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Expert Review of Clinical Immunology
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20
Coronavirus disease 2019: investigational
therapies in the prevention and treatment of
hyperinflammation
Isabelle Amigues, Alexander H Pearlman, Aarat Patel, Pankti Reid,
Philip C. Robinson, Rashmi Sinha, Alfred Hj Kim, Taryn Youngstein,
Arundathi Jayatilleke & Maximilian Konigon behalf of the COVID-19 Global
Rheumatology Alliance
To cite this article: Isabelle Amigues, Alexander H Pearlman, Aarat Patel, Pankti Reid, Philip C.
Robinson, Rashmi Sinha, Alfred Hj Kim, Taryn Youngstein, Arundathi Jayatilleke & Maximilian
Konigon behalf of the COVID-19 Global Rheumatology Alliance (2020) Coronavirus disease 2019:
investigational therapies in the prevention and treatment of hyperinflammation, Expert Review of
Clinical Immunology, 16:12, 1185-1204, DOI: 10.1080/1744666X.2021.1847084
To link to this article: https://doi.org/10.1080/1744666X.2021.1847084
Published online: 25 Nov 2020. Submit your article to this journal
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REVIEW
Coronavirus disease 2019: investigational therapies in the prevention and
treatment of hyperinflammation
Isabelle Amigues
a
*
, Alexander H Pearlman
b
*
, Aarat Patel
c
, Pankti Reid
d
, Philip C. Robinson
e
, Rashmi Sinha
f
,
Alfred Hj Kim
g,h,i
, Taryn Youngstein
j
, Arundathi Jayatilleke
k
and Maximilian Konigon behalf of the COVID-19 Global
Rheumatology Alliance
l
a
Division of Rheumatology, Department of Medicine, National Jewish Health, Denver, CO, USA;
b
Division of Rheumatology, The Johns Hopkins
University School of Medicine, Baltimore, MD, USA;
c
Bon Secours Rheumatology Center and Division of Pediatric Rheumatology, Department of
Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA;
d
Division of Rheumatology, Department of Internal Medicine,
Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago Medical Center, Chicago, IL, USA;
e
School of Clinical Medicine,
University of Queensland Faculty of Medicine, Queensland, Australia;
f
Department of Medicine, Systemic Juvenile Idiopathic Arthritis Foundation,
Cincinnati, OH, USA;
g
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA;
h
Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA;
i
Andrew M. And Jane M. Bursky Center of Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint
Louis, MO, USA;
j
Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK;
k
Division of Rheumatology, Department of Medicine,
Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA;
l
Division of Rheumatology, Department of Medicine, The Johns Hopkins
University School of Medicine, Baltimore, MD, USA
ABSTRACT
Introduction: The mortality of coronavirus disease 2019 (COVID-19) is frequently driven by an injurious
immune response characterized by the development of acute respiratory distress syndrome (ARDS),
endotheliitis, coagulopathy, and multi-organ failure. This spectrum of hyperinflammation in COVID-19 is
commonly referred to as cytokine storm syndrome (CSS).
Areas covered: Medline and Google Scholar were searched up until 15th of August 2020 for relevant
literature. Evidence supports a role of dysregulated immune responses in the immunopathogenesis of
severe COVID-19. CSS associated with SARS-CoV-2 shows similarities to the exuberant cytokine produc-
tion in some patients with viral infection (e.g.SARS-CoV-1) and may be confused with other syndromes
of hyperinflammation like the cytokine release syndrome (CRS) in CAR-T cell therapy. Interleukin (IL)-6,
IL-8, and tumor necrosis factor-alpha have emerged as predictors of COVID-19 severity and in-hospital
mortality.
Expert opinion: Despite similarities, COVID-19-CSS appears to be distinct from HLH, MAS, and CRS, and
the application of HLH diagnostic scores and criteria to COVID-19 is not supported by emerging data.
While immunosuppressive therapy with glucocorticoids has shown a mortality benefit, cytokine inhibi-
tors may hold promise as ‘rescue therapies’ in severe COVID-19. Given the arguably limited benefit in
advanced disease, strategies to prevent the development of COVID-19-CSS are needed.
ARTICLE HISTORY
Received 18 August 2020
Accepted 3 November 2020
KEYWORDS
Coronavirus disease 2019
(COVID-19);
hyperinflammation; cytokine
storm syndrome; cytokine
release syndrome;
hemophagocytic
lymphohistiocytosis
1. Introduction
The Coronavirus disease 2019 (COVID-19) pandemic is an
ongoing threat to global health. COVID-19, caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was
first reported to have emerged in humans in December 2019
and has since spread rapidly worldwide [1]. To date, the
numbers of people infected by the SARS-CoV-2 and deaths
directly attributable to COVID-19 continue to increase or are
again rising in areas with previously declining new case bur-
den. As of October 2020, more than 36 million individuals
worldwide were diagnosed with COVID-19 and more than
1 million deaths were reported [2].
A major cause of morbidity and mortality in SARS-CoV
-2-associated pneumonia is the progression to acute respira-
tory distress syndrome (ARDS) [1]. Data from both experimen-
tal animal models and clinical studies of other viral syndromes
suggest a model of immune-mediated damage caused by
virus-associated dysregulation of immune responses in the
genetically or immunologically susceptible host [3–5]. In infec-
tion with two other highly pathogenic coronaviruses, SARS-
CoV-1 and MERS-CoV, this state of hyperinflammation has
been likened to a cytokine storm syndrome (CSS). Evidence
suggests that COVID-19 is similarly characterized by
a deleterious activation of proinflammatory pathways, poten-
tially related to dysregulated T cell responses, delayed type
CONTACT Maximilian Konig konig@jhmi.edu MD, Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine,
Baltimore, MD, USA; Arundathi Jayatilleke arundathi.jayatilleke@tuhs.temple.edu Division of Rheumatology, Department of Medicine, Lewis Katz School of
Medicine at Temple University, Philadelphia, PA, USA
*
These authors equally contributed to this work.
EXPERT REVIEW OF CLINICAL IMMUNOLOGY
2020, VOL. 16, NO. 12, 1185–1204
https://doi.org/10.1080/1744666X.2021.1847084
© 2020 Informa UK Limited, trading as Taylor & Francis Group
I interferon (IFN) responses, and exuberant production of
cytokines, accompanied by increases in morbidity and mortal-
ity [3,4]. Targeting immune dysregulation with the goal to
ameliorate ARDS and prevent multi-organ failure holds some
promise as a potential therapeutic pathway. However, caution
must be exercised, as immunomodulatory therapy may blunt
host innate and adaptive responses during active viral replica-
tion. In this review, we summarize the evolving evidence
supporting hyperinflammation as a pathogenetic mechanism
for severe COVID-19 infection as well as therapeutic strategies
currently in use and under investigation.
Given the rapid evolving changes in Covid19 knowledge,
the authors chose to use Google search in addition to
a Medline search using ‘Covid-19, SARS-CoV-2, Cytokine
storm.’ The last search date was 15 August 2020.
2. Hyperinflammation in COVID-19 and infection
with other virulent coronaviruses
2.1. Immune dysregulation in severe coronavirus
infection
2.1.1. Animal and in vitro models of severe respiratory
coronavirus infection
Coronaviruses are a family of enveloped non-segmented posi-
tive-sense RNA viruses broadly distributed in humans and
animals. Of the coronaviruses known to cause infection in
humans, three are now recognized to cause fatal respiratory
disorders: the severe acute respiratory syndrome coronavirus
(SARS-CoV-1) and SARS-COV-2, and Middle East respiratory
syndrome coronavirus (MERS-CoV) [5].
Although no direct evidence implicates proinflammatory
cytokines as the cause of lung damage, the observation of
patterns of proinflammatory cytokine production in animal
and in-vitro models of SARS-CoV-1 and MERS-CoV infection
supports the idea of a shared pathophysiology of immune
dysregulation. Chu et al. examined the comparative abilities
of MERS-CoV and SARS-CoV-1 to trigger a cytokine response in
monocyte-derived dendritic cells and found that both induced
upregulation of TNF-α and IL-6 during the same time frame
that peak viral titers were observed in culture [6]. Zhou et al.
similarly examined infectivity and innate immune response-
related cytokines in monocyte-derived macrophages (MDMs)
and found that MERS-CoV and SARS-CoV-1 showed
a sustained induction of MCP-1, MIP-1α, and IL-8, whereas
MERS-CoV-infected MDMs produced higher levels of these
chemokines [7]. As expected, TNF-α and IL-6 were induced at
high levels by both MERS-CoV and SARS-CoV-1. Interestingly,
IFN-γ induction in MDMs was much more prominent than IFN-
α and IFN-β [7]. Lau et al. examined cytokine profiles in MERS-
CoV- and SARS-CoV-1-infected polarized airway epithelial
Calu-3 cells and found that both viruses caused a delayed
induction of IL-1β, IL-6, and IL-8, with MERS-CoV triggering
a stronger response than SARS-CoV-1 [8]. Animal models of
MERS and SARS are more heterogeneous in terms of symptom
severity, limiting the usefulness of rodent models. However, in
more rapidly lethal and systemically symptomatic models,
elevations of pro-inflammatory cytokines such as IL-6, IP-10,
and IL-8 were observed in lung and brain tissues [9–11].
