of infection.
• Baricitinib in combination with remdesivir for hospitalized patients with COVID-19 when corticosteroids can be used
• Colchicine for nonhospitalized patients with COVID-19
• Fluvoxamine
• Interleukin (IL)-1 inhibitors (e.g., anakinra)
• Interferon beta for the treatment of early (i.e., <7 days from symptom onset) mild to moderate COVID-19
• Sarilumab for patients who are within 24 hours of admission to the intensive care unit (ICU) and who require invasive
mechanical ventilation, noninvasive ventilation, or high-flow oxygen (>0.4 FiO2
/30 L/min of oxygen flow)
• Tocilizumab for most hospitalized patients with hypoxemia who require conventional oxygen therapy (see Therapeutic
Management of Adults With COVID-19 for more detailed information)
The Panel recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a
clinical trial:

35. KHUYẾN CÁO TRONG ĐIỀU TRỊ: NIH 2021
• Interferon beta for the treatment of early (i.e., <7 days from symptom onset) mild to moderate COVID-19
• Sarilumab for patients who are within 24 hours of admission to the intensive care unit (ICU) and who require invasive
mechanical ventilation, noninvasive ventilation, or high-flow oxygen (>0.4 FiO2
/30 L/min of oxygen flow)
• Tocilizumab for most hospitalized patients with hypoxemia who require conventional oxygen therapy (see Therapeutic
Management of Adults With COVID-19 for more detailed information)
The Panel recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a
clinical trial:
• Baricitinib without remdesivir (AIII)
• Colchicine for hospitalized patients with COVID-19 (AIII)
• Interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19 (AIII)
• Kinase inhibitors:
• Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) (AIII)
• Janus kinase inhibitors other than baricitinib (e.g., ruxolitinib, tofacitinib) (AIII)
• Non-SARS-CoV-2-specific intravenous immunoglobulin (IVIG) (AIII). This recommendation should not preclude
the use of IVIG when it is otherwise indicated for the treatment of complications that arise during the course of
COVID-19.
• Sarilumab for patients who do not require ICU-level care or who are admitted to the ICU for >24 hours but do not
require invasive mechanical ventilation, noninvasive ventilation, or supplemental oxygen administered through a high-
flow device (BIIa)
• The anti-IL-6 monoclonal antibody siltuximab (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional

36. KHUYẾN CÁO ĐIỀU TRỊ: BỘ Y TẾ VN 2021
• Khuyến cáo sử dụng corticosteroid toàn thân (đường tiêm, uống)
trong những trường hợp sau:
• Bệnh nhân mắc COVID-19 mức độ vừa, nặng hoặc nguy kịch theo mục 4, 5
mục phân loại các mức độ lâm sàng
• Hội chứng viêm hệ thống ở trẻ em liên quan tới COVID-19 (Multisytem
Inflammatory Syndrome in Children- MIS-C)
• Những trường hợp covid-19 có bệnh nền cần phải tiếp tục điều trị bệnh nền
bằng corticosteroid toàn thân

37. KHUYẾN CÁO ĐIỀU TRỊ: BỘ Y TẾ VN 2021
Đối với bệnh nhân người lớn
• Bệnh nhân mắc COVID-19 mức độ vừa, nặng hoặc nguy kịch
• Dexamethasone, 6mg/ngày trong 7 – 10 ngày, IV hoặc PO
• Nếu không có sẵn Dexamethasone, có thể sử dụng các loại steroid
thay thế với liều lượng tương đương như sau:
• Hydrocortison: 50mg IV TID hoặc 100mg IV BID
• Methylprednisolone: 16mg IV BID

38. LỌC MÁU HẤP PHỤ
VÀ CÁC PHƯƠNG PHÁP
LOẠI BỎ CYTOKINE

39. DAMPs: damage-associated molecular patterns
HCO: high cut-off
HP: haemoperfusion
MCO: medium cut-off
PAMPs: pathogen-associated molecular patterns
COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup
• Cytokines gây viêm, DAMPs,
PAMPs, gồm cả nội độc tố và các
phần tử của virus được cho rằng
đóng góp vào tình trạng tổn
thương (đa) cơ quan.
• Lọc máu ngoài cơ thể có tiềm
năng loại bỏ các phần tử này.
TIỀM NĂNG CỦA LỌC MÁU NGOÀI CƠ THỂ

