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1. Introduction

In December 2019, a novel coronavirus was isolated from a group of patients hospitalized with pneumonia, who had connections with a seafood and wildlife market in Wuhan, in the Hubei province of China [1]. The virus was named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV2). The term “Coronavirus disease-19” (COVID-19) was coined by the World Health Organization (WHO) in February 2020 to refer to the related syndrome caused by the virus [2]. The virus is transmitted through droplets and aerosols, which are expelled during the respiratory act or when an infected person coughs, sneezes, or speaks. The most typical clinical picture in SARS-CoV-2 is mainly characterized by upper respiratory infection apparently indistinguishable from any other respiratory infection. However, an exacerbation may occur with a clinical picture of pneumonia (mostly bilateral) characterized by marked dyspnea [3], tachypnea (>30 breaths/minute), hypoxemia (SpO2 < 90% in ambient air), and severe lymphopenia with increased acute phase proteins [4], associated with a state of hypercoagulability, an important increase of proinflammatory cytokines interleukin (IL)-2, IL-7, IL-10, G(M)-CSF, IP-10, MCP-1, MIP-1a, TNF, IL-1β, and IL-4 [5]. This uncontrolled pulmonary inflammation is probably one of the main causes of mortality in the severe forms of SARS-CoV-2 infection. Although initially regarded as a ‘cytokine storm’, current evidence does not seem to fully support this classification and this terminology should be used with caution. Cytokine storm syndrome is a relatively ill-define concept, with a number of different triggers and underlying conditions ^[6][7][6,7]. Elevated levels of a broad spectrum of cytokines invited comparisons with other viral infections that lead to dysregulated immune responses, and similarities with other cytokine storm syndromes were proposed [8], such as secondary hemophagocytic lymphohistiocytosis (sHLH) or Macrophage Activation Syndrome (MAS). However, not all severe COVID-19 patients fulfilled sHLH criteria [9], although falling into the umbrella of the phenotype of the hyperferritinemic syndromes. Results from COVID-19 suggest that it may be considered as a unique form of hyperinflammatory response. In this regard, it is important to note that most of the cytokine storm syndromes are relatively rare conditions and derived from non-communicable diseases. Hence, this concept may be difficult to translate to a pandemic-dimensioned infectious disease. Therefore, the idea of the ‘threshold concept’ needs to be considered [10]. Importantly, median IL-6 serum levels are one or two magnitude [11] order lower in COVID-19 compared to fully blown cytokine storm syndromes ^[8][12][8,12], thus supporting that a differential pathogenic scenario is plausible, distinct from the classical cytokine storm framework. However, controversial results have been published elsewhere [6]. Actually, specific criteria have been developed [9] for this condition, hence strengthening the differences observed. Importantly, a mechanism-based rather than clinical context-based taxonomy in cytokine storm is crucial not only for gaining understanding toward pathogenesis but also to better guide the therapy decision-making process [7]. While waiting for the development of specific antiviral therapies, monoclonal neutralizing antibodies and vaccines, which will be able to neutralize the etiological agent, an effective therapeutic strategy could be to counteract the hyperinflammatory status, which is responsible for the most severe clinical cases. In this scenario, the long-lasting experience in rheumatology not only with the use of different immunomodulatory agents but also with disease stratification and complex disease stages’ management could provide valuable therapeutic approaches. In fact, if a timely and effective intervention could be adopted in the moment when the enhanced cytokine release is triggered, the risk for the patient of needing support with invasive mechanical ventilation and developing MAS-like forms would be significantly reduced. However, adaptations from the rheumatology framework are needed in the light of the pathogenic divergences [8]. To date, taking into account published studies, no antiviral or anti-inflammatory treatment has been shown to be clearly effective for SARS-CoV-2 infection and, unfortunately, different studies often show contradictory results. The frenzy to desperately respond to the COVID-19 pandemic prompted a plethora of small-sized, powerless, largely heterogeneous observational trials that have mostly led to inconclusive results on the efficacy of several therapeutic approaches. Too many observational and powerless studies have been conducted and no randomized, double-blind, clinical trials have seen the light. The lack of appropriate control groups, no randomized design, and the different timing of administration of these treatments during infection are the three most important causes that may explain the contradictory findings among studies. Specifically, the critical point in treating the inflammatory phase of COVID-19 is deciding when, how, and to what extent to use anti-inflammatory therapies. Moreover, the results obtained to date may also highlight important differences in immune circuits between COVID-19 and rheumatoid conditions that warrant further research in order to implement efficacious therapeutic regimens.

