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Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome

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In Coronavirus disease 2019 (COVID-19), the initial viral-replication phase is often followed by a hyperinflammatory reaction in the lungs and other organ systems that leads to acute respiratory distress syndrome (ARDS), the need for mechanical ventilation, and death despite maximal supportive care. As no antiviral treatments have yet proven effective, efforts to prevent progression to the severe stages of COVID-19 without inhibiting antiviral immune responses are desperately needed. We have previously demonstrated that a common, inexpensive, and well-tolerated class of drugs called alpha-1 adrenergic receptor (α 1 -AR) antagonists can prevent hyperinflammation (“cytokine storm”) and death in mice. We here present clinical data that supports the use of α 1 -AR antagonists in the prevention of severe complications of pneumonia, ARDS, and COVID-19.
Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome
Maximilian F. Konig1,2, Mike Powell3, Verena Staedtke4, Ren-Yuan Bai5, David L. Thomas6, Nicole
Fischer7, Sakibul Huq5, Adham M. Khalafallah5, Allison Koenecke8, Ruoxuan Xiong8, Brett Mensh9,
Nickolas Papadopoulos1, Kenneth W. Kinzler1, Bert Vogelstein1, Joshua T. Vogelstein3*, Susan Athey10*,
Shibin Zhou1*, Chetan Bettegowda1,5*
1Ludwig Center, Lustgarten Laboratory, and the Howard Hughes Medical Institute at The Johns Hopkins
Kimmel Cancer Center, Baltimore, MD, USA
2Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Department of Biomedical Engineering, Institute of Computational Medicine, The Johns Hopkins
University, Baltimore, MD, USA
4Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
5Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
6Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, MD,
7The Johns Hopkins University School of Medicine, Baltimore, MD, USA
8Institute for Computational & Mathematical Engineering, Stanford University, Stanford, CA, USA
9Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA and Optimize Science
10Stanford Graduate School of Business, Stanford University, Stanford, CA, USA
*To whom correspondence should be addressed.
In Coronavirus disease 2019 (COVID-19), the initial viral-replication phase is often followed by a
hyperinflammatory reaction in the lungs and other organ systems that leads to acute respiratory distress
syndrome (ARDS), the need for mechanical ventilation, and death despite maximal supportive care. As no
antiviral treatments have yet proven effective, efforts to prevent progression to the severe stages of COVID-
19 without inhibiting antiviral immune responses are desperately needed. We have previously demonstrated
that a common, inexpensive, and well-tolerated class of drugs called alpha-1 adrenergic receptor (1-AR)
antagonists can prevent hyperinflammation (cytokine storm) and death in mice. We here present clinical
data that supports the use of 1-AR antagonists in the prevention of severe complications of pneumonia,
ARDS, and COVID-19.
Dysregulated host immune responses are drivers of mortality in pneumonia and acute respiratory
distress syndrome (ARDS) caused by a wide range of infections. In Coronavirus disease 2019 (COVID-
19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an exuberant local or systemic
immune response in the lung and other sites of viral replication, compromising organ function and leading
to high morbidity and mortality(14).
Emerging evidence suggests that a subset of COVID-19 is characterized by the development of a
cytokine storm syndrome (CSS) that resembles cytokine release syndrome (CRS) in chimeric antigen
receptor (CAR)-T cell therapy(2, 4, 5). Hyperinflammation in COVID-19 is associated with elevation of
pro-inflammatory cytokines including interleukin (IL)-6, IL-2R, IL-8, tumor necrosis factor-α, and
granulocyte-colony stimulating factor(4, 6), similar to the exuberant cytokine production by lung-
infiltrating monocytes/macrophages and pneumocytes observed in SARS-CoV-1 and MERS-CoV
infection(7). Alveolar inflammation and diffuse alveolar damage impair the infected lungs’ local ability to
participate in gas exchange, culminating in ARDS and necessitating mechanical ventilation(8). ARDS is
the main driver of mortality of COVID-19. Thus, preventing the hyperinflammation in COVID-19 is critical
for avoiding this progression.