40. KHUYẾN CÁO VỀ LỌC MÁU – ADQI 25
• Chưa có đồng thuận về tiêu chuẩn lâm sàng, ngưỡng xét nghiệm cho
việc bắt đầu, theo dõi, ngừng lọc máu ngoài cơ thể cho bn COVID-19
nặng
• Các biện pháp có thể được sử dụng
• Lọc máu hấp phụ
• Thay huyết tương
• CRRT với
• Màng lọc AN69 hoặc PMME
• Màng lọc có cut-off trung bình đến cao
COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup

41. TLPT CÁC CYTOKINE VÀ CUT-OFF MÀNG
Trọng lượng phân tử các cytokin
Màng B.Braun
Màng M100, Oxiris

42. • Hiện nay tại Việt Nam
chúng ta có khá đầy đủ
các phương thức hỗ trợ
cơ quan ngoài cơ thể:
phổi, tim,
• Thay huyết tương có thể
lấy không chọn lọc hoặc
tách huyết tương lấy chọn
lọc chat
MÔ HÌNH HỖ TRỢ CƠ QUAN NGOÀI CƠ THỂ
CPFA
(Coupled plasma filtration absorption)
Ronco, C., et al. (2021). "Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during
COVID-19 Pandemic: Expert Review and Recommendation." Blood Purification 50(1): 17-27.

43. COVID-19
Cytokine Removal
-Hemoadsorption
-Hemofiltration - CVVH
-High dose CVVH
Systemic Interventions
-Positive Fluid Balance
Continuous
ultrafiltration +
Diuretics
-Endothelial damage +
Third space fluid loss +
Hypotension
Vasopressors + Fluid
expansion
-Nephrotoxins
-Metabolic acidosis
-Hypercalemia
CRRT
Crosstalk Interventions
-Cardiomyopathy
LVAD; AV ECMO
-Peak airway pressure +
IAH VV ECMO,
ECCO2R, CRRT
-Rhabdomyolysis
CRRT, HCO or MCO
membranes
Pore density
Cytokine Removal
--HCO membrane
-MCO membrane
Crosstalk
-Cardiomyopathy
Cardiorenal syndrome
type 1
-Alveolar damage
Renal medullary
hypoxia
-Peak airway pressure +
IAH Renal
compartiment
syndrome
-Rhabdomyolysis
Tubular toxicity
Cytokines
-Cytokine release
syndrome
-Mechanical ventilation
-ECMO
-CRRT circuit
-Hemophagocytic
syndrome
Systemic
-Positive Fluid Balance
Renal compartiment
syndrome
-Endothelial damage +
Third space fluid loss +
Hypotension Renal
hypoperfusion
-Nephrotoxins
-Metabolic acidosis
-Hyperkalemia
Albumin 66 kDa
MCO
Myoglobin 17 kDa
2MG 12 kDa
a c d
b
e f
Pore
density
Color
version
available
online
Fig. 3. Pathways of kidney damage and proposed treatments in
COVID-19 infections. Didactically 3 broad aspects are involved in
with tolerable albumin loss. e ECMO circuit. f Filter used in CRRT
for fluid balance control, removal of nephrotoxins, correction of
• Các biện pháp lọc máu
cung cấp nhiều mô thức
khác nhau để loại bỏ
các thành phần gây
bệnh
• Can thiệp vào tương tác
cơ quan-cơ quan trong
diễn tiến suy đa cơ
quan/bệnh nhân nặng
ĐA MÔ THỨC TRONG LỌC MÁU VÀ ECOS
Ronco, C., et al. (2021). "Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and
Recommendation." Blood Purification 50(1): 17-27.