Animal models that model human COVID-19 are emerging.
Mouse models – without genetic modification – do not sup-
port SARS-CoV-2 infection due to the inability of spike protein
to bind the murine ortholog of its cognate receptor human
angiotensin-converting enzyme 2 (hACE2) [12]. Recent efforts
to overcome these limitations using transgenic and adeno-
associated virus-mediated expression of hACE2 in mice allow
for SARS-CoV-2 infection and replicate features of COVID-19
[12–14]. Israelow et al. found expansion of infiltrating myeloid-
derived inflammatory cells and inflammatory monocyte-
derived macrophages (CD64+ CD11c-CD11b+Ly6C+) in the
diseased lungs at days 2 and 4 post-infection, which was
paralleled by increases in activated CD4+ and CD8 + T cells
as well as natural killer (NK) cells. These cellular changes in the
lungs were associated with increased cytokines and interferon-
stimulated gene signatures, including a subset of 45 genes
specific to type I IFN signaling, similar to what has been
observed in the lungs of patients with COVID-19 [12]. IFN-α
receptor- and IFN regulatory transcription factor 3/7-deficient
mice showed markedly decreased recruitment of monocytes/
macrophages, and activation of CD4 + T cells, CD8 + T cells,
and NK cells in infected lungs, highlighting the role of type
I IFNs in the immunopathology of SARS-CoV-2 pneumonia
[12]. Unlike the sequelae observed in human disease, this
model of SARS-CoV-2 infection in young mice did not recapi-
tulate the mortality observed in COVID-19-ARDS and CSS. In
another model of hACE2 transgenic mice, SARS-CoV-2 infec-
tion resulted in isolated pulmonary pathology with interstitial
pneumonia and was associated with transient weight loss, but
otherwise did not recapitulate COVID-19-CSS [14]. By contrast,
HFH4-hACE2 transgenic C3B6 mice showed evidence of
a multi-system disease (including interstitial pneumonia, ele-
vation in CPK and AST, cardiac muscle edema and myocyte
necrosis, sporadic neuro-invasion) and variably showed weight
loss, respiratory distress, neurological symptoms, and mortal-
ity, reminiscent of human disease [13]. Cynomolgus macaques
were permissive to SARS-CoV-2 infection and showed limited
pulmonary lesions with evidence of diffuse alveolar damage
but remained asymptomatic at day 4 post-infection [15]. It
remains unclear whether SARS-CoV-2-related hyperinflamma-
tion is replicated in non-human primate models, similar to the
cytokine storm observed during lethal infection with 1918
influenza virus in macaques [16]. Animal models that compre-
hensively replicate the dysregulated immune responses and
Article highlights
●Some patients with COVID-19 enter a hyperinflammatory state char-
acterized by highly elevated D-dimer, elevated CRP, and elevated
ferritin.
●Development of hyperinflammation corresponds to a worsening clin-
ical status including oxygen requirements and respiratory status,
multi-organ failure, and death.
●Despite similarities, COVID-19-CSS appears to be distinct from HLH,
MAS, and CRS, and the application of HLH diagnostic scores and
criteria to COVID-19 without further study is not supported by emer-
ging data and discouraged.
●While glucocorticoids have shown a mortality benefit, more studies
are needed to evaluate cytokine inhibitors in severe COVID-19.
●Strategies to prevent the development of COVID-19-CSS are needed.
1186 I. AMIGUES ET AL.
associated immunopathology of COVID-19, can model the
response to prophylactic and immunosuppressive therapies,
and inform their timing will remain a priority.
2.1.2. Proinflammatory cytokines are associated with
disease severity in coronavirus infection
Macrophage infiltration of the lungs, their presence in bronch-
oalveolar lavage (BAL) fluid, high concentrations of pro-
inflammatory mediators, and hemophagocytosis suggest that
host responses contribute to the immunopathogenesis of
SARS and MERS [3,4,17–20]. Understanding this hyperinflam-
matory state and relative contributions of host immune
responses to morbidity and mortality is of interest in identify-
ing targets for potential treatment. Several pro-inflammatory
cytokines have been found to be elevated in patients with
severe pneumonia associated with SARS-CoV-1 and MERS-CoV,
including IL-1β, IL-6, IL-12, IL-15, IL-17, IFN-γ, IP-10, and MCP-1
[4,21]. More severe courses of SARS and MERS are associated
with persistent fever, lung infiltrates, and higher plasma levels
of proinflammatory cytokines including IL-6, MCP-1, and IP-10
[3,4]. The difference is most pronounced in the second week
of illness, days after peak viral loads were observed. Elevated
levels of IL-6 and IL-8 were observed in SARS patients, and IL-6
and IP-10 in MERS patients, suggesting that a dysregulated
immune response phase occurs after the viral replication
stage. Similar findings of elevated levels of pro-inflammatory
cytokines have been reproducibly demonstrated in COVID-19
[3,22]. IL-6 elevation in particular has received considerable
attention as a marker of disease severity and in-hospital mor-
tality [23–29]. Several other cytokines have been associated
with disease severity in COVID-19, including IL-2 R, IL-8, IL-10,
TNF-α, IP-10, MCP-3, IL-1RA, but not IL-1β [27,28,30,31]. In
a large cohort of 1,484 patients TNF-α and IL-6 were the only
two cytokines that significantly and independently predicted
mortality [27]. In an early study, patients requiring ICU admis-
sion had higher concentrations of IL-2, IL-7, IL-10, IL-12, G-CSF,
MCP-1, MIP-1A, and TNF-α than did those not requiring ICU
admission [32]. Elevation of other chemokines and cytokines
has been reported in target tissues and circulation however,
elevation of IL-6 and other cytokine levels alone may not
reliably differentiate moderate from severe COVID-19 or even
signify a hyperinflammatory state [33,34]. One study of per-
ipheral blood mononuclear cells (PBMCs) found increased
polyclonal granulocyte-macrophage colony-stimulating factor
(GM-CSF)+ CD4 T cells in COVID-19 patients compared to
healthy controls and GM-CSF-responsive CD14+ CD16+ mono-
cytes capable of producing IL-6, suggesting a mechanism by
which dysregulation of T cell responses can contribute to the
overproduction of cytokines seen in hyperinflammation [35].
Despite the association between high levels of pro-
inflammatory cytokines and increased disease severity, it
should be emphasized that this observation does not establish
a causal relationship. Conversely, while the cryopyrin-
associated periodic syndromes (CAPS) are driven by deregu-
lated release of IL-1β and can be treated effectively with
anakinra or other IL-1 blocking agents [36] Serum levels of
IL-1β are below the level of detection even during CAPS flares.
More mechanistic research will be needed to determine the
roles of specific cytokines in COVID-19 pathophysiology.
2.1.3. Delayed type I IFN responses may lead to more
severe coronavirus infection
IFNs are produced during a viral infection and are critical to
orchestrate innate and adaptive antiviral immune responses
[5]. IFNs induce the production of antiviral effector proteins,
thereby inhibiting intracellular viral replication. Type 1 IFNs
(IFN-I) activate interferon-stimulated genes (ISG) that are
involved in inflammation, signaling, and immunomodulation.
A deficient IFN-I response can lead to reduced antiviral activ-
ity. In addition, IFN-I treatment has been studied in MERS-CoV
and SARS-CoV-1 infection alone or in combination with other
antivirals, glucocorticoids, or IFN-γ, although studies in
patients have thus far been disappointing [5,6]. Some have
used IFN-α2b sprays to reduce the infection rate of SARS-CoV
-1 in children [37]. In an elegant demonstration,
Channappanavar et al. showed that a robust viral replication
and delayed IFN-I responses were detrimental in SARS-CoV
-1-infected mice due to influx of inflammatory monocytes-
macrophages into target tissue, which led to severe forms of
SARS [37]. Additionally, they found that inflammatory mono-
cytes-macrophages were the predominant source of the
proinflammatory cytokines CCL2, TNF-α, and IL-6 in SARS-
CoV-1-infected lungs. A strong and persistent expression of
IFN and ISGs, associated with impaired T cell and antibody
responses, was also associated with fatal cases of SARS [38].
