The Cytokine Storm Syndrome: Comparison
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The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a high-risk viral agent involved in the recent pandemic stated worldwide by the World Health Organization. The infection is correlated to a severe systemic and respiratory disease in many cases, which is clinically treated with a multi-drug pharmacological approach. 

  • SARS-CoV-2
  • COVID-19
  • pandemics
  • resveratrol
  • oral mucosa
  • furin
  • cytokine storm syndrome

1. Introduction

1.1. Epidemiological and Demographic Characteristics

1.1. Epidemiological and Demographic Characteristics

Among the most common clinical symptoms of COVID-19, are fever, dyspnea, asthenia, cough, anosmia, and dysgeusia. Additionally, are listed as well as few gastrointestinal symptoms, headache, and sore throat are observed, leading in the most severe cases to acute respiratory distress syndrome with bilateral interstitial acute pneumonia, multiple organ failure, and death [1][2][3][4][5][6][7]. SA studies have showny showed that chilblains, urticaria, and tremors can also behave been reported as associated symptoms of the patient with COVID-19 [8][9][10][11][12][13]. Some isolated cases havwe beenre recorded, such as; there were only three cases in Madrid (two suspected and one confirmed) involvingof herpetic-like vesicular lesions in the oral cavity with pain, desquamative gingivitis, and ulcers [14][15].

The average age of patie2019-ntsCov infected with SARS-CoV-2 patients is 55.5 years, while the average age of for mortality (case fatality rates, CFR) CFR), age is 75 years with rates increasing, and it gets higher in those aged 80 and abovee 80s age group [16]. The number of deaths is higher in the elderly population with comorbidity, which enforces the key role that the immune system plays in the control of persistency of the SARS-CoV-2 virus [16]. Immunt ity tends to decline with age, making the respiratory tract more susceptible to the virus in in os noted that the decay of the immunity is observed in ageing and, therefore, the SARS-CoV-2 virus may get an easier access on the respiratory tract in elder patients. Men are more affected than women (67%), which may be attributed to higher smoking rates among men and a strongeras there are more smokers in the male population and the female immune system response linkhas a better antibody system lined to to the X chromosome in women [7][17][18][19][20][21][22][23][24][25][26][27].

S The role of smoking has been initially hypothesized as risk factor for the COVID-19. SIndeed, smokers and patients withaffected by chronic obstructive pulmonary disease (COPD) have a higher levelsquantity of ACE2 receptors, which facilitatalso are the entry ofreceptors of access for the COVID-19 virus. Moreover, the ex-smokers highlighted a peculiar genic expression included in non-smokers and active smokers [19][20]. A mreta-analysis of port analyzed 28 studies and reported that the smokers were more susceptible to contracting COVID-19 compared to the non-smokers-population [19][28]. Another study reported a percenthatage of 12.4% of smokers hospitalized for COVID-19 requiredin an intensive care with unit with invasive/non-invasive assisted mechanical ventilation, compared to while a percentage of 4.7% of the non-smokers needed of the intensive therapy [19]. A higher predisposition to COVID-19 has been reported for male subjects (67%) compared to the female patients (288 million men vs. 12.6 million of women), while a predominant smoking habit is present in the occidental male population [19]. SiIn angle-cellother study that uses the sequencing study revealof single cells, it has emerged that ACE2the expression iof ACE2 was predominant in Asian men, particularly amongwhich was significantly higher in the current smokers of Asian ethnicity than the non-Asian smokers [29].

Comorb Diditiseases such as diabetes (7.3%), chronical respiratory infections (6.3%), cardiovascular problems (10.5%), hypertension (6%), and tumors (5.6%) increase theare comorbidities constituting a high risk of infection [21][30][31]. The Eearly diagnosis andtogether with adequate preventive measureon methods (social distancing, use of personal protective equipment, such as face masks and wash handing with alcohol solutions) are important to contain and combantrast the 2019-nCoV spread SARS-CoV2ing [10][32]. After several studies, Tthe WHO has confirmed that SARS-CoV-2 the diffusion of the 2019-nCoV mainly spreadoccurs through saliva droplets [33][34][35][36][37][38], and nasal secretions and tears, with lesser transmissionand in a lower measure through feces, urine, sperm, and blood. The refore, the oral cavity serves as is the main access and exit point for the virus. In the assessment of the contagion of saliva, it is important to consider the “time of physical decay” depending on the droplets size (Flügge’s droplets), the speed of emission (sneeze or cough), the moisture content in the room and the air exchange, and the “biological decay”, namely how long the virus keeps infecting in saliva droplets. The biological decay is caused by dehydration, ultraviolet rays, and chemical products [39][40][41].

