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When Does the Cytokine Storm Begin in COVID-19 Patients? a Quick Score to Recognize It

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When Does the Cytokine Storm Begin in COVID-19 Patients? a Quick Score to Recognize It Journal of Clinical Medicine Article When Does the Cytokine Storm Begin in COVID-19 Patients? A Quick Score to Recognize It Stefano Cappanera 1,* , Michele Palumbo 1, Sherman H. Kwan 2, Giulia Priante 1, Lucia Assunta Martella 1, Lavinia Maria Saraca 1, Francesco Sicari 1, Carlo Vernelli 1, Cinzia Di Giuli 1, Paolo Andreani 3, Alessandro Mariottini 3, Marsilio Francucci 4, Emanuela Sensi 5, Monya Costantini 6, Paolo Bruzzone 7 , Vito D’Andrea 8 , Sara Gioia 9, Roberto Cirocchi 10 and Beatrice Tiri 1 1 Clinical Infectious Disease, Department of medicine, St. Maria Hospital, 05100 Terni, Italy; [email protected] (M.P.); [email protected] (G.P.); [email protected] (L.A.M.); [email protected] (L.M.S.); [email protected] (F.S.); [email protected] (C.V.); [email protected] (C.D.G.); [email protected] (B.T.) 2 Department of General Surgery, Royal Perth Hospital, Perth 6000, Australia; [email protected] 3 Hematology and Microbiology Laboratory, St. Maria Hospital, 05100 Terni, Italy; [email protected] (P.A.); [email protected] (A.M.) 4 Department of General and Oncologic Surgery, St. Maria Hospital, 05100 Terni, Italy; [email protected] 5 Department of Critical Care Medicine and Anesthesiology, St. Maria Hospital, 05100 Terni, Italy; [email protected] 6 Pharmacy Unit, St. Maria Hospital, 05100 Terni, Italy; [email protected] 7 Department of General and Specialist Surgery “Paride Stefanini”, 00185 Rome, Italy; [email protected] 8 Department of Surgical Sciences, Sapienza University of Rome, 00161 Rome, Italy; [email protected] 9 Legal Medicine, University of Perugia, 06123 Perugia, Italy; [email protected] 10 Department of General and Oncologic Surgery, University of Perugia, St. Maria Hospital, 05100 Terni, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-074-420-5089 Citation: Cappanera, S.; Palumbo, M.; Kwan, S.H.; Priante, G.; Martella, Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that is respon- L.A.; Saraca, L.M.; Sicari, F.; Vernelli, sible for coronavirus disease 2019 (COVID-19), which has rapidly spread across the world, becoming C.; Di Giuli, C.; Andreani, P.; et al. a pandemic. The “cytokine storm” (CS) in COVID-19 leads to the worst stage of illness, and its timely When Does the Cytokine Storm Begin control through immunomodulators, corticosteroids, and cytokine antagonists may be the key to in COVID-19 Patients? A Quick Score reducing mortality. After reviewing published studies, we proposed a Cytokine Storm Score (CSs) to to Recognize It. J. Clin. Med. 2021, 10, identify patients who were in this hyperinflammation state, and at risk of progression and poorer 297. https://doi.org/10.3390/ outcomes. We retrospectively analyzed 31 patients admitted to Infectious Disease Department in jcm10020297 “St. Maria” Hospital in Terni with confirmed SARS-CoV-2 infections, and analyzed the “CS score” Received: 12 December 2020 (CSs) and the severity of COVID-19. Then we conducted a prospective study of COVID-19 patients Accepted: 13 January 2021 admitted after the definition of the CSscore. This is the first study that proposes and applies a new Published: 15 January 2021 score to quickly identify COVID-19 patients who are in a hyperinflammation stage, to rapidly treat them in order to reduce the risk of intubation. CSs can accurately identify COVID-19 patients in Publisher’s Note: MDPI stays neu- the early stages of a CS, to conduct timely, safe, and effect administration of immunomodulators, tral with regard to jurisdictional clai- corticosteroids, and cytokine antagonists, to prevent progression and reduce mortality. ms in published maps and institutio- nal affiliations. Keywords: COVID-19; cytokine storm; ARDS Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. 1. Introduction This article is an open access article Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged for the distributed under the terms and con- first time in Wuhan, China, in December 2019. The virus is responsible for coronavirus ditions of the Creative Commons At- disease 2019 (COVID-19), which has rapidly spread across the world. The World Health tribution (CC BY) license (https:// Organization (WHO) declared COVID-19 a pandemic in March 2020 [1]. creativecommons.org/licenses/by/ 4.0/). J. Clin. Med. 2021, 10, 297. https://doi.org/10.3390/jcm10020297 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 297 2 of 12 As of August 21, 2020, the WHO reported 22.536.278 confirmed cases of coronavirus disease 2019 (COVID-19) worldwide. Ref. [2] As of August 21, there have been 256,118 con- firmed cases with 35,418 deaths for COVID-19 in Italy [3]. Patients with coronavirus disease 2019 (COVID-19) exhibited a broad spectrum of clinical symptoms. The disease often begins with flu-like symptoms, such as fever, fatigue, dry cough, shortness of breath, headaches, chest tightness, chest pain, and muscle pain. Some patients also present with nausea, vomiting, and