Foreword for the special issue advances in COVID-19: Biology and clinic.

In this special issue of Advances in Biological Regulation, there are seven articles which discuss some basic aspects of COVID-19, namely the origins, epidemiology and containment strategies of SARS-CoV-2, the virus responsible for COVID-19, some basic aspects regarding the SARS-CoV-2 genome and replication, the interactions of COVID-19 with the innate and adaptive immune system, the thromoboembolic events associated with COVID-19, the effects of the COVID-19 pandemic on cancer treatments, and the potential of repurposing existing drugs, vitamins, nutraceuticals and trace minerals to treat patients suffering from COVID-19. This special issue attempts to provide a brief overview of COVID-19 and key clinical, immunological, and biological properties of infection with SARS-CoV-2.

In the manuscript by Acuti Martellucci et al. (2020), the origins of SARS-CoV-2 are discussed as well as the modes of transmission and diagnosis, and the epidemiological parameters required to support containment policies. Droplet transmission is believed to be the most effective mode of virus transmission. The duration of the disease in patients with COVID-19 is also discussed. Most infected patients have the capacity to transmit the disease for at least fourteen days, some more than thirty days. The symptoms may occur approximately two to five days after contact with the SARS-CoV-2 virus. Most individuals infected with SARS-CoV-2 remain asymptomatic or mildly symptomatic. Patients with severe forms of the disease may die after approximately fourteen days dependent on the therapeutic interventions provided to the patient.

Models have suggested that one person can infect two to six people with the virus. The symptoms of infection can occur after varying time periods of exposure, from two to five days. In a house-hold with an infected individual, the secondary attack rate is predicted to be close to 12%. The authors estimated the average risk of causing severe/lethal COVID-19 in the Italian population and the risks of infecting other people with the virus, and highlighted the necessity of using epidemiological parameters in order to find the most correct, balanced containment strategies, which should take into account also the potential harms of lockdown measures.

Various risk factors have been associated with the morbidity of patients infected with SARS-CoV-2. Risk factors include age (>65 years old), diabetes, obesity, heart disease, sex (higher in males in females), imunosuppression and ABO blood types (higher in A type than O type).

The authors have discussed that the lethality of COVID-19 could be decreasing due to the presented attenuated virus in the population. However, it should be mentioned that this is a virus with a single-stranded RNA genome and may have a high mutation rate which could complicate the development of effective vaccines.

Different types of diagnostic polymerase chain reaction (PCR) are employed to detect the virus. Different PCR primers have been evaluated. Reverse transcriptase PCR (RT-PCR) is a standard assay to detect SARS-CoV-2, however droplet digital PCR may be better than RT-PCR. However, these tools may not be available in certain settings (e.g., patients on cruise ships, or countries with limited resources). Serological tests are also performed to detect antibody responses to viral infection. However, in certain cases, antibodies can only be detected weeks after infection.

In the review article by Akula and McCubrey (2020), some of the basic virological aspects of the SARS-Cov-2 virus and pandemic are elaborated upon. This review also discusses some of the related coronaviruses and their distribution in animals. The proteins encoded by SAR2-Cov-2 are defined as are the clinical manifestations and predictors of disease severity. Methods of disease prevention are also covered such as the potential of nutritional supplements in management of COVID-19 infected patients. Antiviral and antibiotic treatment strategies are also discussed as well as the potential to develop a potential vaccine to suppress SARS-CoV-2 infection by inducing neutralizing antibodies to the spike (S) protein. A problem with the development of vaccines to SARS-CoV-2 could be the high mutation rates of single stranded RNA viruses.

The roles of natural killer (NK) cells as part of the innate immune responses was examined in the review by Masselli et al. (2020). Lymphopenia, and specifically NK cell count reduction are associated with severe cases of COVID-19 patients. So far, hypothesized mechanisms underlying reduced NK function and number are: i) redistribution in infected sites, i.e., the lung, which is a common feature of other non-COVID-19 coronavirus infections; ii) apoptosis, due to the upregulation of proapoptotic gene in viral-infected cells; iii) functional exhaustion of peripheral NK cells, likely triggered by the overexpression of the inhibitory receptor NKG2A. Therefore a detrimental, doubled-sided mechanism of SARS-CoV-2/NK cells interaction can be envisioned, characterized by exhausted/apoptotic NK cells in the circulation, eliciting virus spreading on one side and on the other side activated pro-inflammatory NK cells in the lung, facilitating organ damage.

The central role of oxidative stress, for the formation of neutrophil extracellular traps (NETs), and T cell suppression and their influence on COVID-19 disease progression and therapy is discussed in the review by Günther Schönrich et al. (2020)). Production of reactive oxygen species (ROS) after SARS-CoV-2 infection leads to oxidative stress which is a major cause of local or systemic tissue damage that can result in severe COVID-19. It increases the formation of NETs and suppresses the adaptive arm of the immune system, i.e. T cells necessary to kill virally-infected cells, preventing a specific immune response against SARS-CoV-2. This also suggests that reducing ROS levels with anti-oxidants such as vitamin C and N-acetyl cysteine (NAC) and others may be therapeutic approaches to prevent infection with COVID-19 from becoming severe. This review also discusses the role of immune responses, cytokines, the effects of aging and comorbidities with enhanced ROS levels like diabetes on the development and severity of COVID-19 disease progression. There are 17 clinical trials with vitamin C and COVID-19 listed on clinicaltrials.gov. There are four clinical trials with NAC and COVID-19 listed on clinicaltrials.gov.

The roles of thromboembolic events in COVID-19 patients were examined in the review article by Ribes et al. (2020). The systemic inflammatory cytokine storm that develops in severe COVID-19 patients can result in severe detrimental changes in multiple organs, especially the lung. Cytokine storm in severe COVID-19 patients contributes to thrombogenicity and multiple organ failure and death. In severe patients, unusually high incidences of thromboembolic events occur which are associated with patient death. Disturbed hemostasis and coagulopathy are observed and associated with poor patient outcome. The modalities of anticoagulant treatment are also discussed.

The COVID-19 pandemic has affected certain “standard” operating protocols in the hematology department such as the scheduling of certain procedures such as transplantations, blood collections and transfusions and other operations. Some common treatments (e.g., treatment with certain chemotherapeutic or immunosuppressive drugs) have been delayed as they are immunosuppressive in nature, and it is important to prevent the infection of hematological patients with SARS-CoV-2. This is summarized in a review by Finelli and Parisi (2020) in hematological settings. Certain hematological conditions such thrombocytopenia, lymphopenia and coagulation abnormalities, may be useful for the prognostic evaluation of SARS-CoV-2-infected patients.

In the review by Akula et al. (2020) the effects of the COVID-19 pandemic on various cancer treatments are discussed. Although there have been tendencies to delay cancer treatments or screening when possible this is not always the optimal clinical protocol. In some cases, increased doses of cancer inhibitors have been prescribed into order to prevent multiple trips to the hospital and reduce the potential for patient exposure to SARS-CoV-2. The problems associated with sterility and prevention of infections in the operating room are considered. This review also discussed some of the approaches used to identify cellular targets of SARS-CoV-2 which may allow the use of more specific targeted therapeutics. This review also discusses the repurposing of existing FDA-approved drugs to treat COVID-19 patients. Finally, the use of vitamins, nutraceuticals and trace minerals in prevention of infection and treatment of COVID-19 patients is considered.