key: cord-326805-c5co9cfq authors: Lin, Shi-hui; Zhao, Yi-si; Zhou, Dai-xing; Zhou, Fa-chun; Xu, Fang title: Coronavirus Disease 2019 (COVID-19): Cytokine Storms, Hyper-Inflammatory Phenotypes, and Acute Respiratory Distress Syndrome date: 2020-06-29 journal: Genes Dis DOI: 10.1016/j.gendis.2020.06.009 sha: doc_id: 326805 cord_uid: c5co9cfq Abstract Coronavirus Disease 2019 (COVID-19) was first identified in China at the end of 2019. Acute respiratory distress syndrome (ARDS) represents the most common and serious complication of COVID-19. Cytokine storms are a pathophysiological feature of COVID-19 and play an important role in distinguishing hyper-inflammatory subphenotypes of ARDS. Accordingly, in this review, we focus on hyper-inflammatory host responses in ARDS that play a critical role in the differentiated development of COVID-19. Furthermore, we discuss inflammation-related indicators that have the potential to identify hyper-inflammatory subphenotypes of COVID-19, especially for those with a high risk of ARDS. Finally, we explore the possibility of improving the quality of monitoring and treatment of COVID-19 patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper- and hypo-inflammatory subphenotypes of COVID-19. However, there is currently little clinical data available in regard to evidence for cytokine storms 31 in COVID-19. The expression levels of interleukin-2 receptor (IL-2R) and IL-6 in the sera of 32 critical care cases were found to be significantly higher (P < 0•05) than those of severe cases of 33 In contrast, there were no statistically significant differences in serum tumor 34 necrosis factor alpha (TNF-α, IL-1, IL-8, or IL-10 between these two groups (P > 0•05). [26] 35 However, following initially high expression of Th1 cytokines (e.g., interleukin (IL)-1β, interferon 1 (IFN)-γ, interferon-inducible protein 10 (IP10), and monocyte chemoattractant protein-1 (MCP1) 2 Th2 cytokines (e.g., IL-4 and IL-10) may subsequently suppress inflammation during SARS-CoV-2 3 infection. [12, 27] Furthermore, other observational COVID-19 studies have suggested that cytokine 4 storms (comprised of IL-1β, IL-1RA, IL-7, and IL-8) may be associated with disease severity.[7, 12, 5 28] For example, higher concentrations of granulocyte colony-stimulating factor (GCSF), IP10, 6 MCP1, MIP1A, and TNF-α were found in patients who required admission into an intensive care 7 unit (ICU). [12, 27] Taken together, we posit that cytokine storms may be associated with the 8 severity of COVID-19. However, it is not feasible to conduct a prospective study of COVID-19 at 9 present, and current evidence for cytokine storms in COVID-19 has been derived from small 10 sample sizes. It is also important to consider that patients at different phases of inflammation when 11 corresponding samples are collected will likely also contribute to increased variability of cytokine 12 storm metrics. However, the close relationship between cytokine storms and ARDS strongly 13 suggests that excessive and maladaptive cytokine release contributes to the unfavorable initiation, 14 strengthening, and promotion of ARDS in COVID-19. 15 Some other biological indicators are also closely related to hyper-inflammatory subphenotypes 28 of ARDS. As a novel indicator of inflammation, endocan is a promising biomarker to predict 29 disease severity and mortality in patients with ARDS. [48] A decrease in the plasmatic endocan 30 cleavage ratio (ECR) is associated with hyper-inflammatory phenotypes of ARDS. Also, a change 31 in ECR < -4•5% is the optimal cutoff value for the diagnosis of a hyper-inflammatory subphenotype 32 (sensitivity of 0•86; specificity of 0•82). [49] Early vascular injury and disrupted alveolar-capillary 33 barrier integrity can also reflect differences in subtypes of inflammatory responses. Early-onset 34 ARDS is associated with higher levels of the biomarkers sRAGE and Ang-2. [42] Subphenotypes 35 with higher Ang-2 levels, which are characterized by higher inflammatory biomarkers and 1 hypotension, may reflect more endothelial permeability and predilection for extravascular fluid 2 accumulation that responds favorably to fluid restriction. [37] However, uncertainty remains 3 regarding how diverse initial environmental injuries result in a sequence of events culminating in 4 the clinical syndrome of ARDS, involving various molecular pathways along with a general 5 imbalance between injurious and reparative mechanisms. Classification of patients with ARDS into 6 hyper-and hypo-inflammatory subphenotypes using plasma biomarkers may facilitate more 7 effective targeted therapies. [30] Therefore, further elucidation of phenotypes and identifying 8 treatable traits represent the future of personalized medicine for ARDS. 9 In COVID-19, there is also suggestive evidence of hyper-inflammatory subphenotypes of ARDS. Clinical evidence helps to progress patient-level and population-level decision making. 