Emerging information implicates impairment of the type
I interferon response in the pathogenesis of severe COVID-19
infection. Blanco-Melo et al. found that SARS-CoV-2 impairs
expression of type I and III IFN genes in a SARS-CoV-2 animal
model as well as in lung tissue and sera from patients with
COVID-19 [39]. Trouillet-Assant et al. examined the kinetics of
the plasma IFN-I response in 26 critically ill patients with
COVID-19 and found that all (5 out of 5) patients with sus-
tained lack of IFN-α2 production required invasive ventilation
compared to 9 out of 21 patients with the expected peak of
IFN-α2 8–10 days after onset of symptoms; all patients had
sustained elevation of C-reactive protein (CRP) and IL-6 levels
[40]. Hadjadj et al. reported that plasma levels of IFN-α2 at
8–12 days after symptom onset were lower in 18 critically ill
patients with COVID-19 than in 15 patients with mild-to-
moderate symptoms [41]. Gene expression analysis also
showed that ISGs such as MX1, IFITM1, and IFIT2 were down-
regulated, but serial measurements were not reported [41].
Taken together, these findings support the concept of delayed
or impaired IFN responses causing delayed viral clearance and
increased proinflammatory cytokine release, ultimately caus-
ing severe disease. While we are still striving to fully under-
stand the pathophysiology of COVID-19, this model could
explain part of the wide range of clinical presentations of
SARS-CoV-2 infection.
2.2. Clinical presentation of COVID-19
2.2.1. Progression of COVID-19
Infection with SARS-CoV-2 leads to a wide range of clinical
manifestations ranging from asymptomatic to severe, life-
threatening disease with a median time from illness onset to
clinical resolution of 22 · 0 days (IQR 18 · 0–25 · 0). In the adaptive
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1187
immune phases of infection, COVID-19 may be complicated by
ARDS, multi-organ failure (including heart and kidney failure),
sepsis/septic shock, and death [1,42]. The outcome of COVID-19
is thought to be largely governed by the interplay between the
virus and host antiviral immune responses [43]. Although more
studies are needed to establish a reliable clinical staging system,
the initial state of COVID-19 infection appears to be relatively
mild, with nonspecific symptoms such as malaise, fever, myalgia,
dry cough, and diarrhea. While the virus multiplies in the host
cells, primarily affecting the lower respiratory system but also the
gut and nasopharynx, mild respiratory and systemic symptoms
predominate (stage 1). In a second stage of the infection,
patients develop a viral pneumonia with bilateral infiltrates and
ground-glass opacities, leading in some patients to dyspnea (7 · 0
(IQR 4 · 0–9 · 0) days from illness onset) or hypoxemia requiring
hospitalization (stage 2) [1]. A minority of patients will progress
to the most severe form of illness, characterized by ARDS with or
without an extrapulmonary systemic hyperinflammation syn-
drome, commonly referred to as CSS (stage 3) [44] (Figure 1).
2.2.2. Clinical and laboratory features of severe COVID-19
The severe presentation of COVID-19 peaks around 7–14 days
after onset of illness and is associated with respiratory distress,
and hyperinflammation [1,45]. Compared to moderate cases,
patients with severe cases of COVID-19 have more chest tight-
ness, tachypnea, and dyspnea with frequent hypoxemia
requiring invasive mechanical ventilation [46] (see Table 1).
Despite an increase in white blood cell count, severe SARS-
CoV-2 infection is associated with lymphopenia (particularly in
CD4 + T cells and CD8 + T cells but not in B cells). As we
discussed, the levels of proinflammatory cytokines IL-6, IL-2 R,
IL-10, and TNFα are markedly elevated in severe cases.
Elevated levels of transaminases, creatinine, creatine kinase,
LDH, D-dimer, ferritin, cardiac troponin, and NT-pro-BNP were
all more frequently seen in deceased patients [1,33]. In our
experience, elevations of these acute phase proteins and pro-
inflammatory cytokines correspond to COVID-19 disease pro-
gression. In particular, some patients with severe disease
appear to have a hyperinflammatory state characterized by
very high D-dimer levels, elevated CRP, and elevated ferritin.
Coagulopathy with pulmonary thrombosis, microangiopathy,
and multi-organ system dysfunction, including acute kidney
injury and cardiomyopathy, can also be seen [47].
2.2.3. Pathological studies of COVID-19
There are relatively few reports of histopathological data from
patients with COVID-19. In autopsies of 75 fatal cases of
COVID-19 pneumonia, the main pulmonary findings included
diffuse alveolar damage with hyaline membrane formation,
fibrin exudates, epithelial damage, and diffuse type II pneu-
mocyte hyperplasia [34,35,48]. Interstitial lymphocytic inflam-
matory infiltrates were seen in only one patient; in the same
patient, multinucleated syncytial cells with atypical enlarged
pneumocytes and viral cytopathic-like changes in the intra-
alveolar spaces were also visible [34]. Another case series
revealed evidence of predominantly thrombotic injury without
similar fibroproliferative or viral cytopathic changes in the
lung [49]. Thrombotic microvascular injury with complement
C5b-9 deposition was seen in skin tissue of three and lung
tissue of two of these five patients [49]. Similarly, lung pathol-
ogy of four patients who died of COVID-19 revealed small, firm
thrombi in sections of the peripheral parenchyma, platelets,
and thrombi in small vessels, and foci of hemorrhage [50].
Similar findings were seen in the form of deep venous throm-
bosis and pulmonary thromboembolism in a series highlight-
ing COVID-19-associated coagulopathy [51]. In patients who
had their hearts examined, there was scarce evidence of
inflammation. While some had only few interstitial mononuc-
lear inflammatory infiltrates and no other substantial damage,
others also had evidence of scattered individual cell myocyte
necrosis [34,35,50]. None had a significant lymphocytic inflam-
matory infiltrate consistent with the typical pattern of viral
myocarditis [34,35,50]. Reports of hemophagocytosis among
autopsy series are relatively sparse, especially from bone mar-
row biopsy specimens [52,53]. While the presence or absence
of hemophagocytosis by itself does not define cytokine storm,
this sparsity may suggest a divergence between COVID-19-CSS
and other hyperinflammatory syndromes.
2.2.4. Predictors of mortality and severity in severe
COVID-19
Age, male sex, chronic hypertension, and other cardiovascular
comorbidities are risk factors for death due to COVID-19 [33].
Leukocytosis, persistent and severe lymphopenia, as well as
elevated transaminases, creatinine, creatine kinase, LDH,
D-dimer, ferritin, cardiac troponin, and NT-pro-BNP were all
more frequently seen in patients who died from COVID-19
[1,33]. In a multivariable logistic regression model, older age,
higher Sequential Organ Failure Assessment (SOFA) score, and
elevated D-dimer were associated with increased odds of
death [1]. Concentrations of IL-6, IL-8, IL-10, TNF-α, and IL-2-
receptor were also significantly higher in patients who died
than those who recovered [1,33]. In a study from Germany, the
authors found that IL-6 levels above 80 pg/mL were strongly
associated with the need for mechanical ventilation and may
identify patients at highest risk of respiratory failure [54]. While
it remains unclear whether IL-6 directly contributes to organ-
damage in severe COVID-19 or merely represents a biomarker,
its elevation in severe COVID-19 patients has raised suspicion
that it can trigger or sustain cytokine storm.
Hyperinflammatory syndromes such as MAS, HLH, CRS, and
the viral response to SARS-CoV-2, while similar in their cyto-
kine profile and associated laboratory parameters, should be
differentiated and compared with caution.
3. Comparison of severe COVID-19 to other
syndromes with hyperinflammation
3.1. HLH and MAS
HLH is the prototypical hyperinflammatory syndrome that is
driven by T and NK cells and associated with an often fatal
cytokine storm [55,56]. HLH is subdivided into two categories.
Familial or primary HLH is associated with various genetic
defects in the perforin cytotoxic pathway and commonly auto-
somal recessive in inheritance. Patients with secondary or
reactive HLH (rHLH) can also have underlying mutations and/
or polymorphisms affecting genes of the perforin pathway
1188 I. AMIGUES ET AL.
and have identifiable triggers including cancer or infection,
commonly Epstein Barr virus (EBV), cytomegalovirus (CMV),
human immunodeficiency virus (HIV), or influenza [56,57].
When triggered by an autoinflammatory/autoimmune disor-
der, the term macrophage activation syndrome (MAS) is com-
monly applied in the literature [58,59].
Clinical manifestations of HLH include fever, lymphadenopathy,
hepatosplenomegaly, and at times complicating neurological
symptoms. Laboratory features include marked cytopenia, ele-
vated liver enzymes, hypertriglyceridemia, hyperferritinemia, and
hypofibrinogenemia. Bone marrow findings include many well-
differentiated macrophages phagocytosing other hematopoietic
elements (e.g. erythrocytes, platelets, or granulocytes). A decrease
in ESR elevation has been proposed as a characteristic feature that
is secondary to fibrinogen consumption and liver dysfunction [60].