One potential target is the IL-6 signaling pathway. IL-6 levels diverge profoundly between
survivors and non-survivors in the third week after symptom onset and are predictors of COVID-19 severity
and in-hospital mortality(1, 6, 9). Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, is
currently being investigated for the treatment of patients with COVID-19-CSS(10). Pending data from
randomized controlled trials, retrospective data from 21 patients with severe or critical COVID-19 treated
with tocilizumab suggests that inhibition of the IL-6 signaling axis is highly effective(11). However, given
the cost, immunosuppression, and potential adverse reactions of tocilizumab, this strategy will likely be
restricted to select patients in developed countries.
We have recently shown that CRS observed with bacterial infections, CAR-T cells, and other T
cell-activating therapies is accompanied by a surge in catecholamines(12). Catecholamines enhance
inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying
feed-forward loop in immune cells that requires alpha-1 adrenergic receptor (1-AR) signaling(12).
Prophylactic inhibition of catecholamine synthesis with metyrosine, a tyrosine hydroxylase antagonist,
reduced levels of catecholamines and cytokine responses and resulted in markedly increased survival
following various inflammatory stimuli in mice. Similar protection against a hyperinflammatory stimulus
was observed with the well-tolerated 1-AR antagonist prazosin (but not with beta-adrenergic receptor [β-
AR] antagonists), demonstrating that this class of drugs can also prevent cytokine storm(12).
To date, no controlled trials have examined the potential benefits of 1-AR antagonism for the
prevention of CSS and mitigation of ARDS in human subjects. To investigate a role for 1-AR antagonists
in preventing poor outcomes resulting from pulmonary hyperinflammatory responses, we conducted a
retrospective analysis of two cohorts of 45-64 year-old hospitalized patients from the MarketScan Research
Database (2007-2015). Some of these patients would be expected to be taking 1-AR antagonists for the
treatment of chronic conditions unrelated to ARDS such as benign prostatic hyperplasia or hypertension.
Due to the difficulty of determining from claims data whether individuals were taking their prescribed
medication at any given time, we defined prior use as patients having filled 1-AR antagonist prescription
(doxazosin, prazosin, silodosin, terazosin, or tamsulosin) in the year preceding the event for more than an
aggregate of 180 days. Logistic regression models were used to estimate odds ratios (OR), adjusted odds
ratios (AOR), and confidence intervals (CI) correlating receipt of 1-AR antagonists with two separate
outcome measures: a) progression to requiring invasive mechanical ventilation while in the hospital and b)
further progression to death while ventilated. Models were adjusted for comorbid hypertension, ischemic
heart disease, acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, diabetes
mellitus, and post-traumatic stress disorder identified from health care encounters in the prior year as well
as age and year.
The first cohort consisted of patients identified with International Classification of Diseases (ICD)-
9 code 518.82 (which encompasses acute respiratory failure including ARDS). Of the 13,125 men in this
cohort, we found 655 patients (5.0%) with prior use of 1-AR antagonists. Overall, 15.9% of all patients
received invasive mechanical ventilation and 8.2% both were ventilated and died in the hospital. We found
that patients with prior use of 1-AR antagonists had ~22% lower incidence of invasive mechanical
ventilation compared to non-users (OR=0.75, 95% CI 0.59-0.94, p=0.015; AOR=0.75, 95% CI 0.59-0.95,
p=0.019) (Figure 1 B,C). Perhaps more importantly, those patients had a ~36% lower incidence of both
being ventilated and dying in the hospital (OR=0.63, 95% CI 0.37-1.01, p=0.074; AOR=0.59, 95% CI 0.34-
0.95, p=0.042) (Figure 1 B,D). By contrast, prior use of beta-adrenergic receptor (β-AR) antagonists was
not correlated with either outcome in this cohort (Figure 1 C,D).