44. KHUYẾN CÁO VỀ LỌC – HẤP PHỤ CYTOKIN Ở
BN COVID-19
• Thải cytokine ở các bn có phản ứng viêm mạnh: tăng IL-6, IL-8, điểm
SOFA cao, có RL huyết động cần dùng vận mạch, có dấu khởi đầu của
RL điều hoà miễn dịch, RL đông máu
• Màng Polymycin có thể sử dụng trong trường hợp NKH (tăng
procalcitonin và /hoặc cấy ra VK) hoặc nồng độ endotoxin cao, sử
dụng trong 2 – 3 ngày, mỗi ngày 2 giờ.
• Sau hấp phụ nội độc tố, tiếp tục sử dụng quả lọc hấp phụ cytokine
CytoSorb hoặc HA-330/380.
Ronco, C., et al. (2021). "Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and
Recommendation." Blood Purification 50(1): 17-27.

45. • High-volume hemofiltration
• Cascade hemofiltration
• Plasma exchange
• Coupled Plasma Filtration
Adsorption (CPFA)
• Hemoperfusion
• High cut-off membranes
• Highly adsorptive membranes
• Functionalized membranes
CÁC BIỆN PHÁP LỌC HẤP PHỤ
PMX CYTOSORB HA- 330 OXIRIS LPS- ADSORBER

46. Ankawi, G., Neri, M., Zhang, J. et al. Extracorporeal techniques for the treatment of critically ill patients with sepsis beyond conventional blood purification therapy: the promises and
the pitfalls. Crit Care 22, 262 (2018). https://doi.org/10.1186/s13054-018-2181-z
CÁC LOẠI CỘT LỌC HẤP PHỤ

47. HẤP PHỤ CYTOKINE – CYTOSORB®

48. QUẢ LỌC OXIRIS

49. QUẢ LỌC HA330/HA380

50. Kết nối quả lọc hấp phụ cytokin
với quả lọc máu
Kết nối quả lọc hấp phụ bilirubin
với quả lọc máu

51. 4 sessions of HP 330/380 + CRRT

52. Ugurov, P., et al. (2020). "Early Initiation of Extracorporeal Blood Purification Using the AN69ST (oXiris®) Hemofilter as a Treatment Modality for COVID-19 Patients: a
Single-Centre Case Series." Braz J Cardiovasc Surg.
Braz J Cardiovasc Surg 2020 - Ahead of print: 1-13
d male
is 4th
were
ever,
ating
were
mbed
U.
ation
filter,
pport
f 15
oreal
emic
veral
ation
North
The
since
owly
Braz J Cardiovasc Surg 20
Ugurov P, et al. - Extracorporeal Blood Purification to Control COVID-19
Cytokine Storm
CẢI THIỆN TỔN THƯƠNG PHỔI VÀ MARKER
ĐÁP ỨNG VIÊM KHI SỬ DỤNG OXIRIS
10
Brazilian Journal of Cardiovascular Surgery
Fig. 6 -Inflammatorymediatoranalysis;systemiclevelsofinterleukin(IL)-6,IL/chemokine(C-X-Cmotif)ligand8(CXCL-8),andtumournecro
factor alpha (TNF-α). Individual cytokine profile (A – O) IL-6, IL-8, and TNF-α are plotted on the left y-axis (pg/mL), and C-reactive protein (CR
is plotted on the right y-axis (mg/L). The start of oXiris® hemofiltration 24-cycle is shown on the x-axis. One patient (Panel B) also receiv
Tocilizumab (= anti-IL-6 receptor mAb). Cytokine data are plotted on the left y-axis; CRP (grey checkered line) values are plotted on the rig
y-axis. Panels (P, Q, and R) show combined data during hospitalisation for IL-6, IL-8, and TNF-α. The coloured (red #1) (purple #2) symbols sho
the values for the two mortality cases.

