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 Table of Contents  
EDITORIAL
Year : 2020  |  Volume : 15  |  Issue : 2  |  Page : 65-69

Interleukin-6 and other cytokine blockade in COVID-19 hyperinflammation


1 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Paediatric Rheumatology, University Hospitals Bristol NHS Foundation Trust and Translational Health Sciences, University of Bristol, Bristol, UK

Date of Web Publication29-May-2020

Correspondence Address:
Prof. Athimalaipet V Ramanan
Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudline Street, Bristol, BS28 BJ
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_64_20

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How to cite this article:
Gupta L, Agarwal V, Ramanan AV. Interleukin-6 and other cytokine blockade in COVID-19 hyperinflammation. Indian J Rheumatol 2020;15:65-9

How to cite this URL:
Gupta L, Agarwal V, Ramanan AV. Interleukin-6 and other cytokine blockade in COVID-19 hyperinflammation. Indian J Rheumatol [serial online] 2020 [cited 2020 Aug 6];15:65-9. Available from: http://www.indianjrheumatol.com/text.asp?2020/15/2/65/282103



The outbreak of COVID-19 virus, subsequent to initial reports from Wuhan, Hubei Province, in China in December 2019, has rapidly spread across geographic borders to evolve into a pandemic, with estimated crude fatality rates of 3.7%.[1] Thus far, more than 693,224 cases of COVID-19 have been reported in over 177 countries, resulting in more than 33,103 deaths.[2] It is clear that a proportion of patients develop serious complications, including pneumonia, acute respiratory distress syndrome (ARDS), and multiorgan failure.

One of the first reports from Wuhan described consolidation in 40 of the 41 patients, alongside lymphopenia and elevated cytokines (interleukin [IL]-1, granulocyte-colony stimulating factor (GM-CSF), and interferon), with a 15% mortality in this cohort.[3] This led to the speculation of a hyperinflammatory state, with a predilection for elderly males with comorbidities.[4],[5] The median time from the first symptom to dyspnea, hospital admission, and ARDS was 5, 7, and 8 days, respectively.[4] Thus, it seems plausible that a significant minority of patients will get critically ill and in a short span of time. Antiviral therapies and immunomodulators such as hydroxychloroquine are likely to be limited benefit, if any, in this critically ill group. Trials of glucocorticoid usage have been limited, due to past reports of a delayed viral clearance without improving mortality in other similar viral illnesses such as Middle east respiratory virus (MERV).[6]

There are increasing reports that up to three-fourths of the critically ill patients exhibit a picture consistent with a cytokine release syndrome (CRS), with features including unremitting fever, acute lung injury, high IL-6 levels, and multiorgan dysfunction.[1],[7],[8] These patients also exhibited decreased CD4, CD8, and natural killer (NK)-cell numbers, with an increased CD4/CD8 ratio. This led to a hypothesis that the high viral load-induced immune cell activation could initiate a cytokine storm with accelerated acute lung injury. Interestingly, this could be predicted by an early rise in IL-6 levels in the serum, preceding the change in T-helper subsets by a day or two.[7]

Various viral illnesses have been triggered for CRS in the past, and the management strategies have been based on suggested pathogenesis or extrapolated from primary hemophagocytic lymphohistiocytosis (HLH).[9],[10] In a large case series from India, infections were the identified cause in 43% of children with HLH, of which two-thirds were viruses.[11] Likewise, the viral hemorrhagic fever syndromes are also attributed to reactive hemophagocytosis in the bone marrow driven by a viral triggered cytokine storm variously referred to as reactive hemophagocytic syndrome, macrophage activation syndrome, or cytokine storm syndrome.[12] Although the criteria for HLH, such as H-score (https://www.mdcalc.com/hscore-reactive-hemophagocytic-syndrome), can guide a clinician in the intensive care unit (ICU), the utility of these in COVID-19-specific HLH is not completely established.[8] However, as is seen for most other cases of HLH, irrespective of the cause, timely diagnosis can be life-saving. The ideal treatment for COVID-19-induced CRS is still unclear and dependent on evidence from the various randomized studies that are currently ongoing. Until then, drawing parallels from previous successful management of CRS with anticytokine therapies, it is essential to consider evaluating the potential of these therapies. Of these, anti-IL-6 therapy might be a viable option in a country like India, where anti-IL-1 therapies are not available yet. This is similar to the situation in China, where IL-1 inhibitors are not yet widely available.