The second cohort consisted of patients admitted with pneumonia, identified by the Agency for
Healthcare Research and Quality’s (AHRQ) pneumonia category, which comprises a number of codes from
the ICD-9 and ICD-10, respectively. Of the 108,956 subjects in this cohort, 5,498 patients (5.0%) were
taking 1-AR antagonist. Overall, 8.9% of all patients received invasive mechanical ventilation and 2.1%
both were ventilated and died in the hospital. We found that patients with prior use of 1-AR antagonists
had ~13% lower incidence of invasive mechanical ventilation compared to non-users (OR=0.86, 95% CI
0.78-0.95, p=0.004; AOR=0.83, 95% CI 0.75-0.92, p<0.001) (Figure 1 E,F). Further, those patients had a
~16% lower incidence of both being ventilated and dying in the hospital (OR=0.84, 95% CI 0.68-1.02,
p=0.087; AOR=0.77, 95% CI 0.62-0.94, p=0.014) (Figure 1 E,G). By contrast, prior use of β-AR
antagonists was not correlated with either outcome in this cohort, with or without adjusting (Figure 1 F,G).
All stated results were robust to multiple propensity weighting approaches, including causal forest
variants(13). These findings suggest that 1-AR antagonists may protect from immune-mediated morbidity
and mortality resulting from common lung injury and infection.
Taken together, these results extend preclinical findings to support a clinical rationale for studying
1-AR antagonists in the prophylaxis of severe COVID-19 and states of local and systemic immune
dysregulation. Prazosin is inexpensive and safe, as has been documented by long-term treatment of millions
of patients with benign prostatic hyperplasia, hypertension, and other conditions. However, all drugs can
have unanticipated side effects in different clinical contexts, and the incompletely understood relationship
between hypertension and COVID-19 suggests caution in using any agent that impacts blood pressure(14).
Given the limitations of retrospective studies (such as this one), prospective clinical trials of 1-AR
antagonists in high-risk patients will therefore be required to assess their utility in preventing COVID-19-
CSS. We emphasize that the extensive experience with using prazosin for other indications should prioritize
not obviate rigorous, controlled clinical research rather than indiscriminate off-label use in patients
exposed to or infected with SARS-CoV-2. Such trials could be expeditiously implemented in areas suffering
from high infection rates that are overwhelming hospital capacity. To that end, we are actively pursuing
clinical trials at multiple institutions and will make our protocols available on when
approved by the Johns Hopkins Internal Review Board. We encourage readers to contact us and/or launch
trials based on these or other compelling retrospective analyses coupled with pathophysiological
mechanistic explanations.
Figure 1. (A) A model of the clinical progression of COVID-19 from local infection to systemic
hyperinflammation (cytokine storm”). The timing and relation of hyperinflammation to specific organ
manifestations of severe COVID-19 is an area of uncertainty and investigation. (B-D) Patients from
MarketScan Research Database identified by ICD-9 code 518.82 (approximating the diagnosis of ARDS).
(B) Number and proportion of patients requiring ventilation (left) or progressing to death (right) with vs
without prior use of an 1-AR antagonist. (C, D) Forest plots showing odds ratios and 95% confidence
intervals (error bars) of progression to invasive mechanical ventilation (C) or progression to death while
ventilated (D) with use of 1-AR antagonists and β-AR antagonists (control). (E-G) Same as (B-D) but for
patients identified with pneumonia (AHRQ category code). The results from both (B-D) and (E-G) are
qualitatively similar: 1-AR antagonist users have a significantly reduced likelihood of mechanical
ventilation and death, whereas β-AR antagonists have no meaningful impact. p and p* correspond to p-
values for the unadjusted and adjusted models, respectively.