53. Views & Commen
A Promising
Artificial-Liv
Yimin Zhang a
, L
a
State Key Laboratory for
and Treatment of Infectiou
b
Department of Infectious
The coronavirus D
ing from infection w
also known as seve
(SARS-CoV-2), is cu
worldwide; however
challenging in many
third fatal coronavir
following SARS-CoV
(MERS)-CoV [2]. Th
infection and related
there have been 80
mainland of China [
of 3.88%. Because th
patients (the estima
4794 of 17 721) [3],
Hypercytokinemi
quently occurring fe
H5N1 influenza, and
severity and is a pre
shown that elevate
leukin (IL)-1, IL-6, I
protein 10 (IP-10),
(MCP-1) are associat
in the lung [7]. Elev
necrosis factor-a (TN
[8]. Similarly, serum
Views & Comments
A Promising Anti-Cytokine-Storm Targeted Therapy for COVID-19: The
Artificial-Liver Blood-Purification System
Yimin Zhang a
, Liang Yu a
, LingLing Tang b
, Mengfei Zhu b
, Yanqi Jin a
, Zhouhan Wang a
, Lanjuan Li a
a
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis
and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
b
Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou 310022, China
The coronavirus Disease 2019 (COVID-19) pan-epidemic, result-
ing from infection with the 2019 novel coronavirus (2019-nCoV),
also known as severe acute respiratory syndrome-coronavirus-2
(SARS-CoV-2), is currently the source of public health concern
worldwide; however, treatment of this infection has been clinically
challenging in many patients [1]. Importantly, 2019-nCoV is the
third fatal coronavirus that has emerged in the past two decades,
following SARS-CoV and the Middle East respiratory syndrome
(MERS)-CoV [2]. The numbers of confirmed cases of COVID-19
infection and related deaths are still rising. As of 9 March 2020,
there have been 80 754 confirmed cases and 3136 deaths in the
mainland of China [3], corresponding to a total crude mortality
of 3.88%. Because the mortality is higher (14.4%) in severely ill
patients (the estimated percentage of severe patients is 27.1%;
4794 of 17 721) [3], treatment strategies are urgently needed [4].
Hypercytokinemia, also known as ‘‘cytokine storm”, is a fre-
quently occurring feature of severe infections with SARS, MERS,
H5N1 influenza, and H7N9 influenza; it is associated with disease
cytokine storm was correlated with disease severity [2]. Studies
revealed that the lethality of coronavirus or influenza virus is
related to the induction of an excessive and aberrant immune
response associated with severe lung pathology, with frequently
fatal consequences [2,6,9–11]. Therefore, curbing the overt inflam-
matory response induced by COVID-19 may be essential for reduc-
ing mortality among severely and critically ill patients with COVID-
19 infection [2,12,13]. However, clinical management of severe
patients infected with SARS or MERS has revealed that corticos-
teroid therapy did not reduce mortality; in contrast, it led to
delayed viral clearance [14,15]. In tertiary hospitals in Hubei Pro-
vince, China, systemic corticosteroids were used to treat severely
ill patients with COVID-19 infection who exhibited significant
acute pulmonary progression in imaging examinations; however,
limited experience has shown that this strategy does not result
in significant improvement [13].
In patients with SARS-CoV-related acute respiratory distress
syndrome, cytokine-storm-targeted therapy was recommended
severely or critically ill COVID-19 patients with cytokine storm
[21].
Based on the above-described evidence, the Expert Consensus
on the Application of Artificial-Liver Blood-Purification System in
the treatment of severe COVID-19 was recently released [22]. This
work recommends artificial-liver blood purification for the treat-
ment of patients with COVID-19 infection who exhibit cytokine
storm and rapid disease progression, as confirmed by lung
involved in cytokine storm onset in COVID-19; these will benefit
the understanding of artificial-liver support system treatment for
alleviating cytokine storm to reverse the disease process in
patients with severe COVID-19 infection by rebalancing the
immune system. By acting as an anti-cytokine-storm targeted ther-
apy, artificial-liver blood-purification systems hold excellent
potential for reducing mortality in severely and critically ill
patients with COVID-19 infection.
Fig. 1. The artificial-liver blood-purification system eliminates inflammatory cytokines/chemokines and alleviates cytokine-storm-induced damage in 2019-nCOV infection.
2
HỆ THỐNG LỌC GAN NHÂN TẠO
Zhang, Y., et al. (2020). "A Promising Anti-Cytokine-Storm Targeted Therapy for COVID-19: The Artificial-Liver Blood-Purification System." Engineering (Beijing, China):
10.1016/j.eng.2020.1003.1006.
“…recommends artificial-liver blood
purification for the treat- ment of
patients with COVID-19 infection
who exhibit cytokine storm and rapid
disease progression, as confirmed
by lung imaging. The similar
recommendation was made in the
Guideline for the Diagnosis and
Treatment of COVID-19 (7th
version)…”