However, as in the management of other viral illnesses such as influenza, the right timing of drug administration is vital to a good outcome. For instance, the usage of oseltamivir within 6 h of contracting the influenza virus can reduce the symptoms period by 4 days as compared with a 3-day delayed intake, which shortens symptoms by only a day or less.[13] The study by Wejung et al. suggests that an early spike in the serum IL-6 levels could be a critical determinant of the time of intervention. Moreover, serum ferritin levels above 9083 μg/L have previously been shown to be a distinctive predictor of HLH in critically ill patients, with 92.5% sensitivity and 91.9% specificity (area under the curve 0.963), irrespective of the cause.[14] Neutrophil-lymphocyte and platelet-lymphocyte ratios have also been found to offer discriminatory potential between critically ill patients versus those who do not require ICU care.[15],[16] Since the characteristics of patients with COVID-19 who died were in line with the Multilobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension and Age Score in early reports, it might be possible to devise an early warning module with the inclusion of IL-6 and ferritin levels for predicting mortality and instituting a triage protocol for the use of anticytokine therapies.[4]

While recessive null mutations in PRF1, UNC13D, STXBP2, STX11, RAB27A, and LYST, which adversely affect granule processing and cytotoxic T-lymphocytes and NK cells function, are known to be associated with HLH in childhood, there is increasing evidence to suggest that the susceptibility to cytokine storms could be along a continuum of genetic deficiency, with monoallelic, bi-allelic, and polygenic monoallelic defects adding up to increased risk in adulthood.[17],[18] While data on population susceptibility would take a much longer time to emerge than the imminent need, it is noteworthy that peripheral blood markers can potentially substitute for the predictive genetic models.[19] Their utility in the setting of COVID-19 remains to be determined.

Based on early data from China of critically ill patients with high IL-6 levels and a clinical picture in keeping with CRS, trials of IL-6 therapy have been initiated there. [Table 1] lists the ongoing/planned trials of IL-6 inhibition in China, Europe, and the USA as searched on clinical trials.gov on March 29, 2020. Most of these studies are using or plan to use doses of tocilizumab similar to that used in CRS associated with chimeric antigen receptor T-cells therapy.[20],[21]
Table 1: Ongoing trials for management of cytokine storm syndromes in COVID-19 infection

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It is likely that if India does have a trajectory of COVID similar to China, Europe, and the USA, we are likely to see some patients becoming critically ill with high C-reactive protein and features of CRS.

We believe it is vital that IL-6 blocker or other cytokine blockade is done only within the context of a randomized clinical trial registered by the Clinical Trials Registry of India.

Using drugs such as tocilizumab, outside the context of clinical trials without the right safeguards, would be highly inappropriate and also results in not having a clear evidence base, as has been previously reported during the Ebola virus outbreak in 2014.[22] Rapid upscaling of medical facilities while simultaneously testing drugs in randomized controlled trials can be the only way to move ahead in a scientific manner for developing safe and effective treatments for COVID-19. The various emerging reports of sudden cardiac deaths in patients using azithromycin with hydroxychloroquine for COVID-19 (subsequent to few open-label studies), both of which are known to cause the adverse effect of QTc prolongation, are another such example of a medical faux pas.[23],[24] This further led to experts to relook into the first reports of the COVID-19 infections, to learn that the risk of such adverse outcome can potentially be a more significant issue than the primary viral infection.[25]

As India is possibly lagging in the epidemic curve, we may have much to offer in terms of timely intervention in critically ill patients. Intervention in the peri-ventilation phase, when the T-cells engage in massive cytokine release into the peripheral circulation, may prevent endothelial injury and diffuse alveolar damage. This is of particular importance in a setting where the numbers of ventilators are limited, as in India.

We would urge that the clinical community to work closely with clinical epidemiologists and governmental bodies to ensure appropriately designed clinical trials is the only source of access to novel agents such as IL-6 blockers in this pandemic, which would help provide the best evidence in real time to move forward in managing those who are critically ill with COVID-19.