pneumoniaCOVID-19 eaD - mui-oan
infection inammation hyperinammation
cytokine storm
local systemic
0.0% 16.1%12.5%
α1−AR antagonists
0.0% 8.9%7.8%
α1−AR antagonists
0.0% 3.8%2.4% 0.0% 2.1%1.8%
Pneumonia“Acute Respiratory Distress Syndrome” (CD 
requiring ventilation
to ventilation an eat
requiring ventilation
ventilation an eat
α1AR antagonists
AR antagonists
α1AR antagonists
AR antagonists
s ratio or patients requiring ventilation
s ratio or patients requiring ventilation
p = 0.20
0.6 0.7 0.8 0.9 1.0 1.1 1.2
avors rug isavors rug
s ratio or patients it progression to ventilation an eat
s ratio or patients it progression to ventilation an eat
0.7 0.8 0.9 1.0 1.1
avors rug isavors rug
α1AR antagonists
AR antagonists
α1AR antagonists
AR antagonists
0.6 0.7 0.8 0.9 1.0 1.1 1.2
avors rug isavors rug
0.4 0.6 0.8 1.0 1.2 1.4 1.6
avors rug isavors rug
p = 0.47
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Acknowledgements: We thank Adam Sacarny (Columbia University) for advice in processing and
analyzing health care claims data. Dr. Sacarny was not compensated for his assistance. This study used the
IBM MarketScan Research Databases. Research including data analysis has been partially supported by
funding from Microsoft Research.
Disclosure: In 2017, The Johns Hopkins University (JHU) filed a patent application on the use of various
drugs to prevent cytokine release syndromes, on which V.S., R.B., N.P., B.V., K.W.K., and S.Z. are listed
as inventors. JHU will not assert patent rights from this filing for treatment related to COVID-19.
... It has been reported that α1-AR antagonists help mitigate the cytokine storm and reduce mortality in mice [65]. Additionally, the preprinted results from a recent retrospective clinical group study revealed that α1-AR antagonists could regulate immune responses and prevent COVID-19 patients from developing into severe cases [66]. Based on these results, prazosin (NCT04365257) has been advanced into clinical trials for COVID-19. ...
Full-text available
The coronavirus disease 19 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a rapidly increasing prevalence and has caused significant morbidity/mortality. Despite the availability of many vaccines that can offer widespread immunization, it is also important to reach effective treatment for COVID-19 patients. However, the development of novel drug therapeutics is usually a time-consuming and costly process, and therefore, repositioning drugs that were previously approved for other purposes could have a major impact on the fight against COVID-19. Here, we first identified lung-specific gene regulatory/interaction subnetworks (COVID-19-related genes modules) enriched for COVID-19-associated genes obtained from GWAS and text mining. We then screened the targets of 220 approved drugs from DrugBank, obtained their drug-induced gene expression profiles in the LINCS database, and constructed lung-specific drug-related gene modules. By applying an integrated network-based approach to quantify the interactions of the COVID-19-related gene modules and drug-related gene modules, we prioritized 13 approved drugs (e.g., alitretinoin, clocortolone, terazosin, doconexent, and pergolide) that could potentially be repurposed for the treatment of COVID-19. These findings provide important and timely insights into alternative therapeutic options that should be further explored as COVID-19 continues to spread.
... Indeed, high catecholamine levels interact with proinflammatory cytokines in the progression of capillary leak syndrome and the development of MOF (87). These findings confirm the potential nexus between SS and CS in the development of MOF in patients with severe Covid-19 (88). An experimental study showed that interruption of catecholamine synthesis and release by metyrosine inhibits the development of CS in mice induced by T cell targeting antibodies (89). ...
Full-text available
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. β2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. β-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, β-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of β-blockers in the management of Covid-19.
... Similarly, Koenecke et al. [75] reported 34% relative risk reduction for death or the need to mechanical ventilation with the use of α1-adrenergic antagonists in patients with lower respiratory tract infection. On the same context Konig et al. [76] concluded that α 1 -adrenergic antagonists may protect from ARDS and cytokine storm. ...