There perare some studies performed about the persistence of SARS-CoV-2y of the 2019-nCoV in aerosols and on various s and different surfaces (plastic, steel, copper, carton) has been studied [24][42][43][44][45][46]. The virus shows different sttability depending on theof SARS-CoV-2 on different surface and environmental conditions (s has been studied by infecting them in a room at 22 °C and with a moisture rate of about 65%). N. The results have shown that no traces of the virus were foundhave been reported after half an hour on printed apaper and tissue paper and smooth surfaces such as wood and banknotes, and after 30 minutes. Oseven days there were no traces on plastic and stainless steel, no traces were detected after seven days. However, significant traces of active virus were found on . Instead, the data about the surgical face masks are interesting, where on the external surfaces of surgical face masks even after seven day, after seven days, there have been some important traces of active virus [39][47][48]. Some recent studies showed that SARS-CoV-2 remains active for up to nine days, with. The plastic and the stainless steel being the most favorable sare the surfaces for iton which the SARS-CoV-2 virus lives longevityr. The virus's survival is biological decay depends on temperature-dependent, expiring e (at 30–40°C, while a °C, virus expires), and at a temperatures below 4°C, it of less than 4 °C, SARS-CoV-2 may remain active for up to 28 days. DUsing for the disinfection usingof surfaces: 0.1% sodium hypochlorite or 62–71% ethanol significantcoronavirus notably reduces the virus'sits infectivity on ng action on the surfaces within one minute1 min of exposure [28][40][43][49][50][51].

A Shanna Ratnestudy has shown that sunar-Shumate et al. showed some encouraging results about the capacity of the sun light canto quickly indisactivate the SARS-CoV-2 virus. N Data show that the natural light exhibits a stronghas a higher disactivating power, and may effectively disinfecting the virus on nonporous contaminateding materials [52]. SEven the simulated sun light has inactivated 90% of the the coronavirus in a salivary solution SARS-CoV-2 on infected samples performed on stainless steel. The virus has been disactivated in 90% in just 6.8 minutes and in a salivary solution, while in 14.3 minutes in in the laboratory on lands of culture [52]. SARS-CoV-2 remainsed active in the air fup to three hours duringor the duration of the experiment, namely 3 h.

1.2. COVID-19 in Children

1.2. COVID-19 in Childrens

Some studies from on the ongoing infections in babies based on some recent epidemiological data coming from Norway, Iceland, South Korea, and China indicated that children , even if analyzed on different sized samples, all confirm the same infection rate, namely that babies represent 1–5% of the infected population, with the most cases being and most of them are asymptomatic or showing mild tothey show a slight or moderate symptoms, more common iatology, higher in the male population boys [53][54][55][56][57][58][59][60][61]. The 90% of babies with severe cases in children occur in those agedevolution of the disease interests the age group from zero to two years [58]. IA study performed on South Korea, babies showed that the rate of severe cases werehas been 10.6% in infants under of babies aged less than one year, 7.3% in childrenthe group aged ofrom one to five, 4.2% in thoseof babies aged from six to ten10, 4.1% in the evelven to fifteen age groupof those aged between 11 and 15, and 3.0% in individuals sixteen or olderamong people aged 16 or more [58]. Theose numbers are uncertain, especially for for above all for younger children, as 71% werein which a high rate (71%) has been diagnosed without testing, and 13% were aa test and in 13% of cases without symptomatics [58].

A stLudy reported that out of et al. have issued a similar report; on 1391 children undersubjects less than six years old, 171 (12.3%) teshave resulted positive. Only three requirof them needed intensive care, all of whom had preexisting; all three cases were already affected by severe conditiondiseases (hydronephrosis, leukemia, and intestinal invagination) [57]. Of Twenthe 171 positive cases, 27y-seven babies on 171 (15.8%) were adid not have symptomatics or radiological signs of pneumonia [57][58][62],. and tThe average age of the infection was of 6.7 years. Common symptoms included fever (41.5%),The fever was always present in the 41.5% of babies. Frequent cough, and pharyngeal erythema, increased heart rate, respiratory frequency, and gastrointestinal diseases. Radiological findings oftenA total of 27 patients (15.8%) showed no clinical symptoms of infection or radiological signs of pneumonia. A total of 12 asymptomatic patients showed bilateral lungradiological signs of pneumonia, while the most common radiological evidence was the bilateral opacitiey of lungs (32.7%). In March 2020, a the death of a 10-month-old baby withaffected by an intestinal invagination andwith multiorgan failure dwas reported; the subject died after four weeks offrom the hospitalization [59][63].