54. THAY HUYẾT TƯƠNG TRONG COVID-19
• Phân tách huyết tương có thể thực hiện bằng 2 phương pháp : ly tâm hoặc
dùng màng lọc
• Khả năng loại bỏ các thành phần gây bệnh trong máu, nhưng cũng đi kèm khả
năng loại bỏ các yếu tố có lợi cho quá trình phục hồi

55. HIỆU QUẢ CỦA TPE LÊN MARKER VIÊM
Oxygen saturation at that time
was 96% at Fio2
80%. Labora-
tory test showed CRP 22.76mg/
dL, procalcitonin 2.93ng/mL,
creatinine 2.36mg/dL, LDH
682 U/L, ferritin 1,396ng/mL,
troponin 224.7ng/L, lactate
28.8mg/dL, and d-dimer greater
than 10.000ng/mL (Supplemen-
tary Table 1, Supplemental Dig-
ital Content 2, http://links.lww.
com/CCM/F804). Blood cell
counts disclosed leukocytosis
and thrombocytopenia (25.93
and 52.0×109
/L, respectively).
Echocardiogram was normal.
An angio-CT-scan showed bi-
lateral infiltrates suggestive of
COVID-19 pneumonia, lobar
and segmental acute right pul-
monary thromboembolism,
and multiple nonocclusive arte-
rial thrombosis in distal aortic
arch, splenic artery, aortoiliac
bifurcation, iliac arteries, and
right femoral artery. PCR for
SARS-CoV-2 in nasopharyn-
geal swab was positive. The pa-
tient was admitted to the ICU
for respiratory (high flow nasal
cannula) and vasopressor sup-
port (norepinephrine: 0.56 ug/
Kg/min). He was started on
lopinavir/ritonavir, hydroxy-
chloroquine, azithromycin, and
piperacillin-tazobactam. IV
dexamethasone and heparin
sodium infusion were also initi-
ated. After initial improvement,
the patient presented symptoms
of acute limb ischemia on day
14 and required urgent bilateral
transpopliteal embolectomy.
Screen for thrombophilia fac-
tors identified positive immuno-
globulin G (IgG) anticardiolipin
serum antibodies. On day 15,
catastrophic antiphospholipid
Figure 1. Effects of therapeutic plasma exchange on serum levels of creatinine (A), ferritin (B), and D-dimer (C)
in the four patients included in the study. Day 0 is the day of first plasma exchange. Days in negative numbers
correspond to the period prior to initiate plasma exchange. Large dots denote the days of plasma exchange in
each patient. Therapeutic plasma exchange induced a marked and sustained decrease in the serum levels of
Fernandez et al
Figure 2. Effects of therapeutic plasma exchange on plasma levels of different cytokines and chemokines in the three patients in whom samples were
obtained before and after the procedure. Baseline values are the median of the average of the first two samples. Values after treatment are the average
of the rest of available values. Patients presented an hyperinflammatory state with extremely high plasma levels of tumor necrosis factor (TNF)-alpha,
granulocyte colony- stimulating factor (G-CSF), interleukin (IL)-1ra, IL-10, and chemokines. Therapeutic plasma exchange induced a marked decrease
Fernandez, J., et al. (2020). "Plasma Exchange: An Effective Rescue Therapy in Critically Ill Patients With Coronavirus Disease 2019 Infection." Crit Care Med.