Marked elevation in ferritin is seen and reflects activation and
Figure 1. Clinical phases of COVID-19 and potential strategies for the prevention and treatment of hyperinflammation (‘cytokine storm’). Disease progression in
COVID-19 can be categorized based on the severity of clinical signs and symptoms in addition to the development of objective imaging and laboratory
abnormalities. A hyperinflammatory state – following an initial viral replication phase – can be present in patients with severe disease. Potential approaches to
ameliorate COVID-19 include strategies to reduce binding of SARS-CoV-2 to its cognate receptors (not shown), antiviral therapy (e.g. remdesivir), and the prevention
and treatment of hyperinflammation and immune-mediated end-organ damage. ARDS: acute respiratory distress syndrome. ARDS: acute respiratory distress
syndrome. IFN: interferon. IL: interleukin. JAK: Janus kinase. TNF: tumor necrosis factor.
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1189
active production by macrophages. NK cell function is abnormal
due to cytotoxic pathway defects and soluble IL-2 R is elevated due
to ineffective immune cell activation when target cell killing is
impaired [61]. Despite many clinical and laboratory abnormalities,
there is no pathognomonic feature of this cytokine storm and
several classifications have been proposed (Table 1).
Unfortunately, classification criteria for HLH and MAS most likely
cannot be directly applied to COVID-19-CSS [62,63].
3.2. Cytokine release syndrome (CRS)
Cytokine-release syndrome (CRS) is a dysregulated systemic
inflammatory response seen as a common and severe compli-
cation of cancer immunotherapy as well as other forms of
immunomodulatory therapy [64–66]. More recently, CRS has
drawn attention as a complication of chimeric antigen recep-
tor (CAR) T cell therapy, an approved treatment for multiple
B cell malignancies [67–70]. In these cases, simultaneous acti-
vation of a large number of CAR T cells by engagement with
their cognate antigen on cancer cells causes release of inflam-
matory cytokines and chemokines, triggering further cytokine
release from monocytes, macrophages, dendritic cells, and
other immune cells [71,72]. Biomarkers can include expansion
of CAR T cell numbers and elevation in a variety of inflamma-
tory proteins, chemokines, and cytokines including IL-6
[73,74].
CRS can manifest clinically on a spectrum of acuity ranging
from constitutional symptoms of fever, fatigue, headache, and
myalgia to severe end-organ toxicity, hemodynamic shock,
respiratory failure, and death [67,68,70]. In rare cases, CAR T cell
therapy has been linked to the induction of an rHLH/MAS-like
syndrome, which may be a progression to the most severe end of
the CRS spectrum [75,76]. Common features of CRS as well as
HLH and MAS are shown in Table 1. Both treatment factors such
as the CAR construction, target, and dose, as well as patient
characteristics such as age, comorbidities, and tumor burden
are believed to affect the risk, severity, and presentation of CRS.
3.3. Management of HLH, MAS, and CRS
3.3.1. Management of pHLH and rHLH/MAS
In all cases of HLH, early recognition and treatment initiation is
key to reduce morbidity and mortality. In children, the primary
goal of pHLH is to suppress the life-threatening inflammatory
process, often using an etoposide-based treatment induction
regimen (dexamethasone, etoposide, intrathecal methotrex-
ate, and cyclosporine) [77]. The goal of aggressive induction
therapy in pHLH is to achieve remission and bridge to allo-
geneic hematopoietic stem cell transplantation (HSCT) [78]. In
adults, tailored treatment approaches with dose reduction and
duration as well as a modified diagnostic approach that fac-
tors in age and potential alternative drivers of the disease
needs to be considered [79].
For rHLH secondary to malignancy, the underlying malig-
nancy is usually targeted, with additional HLH-specific treat-
ment including glucocorticoids and etoposide. In rHLH
secondary to infection, treatment of the underlying infection
is balanced with additional HLH-specific treatments including
glucocorticoids, etoposide, and cytokine targeted therapy,
including IL-1 and/or IL-6 pathway inhibition, as well as ritux-
imab in the case of EBV-related rHLH [79,80]. Emapalumab, an
interferon-γ neutralizing antibody, has also been successfully
used in the treatment of refractory HLH as well as in a case
series of patients with rHLH/MAS [81,82].
A targeted treatment approach is also followed by both
pediatric and adult rheumatologists when treating MAS. Due
to low event rates, phase 3 clinical trials in patients with MAS
are difficult to perform, and most treatments used are extra-
polated from our understanding of systemic juvenile idio-
pathic arthritis (sJIA), one of the most common underlying
disorders associated with MAS. IL – 1β, IL – 6, and IL-18 have
been implicated in the immunopathogenesis of sJIA and pos-
sible therapeutic targets in MAS. Both IL-1 pathway inhibition
with anakinra, a non-glycosylated form of human IL – 1Ra that
competitively inhibits binding of IL-1α and/or IL-1β, and cana-
kinumab, a human monoclonal anti-IL-1β antibody, as well as
IL-6 R inhibition with tocilizumab have shown promising
results in treating sJIA, but do not prevent the development
of MAS in all patients that achieve control of their arthritis
[59,83,84]. Anakinra is also used in the treatment of MAS
despite difficulties in performing clinical trials in MAS and
lack of phase III clinical trials, it can be effective in patients
who fail to achieve remission with glucocorticoids and cyclos-
porine alone [85]. Higher doses of anakinra may be required to
treat MAS than sJIA. Interestingly, phase III trials of canakinu-
mab in sJIA did not show a dramatic reduction in the inci-
dence of MAS, which was usually triggered by infection [84].
Indeed, the occurrence of new-onset MAS in patients with sJIA
in clinical trials of tocilizumab and canakinumab demonstrates
that the inhibition of either IL-1 or IL-6 alone does not provide
full protection against MAS [59]. While IL-1 and IL-6 may be
contributing factors in the development of MAS, other cyto-
kines may be critical drivers of immunopathogenesis when
these cytokine signaling pathways are inhibited. IL-1- or IL-
6-targeted therapies may also benefit those with hypomorphic
genetic variants, as they are susceptible to MAS triggered by
infection.
3.3.2. Management of CRS
Management strategies for CRS with CAR T cell therapies have
traditionally weighed the need to mitigate CRS effects against
the potential for immunosuppression to abrogate anti-tumor
efficacy and increase infection susceptibility. As such, mild or
moderate CRS is managed with supportive care and often
resolves without the need for pharmacologic intervention.
Informed by the elevation of IL-6 in CRS, high-grade CRS is
managed with anti-IL-6 or anti-IL-6 R blocking antibodies
[68,70]. Tocilizumab is an FDA-approved anti-IL-6 R monoclo-
nal antibody for treating CRS. Glucocorticoids are also admi-
nistered, typically only when severe CRS is refractory to
tocilizumab [68,70,86,87]. In current practice, immunosuppres-
sive therapies are generally withheld until the presentation of
severe CRS with the intention of preserving immune treatment
efficacy. However, emerging evidence suggests that targeted
therapies inhibiting IL-6 signaling and glucocorticoids may not
decrease response rates or durability [88]. Whether
immunosuppressive treatments can be applied earlier in the
1190 I. AMIGUES ET AL.
Table 1. Clinical and laboratory features of COVID-19-CSS in comparison to other states of hyperinflammation/immune dysregulation. COVID-19-CSS shares clinical and laboratory features with HLH, MAS, CRS, and sepsis but
does not recapitulate any one of these related conditions entirely. ARDS: acute respiratory distress syndrome. CD: cluster of differentiation. CRS: cytokine-release syndrome. CSS: cytokine storm syndrome. HLH: hemophagocytic
lymphohistiocytosis. IL: interleukin. MAS: macrophage activation syndrome. NK: natural killer. *Five out of eight criteria must be fulfilled unless family history or molecular diagnosis is consistent with HLH. **Required in
patients with known or suspected sJIA, in addition to any two of the other laboratory abnormalities.
HLH-04 Criteria* HScore MAS Criteria
CRS
features
Sepsis
features COVID-19-CSS features
Fever x x x** x x (or hypothermia)
x
Organomegaly splenomegaly splenomegaly
and
hepatomegaly splenomegaly and hepatomegaly
hepatomegaly
(may be driven
by congestion
and thrombosis)
Cytopenias
Anemia x x x x x
Thrombocytopenia x x ≤181 x10^9/mL x x x
Neutropenia x x x x x
Hypertriglyceridemia x ≥132.7 mg/dL >156 mg/dL Unknown
or
hypofibrinogenemia
x ≤250 mg/dL ≤360 mg/dL x x x
Hemophagocytosis
on biopsy
x x x x x Limited evidence
Low/absent NK cell
activity
x Unknown
Hyperferritinemia x ≥2000 ng/mL >684 ng/mL** x x x
Elevated soluble CD25
(soluble IL-2
receptor)
x x x x
Organ system
dysfunction
x x x x
Liver enzyme
elevation
Elevated
AST≥30 IU/
L
AST>48 IU/L AST/ALT elevated AST/ALT
elevated
AST/ALT elevated
Other evidence of
organ system
dysfunction
Acute kidney injury not attributable to
other cause; respiratory failure; altered
mental status; hypotension and potential
cardiac failure; coagulopathy.
