Table 2.

Cytokines involved in SARS-CoV-2 infection.

Reference	Methodology	Objective	Main Results
Chen et al. [16]	Retrospective study	To describe the epidemiological and clinical features of SARS-CoV-2 pneumonia in patients from Wuhan Jinyintan Hospital	Approximately 50 % of the subjects who developed the disease had been exposed to the Huanan seafood market. It affects men more often, with an average age of 55. Approximately half of the subjects had other comorbidities. The main symptomatology is characterized by fever, cough, shortness of breath, muscle pain among others. CT scan revealed that 75% of patients developed bilateral pneumonia and some cases evolved into acute respiratory distress syndrome (ARDS) or died from multiple organ failure.
Huang et al. [17]	Descriptive study	To describe the epidemiological, clinical, laboratory and radiological characteristics, treatment and outcomes of patients infected with COVID-19 in Wuhan and make a comparison between patients in the intensive care unit (ICU) and those who are not	Infection by SARS-CoV-2 caused clusters of severe respiratory disease and was associated with ICU admission and high mortality. Most of the infected patients were male, with different comorbidities and an average age of 49 years. The disease is mainly manifested by fever, cough, and myalgia or fatigue. Dyspnea occurred in more than 50 % of the patients. Lymphopenia was present in 63 % of the cases. Patients admitted to the ICU were found to have higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
Liu et al. [30]	Descriptive study	To describe the epidemiology, clinical features, possible treatments and prognosis of patients infected with SARS-CoV-2 in Hubei	The initial manifestations of SARS-CoV-2 were fever, cough and muscle pain or fatigue. Most patients had a normal or decreased white blood cell count, and 72.3 % had lymphocytopenia. Lung involvement was observed in all cases. Treatment was based on symptom control and respiratory support. Immunoglobulin G was administered to some critically ill patients while systemic corticosteroids showed no significant benefit. The risk of death was related to age, comorbidities and the period between initial symptoms and dyspnea.
Wang et al. [31]	Retrospective study	To describe the Cytokine release syndrome-like (CRSL) that occurs in patients affected by COVID-19 pneumonia and to identify risk factors and possible treatments.	Average age: 58 years old. Gender: men mostly. Extensive pulmonary inflammation and ARDS: 83,3%. Symptoms: fever, hypoxia and shock (28,6%). Laboratory findings: Decrease of CD3, CD4, CD8, NK cells. Increase of IL-6, CD4/CD8 ratio. CRSL: 72, 7%, manifested by: pulmonary inflammation, decrease of CD4, CD8 and NK, increase of IL-6 and dysfunction of non-pulmonary organs. Management: ventilation, anti-inflammatory therapy, mechanical-ventilation
Chen et al. [43]	Literature review	To review the literature on the relationship between COVID-19 and the cytokine storm as well as the possible immutherapic treatments available	The effectiveness of some therapies was demonstrated such as the use of stem cells that inhibit the activation of T-lymphocytes, macrophages and induce their differentiation into regulatory subpopulations of T-cells and anti-inflammatory macrophages, but also inhibit the secretion of IL-1α, TNF-α, IL-6, IL-12, and γ-interferon, controlling the cytokine storm.
Conti et al. [52]	Literature review	To clarify the relationship between IL-1 and IL-6 pro-inflammatory cytokines and lung inflammation. Anti-inflammatory strategies	Infection with COVID-19 causes a release of IL-1β and IL-6 which will lead to lung inflammation, fever and fibrosis. The therapeutic potential of several cytokines, such as IL-37 and 38, capable of inhibiting molecules such as those previously mentioned, has been demonstrated
Mehta et al. [53]	Correspondence	To define the cytokine storm syndrome that occurs in severe COVID-19 states and to identify possible treatments	Cytokine storm syndrome is characterized by increased interleukin (IL)-2, IL-7, IL-6 granulocyte- colony stimulating factor, interferon-γ inducible protein 10, monocyte chemo- attractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosisfactor-α. Immunosuppressors such as tozulimab or anakinra appear to work in states of hyperinflammation as described in severe COVID-19 states
Wan et al. [54]	Observational study	To characterize the state of the immune system and the implications of different cytokines in SARS-CoV-2 patients and to study their relationship with the severity of the process	Lower levels of CD4 + T and CD8 + T and higher levels of IL-6 and Il-10 were observed in the more severe NCPs. These markers may help predict the worsening of mild patients.
Yang et al. [55]	Observational study	To study the different cytokine profiles in patients infected with SARS-CoV-2 and their relationship to the severity of the disease.	A total of 14 cytokines were shown to be elevated in patients with COVID-19, with particularly high levels of IP-10, MCP-3, and IL-1ra in severe patients. These markers were predictors of the evolution of the disease towards more severe and even fatal states.