Full-text available
Arrhythmia, one of the most common complications of COVID-19, was reported in nearly one-third of diagnosed COVID-19 patients, with higher prevalence rate among ICU admitted patients. The underlying etiology for arrhythmia in these cases are mostly multifactorial as those patients may suffer from one or more of the following predisposing mechanisms; catecholamine surge, hypoxia, myocarditis, cytokine storm, QTc prolongation, electrolyte disturbance, and pro-arrhythmic drugs usage. Obviously, the risk for arrhythmia and the associated lethal outcome would rise dramatically among patients with preexisting cardiac disease such as myocardial ischemia, heart failure, cardiomyopathy, and hereditary arrhythmias. Considering all of these variables, the management strategy of COVID-19 patients should expand from managing a viral infection and related host immune response to include the prevention of predictable causes for arrhythmia. This may necessitate the need to investigate the role of some drugs that modulate the pathway of arrhythmia generation. Of these drugs, we discuss the potential role of adrenergic antagonists, trimetazidine, ranolazine, and the debatable angiotensin converting enzyme inhibitors drugs. We also recommend monitoring the level of: unbound free fatty acids, serum electrolytes, troponin, and QTc (even in the absence of apparent pro-arrhythmic drug use) as these may be the only indicators for patients at risk for arrhythmic complications.
... The SARS-CoV-2 virus binds to angiotensin converting enzyme 2 (ACE2) receptors and cellular entry is facilitated by TMPRSS2 protease [16]. Current therapeutic approaches include a number of agents such as anti-inflammatory agents that block IL-6, steroids, anti-viral agents, convalescent serum and alpha receptor blockers [17][18][19][20][21]. There are ongoing approaches for drug discovery and drug repurposing [22,23]. ...
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COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. In serum-deprived and stimulated cells treated with remdesivir and MEKi we observed correlations between pRB, pERK, and ACE2 expression further supporting role of proliferative state and MAPK pathway in ACE2 Priority Research Paper Oncotarget 4202 regulation. We show elevated cytokines in COVID-19-(+) patient plasma (N = 9) versus control (N = 11). TMPRSS2, inflammatory cytokines G-CSF, M-CSF, IL-1α, IL-6 and MCP-1 are suppressed by MEKi alone or with remdesivir. We observed MEKi stimulation of NK-cell killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. Pseudotyped SARS-CoV-2 virus with a lentiviral core and SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope infected human bronchial epithelial cells, small airway epithelial cells, or lung cancer cells and MEKi suppressed infectivity of the pseudovirus. We show a drug class-effect with MEKi to stimulate NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells. MEKi may attenuate SARS-CoV-2 infection to allow immune responses and antiviral agents to control disease progression.
... Tocilizumab, a well-tolerated blocker of the IL-6 receptor, may have potential to dampen cytokine release syndrome in COVID-19 . Because catecholamines augment the production of IL-6 and other inflammatory cytokines, a-1 adrenergic receptor inhibition (e.g., prazosin) has also been suggested as a candidate that may provide prophylactic benefit against cytokine storm (Konig et al., 2020). ...
Full-text available
With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19. The pathway is consistent with a broad range of observed clinical features and biological markers and captures key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provoke an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in IFN-λ–dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g., FcγRIIA) and downstream signaling pathways (e.g., NF-κB p65 and p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Endothelial barrier degradation and capillary leakage contribute to alveolar cell damage. Inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-α/IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and CRP, high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions. Initial candidate interventions include prophylaxis to augment epithelial defense (e.g., AT1 receptor blockade, type III and type I interferons, melatonin, calcitriol, camostat, and lopinavir) and to reduce viral load (e.g., remdesivir, ivermectin, emetine, Abelson kinase inhibitors, dopamine D2 antagonists, and selective estrogen receptor modulators). Additional interventions focus on tempering inflammatory signaling and injury (e.g., dexamethasone, doxycycline, Ang1-7, estradiol, alpha blockers, and DHA/EPA, pasireotide), as well as inhibitors targeted toward molecular mediators of the maladaptive COVID-19 immune response (e.g., IL-6, TNF-α, IL-17, JAK, and CDK9).