56. CẢI THIỆN TỔN THƯƠNG PHỔI SAU TPE
from mechanical ventilation and extubated, survived and were
discharged from the hospital to home isolation after 20 days (IQR:
4. Discussion
Fig. 1. Contrast chest computed tomography scan in a life-threatening COVID-19 patient (case 3; Table 2) showing diffuse bilateral mixed ground glass opacities and consolidation with
airbronchogram associated with septum thickening and mild right pleural effusion prior to plasma exchange (left panel); and after five plasma exchange sessions showing gradual
improvement (right panel).
3
F. Faqihi et al. / Journal of Critical Care xxx (2020) xxx
• Báo cáo loạt ca: thay huyết tương ở 7 bệnh nhân COVID-19 nặng
• Bình thường hoá các chỉ số SOFA, P/F, số lượng bạch cầu, LDH, ferritin, CRP và IL-6 sau TPE. Cải
thiện tổn thương phổi sau TPE
Faqihi, F., et al. (2020). "Therapeutic plasma exchange in adult critically ill patients with life-threatening SARS-CoV-2 disease: A pilot study." J Crit Care.

57. A
Ms. Janet Johnson
Terumo BCT, Inc.
10811 W. Collins Avenue
Lakewood, CO 80215
Dear Ms. Johnson:
This letter is response to a request from the B
behalf of Terumo BCT, Inc. and Marker Ther
Administration (FDA) issue an Emergency U
Spectra Optia Apheresis System1
with the De
as an extracorporeal blood purification (EBP)
with confirmed Coronavirus Disease 2019 (C
(ICU) with confirmed or imminent respiratory
levels, pursuant to Section 564 of the Federal
U.S.C. §360bbb-3).
On February 4, 2020, pursuant to section 564
Act (the Act), the Secretary of the Departmen
that there is a public health emergency that ha
or the health and security of United States cit
causes COVID-19.2
Pursuant to section 564
the Secretary of HHS then declared on March
TERUMO BCT Spectra Optia® Apheresis System
With Depuro D2000 Adsorption Cartridge was approved by FDA
Page 3
patient with confirmed COVID-19 who is admitted to the ICU with confirmed or imminent
respiratory failure is a patient 18 years of age or older who has any one of the following
conditions:
a) Early acute lung injury (ALI)/early acute respiratory distress syndrome (ARDS); or
b) Severe disease, defined as:
1) dyspnea,
2)
3)
4) partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300,
and/or
5) lung infiltrates > 50% within 24 to 48 hours; or
c) Life-threatening disease, defined as:
1) respiratory failure,
2) septic shock, and/or
3) multiple organ dysfunction or failure.
Chỉ định:
THAY HUYẾT TƯƠNG SỬ DỤNG MÁY OPTIA

58. CYTOSORB Ở BỆNH NHÂN COVID-19 NẶNG
• TNLS ngẫu nhiên, đơn trung tâm, nhãn mở
• Đánh giá hiệu quả can thiệp lọc cytokine ở bệnh nhân COVID-19 viêm phổi nặng cần hỗ trợ
ECMO
• Sử dụng quả lọc Cytosorb, thay quả lọc mỗi 24 giờ trong tổng thời gian 72 giờ can thiệp
• Kết cục chính: nồng độ IL-6 sau 72 giờ can thiệp; Kết cục phụ: sống còn ICU, tử vong 30
ngày, ...
Articles
Lancet Respir Med 2021
Published Online
May 14, 2021
https://doi.org/10.1016/
S2213-2600(21)00177-6
See Online/Comment
https://doi.org/10.1016/
S2213-2600(21)00207-1
Department of Medicine III
(Interdisciplinary Medical
Intensive Care), Medical Center,
(A Supady MD, M Rieder MD,
A Lother MD,T Niklaus BA,
T Zahn, F Frech, S Müller, M Kuhl,
Cytokine adsorption in patients with severe COVID-19
pneumonia requiring extracorporeal membrane
oxygenation (CYCOV): a single centre, open-label,
randomised, controlled trial
Alexander Supady, EnyaWeber, Marina Rieder, Achim Lother,Tim Niklaus,Timm Zahn, Franziska Frech, Sissi Müller, Moritz Kuhl, Christoph Benk,
Sven Maier, GeorgTrummer, Annabelle Flügler, Kirsten Krüger, Asieb Sekandarzad, Peter Stachon,Viviane Zotzmann, Christoph Bode,
Paul M Biever, Dawid Staudacher,TobiasWengenmayer, Erika Graf, Daniel Duerschmied
Summary
Background We sought to clarify the benefit of cytokine adsorption in patients with COVID-19 supported with
venovenous extracorporeal membrane oxygenation (ECMO).
Methods We did a single-centre, open-label, randomised, controlled trial to investigate cytokine adsorption in adult
patients with severe COVID-19 pneumonia requiring ECMO. Patients with COVID-19 selected for ECMO at the
Freiburg University Medical Center (Freiburg, Germany) were randomly assigned (1:1) to receive cytokine adsorption
using the CytoSorb device or not. Randomisation was computer-generated, allocation was concealed by opaque,
sequentially numbered sealed envelopes. The CytoSorb device was incorporated into the ECMO circuit before
connection to the patient circuit, replaced every 24 h, and removed after 72 h. The primary endpoint was serum
interleukin-6 (IL-6) concentration 72 h after initiation of ECMO analysed by intention to treat. Secondary endpoints
included 30-day survival. The trial is registered with ClinicalTrials.gov (NCT04324528) and the German Clinical Trials
Register (DRKS00021300) and is closed.