Similar to
CRS, HLH,
MAS
Similar to CRS, HLH, MAS with
lung-predominant organ
system dysfunction (hypoxemia,
ARDS); prominent
coagulopathy.
Genetic testing
supporting the
diagnosis
Genetic mutations in
PRF1, UNC13D,
STX11, STXBP2
gene, among
others.
Genetic mutations in primary HLH-associated genes (most
commonly PRF1, UNC13D) are found in MAS: at least 1
heterozygous variant is found in 45% of MAS; >1 variant
is identified in a majority of those.
Unknown Unknown Unknown
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1191
course of CRS without compromising efficacy remains an
active area of investigation.
3.3.3. Consideration for the treatment of
hyperinflammatory syndrome secondary to SARS-CoV-2
While considering similarities between hyperinflammation in
CRS and COVID-19, it is also important to appreciate distinctions
in pathophysiology, clinical setting, and treatment goals that
may influence the potential translatability between treatments
and biomarkers for COVID-19-CSS and CRS. CSS in COVID-19
develops after a prolonged period of crosstalk between the
innate and adaptive arms of the immune system in response to
viral dynamics, whereas CRS is triggered by the abrupt infusion
of a large number of activated T cells [89]. In CRS, synthetic
constructs drive signaling pathways that are qualitatively and
quantitatively distinct from signaling driven through natural
TCRs [90]. Lymphodepleting regimens administered prior to
CAR T cell therapy infusion influence cytokine signaling along
with immune cell interactions [91]. Treatment goals and accep-
table downsides also differ between CRS and COVID-19-CSS. For
example, anti-IL-6(R) therapies may not decrease anti-cancer
activity for CAR T therapies but could blunt antiviral innate and
adaptive immunity at a time of active viral replication in the
infected host [92]. Thus, caution should be used in considering
evidence of hyperinflammation in cases of patients with COVID-
19 prior to recommending immunomodulatory therapy.
4. Approaches in the treatment of COVID-19-CSS
There is a paucity of published randomized controlled trials that
can inform the use and timing of immunosuppressive therapy in
patients with severe COVID-19. Clinical trial registries reflect the
large and ever-growing spectrum of approaches hypothesized to
ameliorate COVID-19-CSS. While the ‘compassionate’ off-label
use of some of these medications may be appropriate in critically
ill patients (especially when clinical trials are not available to
treating physicians and supportive care is insufficient), cautious
and judicious use of these drugs is paramount until reliable data
regarding their efficacy from clinical trials becomes available and
their safety in this unique patient population is established. A list
of current prospective clinical trials on immunosuppressive and
immunomodulatory agents in COVID-19 can be found through
a variety of COVID-19 clinical trial trackers [93–96]. Figure 2
summarizes the mechanisms of many of the targeted therapeu-
tic strategies discussed below.
4.1. Biologics
4.1.1. IL-6 pathway inhibition
The observation of systemically elevated IL-6 levels in patients
with severe COVID-19 suggests a potential role for anti-IL-6 or
anti-IL-6 R antibodies in the treatment of COVID-19-ARDS and
CSS. Drawing from immuno-oncology, the success of tocilizu-
mab in managing CAR-T cell-related CRS provides a further
clinical rationale for studying therapeutics modulating the IL-6
axis in COVID-19-CSS [68,70,97]. Candidate agents include
tocilizumab and sarilumab, both of which target the IL-6 R,
and siltuximab, which neutralizes IL-6 directly.
Several studies have reported anti-IL-6/IL-6 R treatment in
COVID-19. The National Clinical Trial (NCT) registry reflects tocili-
zumab’s position as the main IL-6/IL-6 R antagonist under investi-
gation (see www.clinicaltrials.gov), with most trials studying IL-6/
IL-6 R antagonists at dosing approved for CAR-T-associated CRS.
Primary endpoints for these trials range from acute changes in
vital signs and laboratory parameters of uncertain clinical signifi-
cance (e.g. defervescence or reduction in CRP) to ICU length of
stay and mortality measures (e.g. 28-day survival). Tocilizumab was
the first monoclonal antibody of this class reported to be of
potential benefit in severe COVID-19, mirroring its success in
treating CRS associated with CAR-T cell therapy [68,70,98].
Notably, however, a randomized-controlled trial of tocilizumab in
severe COVID-19-associated pneumonia reported no difference in
clinical status or mortality in patients who received tocilizumab
compared to those who received placebo [99]. Another rando-
mized controlled trial of sarilumab in patients with COVID-19
receiving mechanical ventilation also did not reveal a significant
mortality benefit [100]. However, in these studies, treatment was
neither given nor assessed based on the inflammatory state, leav-
ing open the possibility that hyperinflammation could respond to
inhibition of the IL-6 pathway [101]. Moreover, trends toward
potential benefit in more severe disease were noted.
A historically controlled study of 172 patients with COVID-19-
associated hyperinflammation found a benefit in respiratory
status, length of hospital stay, and mortality in patients treated
with tocilizumab and glucocorticoids compared to glucocorti-
coids alone, in addition to low-quality evidence from case series.
The largest published series of 100 tocilizumab-treated patients
with hyperinflammatory syndrome or ARDS related to COVID-19
found an improvement in respiratory status in 77%, though 20%
died despite treatment [102]. Smaller case series of moderately
to critically ill patients have reported similar findings of improve-
ment in respiratory status after one to three doses of tocilizumab
[98,103,104]. Data from another uncontrolled case series of sil-
tuximab in 21 patients with COVID-19-ARDS revealed that 7
(33%) were clinically improved, 9 (43%) had no change in clinical
status, and 5 (24%) had a deterioration in condition after
a median of 8 days of follow-up [105]. A potential disconnect in
effect sizes reported in cases series and uncontrolled studies on
one hand and those observed in placebo-controlled clinical trials
of IL-6 signaling pathway inhibitors on the other is noted.
While some of these preliminary studies show promise in
select populations, care must be taken in critically assessing
measures of clinical response used in these studies. As
a reduction in CRP and other acute-phase reactants is expected
with IL-6/IL-6 R inhibitor therapy, these changes may not reflect
normalization on the target tissue level and cannot be equated
with meaningful clinical improvement. Treatment with anti-IL
-6/IL-6 R therapies in the setting of clinical trials is recom-
mended, especially given the lack of established efficacy of
these agents in severe COVID-19-associated pneumonia.
When such trials are not available, decisions on compassionate
use of these drugs are best made in an interdisciplinary team of
infectious disease physicians, pulmonologists, rheumatologists,
1192 I. AMIGUES ET AL.
hematologists, and other primary team members following
local guidance documents.
4.1.2. IL-1 pathway inhibition
Data examining the use of anakinra in patients with sepsis and
severe organ dysfunction showed some benefit in a subgroup
of patients with sepsis and concurrent features of HLH/MAS
[106]. Based on its safety profile in sepsis and its efficacy in
rHLH/MAS, IL-1 inhibition has been proposed as a treatment of
COVID-19-CSS [59,107,108].
While anakinra and canakinumab are being used off-label
in the treatment of severe COVID-19, we are limited to
observational studies on the safety and efficacy of IL-1 antag-
onism in COVID-CSS. A proof of concept study using anakinra
in nine patients with moderate to severe COVID-19 pneumo-
nia showed improvement in oxygen requirements, markers of
inflammation, and clinical outcomes [109]. Another retrospec-
tive cohort study comparing intravenous (IV) and lower dose
subcutaneous (SC) anakinra to standard of care demonstrated
that IV anakinra slowed systemic inflammation and improved
respiratory function in those with moderate to severe COVID-
19 ARDS in a non-ICU setting, but no evidence of benefit for
SC anakinra in this study [110]. Another larger case–control
study compared outcomes in 52 consecutive hospitalized
Figure 2. Summary of key therapeutic strategies investigated for the prevention or treatment of COVID-19-CSS and ARDS. Model of an inflammatory feed-forward
loop in immune cells (e.g. lung-infiltrating monocytes and macrophages) in response to SARS-CoV-2 infection that results in exuberant cytokine production and
cytokine storm. Drugs currently investigated for the treatment or prevention of severe COVID-19 and their respective targets are shown. Catecholamine and cytokine
feed-forward loops are shown in magenta and green, respectively. ⍺-1 AR: ⍺-1 adrenergic receptor. BTK: Bruton tyrosine kinase. C5: Complement factor 5. IFN:
interferon. IKK: I kappa B kinase. IL: interleukin. IRAK: Interleukin-1 receptor-associated kinase. JAK: Janus kinase. NFκB: Nuclear Factor kappa-light-chain-enhancer of
activated B cells. R: receptor. STAT: signal transducers and activators of transcription. TNF: tumor necrosis factor.
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1193
patients with COVID-19 receiving SC anakinra at a single cen-
ter in France with 44 historical controls who received standard
of care. Anakinra use was associated with significantly lower
risk of admission to the ICU and death (25% vs.73%, HR:0.22;
95% CI 0.11–0.41) [111]. Major limitations of these studies are
the use of historical comparator groups and small cohort sizes.