... 1 Given the report of "cytokine storming" in patients with COVID-19, 2 Dr Bettegowda has launched a clinical trial to investigate the efficacy of the α1-adrenergic antagonist prazosin as a prophylactic for patients with COVID-19. 3 First Steps to Pivoting your Research to When discussing their transition to a new field, both panelists felt that critically appraising their own skill set, reflecting on their clinical/scientific observations, and asking, "How does my expertise apply to COVID-19?" were key steps in identifying how best to pivot their research. Once they identified an area to pursue, they described a mindset that facilitated pivoting: a willingness to tackle new problems, embracing a steep learning curve, and a commitment to working with others outside of their traditional field. ...
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Since the advent of the twentieth century, several severe virus outbreaks have occurred—H1N1 (1918), H2N2 (1957), H3N2 (1968), H1N1 (2009) and recently COVID-19 (2019)—all of which have posed serious challenges to public health. Therefore, rapid identification of efficacious antiviral medications is of ongoing paramount importance in combating such outbreaks. Due to the long cycle of drug development, not only in the development of a “safe” medication but also in mandated and extensive (pre)clinical trials before a drug can be safely licensed for use, it is difficult to access effective and safe novel antivirals. This is of particular importance in addressing infectious disease in appropriately short period of time to limit stress to ever more interlinked societal infrastructures; including interruptions to economic activity, supply routes as well as the immediate impact on health care. Screening approved drugs or drug candidates for antiviral activity to address emergent diseases (i.e. repurposing) provides an elegant and effective strategy to circumvent this problem. As such treatments (in the main) have already received approval for their use in humans, many of their limitations and contraindications are well known, although efficacy against new diseases must be shown in appropriate laboratory trials and clinical studies. A clear in this approach in the case of antivirals is the “relative” simplicity and a high degree of conservation of the molecular mechanisms that support viral replication—which improves the chances for a functional antiviral to inhibit replication in a related viral species. However, recent experiences have shown that while repurposing has the potential to identify such cases, great care must be taken to ensure a rigourous scientific underpinning for repurposing proposals. Here, we present a brief explanation of drug repurposing and its approaches, followed by an overview of recent viral outbreaks and associated drug development. We show how drug repurposing and combination approaches have been used in viral infectious diseases, highlighting successful cases. Special emphasis has been placed on the recent COVID-19 outbreak, and its molecular mechanisms and the role repurposing can/has play(ed) in the discovery of a treatment.
After wreaking havoc on a global level with a total of 5,488,825 confirmed cases and 349,095 deaths as of May 2020, severe acute respiratory syndrome coronavirus 2 is truly living up to the expectations of a 21st-century pandemic. Since the major cause of mortality is a respiratory failure from acute respiratory distress syndrome, the only present-day management option is supportive as the transmission relies solely on human-to-human contact. Patients suffering from coronavirus disease 2019 (COVID-19) should be tested for hyper inflammation to screen those for whom immunosuppression can increases chances of survival. As more and more clinical data surfaces, it suggests patients with mild or severe cytokine storms are at greater risk of failing fatally and hence these cytokine storms should be targets for treatment in salvaging COVID-19 patients.
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been a major threat to global public health. In Indonesia, the cases have rapidly increased, and the case fatality rate remains high. With COVID-19, most of the deaths have been caused by acute respiratory distress syndrome and dysregulation of the immune response. A lung biopsy from a patient with COVID-19 showed inflammatory cellular infiltration with diffuse alveolar damage. Massive pulmonary destruction has also been reported as a result of highly increased levels of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, interferon-γ (IFN-γ), induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1). IL-6 is an inflammatory cytokine produced by various cell types, including immune cells and nonleukocytes, such as endothelial cells, fibroblasts, epithelial cells, type II pneumocytes, and certain tumor cells. Several studies have shown that IL-6 contributes to the severity and mortality of COVID-19. In this review, we would like to explore the immune response in COVID-19 and the role of IL-6 in the immunopathogenesis of COVID-19.