59. NGHIÊN CỨU CYCOV
Articles
Cytokine adsorption group (n=17) Control group (n=17) p value
Primary endpoint
Serum interleukin-6 after 72 h 98·6 (71·0 to 192·8)* 112·0 (48·7to 198·5)* 0·54†
Other endpoints
30-day survival 3 (18%) 13 (76%) 0·0016‡
Discharged from intensive care unit until day 30 0 3 (18%) 0·23‡
Serum lactate after 72 h, mmol/L 1·35 (1·05–1·58)* 1·25 (0·93–1·85)* 0·80§
Willebrand factor antigen after 72 h, % 426·0 (396·0–501·0)¶ 311·5 (287·8 to 405·8)* 0·021§
D-dimers after 72 h, mg/L FEU 8·77 (3·90 to 35·19)* 15·23 (5·79 to 34·23)* 0·48§
SOFA score after 24 h 7·0 (6·0 to 9·5) 8·0 (6·0 to 10·0) 0·59§
SOFA score after 48 h 8·0 (6·5 to 9·5) 8·0 (6·0 to 10·5) 0·95§
SOFA score after 72 h 7·5 (6·0 to 10·8)* 8·5 (6·0 to 10·0)* 0·81§
Norepinephrine support at 72 h, µg/kg per min|| 0·07 (0·03 to 0·13)* 0·00 (0·00 to 0·10)* 0·04§
Cumulative fluid balance for 72 h after initiation
of ECMO, mL
2665·0 (663·5 to 5152·0) 2145·0 (−92·5 to 3002·0) 0·29§
Fluid substitution during the first 72 h after
implementation of venovenous ECMO, mL
11773 (8959 to 13 468) 8344 (7304 to 10866) 0·0068§
Intensive care unit and ECMO treatment
Prone positioning after initiation of ECMO 15 (88%) 15 (88%) 0·99‡
Retrieval on ECMO by mobile ECMO retrieval
team from another hospital
3 (18%) 4 (234%) 0·99‡
Cytokine adsorption treatment
Cytokine adsorption 17 (100%) ·· ··
Delay between initiation of ECMO and start of
cytokine adsorption, h
0·00 (0·00 to 0·75)** ·· ··
• Khả năng loại bỏ các yếu tố bảo vệ (protective factors)
• Kích hoạt các con đường đông máu gây ra bởi quả lọc Cytosorb
• Nhóm được can thiệp có khuynh hướng nặng hơn
• Chưa kết luận hẳn vai trò của Cytosorb® ở nhóm bệnh nhân này
• Giảm nồng độ IL-6
sau can thiệp so với
nhóm chứng (không
ý nghĩa TK)
• Không cải thiện chỉ
số suy cơ quan
• Sống còn 30 ngày
thấp hơn rõ !