A number of 21 patients were in stable conditions in general departments, and 149 were released from the hospital. Skin lesions, similar to vesicles on hands and feet, are among the new clinical signs; it is supposed that they are related to the peripheral circulatory system, which may lead to necrosis areas [64][65][66]. The presumed lower occurrence of infection in babies may be linked to the structural and functional immaturity of the cellular receptor ACE2 site by offering less affinity to the virus spike [67]. Differently to the infected adults, most of the infected babies seems to be a milder clinical course. Frequent symptomatic infections are a sign that infected babies may be a silent element of infection [68]. This is an important consideration for prevention and containment measures. On March 31, seven deaths have been reported in the world [62].

More recent studies reported that SARS-CoV-2 manifests itself with a more favorable clinical prognosis in pediatric patients compared to the adult subjects. In fact, children have a lower mortality than adults, which is around 0.06% in the 0–15 age group [69]. Studies on the Italian population reported that the total confirmed pediatric cases were 1.8%, with an average age of 11 years and with a slight prevalence of males; of these, 13% were hospitalized, and 3.5% were hospitalized in intensive care. The risk increases inversely proportional to age and the presence of comorbidities and the patients that showed critical clinical evolution are 0.6% of the children, but 50% of them are less than one year old [69][70]. In symptomatic children, with/without non-severe clinical symptoms, SARS-CoV-2 remains longer in the upper respiratory tract and in the faeces, manifesting symptoms not very present in adults: increased secretions in the upper respiratory tract and phenomena of gastroenteritis that facilitate the spread of the virus through the respiratory and fecal–oral route [71][72][73].

The English variant SARS-CoV-2 B.1.1.7 seems to have had greater diffusion among children and adolescents, although the type of clinical course proved to be equally not critical as the initial strain. There were no age differences or differences in patients with comorbidities or percentages of black and Asian patients [74]. From data reported in the scientific literature, in the pediatric and adolescent population there appears to be a correlation between SARS-CoV-2 infection and the onset of a new rare syndrome, called multisystem acute inflammatory syndrome (MIS-C), which, presenting some clinical manifestations typical of Kawasaki disease, is also called “Kawasaki syndrome” [65]. Children are less affected than adults for various hypotheses. Some studies report a lower presence of the angiotensin converting enzyme 2 receptor (ACE2) and a difference in the distribution, maturation, and functioning of this viral receptor, and possibly a lower presence of ACE2 in children’s lungs [61]. Another possible hypothesis is the lower presence of endothelial damage related to age, cardiovascular disease, diabetes mellitus, smoking, and lack of vitamin D, all of which are considered risk factors for severe COVID-19. In fact, the presence of endothelial damage facilitates and increases the inflammatory response from SARS-CoV-2 that causes vasculitis and activates the coagulation pathways and the formation of microthrombi that cause serious thrombotic complications such as heart attacks and strokes [61]. In addition, children and adolescents do not have an aging immune system or immunosenescence, which reduces the ability of B cells to produce antibodies against new antigens and to recognize pathogens [61].

F According children with COVID-19, pharmacological treatment ito the literature concerning the therapies recommended only in severe cases,in children infected with supportive therapy being the primary approach due to the generallyCOVID-19, it was established that children and adolescents, having a benign clinical course in pediatric patients, should choose the pharmacological treatment other than supportive therapy only in the most serious cases [75].

1.3. Dental Medical Care

1.3. Dental Medical Care

During everyday dental activity, there is a strong chance that the aerosol material includes supra-and-subgingival virus, blood, and microorganisms [24][44][45][46][48]. At the moment, it is impossible to determine the exact infection risk represented by the aerosol material, but it is a real risk, and we need to eliminate or reduce it as much as possible during clinical procedures. The use of personal protective barriers such as face masks (surgical face masks, FFP2, P 100, FFP3), gloves and eye protection, single-use-gowns, visors, double-inlet, and premises sanitization, will eliminate a great part of danger included within droplets coming from the operating sites [27][44][75][76].

A The aerosol or the droplets may be present in the air of the operating room after a procedure even for three hours [44]. This means that, after a dental procedure, if the operator removes a protecting barrier, such as a face mask, in order to talk to his patient, there is a potential contact with contaminated material in the air. Therefore, there is the need to keep on wearing the protection equipment [53]. Moreover, a contaminated substance on the air may penetrate the ventilation system and spread all over the premises [45]. Another chance may be the use of a high efficiency particulate air filter, or HEPA filter, as well as the use of UV rays chambers in the ventilation system. Even though those systems are very expensive, they seem to reduce air contamination. A UV system is nowadays prohibitive for most dental practices. The use of silver salts and ozone sanitizers may be performed only at the end of the day for the long time required by both systems. This is not feasible because of the great quantity of the daily dental visits [76].