2. Pathogenesis

SARS-CoV-2 virus, as well as SARS-CoV-1 (coronavirus strain causing an outbreak in 2003), penetrates into the cells through the bond of the spike glycoprotein of the viral envelope with the angiotensin-converting enzyme 2 (ACE2), a receptor on the host cells’ surface [13]. ACE2 is a type I membrane protein expressed on type II pneumocytes, but it can be also found on renal, heart, gastrointestinal, and blood vessel cells [14]. SARS-CoV-2 infection leads to a wide range of pathogenic phenotypes, from asymptomatic individuals to COVID-19, which may exhibit severe clinical manifestations such as ARDS or MAS-like features. MAS causes hyperferritinemia, hepatic dysfunction, and disseminated intravascular coagulation (DIC) [15]. However, not all features of MAS are consistently found in COVID-19, as previously discussed, and COVID-19 seems to be associated with a relatively unique hyperinflammatory profile. Severe COVID-19 manifestations seem to be caused by a dysfunction of the immune system and to an uncontrolled release of several proinflammatory cytokines and chemokines. Furthermore, in patients with more severe clinical manifestations, higher levels of TNF-α, IL-1, IL-10, IL-6, and GM-CSF, among others, have been detected [10] (Figure 1).

Figure 1. SARS-CoV-2-induced cytokine storm, the inflammatory pathway, and mechanisms of actions of the different drugs used to blocks this.

The mechanisms underlying this uncontrolled release of inflammatory cytokines are not entirely clear to date. However, the replication rate of the virus can cause pyroptosis, that is, the inflammatory death of epithelial and endothelial cells, hence triggering the release of proinflammatory cytokines and chemokines [16]. This phenomenon also involves macrophages and lymphocytes and it may be the cause of peripheral lymphopenia in patients with severe COVID-19 [17]. Additionally, profound aberrations in the innate immunity have been described. Type I interferons (IFN-I) control viral replication and engage mediators of the adaptive response. In both SARS-CoV and MERS-CoV, the IFN-I response to the viral infection is either suppressed or profoundly impaired, hence causing an insufficient viral clearance together with a perpetuation of immune aberrations [18]. Moreover, the role of the adaptive immunity in this scenario cannot be entirely explained without considering the involvement of CD4⁺ and CD8⁺ T lymphocytes, since CD8⁺ cytotoxic T-cells (CTL) are able to secrete molecules such as perforine, granzymes, and INF-γ to eradicate the virus from the host cells [19], whereas helper CD4⁺ T lymphocytes (Th) assist CTL and B-cells by producing inflammatory cytokines and causing T-dependent B-cell activation [20].

IL-6 production can be directly induced by SARS-CoV-2, as well as by the stimulation of other cells of the immune system [21]. In fact, it has been proven that in COVID-19 infection, CD4⁺ T-cells are rapidly activated to differentiate into pathogenic Th1 cells, thus generating IFN-g and GM-CSF, among other proinflammatory cytokines. These mediators stimulate, in turn, the activation of monocytes, thereby causing high IL-6 release [22]. The activation of IL-6 is complex and requires the involvement of IL-6, its receptor (IL-6R) that is anchored to the membrane, and the gp130 co-receptor [23]. Nevertheless, many non-immune cells, including stromal and epithelial cells, can induce strong inflammatory responses when IL-6 and its soluble receptor attach to the membrane along with gp130 (trans-signaling), hence amplifying the inflammatory response [24].