The effects of IL-1 inhibition on antiviral immunity and
clearance of SARS-CoV-2 are not known, and safety profiles
may vary independent of mechanism of action based on
pharmacokinetics alone, as half-lives are significantly longer
for canakinumab (26 days) and rilonacept (7 days) compared
to anakinra (4–6 hours) [112–114]. The observational studies
above cannot be interpreted for safety outcomes.
Consequently, the results of ongoing clinical trials will be
helpful in evaluating efficacy and safety of IL-1 inhibitors
alone or in combination with other agents compared to stan-
dard of care in COVID-19-CSS (NCT04324021).
4.1.3. Tumor necrosis factor-α inhibition
Anti-TNF-α therapies are widely used in the treatment of auto-
immune diseases including rheumatoid arthritis and inflamma-
tory bowel disease. In these conditions, TNF-α appears to
represent a critical signaling node, and inhibition has proven
effective in a subset of patients despite upregulation of numer-
ous cytokines. Case reports describe effective use of the anti-
TNF-⍺ agent etanercept in MAS, although other case reports
suggest that etanercept can induce or exacerbate MAS [115–-
115–120]. Feldmann et al. has postulated that a single infusion
of an anti-TNF-α agent may be able to reduce lung inflamma-
tion in COVID-19 [121,122]. Registry data from the COVID-19
Global Rheumatology Alliance showed that in 600 patients the
adjusted odds ratio for hospitalization was 0.40 (95% CI 0.19–-
0.81) compared to no disease-modifying anti-rheumatic drug
[123]. Data from the SECURE-Inflammatory Bowel Disease
Registry demonstrated that anti-TNF reduced the adjusted
odds of hospitalization or death 0.60 (95% CI 0.38–0.96), but
not death alone or the composite outcome of ICU, hospitaliza-
tion, or death [124]. However, these registries do not address
COVID-19-associated hyperinflammation. The prospect of using
anti-TNF for the treatment of coronavirus infection has also
been proposed prior to the current SARS-CoV-2 pandemic on
the basis of its potential to reduce severe inflammatory seque-
lae [125]. While they should be interpreted with caution there
are also eight reported cases of COVID-19 being treated with
anti-TNF and showing clinical improvement [126–128]. The
effects of anti-TNF-α therapies on viral replication in SARS-CoV
-2 infection are not known [129]. However, a signal for
improved outcomes from two large registries of patients with
autoimmune disease and COVID-19 is reassuring. Notably,
patients with these conditions are treated with anti-TNF-α
therapies at baseline for their underlying inflammatory disease
(i.e. prior to infection), suggesting that these drugs may have
a role in the prevention of severe COVID-19.
4.1.4. Interferon-γ inhibition
The involvement of IFN-γ in the pathogenesis of the hyperin-
flammatory syndrome is complex and potentially complicated
by its antiviral role. Emapalumab, an interferon-γ neutralizing
antibody, has been approved for the treatment of refractory
HLH. Remarkably, in one case report of refractory HLH in the
setting of multiple viremias, viral clearance was not negatively
impacted [81]. Emapalumab was also used in a series of
patients with rHLH/MAS related to sJIA who had not improved
on high-dose glucocorticoids; patients had improvement in
clinical and laboratory parameters [130]. Potential interference
with antiviral host immune responses may be expected in
early use of anti-INF-γ therapy, and the safety of this approach
needs to be established. Emapulumab is currently being stu-
died along with anakinra in reducing hyperinflammation in
COVID-19 (NCT04324021). However, in light of conflicting data
on levels of IFN-γ in severe COVID-19, emapalumab should not
be used outside of clinical trials and controlled studies are
needed to evaluate its efficacy, optimal timing of administra-
tion, and safety.
4.1.5. GM-CSF inhibition
GM-CSF has pleiotropic and complex roles in homeostasis and
inflammation, leading to varied hypotheses on the effects of
increasing or decreasing GM-CSF signaling as a therapeutic
strategy for COVID-19 [131,132]. The role of GM-CSF in pro-
moting proliferation of pulmonary epithelial cells and main-
tenance of alveolar macrophage function supports the
hypothesis that increasing GM-CSF signaling may be beneficial
in early stages of COVID-19. A trial investigating the adminis-
tration of the recombinant GM-CSF sargramostim is underway.
In contrast, GM-CSF also has roles in inflammatory signaling
cascades, suggesting that inhibition of GM-CSF signaling may
ameliorate COVID-19-CSS. A prospective cohort study of
patients with severe COVID-19 treated with the anti-GM-CSF
receptor antibody mavrilumab found that treatment was asso-
ciated with improved clinical outcomes. Compared to 26
patients in a standard of care control group, 13 patients in
the mavrilumab treatment group had a decreased risk of
death and a shorter time to clinical improvement [133].
Additional trials of mavrilumab for patients with COVID-19
are ongoing, as are trials of the anti-GM-CSF agents gimsilu-
mab, lenzilumab, namilumab, otilimab, and TJM2. Data from
these larger and randomized trials will be necessary to deter-
mine the efficacy of this potentially promising strategy for
COVID-19-CSS.
4.1.6. Complement factor 5 inhibition
Drugs that inhibit the complement pathway can reduce
immune-mediated damage in complementopathies and cer-
tain autoimmune rheumatic diseases [134]. Not surprisingly,
complement pathway activation has been observed to regu-
late inflammatory responses in animal models of SARS-CoV-1
and influenza infection [135,136]. Inhibition of complement C5
has been found to attenuate CSS and inflammatory lung injury
in animal models [136,137]. In addition, reports of microangio-
pathy associated with complement deposition in patients with
COVID-19 suggest a potential pathogenetic role for comple-
ment pathway activation, and role for complement inhibition,
in COVID-19 [49]. A recently developed C3 inhibitor (AMY-101),
the anti-C5 antibody eculizumab, and BDB-001, another C5
antagonist currently in development, have been used in
small case series of one, four, and two patients with severe
COVID-19, respectively, with reported improvement in clinical
1194 I. AMIGUES ET AL.
and laboratory parameters. C5 antagonists are currently being
studied in COVID-19 (NCT04288713, 2020L00003) [138–140].
4.2. Small molecules
4.2.1. Janus kinase (JAK) inhibition
Small molecules that inhibit intracellular signaling through the
JAK/signal transducers and activators of transcription (JAK-
STAT) pathway, including baricitinib, tofacitinib, and ruxoliti-
nib, reduce downstream production of cytokines and thereby
inflammation [141]. Tofacitinib and baricitinib are commonly
used in the treatment of autoimmune disorders and rheumatic
diseases [142]. The JAK1/2 inhibitor ruxolitinib has shown
promise in rHLH [143]. Beyond its effects on JAK-STAT signal-
ing, baricitinib was predicted to have a direct antiviral activity
by interrupting viral entry into cells by interfering with AP2-
associated protein kinase 1 (AAK1) which is involved in recep-
tor-mediated endocytosis [144,145]. How these in-silico predic-
tions translate into clinical practice remains to be determined.
In an exploratory open-label, non-randomized study of
patients with moderate COVID-19 pneumonia, 12 consecutive
patients who received baricitinib plus ritonavir-lopinavir for
two weeks were compared to a prior cohort of 12 consecutive
patients who received ritonavir-lopinavir plus hydroxychloro-
quine. Fever, oxygenation, and CRP significantly improved in
the baricitinib-treated group compared with historical con-
trols, and no escalation of therapy to ICU level care was
required in the former group [146]. Clinical trials examining
the efficacy and safety of JAK inhibitors in COVID-19 are
ongoing (see www.clinicaltrials.gov). Ruxolitinib in addition
to standard of care was evaluated in a small (n = 14) pilot
study; 11/14 patients showed sustained clinical improvement,
and particularly improvement in markers of inflammation,
without significant short term toxicity. A multicenter phase-II
clinical trial has been initiated (NCT04338958). Despite these
promising preliminary data, caution should be used with JAK
inhibitors due to their association with increased risk of throm-
boembolic events, which is of particular concern in patients
with severe COVID-19, in addition to the well-characterized
activity of all JAK inhibitors in suppressing antiviral interferons
[1,147].