26 Therefore, we need to build upon prior experience and identify similarities versus differences 27 among COVID-19 patients. [53] From the evidence that we were able to retrieve, we found that 28 During the time from the onset of symptoms to MV, which was reported to be 10•5 days (7•0-14•0 19 days),[12] if patient was identified as having a hyper-inflammatory subphenotype of COVID-19 20 and given targeted therapy, this approach would be expected to ameliorate the probability of the 21 patient progressing to a severe or critical condition. Therefore, the key treatment for ARDS, a key 22 factor in COVID-19 deterioration, is closely related to the identification and monitoring of hyper-23 inflammatory subphenotypes. 24 It is difficult to distinguish the hyper/hypo inflammatory subphenotypes of COVID-19 since 27 there is currently little data on this phenomenon. C-reactive protein (CRP) levels of most patients 28 are above the normal range.[9, 24] Additionally, hypersensitive CRP (hs-CRP) has also been found 29 to be increased. The authors declare that there are no competing interests regarding the publication of this paper. 20 Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Pulmonary pathology of early phase 2019 1 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. Journal of 2 thoracic oncology : official publication of the International Association for the Study of Lung 3 Cancer COVID-19): A critical care perspective beyond China 8 Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of 9 Ang 11 LW, Mak TM et al: Epidemiologic Features and Clinical Course of Patients Infected With 12 SARS-CoV-2 in Singapore 14 investigators C: High-flow nasal therapy in adults with severe acute respiratory infection: 15 a cohort study in patients with 2009 influenza A/H1N1v Lung injury prediction scores: Clinical 20 validation and C-reactive protein involvement in high risk patients Lung endothelial cell antigen cross-24 presentation to CD8(+)T cells drives malaria-associated lung injury 27 The emergence of pathogenic TNF/iNOS producing dendritic cells (Tip-DCs) in a malaria 28 model of acute respiratory distress syndrome (ARDS) is dependent on CCR4. Mucosal 29 immunology Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. Critical 32 care Angiotensin-converting enzyme 2 in lung diseases. Current 34 opinion in pharmacology Clinical 36 and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung 37 injury Circulating IL-1ra and 42 IL-10 levels are increased but do not predict the development of acute respiratory distress 43 syndrome in at-risk patients Clinical findings in a group of patients infected with the 2019 novel coronavirus 47 (SARS-Cov-2) outside of Wuhan, China: retrospective case series Corticosteroid therapy in patients with primary viral 50 pneumonia due to pandemic (H1N1) 2009 influenza. The Journal of infection Corticosteroid Therapy for Critically Ill Patients with 2 Middle East Respiratory Syndrome On the use of corticosteroids for 2019-nCoV 5 pneumonia Dexamethasone treatment for the acute respiratory distress 8 syndrome: a multicentre, randomised controlled trial. The Lancet Respiratory medicine Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care 13 medicine = Zhongguo weizhongbing jijiuyixue Efficacy of Xuebijing Injection () on Cardiopulmonary Bypass-15 Associated Pulmonary Injury: A Prospective, Single-center, Randomized, Double Blinded 16 Trial Remdesivir 18 and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) 19 in vitro Cytokine release syndrome: Who is at risk and how to treat. Best practice & 21 research Clinical haematology Effects of Human Interleukin-10 on Ventilator-Associated 23 Lung Injury in Rats. Inflammation Influenza and SARS-coronavirus 25 activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory 26 and gastrointestinal tracts CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven 29