60. CYTOSORB Ở BỆNH NHÂN COVID-19 NẶNG
E108
| ALHARTHY ET AL.
FIGURE 3 Tukey boxplots with equal whisker lengths of 1.5 interquartile ranges for both whiskers in the thirty five COVID-19 survivors
depicting increased lymphocyte counts (A), and partial arterial pressure of oxygen to fractional inspired concentration of oxygen (PaO2/FiO2) ratio
(B), as well as reduced interleukin-6 levels (C), and Sequential Organ Function Assessment (SOFA) score (D) (all P = .0001), post-continuous
renal replacement therapy with CytoSorb
• Alharthy: 50 bệnh nhân COVID-19 nặng
có tổn thương thận cấp được điều trị với
CRRT kèm quả lọc Cytosorb®
• Các bệnh nhân đều kèm ARDS, sốc
nhiễm trùng và CRS
• Tỉ lệ sống còn 70 %
• Ở các bệnh nhân sống, sau can thiệp với
Cytosorb cải thiện số lượng bạch cầu,
P/F, giảm IL-6 và giảm điểm số SOFA
• Ở nhóm tử vong, không quan sát được
các hiệu quả này
Cải thiện đáp ứng viêm ở nhóm bệnh nhân sống
Alharthy, A., et al. (2021). "Continuous renal replacement therapy with the addition of CytoSorb cartridge in critically ill patients with COVID-19 plus acute kidney
injury: A case-series." Artif Organs 45(5): E101-e112.

61. CYTOSORB Ở BỆNH NHÂN COVID-19 NẶNG
FIGURE 3 Tukey boxplots with equal whisker lengths of 1.5 interquartile ranges for both whiskers in the thirty five COVID-19 survivors
depicting increased lymphocyte counts (A), and partial arterial pressure of oxygen to fractional inspired concentration of oxygen (PaO2/FiO2) ratio
(B), as well as reduced interleukin-6 levels (C), and Sequential Organ Function Assessment (SOFA) score (D) (all P = .0001), post-continuous
renal replacement therapy with CytoSorb
FIGURE 4 Receiver operator curve analysis of post therapy
interleukin-6 values (IL-6), using a cutoff point >620 pg/mL, in
predicting mortality for COVID-19 patients (area-under-the-curve:
FIGURE 5 Receiver operator curve analysis of post therapy
Sequential Organ Assessment Function (SOFA) score values, using a
cutoff point >10, in predicting mortality for COVID-19 patients (area-
under-the-curve: 0.81, 95% confidence-intervals: 0.73-0.86; P = .01)
IL-6 > 620 pg/mL và SOFA >10 sau can thiệp có giá trị tiên lượng tử vong
Alharthy, A., et al. (2021). "Continuous renal replacement therapy with the addition of CytoSorb cartridge in critically ill patients with COVID-19 plus acute kidney
injury: A case-series." Artif Organs 45(5): E101-e112.
AUC = 0.87
95% CI: 0.81-0.93; P = .001
AUC = 0.81
95% CI: 0.73-0.86; P = .01

62. CRRT- LỌC HẤP PHỤ TRÊN BỆNH NHÂN COVID-19

63. TÓM LẠI
• Bão cytokine: do sự gia tăng quá mức các cytokines gây viêm, đe dọa tính
mạng
• Liên quan đến mức độ nặng và tiên lượng của bệnh
• Các can thiệp nhắm đến điều hoà miễn dịch và/hoặc loại bỏ các cytokines
nhằm giảm tổn thương cơ quan, tăng khả năng hồi phục
• Bằng chứng mạnh trên bệnh nhân COVID-19 là việc sử dung
dexamethasone ở các bệnh nhân cần hỗ trợ hô hấp
• Cơn bão Cytokin gây tổn thương đa cơ quan, ngoài điều trị bằng thuốc, các
phương thức lọc máu CVVH, HVHF, sử dụng màng lọc có cut-off cao, sử
dụng quả lọc hấp phụ cytokin, thay huyết tương được thực hiện nhằm mục
đích giảm tổn thương cơ quan.

64. TRÂN TRỌNG CẢM ƠN