4.3. Other approaches
4.3.1. Glucocorticoids
As an immunosuppressive therapy, glucocorticoids could con-
fer a benefit of attenuating hyperinflammation in COVID-19-
CSS patients, though potential benefits must be considered in
light of the risks of broad immunosuppression and other
specific adverse effects. Prior evidence has shown that gluco-
corticoids are not associated with reduced mortality but are
associated with delayed viral clearance in SARS-CoV, MERS-
CoV, and influenza infection, and an analysis in ARDS of any
cause found insufficient evidence to support glucocorticoids
use [148–150]. Retrospective analyses of glucocorticoids use in
COVID-19 patients have reported conflicting results. Some
studies have found associations between glucocorticoids use
and increased risk of mortality or worsened clinical courses
[151–154]. Other studies have suggested that glucocorticoids
use was associated with reduced mortality risk or better clin-
ical courses, and others still have found no association
between glucocorticoids use and outcomes [32,153–160] [-
161–164]. In the COVID-19 Global Rheumatology Alliance phy-
sician-reported registry, chronic use of prednisone dose
≥10 mg/day was associated with higher odds of hospitaliza-
tion [123]. Timing of administration in the disease course,
doses, and patient population characteristics are likely contri-
buting to the contrasting data. In fact, a preliminary analysis of
the controlled, open-label, RECOVERY trial found that in
patients hospitalized with COVID-19, the use of dexametha-
sone (at a dose of 6 mg daily for up to 10 days) resulted in
lower 28-day mortality among those who were receiving oxy-
gen or invasive mechanical ventilation than usual care. For
patients on ventilators, the treatment was shown to reduce
mortality by about one-third, and for patients requiring only
oxygen, mortality was reduced by about one-fifth. Importantly,
this was not observed in patients who did not require oxygen
or respiratory support [163]. Based on this report, the WHO is
currently revising its guidelines which until now indicated that
glucocorticoids should not be routinely given for the treat-
ment of patients with COVID-19 requiring respiratory sup-
port 164].
4.3.2. Colchicine
Colchicine is a nonselective inhibitor of NLRP3 inflammasome
that reduces the production of IL-1β [165]. The NLRP3 inflam-
masome is thought to play a role in the development of ARDS
and acute lung injury and viroporin E, a protein expressed by
SARS-CoV-1, was previously shown to activate the inflamma-
some [165,166 167 168] . In SARS-CoV-2, viroporin E is thought
to play a major role in viral replication. The possibility of
improving vascular inflammation and endothelial dysfunction
has prompted 4 trials studying colchicine use in COVID-19
[168]. Two studies of colchicine use in COVID-19 have been
reported; however, data on patients’ hyperinflammation status
were not reported. In a randomized trial of 105 hospitalized
patients with relatively mild COVID-19 infection, colchicine
was given as a loading dose followed by 1 mg daily. Patients
in the colchicine group had less risk of clinical deterioration
(1.8% vs 14%) and better cumulative event-free 10-day survi-
val rate (97% vs 83%) while there was no difference in CRP or
troponin levels between the groups [169,170]. In the other
series, 122 patients were given 1 mg daily, reduced to 0.5 mg
daily for severe diarrhea (occured in 7.4%); the historical com-
parison standard of care group had 37% mortality while the
colchicine group had 16% mortality [171]. However, 58% of
the colchicine group received dexamethasone, compared to
32% of the historical comparison group. This limited evidence
is not yet sufficient to support use of colchicine in COVID-19-
CSS.
4.3.3. Intravenous immunoglobulin (IVIG)
IVIG therapy can exert immunomodulatory effects to reduce
end-organ damage in autoimmunity and hyperinflammation.
IVIG has been used in attempts to reduce CSS due to HLH,
although there is little evidence for its efficacy [172,173].
A prior case series also suggested a role for IVIG in the treat-
ment of severe SARS and associated cytopenias [174]. Thus far,
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1195
evidence supporting the use of IVIG in severe COVID-19 is
limited to case reports [175,176]. Hyperimmune IVIG and con-
valescent plasma have been pursued as a treatment for
COVID-19 based on prior success in influenza A and small
studies in COVID-19 [176,177]. To date, evidence from con-
trolled trials has been conflicting as to their success in severe
COVID-19, and treatment is not given based on hyperinflam-
mation [178,179]. Due to the current paucity of supporting
evidence and risk of thromboembolic events associated with
IVIG therapy, especially due to reports of hypercoagulability in
severe COVID-19, IVIG, hyperimmune globulin, and convales-
cent plasma remain investigational [1,180].
4.3.4. Plasma exchange
Therapeutic plasma exchange (TPE) has previously been pro-
posed as a rescue therapy in patients with inflammatory condi-
tions in order to remove pathogenic cytokines and other drivers
of inflammation in plasma, and specifically in COVID-19-ARDS
[181]. Use of TPE has been reported in a case series of three
critically ill patients with COVID-19 with subsequent improve-
ment in inflammatory markers; however, one of the three died
from complications of the illness [182]. A larger pilot study
showed laboratory and clinical improvement among 10 patients
with COVID-19-associated ARDS enrolled in a pilot study of TPE
without any documented adverse effects [183]. Another non-
randomized study of 11 critically ill patients treated with TPE in
addition to standard of care showed improved laboratory and
clinical parameters and a possible benefit in 14 and 28 day
mortality compared to patients who did not receive TPE; how-
ever, due to differences in treatments and the low number of
subjects enrolled, these results should not yet be extrapolated to
larger settings without further confirmation [184]. Prior experi-
ence in patients with acute lung injury due to the 2009 pH1N1
influenza A virus showed improvement in hemodynamic status
and PaO2/FiO2 ratio after TPE [185]. Another retrospective obser-
vational study showed improvement in adjunctive use of TPE in
patients with septic shock due to pneumonia [186]. Due to the
limited evidence, TPE should be further investigated regarding
a possible role in treatment of COVID-19-CSS, ideally in rando-
mized clinical trials.
4.3.5. Anticoagulation
Coagulopathy, resulting in both venous thrombosis and
microangiopathy, is a prominent feature in some patients
with severe COVID-19. A prospective study of 150 patients
with COVID-associated ARDS found a high incidence of throm-
boembolic complications (18%) compared to a non-COVID-19-
ARDS cohort (6%); pulmonary embolism was the most com-
mon (16.7%), followed by cerebrovascular ischemic attacks
and deep venous thrombosis [187]. Although the presence
of antiphospholipid antibodies and lupus anticoagulant has
been reported, the significance of these levels, as well as the
nature of this coagulopathic state and its relationship to
hyperinflammation in COVID-19 remains unknown [187,188].
Most studies on anticoagulation in COVID-19 outcomes are
retrospective and reference the use of prophylactic heparin or
low molecular weight heparin; a pilot study of 5 patients with
severe COVID-19 treated with tirofiban and fondaparinux
along with clopidogrel and acetylsalicylic acid had improved
respiratory outcomes; however, control patients were treated
with prophylactic or therapeutic heparin only [189]. Given the
strong association of D-dimer and fibrin split products eleva-
tion with poor prognosis and mortality in COVID-19, the use of
thromboprophylaxis and anticoagulation is currently being
investigated and can be considered in patients at risk and
with a hyperinflammatory phenotypes, though randomized
clinical trials are needed [1,190].
5. Novel approaches in the treatment of
hyperinflammation
5.1. Tyrosine kinase inhibitors
A role for the tyrosine kinase inhibitor dasatinib has been pro-
posed in management of CRS associated with CAR-T cell therapy.
Studies in mice demonstrated that dasatinib can act as an on/off
switch, temporarily halt CAR T cell activity, and protect against
fatal CRS [191,192]. Due to its rapid reversibility and titratable
effect, dasatinib may have a role in interrupting the cascade of
hyperinflammation and associated injury. The short terminal
half-life of dasatinib may mitigate the risk of secondary infection
observed with prolonged immunosuppression. The Bruton’s tyr-
osine kinase (BTK) inhibitor ibrutinib has been hypothesized to
protect against pulmonary injury in COVID-19-infected patients
[193]. A newer BTK inhibitor acalabrutinib may have a role in
interfering with dysregulated BTK-dependent macrophage sig-
naling. In a study of 19 patients with severe COVID-19, treatment
with acalabrutinib was associated with improved oxygenation
and reduced inflammation [194]. Acalabrutinib is being investi-
gated in a randomized, open-label trial compared to standard of
care alone in patients with COVID-19 hospitalized due to respira-
tory complications [195]. Implementation of any of these experi-
mental strategies will require clinical validation.
5.2. Mesenchymal stem cells (MSC)
Novel, experimental approaches for treating hyperinflamma-
tion may be complementary in mechanism to immunomodu-
latory or immunosuppressive drugs. One emerging area of
interest is cellular therapies. Mesenchymal stem cells (MSC)
may reduce immunopathology through complex mechanisms
which include the secretion of anti-inflammatory cytokines
and the promotion of endogenous tissue repair. Although
their efficacy is not yet established in humans, clinical trials
in ARDS have demonstrated that treatment with MSCs is
relatively safe [196]. Early reports of MSCs and MSC-derived
extracellular vesicles in COVID-19 suggest limited toxicity and
a reduction of inflammation [197–199]. Additional trials in the
treatment of COVID-19 are ongoing [200].
6. Approaches in the prevention of
hyperinflammation
6.1. Catecholamine inhibition
Preclinical studies have shown that hyperinflammation in CRS,
lipopolysaccharide-induced cytokine storm, and polymicrobial
sepsis coincides with a surge in catecholamines [201].