Liu et al. [56]	Retrospective study	To characterize the cytokine storm that occurs in patients with COVID-19	Patients with COVID 19 have hypercitokinaemia that manifests itself with an elevation of 38 of the 48 cytokines measured. Patients with lung lesions were observed to have an upregulation of M-CSF, IL-10, IFN-2, IL-17, IL-4, IP-10, IL-7, IL-1ra, G-CSF, IL-12, IFN-γ, IL-1, IL-2, HGF, and PDGF-BB. These biomarkers may be useful as predictors of the severity of the pathology.
Qin et al. [57]	Retrospective study	To analyze the expression of different biomarkers, inflammatory cytokines and lymphocyte subsets in patients infected with COVID-19, and to determine their relationship with the severity of the process.	An increase in neutrophil-lymphocyte-ratio and T lymphocytopenia (especially CD4 + T cells) was observed, which was more pronounced in severe patients. Elevated serum levels of TNF-α, IL-1 and IL-6 and IL-8 were also found in severe cases.
Zhang et al. [58]	Literature review	To study the use of anti-inflammatory drugs in the therapeutic approach of patients infected with COVID-19	Treatment with anti-inflammatory drugs may be useful in managing the cytokine storm that develops in critically ill patients. However, possible immunological alterations of the host should be considered before starting therapy and their individual characteristics should also be considered.
Kritas et al. [60]	Literature review	To determine the cytokine potential of various cytokines of the IL-1 family as a new strategy in the management of inflammation	IL-37, which inhibits IL-1, may be considered in the treatment of patients with COVID-19 because of its anti-inflammatory activity that would help control fever and inflammation.
Chen et al. [64]	Retrospective study	To establish and compare cytokine profiles between moderate and severe stages of COVID-19 in patients from Tongji Hospital.	Severe patients more frequently presented dyspnea, lymphopenia and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin and D-dimer, as well as significantly higher levels of IL-2R, IL-6, IL-10 and TNF-α. The numbers of T-lymphocytes, CD4 + T-cells and CD8 + T-cells were decreased in all cases but more markedly in severe patients. Expression of IFN-γ by CD4 + T cells was lower in severe cases
Chen et al. [65]	Retrospective study	To establish the clinical features of COVID-19 and to study the relationship between the cytokine storm detected in serum and the severity of the process in patients from Tongji Hospital.	The main symptoms of 2019-nCoV pneumonia were fever with or without respiratory symptoms and other systemic symptoms. Serum white blood cell counts were normal or decreased, lymphocyte count decreased, hs-CRP increased, procalcitonin normal, LDH increased and albumin decreased. High resolution CT showed single or multiple frosted glass shadows accompanied by septal thickening. Significantly higher levels of interleukin-2 receptor (IL-2R) and IL-6 were found in the most severe patients. No differences in serum TNF-α, IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH levels were found between the groups
Chu et al. [81]	Ex vivo study	To study replication, cell tropism and the route of immune activation by SARS-CoV-2 in human lung tissues	SARS-CoV-2 infected and replicated in human lung tissues more efficiently than SARS-CoV. In lung tissue, SARS-CoV-2 infected type I and II pneumocytes and alveolar macrophages but did not stimulate production of type I, II, or III interferons and only increased expression of IL6, MCP1, CXCL1, CXCL5, and IP10
Diao et al. [82]	Retrospective study	To analyze figures and markers of T-cell exhaustion in patients with COVID-19	A marked reduction in the overall T-cell count was observed in patients with COVID-19. Total T-cell, CD8 + T-cell, or CD4 + T-cell counts below 800/μL, 300/μL, or 400/μL are negatively correlated with patient survival and serum levels of IL-6, IL-10, and TNF-α. In addition, it was observed that PD-1 (a marker of T-cell exhaustion) is higher in patients with COVID 19 and that its expression is related to the severity of the process.
Dong et al. [83]	Retrospective study	Study the possible vertical transmission of the SARS-CoV-2	A newborn presented IgM antibody to SARS-CoV-2 as well as cytokine alterations although he was negative for RT-PCRs
Pedersen & Ho [86]	Literature review	To describe the cytokine storm that occurs in severe SARS-Cov-2 infected patients	Increased levels of IL-6, IL-10 and TNF-α, lymphopenia (in CD4+ and CD8 + T cells) and decreased expression of IFN-γ in CD4 + T cells in severe patients were evidenced.