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Importance: Currently, there is no unified framework linking disease progression to established viral levels, clinical tests, inflammatory markers, and investigational treatment options. Objective: It may take many weeks or months to establish a standard treatment approach. Given the growing morbidity and mortality with respect to COVID-19, this systemic review presents a treatment approach based on a thorough review of scholarly articles and clinical reports. Our focus is on staged progression, clinical algorithms, and individualized treatment. Evidence Review: We followed the protocol for a quality review article proposed by Heyn et al. (1). A literature search was conducted to find all relevant studies related to COVID-19. The search was conducted between April 1, 2020, and April 13, 2020, using the following electronic databases: PubMed (1809 to present); Google Scholar (1900 to present); MEDLINE (1946 to present), CINAHL (1937 to present); and Embase (1980 to present). The keywords used included COVID-19, 2019-nCov, SARS-CoV-2, SARS-CoV, and MERS-CoV, with terms such as efficacy, seroconversion, microbiology, pathophysiology, viral levels, inflammation, survivability, and treatment and pharmacology. No language restriction was placed on the search. Reference lists were manually scanned for additional studies. Findings: Of the articles found in the literature search, 70 were selected for inclusion in this study (67 cited in the body of the manuscript and 3 additional unique references in the Figures). The articles represent work from China, Japan, Taiwan, Vietnam, Rwanda, Israel, France, the United Kingdom, the Netherlands, Canada, and the United States. Most of the articles were cohort or case studies, but we also drew upon other information, including guidelines from hospitals and clinics instructing their staff on procedures to follow. In addition, we based some decisions on data collected by organizations such as the CDC, FDA, IHME, IDSA, and Worldometer. None of the case studies or cohort studies used a large number of participants. The largest group of participants numbered <500 and some case studies had fewer than 30 patients. However, the review of the literature revealed the need for individualized treatment protocols due to the variability of patient clinical presentation and survivability. A number of factors appear to influence mortality: the stage at which the patient first presented for care, pre-existing health conditions, age, and the viral load the patient carried. Conclusion and Relevance: COVID-19 can be divided into three distinct stages, beginning at the time of infection (Stage I), sometimes progressing to pulmonary involvement (Stage II, with or without hypoxemia), and less frequently to systemic inflammation (Stage III). In addition to modeling the stages of disease progression along with diagnostic testing, we have also created a treatment algorithm that considers age, comorbidities, clinical presentation, and disease progression to suggest drug classes or treatment modalities. This paper presents the first evidence-based recommendations for individualized treatment for COVID-19.
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After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.
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Background: In December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China. Methods: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from January 10 to February 12, 2020, were collected and analyzed. The data of laboratory examinations, including peripheral lymphocyte subsets, were analyzed and compared between severe and non-severe patients. Results: Of the 452 patients with COVID-19 recruited, 286 were diagnosed as severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough and myalgia. Severe cases tend to have lower lymphocytes counts, higher leukocytes counts and neutrophil-lymphocyte-ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most of severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and more hampered in severe cases. Both helper T cells and suppressor T cells in patients with COVID-19 were below normal levels, and lower level of helper T cells in severe group. The percentage of naïve helper T cells increased and memory helper T cells decreased in severe cases. Patients with COVID-19 also have lower level of regulatory T cells, and more obviously damaged in severe cases. Conclusions: The novel coronavirus might mainly act on lymphocytes, especially T lymphocytes. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19.
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Background: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1–5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.
Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/L (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/L could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system. Therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19.