1196 I. AMIGUES ET AL.
Catecholamines augment cytokine production in immune
cells, generating a feed-forward loop [201,202]. Prophylactic
inhibition of catecholamine synthesis or blockade of catecho-
lamine signaling with the α-1-adrenergic receptor (⍺
1
-AR)
antagonist prazosin markedly reduced cytokine storm and
mortality in mouse models [201]. These data are consistent
with other studies suggesting that excessive catecholamine
signaling increases cytokine production and immune-
mediated damage, whereas catecholamine antagonism pro-
tects against injuries [203,204]. Doxazosin has been shown to
abrogate catecholamine-induced IL-6 production in PBMCs
from patients with juvenile rheumatoid arthritis [202].
Prazosin is a first-line treatment for scorpion envenomation,
which involves dysregulated inflammation and can progress
to ARDS [205]. In a retrospective study of >400,000 patients
diagnosed with pneumonia or acute respiratory distress, the
risk of requiring mechanical ventilation and death was signifi-
cantly lower if patients were taking an ⍺
1
-AR antagonist prior
to hospitalization [206]. Because prazosin, doxazosin, and
other ⍺
1
-AR antagonists are widely used in the adult popula-
tion and have a well-established safety profile, they may be
uniquely suited for the prevention of severe COVID-19 in
patients who have mild symptoms (rather than treatment of
severe complications once developed). Prospective controlled
clinical trials are currently ongoing to evaluate whether cate-
cholamine antagonism through prophylactic administration of
prazosin can prevent ARDS, cytokine storm, and death in
hospitalized patients with COVID-19 [207,208].
7. Conclusion
Although the first cases of COVID-19 were only reported a few
months ago, the SARS-CoV-2 outbreak is proving to be the
most challenging pandemic of the 21st century. While the
major feature of COVID-19 is that of severe pneumonia lead-
ing to ARDS in some cases, some, but not all, patients with
COVID-19 enter a hyperinflammatory state characterized by
highly elevated D-dimer, elevated CRP, and elevated ferritin.
Development of hyperinflammation corresponds to
a worsening clinical status including oxygen requirements
and respiratory status, multi-organ failure, and too often
death despite maximal supportive care.
Though similar to HLH/MAS in its deleterious activation of
proinflammatory pathways and exuberant production of cyto-
kines and associated morbidity and mortality, the hyperinflam-
matory state associated with SARS-CoV-2 infection has
a unique fingerprint. For example, organomegaly, elevated
LDH, or triglyceride levels are not a prominent feature.
D-dimer can, on the other hand, be extremely elevated, and
is probably a reflection of the hypercoagulable state and
microthrombi that commonly complicate severe COVID-19
and is observed in autopsy studies. Targeting this immune
dysregulation with the goal of preventing the development
of ARDS and multi-organ failure holds some promise as
a potential therapeutic pathway. However, caution must be
used as immunomodulatory therapy may blunt beneficial host
innate and adaptive responses during active viral replication.
While the ‘compassionate’ off-label use of some of these
medications may be appropriate in critically ill patients
(especially when clinical trials are not available to treating
physicians and supportive care is insufficient), cautious and
judicious use of these drugs is paramount until reliable data
regarding efficacy from clinical trials become available and
their safety in this unique patient population is established.
This is even more important at a time where clinical trial
results are commonly reported in pre-print or in the form of
preliminary press releases, making it difficult to scrutinize the
primary data.
8. Expert opinion
Increasing evidence suggests that poor outcomes in COVID-
19 are associated with a hyperinflammatory state (often
termed ‘cytokine storm syndrome’), typically occurring at
least a week following initial infection and characterized by
marked elevation in inflammatory markers and pro-
inflammatory cytokines. This is consistent with experimental
models of delayed hyperinflammation in SARS-CoV-1 infec-
tion and suggest that dysregulated host response to SARS-
CoV-2 are responsible for much of the detrimental immuno-
pathology in this phase of the disease, including localized and
systemic macrophage activation which drive worsening oxy-
genation and an ARDS phenotype. While these features
resemble other hyperinflammatory states such as HLH, they
are not uniformly similar: organomegaly is not a prominent
feature of severe COVID-19, LDH, triglycerides, and liver
enzymes are only modestly elevated, and cytopenias, most
prominently lymphopenia and to a lesser extent thrombocy-
topenia, are frequently observed.
It is not fully clear how this hyperinflammatory phase
relates to SARS-CoV-2 viral loads in an absolute sense, but
the use of treatments to suppress the host response may be
helpful in controlling excessive inflammation and reducing
organ dysfunction in individual patients. As with other hyper-
inflammatory states, including MAS, rHLH, and viral-induced
HLH, cytokine inhibitors have been used in management.
Emerging data from the inflammatory bowel disease and
rheumatology patient registries suggest that those taking
immunosuppressive agents are not at dramatically increased
risk of severe COVID-19 infection, and raises the possibility
that some patients may have milder disease due to baseline
suppression of specific inflammatory pathways.
Immunomodulatory and immunosuppressive drugs used in
these conditions could thus act to dampen the abnormal
host response to SARS-CoV-2 although optimal timing in rela-
tion to viral replication remains uncertain [123,209–212].
To date, no blinded, placebo-controlled data have been
published, but there are anecdotal reports suggesting efficacy
of inhibitors of the IL-6 and IL-1 signaling axes. Randomized
controlled trials of these and other immunomodulatory drugs
discussed above are ongoing, both individually in pharmaceu-
tical industry-sponsored studies as well as in multi-arm adap-
tive platform studies. The latter may provide head-to-head
data and allow comparison of the efficacy of these agents.
Given the pandemic nature of COVID-19, it is essential that
inexpensive, widely accessible, and ideally oral agents are
explored fully in addition to the more costly inhibitors of IL-
1, IL-6, JAK signaling, or complement activation. While the
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1197
short-term safety of IL-1 inhibitors in COVID-19 has been
demonstrated in small case series, the safety of other immu-
nosuppressive agents including IL-6 and JAK inhibitors is yet
to be demonstrated [110,213]. Long-term follow-up of trial
cohorts and matched controls will be important to delineate
the natural history of the infection and its sequelae. Data from
these trials could help cement the role of cytokine inhibitors in
other hyperinflammatory states, such as rHLH and MAS, where
trial data has been largely lacking.
Immunomodulatory agents have long been posited to
transform outcomes in other infections. Studies in sepsis
have been disappointing; however, induced hyperinflamma-
tory states, such as CRS, can be rapidly and effectively treated
with targeted cytokine inhibition, suggesting that timing of
immunomodulation is crucial. Trials in COVID-19 currently
focusing on immunomodulation have been treating patients
with advanced and severe illness in critical care environments
(generally late in the disease course), where organ dysfunction
of the lungs and other organ systems is established. However,
the reports of macro- and microvascular thrombosis causing
or aggravating end-organ damage suggests that, in the case
of inflammation leading to endothelial dysfunction, immuno-
modulation at this stage may be too late. Use of early immu-
nomodulatory treatment strategies – in combination with
antiviral therapy – is important to consider, but in the absence
of clinical data remains experimental and may blunt the host
antiviral response.
Trials not just of efficacy but of the timing of intervention
with immunomodulatory therapy are essential and may
inform not just the treatment of COVID-19 but also other
forms of hyperinflammation. While ongoing investigative
efforts have primarily focused on identifying effective thera-
pies for patients who developed severe COVID-19, an empha-
sis on prioritizing outpatient clinical trials of preventative
treatment approaches that are safe and scalable to the popu-
lation level is overdue and critically needed.
Declaration of interest
I. Amigues reports personal fees from Abbvie unrelated to this manu-
script. A. Kim was supported by grants from NIH/NIAMS and
Rheumatology Research Foundation, and personal fees from Exagen
Diagnostics, Inc. and GlaxoSmithKline, unrelated to this manuscript.
A. Patel reports personal fees from Abbvie, Celgene and Eli Lilly unre-
lated to this manuscript. M. Konig was supported by the National
Institute of Arthritis and Musculoskeletal and Skin Diseases of the
National Institutes of Health under Award no. T32AR048522, and
received personal fees from Bristol-Myers Squibb and Celltrion, unre-
lated to this manuscript. P. Robinson reports personal fees from Abbvie,
Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Roche and UCB, research grants
from Janssen, Novartis, Pfizer and UCB, and non-financial support from
BMS, all unrelated to this manuscript. The authors have no other rele-
vant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Author contribution
I Amigues and AH Pearlman contributed equally.
Acknowledgments
The views expressed here are those of the authors and participating
members of the COVID-19 Global Rheumatology Alliance, and do not
necessarily represent the views of the American College of
Rheumatology, the European League Against Rheumatism, or any other
organization.
Funding
This paper was not funded.
ORCID
Philip C. Robinson http://orcid.org/0000-0002-3156-3418
Alfred Hj Kim http://orcid.org/0000-0003-4074-0516
Maximilian Konig http://orcid.org/0000-0001-5045-5255
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