Ruan et al. [87]	Retrospective study	To establish predictors of mortality in patients infected with COVID-19	Predictors of mortality in patients infected with SARS-Cov-2 include age, presence of comorbidities, presence of secondary infection, and elevated inflammatory markers in the blood such as lymphocytes, platelets, albumin, total bilirubin, blood urea nitrogen, blood creatinine, myoglobin, cardiac troponin, C-reactive protein (CRP), and interleukin-6
Sun et al. [88]	Retrospective study	To describe epidemiological and clinical features, imaging and laboratory data, clinical treatments and outcomes of severely or critically ill pediatric patients infected with COVID-19 in Wuhan.	Most of the subjects were males between the ages of 2 months and 15 years. The main manifestations included polypnea, fever and cough. Patch-like shadows and ground glass opacity were observed in most patients on chest CT scans. The analyses showed an increase in C-reactive protein, procalcitonin and lactate dehydrogenase, CD3, CD4, CD8, IL-6, IL-10 and IFN-γ and a decrease in CD16 + CD56 and Th/Ts. Treatment was based on symptom control and respiratory support. Two subjects required invasive mechanical ventilation.
Wu et al. [90]	Retrospective cohort study	To describe the clinical features and outcomes in patients with ARDS or who died from COVID-19 Pneumonia	Average age: 51 years old. Gender: men mostly. Background: Hypertension and diabetes. ARDS: 41.8 % manifested by dyspnea. Death: 52.4 %. Risk factors for ARDS and death: age, neutrophilia, organ dysfunction and coagulation, high fever (for ARDS). Treatment: Among patients with ARDS, methylprednisolone
Chen et al. [91]	Retrospective study	To analyze the relationships between the incidence of RNAaemia and the cytokine storm as well as the severity of the disease	There seems to be a relationship between RNAaemia and the severity of the patient's condition, as well as with IL-6 levels, which is particularly high in this group of subjects and may act as a therapeutic target for the management of critically ill patients.
Zhou et al. [92]	Retrospective multicenter study	To describe risk factors for mortality anD clinical course of illness in patients infected with COVID-19 in Wuhan.	Survival: 137/191 subjects. Background: hypertension, diabetes and coronary heart disease. Mortality risk factors: advanced age, high scores on the Sequential Assessment of Organ Failure scale and d-dimer greater than 1 μg/mL on admission. Time of virus excretion: 20 days in survivors although in the deceased it was detectable until death.
Zhou et al. [93]	Retrospective study	To analyze blood samples from patients with SARS-CoV-2 severe pneumonia in order to identify their immune characteristics.	COVID-19 disease leads the activation of CD4+ T cells and generate GM-CSF, among others. The infection generates the secretion of several cytokines that induce inflammatory CD14+ and CD16+ monocytes with the consequent increase of IL-6 expression and the acceleration of inflammatory process.
Akhmerov & Marban [94]	Literature review	To describe the impact of COVID-19 at the cardiovascular level	The mechanisms linking cardiac involvement and SARS-CoV-2 appear to be related to respiratory failure and hypoxemia, direct myocardial infection by the virus, indirect injury by the systemic inflammatory response, or a combination of all three. COVID-19 has been associated with myocarditis, blood pressure abnormalities and arrhythmias, acute coronary syndromes and acute myocardial infarction.
Saghazadeh & Rezaei [131]	Literature review	To describe the epidemiological and immunological features of COVID-19	COVID-19 mainly affects men. One of the main risk factors for infection and death is old age. 30 % of patients affected by COVID-19 had previous pathologies such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer. All these factors condition the transmission of the virus. The first and last alteration caused by SARS-CoV-2 is a lung lesion accompanied by the pro-inflammatory cytokine storm.
Rio & Malani [169]	Viewpoint	To describe the most relevant features of COVID-19	R0: 2.68. Compared to SARS-CoV and MERS, SARS-CoV-2 has a higher infectivity and lower-case fatality rate. Incubation period: between 5.2 days to 14 days. Clinical features: fever, dry cough, difficulty in breathing. Other symptoms are myalgia, headache, sore throat and diarrhoea. Average age: 49–56 years. Severity: most of the cases are mild, all patients admitted to the hospital have pneumonia with infiltrates on chest X-ray and ground glass opacities on chest CT scan. Evolution: ARDS and ICU admission. Treatment: symptomatic and respiratory support
Lin et al. [185]	Literature review	To clarify the pathogenesis of SARS-CoV-2 and compare it with other infections caused by coronavirus	The virus enters the body through the nasal and pharyngeal mucous membranes and reaches the lung parenchyma where it can be incorporated into the circulation causing viremia. Once in the bloodstream it can affect organs that express ACE2. The period from the first symptoms to ARDS is approximately 8 days. At this point a second, much more aggressive stage of the infection begins. In infected patients, lymphopenia and an increase in pro-inflammatory cytokines are detected.
Xiong et al. [186]	Retrospective study	To study transcriptional changes in bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) specimens from COVID-19 patients	An association was observed between the pathogenesis of COVID-19 and the excessive release of cytokines such as CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A and CCL4/MIP1B. In addition, it was postulated that the ability of the virus to activate apoptosis and the P53 signaling pathway in lymphocytes may be the cause of lymphopenia in patients.