D It has been shown that dental practitioners are asubjected t risk ofo exposure at SARS CoV-2 exposure during virus while performing dental treatments, as t. The virus can enter thre organism through the airways, represented by the oral cavity, and nose, and eyes. Therefore, wearing also through the eyes; this is why doctors have to wear protective equipment is crucialn order not to be infected with the virus [44]. A method to reduce the infective risk is uscharacteringzed by a hydrogen peroxide solution diluted withadministration and two parts of water d, repeated more times during the treatments. H. Indeed, the hydrogen peroxide, is naturally generated by oral bacteria, helps and intervenes by regulateting the balance of the oral microsystem and can reduce vir. In epithelial cells, the hydrogen peroxide through the enzymatic activity of the superoxide dismutase is catalyzed in superoxide ion [76]. Through this oxidative stress, the toll load, improving the host'sreceptors and NF-Kb are activated. The same mechanism is triggered, with the viral infections by playing an important role in host immune system. For this reason, the cleansing of the nasal and oral mucosa with hydrogen peroxide would improve the response to iof the host of the viral infection, by reducing the viral load and breaking the diffusion risk [76]. AThe 6% concentration at 6% of H2O2 in oral hygiene is recommended for oral hygiene by in the British Nationally Formulary, while a 3% solution is used in otorhinolaryngology, it is generally used in viral infections for gargling or as a nasal spray in otorhinolaryngologysolution at 3% [76][77][78]. The use Cof a chlorhexidine at 0.2% andor a mouthwashes containing essential oil has not shown high virus-neutralizing capacity for the virus [79][80][81].

Using a rDubber dam durring dental procedures can, the use of a rubber dam would reduce the virus spread, as it isolates the treatment area. Ring, and we also have to take into consideration the root canal disinfection is also critical, as . The only source of contamination in the air comes from the tooth under treatment c[82][83][84]. Additionanlly, be a the contamination sourcen can be reduced [82][83][84].by using Llaser t. The major benefit of this technology, which is that it reduces athe quantity of aerosol production, is another effective measures that is produced [85][86][87]. WHOThe guidelines recommend sed by World Health Organization indicate the use of specific protective equipment (PPE), includingthat is composed of masks with that have to have at least 94% fpower of filtration efficiency, protective eyewearfor the air particles, the use of eye glasses, and costumes that have to be waterproof clothing [17]. HScaranowever, N95 masks can cause discomfort and identified in his study that the use of a specific type of mask (N95) determines the modification of the temperature changes underneath them and discomfort [27]. WThe use of water-cooled rotary instruments and also ultrasonic ones generate largea big amount of aerosols [17]. TIn o mitigatrder to reduce the viral spread, dentists canare able to use lasers, hand instruments forwhen performing root scaling, double surgical suctioners, and dental rubber dam [17].

A In a study performed by Herrera et al. suggest using, the authors indicated the use of a combination of mouth rinses in order to reduce the viral load [88]. The combination includes N-hexadecyl pyridinium chloride, chlorhexidine, citrox, and cetylpyridinium chloride,; also it includes essential oils, and beta cyclodectrin [40].

2. The Cytokine Storm Syndrome (Css)

The cytokine storm leads to the interleukin release (IL)-6, IL-1, IL-12, and IL-18, together with the tumour necrosis factor alpha (TNF-α) and other inflammatory mediators [89][90][91]. The increasing lung inflammatory response may cause an increasing alveolar–capillary gas exchange, making hard the patients’ oxygenation of severe patients. There is a collapse of the lung walls and a severe bilateral respiratory insufficiency, and lesions to many organs with severe functional deficits [92][93][94]. Severe lymphopenia and eosinopenia [95] cause a decay in antiviral immunity and immunity in general. The recommendation is early screening for inflammatory markers, ferritin, c-reactive protein (CRP), and D-dimer 1 [96].

Helper cells of type 1 mediate the delayed inflammatory response, causing the IL-6 activation and other pro-inflammatory cytokines. If it is not treated, the inflammatory reaction may lead to severe lung lesions [97]. The insignificant increase of serum markers before starting the treatment with hydroxychloroquine and azithromycin may lead to deleterious adverse effects; moreover, it may be appropriate to make a differential diagnosis with the active tuberculosis and active fungal infections [98][99][100][101][102][103][104].