diarrhea [4]. Complications during COVID-19 can include severe infections, such as pneumonia and acute respiratory distress syndrome (ARDS); it can also lead to multiple organ dysfunc- tion syndrome (MODS) or even death [5]. Initially recognized as an ARDS disease, it was soon realized that heart, brain, and kidney involvement was also common in COVID-19 [6]. A recent clinical stage proposal categorized COVID-19 as Stage I (mild), Stage II (moderate) with pulmonary involvement without hypoxia (IIa) and with hypoxia (IIb); and Stage III—characterized by ARDS, with a progression, due to a gradual decrease in the virological phase and an increase in the inflammatory one [7]. The cytokine storm (CS) syndrome represents the most feared and serious compli- cation of COVID-19 patients due to an excessive immune response reaction to the virus triggered by inflammatory cell infiltration in the lungs, activation of T-helper 1 reactions, and abundant release of proinflammatory cytokines into the circulation [8]. The CS syn- drome led to MODS and disseminated intravascular coagulation (DIC) and most studies have demonstrated the presence of venous thromboembolism and microthrombi in arteri- oles and venules in COVID-19 patient autopsies [9]. Therefore, some authors suggest that timely control of this CS in its early stage, through immunomodulators, corticosteroids, and cytokine antagonists, is key to reducing the mortality rate of these patients [7]. However, there has yet to be any suggestions or observations on how to recognize when this CS begins. The aim of our study is to report a new smart score that can identify at-risk patients so they may be quickly treated and the progression of COVID-19 may be prevented. 2. Materials and Methods We planned a retrospective analysis of data on COVID-19 patients admitted to the Infectious Disease Department of Terni Hospital, Italy, from March 11 to April 15, 2020. The inclusion criteria applied to participants were: any gender, > or = 18 years old, hospitalized due to clinical/instrumental diagnosis of pneumonia, virological diagnosis of SARS-CoV-2 infection (CFX96 Touch Real-Time PCR Detection System; ®Bio-Rad). Patients were assessed daily and staged according to the three stage criteria by Siddiqi H.K. et al. [8], which was then recorded in patient charts. The staging criteria (by Siddiqi H.K. et al.) organized COVID-19 infections into the following three stages: • Stage I (mild): early infection where the viral response phase is predominant, charac- terized by non-specific symptoms, such as malaise, fever, or cough. • Stage II (moderate): pulmonary involvement without hypoxia (IIa) or with hypoxia (IIb), as defined by shortness of breath or a PaO2/FiO2 ratio ≤ 300. In this stage there were abnormalities on chest imaging. In Stage IIa, the viral response phase is predominant while the inflammation phase is beginning. In Stage IIb, the viral response phase decreases and the host inflammatory response increases. • Stage III (systemic hyperinflammation): the most severe stage of illness manifests as an extra-pulmonary systemic hyperinflammation syndrome characterized by ARDS, shock, and cardiac failure. After careful revision of published studies, we proposed a Cytokine Storm Score (CSs) to identify patients who were in this hyperinflammatory state and at risk of progression and poorer outcomes, such as invasive ventilatory support. (Figure1) J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 12 After careful revision of published studies, we proposed a Cytokine Storm Score (CSs) to identify patients who were in this hyperinflammatory state and at risk of progression and poorer outcomes, such as invasive ventilatory support. (Figure 1) J. Clin. Med. 2021, 10, 297 3 of 12 Figure 1. Cytokine Storm Score (CSs) score identifies coronavirus disease 2019 (COVID-19) patients who are doing a Figurecytokine 1. storm,Cytokine and Storm identifies Score the (CSs) timing score of correctidentifies administration coronavirus ofdisease immunomodulators, 2019 (COVID-19) corticosteroids, patients who andare cytokinedoing a cytokinereceptor storm, antagonists and identifies to prevent the the timing progression of correct of stage administration III COVID-19. of immunomodulators, corticosteroids, and cytokine receptor antagonists to prevent the progression of stage III COVID-19. Lymphopenia was chosen as the first main criterion for this CSs because the dysregu- latedLymphopenia immune response was inchosen COVID-19 as the produces first main an immunecriterion suppressivefor this CSs effect because observed the dysregulatedthrough the reduction immune ofresponse peripheral in CD4COVID-19 T and CD8produces T cells an [10 immune]. Some studiessuppressive suggest effect that observedSARS-CoV-2 through may the be ablereduction to infect of Tperipheral cells directly CD4 [ 11T ,and12]; CD8 however, T cells the [10]. exact Some mechanism studies suggestcausing that lymphopenia SARS-CoV-2 remains may be unknown. able to infect Nonetheless, T cells directly it is associated[11,12]; however, with severity the exact of mechanismCOVID-19.
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