IL-1 also plays an important role in both MAS and in COVID-19. IL-1 is a pleiotropic cytokine involved in inflammatory processes, hematopoiesis, and fibrosis [25]. The release of IL-1β depends on the activity of NLRP3 inflammasome, which responds to different noxious stimuli, including viral RNA [26]. Inflammasomes are large, multi-molecular complexes that are present on innate immunity cells, best known for their ability to control the activation of caspase-1, which, in turn, regulates the maturation of IL-1β and IL-18 [26]. It is increasingly evident that NLRP3 recognizes RNA viruses detecting cellular damage or distress induced by viroporins, pore-forming transmembrane proteins encoded by certain RNA viruses [27]. A recent study showed that the E protein of SARS-CoV creates channels that are permeable to Ca²⁺ ions and activates NLRP3 inflammasome [28]. It is likely that the mode of action of SARS-CoV-2 could be similar, hence supporting the elevated IL-1 concentrations observed in severe COVID-19 patients ^{[29][30][31][32]}[29–32]. Moreover, IL-1β and TNF-α promote the response of Th17, by producing IL-17 [33], although their role in COVID-19 immunopathogenesis is still to be clarified.

In conclusion, profound alterations of the immune response in COVID-19 lead to an uncontrolled hyperinflammatory state that represents the main therapeutic target in this stage. Identifying an effective treatment strategy for critically ill patients with severe manifestations by immunomodulatory drugs is encouraged.

3. Clinical Presentation

COVID-19 presents with a wide spectrum of clinical phenotypes, including:

• Asymptomatic: percentages have not been clarified yet;
• Mild: (approx. 81% of the cases) or mild pneumonia [34];
• Severe: (approx. 14%) dyspnea, respiratory rate >30 breaths/minute, oxygen saturation (SpO2) <93%, lung infiltrates >50% in 24–48 h [35]; and
• Critical: (approx. 5%) multiple organ dysfunction [34], respiratory failure, septic shock.

The incubation period is characterized by a stable full blood count or mild leukopenia, increased viral load, and diffusion of the virus to ACE2-expressing tissues ^[4][36][4,36]. According to the WHO, current estimates indicate that SARS-CoV-2 could take between one to 14 days to incubate. Actually, a study from Taiwan showed that the SARS-CoV-2 median incubation period is about five days [6]. These estimates imply that, under conservative assumptions, 101 out of every 10,000 cases will develop symptoms after 14 days of active monitoring or quarantine [6]. The main symptoms in this phase include fever, which may not be very unresponsive to antipyretic drugs in some patients [35], cough, nasal congestion, general discomfort [35], headache, fatigue, myalgia, and conjunctivitis, apparently indistinguishable from any other respiratory infection. More severe signs and symptoms such as dyspnea are absent [35], and the involvement of the gastrointestinal system with diarrhea is rare.

After 7–14 days from the onset of the symptoms, an exacerbation may occur with a clinical picture of pneumonia: marked dyspnea [36], tachypnea (>30 breaths/minute), hypoxemia (SpO2 <90%), and severe lymphopenia with increased acute-phase proteins [5]. This phase is also associated with a state of hypercoagulability with initially normal levels of coagulation factors and D-dimer [36]. There is also an important increase of proinflammatory cytokines, including IL-2, IL-7, IL-10, G(M)-CSF, IP-10, MCP-1, MIP-1a, TNF-α, IL-1β, and IL-4 [25]. Patients with severe COVID-19 can show typical imaging features at the early stages of the disease. Chest CT plays a major role in the screening and early diagnosis of COVID-19 pneumonia ^[37][38][37,38]. A recent imaging study found that all patients had abnormalities in chest CT and most (98%) of them had bilateral involvement. The CT of COVID-19 patients has special characteristics, including (1) single or multiple ground-glass opacity (GGO), which is mainly a subpleural distribution; (2) crazy paving; (3) patchy GGO with segmental pulmonary consolidation; and (4) pulmonary consolidation [38]. Hospitalized patients with severe disease on admission were more likely to have bilateral multiple lobular and subsegmental areas of consolidation, while admitted patients with mild cases were more likely to have bilateral GGO and subsegmental areas of consolidation [38].

Finally, it is known that COVID-19 is not always confined to the respiratory tract and it may also invade the central nervous system through the hematogenous or retrograde neuronal route, inducing neurological symptoms or diseases such as headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, and epilepsy. Peripheral nervous system symptoms (hypogeusia, hyposmia, dysosmia, hypoxia, neuralgia), skeletal–muscular symptoms, dermatologic manifestations, and thrombotic manifestations were also described [39].

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