The use of IL-10 instead tends to conclude the blocking process of IL-6 by tocilizumab and avoids the formation of damaged interstitial lung tissues in fibrotic tissues. IL-10 is among the last potential biological therapeutic agents [105]. In addition to its ability to regulate the functions of lymphoid and myeloid cells, IL-10 has a powerful anti-inflammatory activity both in vitro and in vivo [105]. In this context, IL-10 has been identified as a potential therapy for inflammatory diseases involving type T helper 1 (Th1) and macrophage responses. In addition, the severity of the onset of secondary bacterial pneumonia during or shortly after COVID-19 infection is determined by a complex interaction between virus, bacteria, and host [106]. The host remains more susceptible to bacterial infections for several weeks after eliminating the virus, which indicates that increased susceptibility is not only due to an increase in viral virulence; in fact, it is known that the infection increases adherence and subsequent colonization with bacterial respiratory pathogens. Bacteria can adhere to the basement membrane after disruption of the epithelial airway layer due to the cytopathic effect of the virus. It has also been suggested that the increased adherence is due to the upregulation of the receptors involved in the attack of these bacteria [107].

Alternatively, COVID-19 alters the host’s innate immune response to subsequent bacterial challenges by becoming more sensitive to bacterial components, such as staphylococcal enterotoxin B and LPS. Cytokines such as IFN-γ, TNF-α, and IL-6 are synergistically up-regulated by staphylococcal enterotoxin B or LPS during influenza infections. These data clearly indicate that COVID-19 significantly alters the innate immune response to bacterial infections in a singular and atypical way; to date, little is known about the mechanism by which the virus modulates the innate and acquired immune response to bacterial infections of the lungs [107][108][109][110][111][112][113][114][115][116]. In vivo, a large part of the destruction of tissues derives from an excessive and unregulated inflammatory response, mainly of a neutrophilic nature which, if not contained, generates tissue damage by lowering the protective and regenerative dynamics [117][118][119]. In addition, the airway epithelial cells of healthy individuals produce IL-10; however, the epithelial cells of COVID-19 patients are deficient in the production of IL-10. Extremely confirmed data from analogous studies with COVID-19 patients reported that the under-expression of IL-10 is mainly due to clones of T lymphocytes [120][113][121][122][123].

It has been shown that SARS-CoV-2 cmany infect the lymphocytes, therefore playing a role in the modulatingon of the autophagy. The use of the medicine targets to the autophagy represents an emerging topic [94]. During the acute respiratory distress syndrome (ARDS), the active lung epithelial cells, together with the adaptive immune and innate filtering cells, are the cause of the aberrant production of proinflammatory molecules (cytokine storm), by encouraging an excessive recruitment of inflammatory cells and the local release of protease and oxidants, which are involved in lung manifestations of the disease [111][124]. With these premises, several cytokines, including IL-6, TNF-α, and IL-1β, are the cause of the inflammatory events associated to the disease caused by SARS-CoV-2 [125]. The local or systemic release of cytokines represents the most severe step of COVID-19. This process compromises the immune response against the virus SARS-CoV-2, giving rise to severe damage to the attacked organs, which leads to the death of the patient [126].

However, innate immune cells are populations that lead to production of cytokines, which respond to the inflammation and infection caused to the organs affected by the SARS-CoV-2, including the endothelial cells, the adipocytes, and mast cells. During the SARS-CoV-2 infection stage, the adipocytes produce IL-6, TNF-α, and IL-1β, by contributing to the worsening of the response of the host to the pathogens [127]. The autophagy was poorly considered and explored in COVID-19, while instead it is very involved both in the activation of lymphocyte and in the access and replication of the SARS-CoV-2 cells; therefore, the autophagy of lymphocytes plays an important role in the COVID-19. Therefore, the anti-rheumatic drugs, now recommended, are able to influence several biological processes, which intervene in the modulation of the autophagy in the lymphocytes and stimulate a reduction of the inflammation in patients infected by SARS-CoV-2 [94].

In healthy individuals, IL-10 has been shown to exert an inhibitory activity for the production of TNF-α, IL-1β, IL-6, and IL-8; therefore, it is possible that the constitutive production of IL-10, as occurs in the lungs of healthy people, may constitute an essential moment of homeostatic and anti-inflammatory balance [128]. In fact, experiments on IL-10 deficient knockout mice spontaneously develop inflammatory syndromes such as irritable bowel syndrome (IBS). Furthermore, in the lung context, IL-10 has been shown to be expressed by alveolar macrophages and stimulated by the bacterial lipopolysaccharide (LPS), by TNF-α [92][107][113][122][129][130][131][132][133][134]. As in the SARS-CoVs, even the 2019-nCoV may be transmitted in a quick way among human beings [34][135].

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