 
  References Top

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Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.  Back to cited text no. 1
    
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Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.  Back to cited text no. 3
    
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Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.  Back to cited text no. 4
    
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Wang Y, Wang L, Saxena R, Wee A, Yang R, Tian Q, et al. Clinicopathological features of He Shou Wu-induced liver injury: This ancient anti-aging therapy is not liver-friendly. Liver Int 2019;39:389-400.  Back to cited text no. 5
    
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Hui DS. Systemic corticosteroid therapy may delay viral clearance in patients with Middle East respiratory syndrome coronavirus infection. Am J Respir Crit Care Med 2018;197:700-1.  Back to cited text no. 6
    
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Wang W, He J, Lie P, Huang L, Wu S, Lin Y, et al. The definition and risks of cytokine release syndrome-like in 11 COVID-19-infected pneumonia critically ill patients: Disease characteristics and retrospective analysis. Medrxiv 2020. https://doi.org/10.1101/2020.02.26.20026989.  Back to cited text no. 7
    
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Cron RQ, Chatham WW. The rheumatologist's role in COVID-19. J Rheumatol 2020: 200334. [doi: 10.3899/jrheum. 200334]  Back to cited text no. 8
    
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Pal P, Giri PP, Ramanan AV. Dengue associated hemophagocytic lymphohistiocytosis: A case series. Indian Pediatr 2014;51:496-7.  Back to cited text no. 9
    
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Chesshyre E, Ramanan AV, Roderick MR. Hemophagocytic lymphohistiocytosis and infections: An update. Pediatr Infect Dis J 2019;38:e54-6.  Back to cited text no. 10
    
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Ramachandran B, Balasubramanian S, Abhishek N, Ravikumar KG, Ramanan AV. Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India. Indian Pediatr 2011;48:31-5.  Back to cited text no. 11
    
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Cron RQ, Behrens EM, Shakoory B, Ramanan AV, Chatham WW. Does viral hemorrhagic fever represent reactive hemophagocytic syndrome? J Rheumatol 2015;42:1078-80.  Back to cited text no. 12
    
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Launes C, García-García JJ, Jordán I, Martínez-Planas A, Selva L, Muñoz-Almagro C. 2009 influenza A H1N1 infections: Delays in starting treatment with oseltamivir were associated with a more severe disease. Pediatr Infect Dis J 2011;30:622-5.  Back to cited text no. 13
    
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Lachmann G, Knaak C, Vorderwülbecke G, Rosée PL, Balzer F, Schenk T, et al. Hyperferritinemia in critically ill patients. Crit Care Med 2020;48:459-65.  Back to cited text no. 14
    
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Qu R, Ling Y, Zhang Y, Wei LY, Chen X, Li XM, et al. Platelet-to-lymphocyte ratio is associated with prognosis in patients with corona virus disease-19. J Med Virol 2020. [doi: 10.1002/jmv. 25767].  Back to cited text no. 15
    
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Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020. doi.org/10.1093/cid/ciaa248.  Back to cited text no. 16
    
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Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol 2001;114:761-9.  Back to cited text no. 17
    
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Meeths M, Bryceson YT. HLH susceptibility: Genetic lesions add up. Blood 2016;127:2051-2.  Back to cited text no. 18
    
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Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection: The perspectives on immune responses. Cell Death Differ 2020. doi: 10.1038/s41418-020-0530-3.  Back to cited text no. 19
    
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Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B Cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra25.  Back to cited text no. 20
    
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Misra DP, Agarwal V, Gasparyan AY, Zimba O. Rheumatologists' perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets. Clin Rheumatol 2020. [In press].  Back to cited text no. 21
    
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Kalil AC. Treating COVID-19–Off-label drug use, compassionate use, and randomised clinical trials during pandemics. JAMA 2020. [doi: 10.1001/jama. 2020.4742].  Back to cited text no. 22
    
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Park A. President Trump Called Hydroxychloroquine a "Game Changer," But Experts Warn against Self-Medicating with the Drug Here's What You Need to Know. Available from: https://time.com/5808894/hydroxychloroquine-coronavirus/.  Back to cited text no. 23
    
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Coronavirus: Some Clinical Trial Data. Available from: https://blogs.sciencemag.org/pipeline/archives/2020/03/19/coronavirus-some-clinical-trial-data.  Back to cited text no. 24
    
25.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus ' cases from the Chinese Center for Disease Control and Prevention. JAMA 2020. doi:10.1001/jama.2020.2648.  Back to cited text no. 25
    



 
 
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