Coronaviruses are a diverse group of single-stranded RNA (ssRNA) viruses which circulate among vertebrates and usually cause mild upper respiratory tract infections in humans . In December 2019, in the city of Wuhan, a novel Betacoronavirus responsible for potentially fatalviral pneumonia was identified, officially named severe acute respiratory syndrome coronavirus 2 (SARS-Co-V-2). As of July 22, 2020, the virus has caused 15,217,434 infections world-wide with a case-fatality rate of 4.09% (622,454/15,217,434).
Clinical presentation of SARS-CoV-2 infection is variable, ranging from lack of symptoms to mild-moderate symptoms including fever, dry cough, and fatigue in majority of cases , however severe infections can present with acute respiratory distress syndrome and multi-organ failure requiring intensive care unit admission . Less frequent symptoms include headache, sputum production, dyspnea, sore throat, nasal and conjunctiva congestion, myalgia, arthralgia, chills, nausea, vomiting and diarrhea, anosmia and aguesia .
Published risk factors for SARS-CoV-2 infections include: advanced age and underlying conditions including Hypertension, Cardiovascular disease, Diabetes, Chronic lung disease, smoking and obesity .
The most characteristic laboratory findings among patients infected with the novel virus are: lymphopenia, neutrophilia, high inflammatory markers (C-reactive protein, pro-inflammatory cytokines (IL-6), and Ferritin), along withhyper-coagulation state indicated by high D-dimers .
Immune mechanisms involved in COVID-19 severity
The physiological response to viral infections is generally initiated at the cellular level following replication. Transcriptional activation by the intracellular virus leads to the stimulation of two antiviral defense mechanisms. One antiviral response is the induction of type I and type III interferons (IFN) with subsequent upregulation of IFN-stimulated genes and viral control. The second antiviral response iscoordinated by cytokines responsible for the recruitment of specific subsets of white blood cells involved in eradicating the infection .
A study that set out to identify the transcriptional signature of SARS-CoV-2, presented data that suggest that the immune response in COVID-19 is imbalanced with regard to controlling viral replicationversus activationof the adaptive immune response . A reduced IFN-I and III response to SARS-CoV-2 was observed, thus viral replication control is weak, while a robust cytokine response (especially IL-6 and IL-1) was noted. The underlying pathophysiology of COVID-19 is still under investigation, but it appears that the virus induces an inflammatory response involving macrophage hyperactivation, leading to a cytokine storm responsible for severe complications [4, 12].
Cytokine release syndrome is a systemic inflammatory response that can be cause by various factors (infections, drugs) characterized by a sharp increase in pro-inflammatory cytokines . Interleukine-6 (IL-6) is a multi-faced cytokine with both anti-inflammatory and pro-inflammatory effects that is produced by T lymphocytes, endothelial cells, fibroblasts, macrophages and monocytes, activated by Interleukin-1b and tumor necrosis factor-alpha . IL-6 has various biological functions: inducing B-cell proliferation and differentiation to produce antibodies (a process that is absent or defective in agammaglobulinemia and CVID), induces cytotoxic T lymphocyte activity and proliferation, strong inducer of acute-phase reactive proteins (CRP) in the hepatocytes, and is associated with hypergammaglobulinemia . Macrophage activation syndrome-like disease seen in severe COVID-19 cases is also responsible for the commonly observed extensive pulmonary microthrombosis . Blockade of implicated cytokines is responsible for spectacular clinical outcomes withimmunosuppressive targeted monoclonal therapy (anti-IL6 receptor, Tocilizumab) and systemic corticosteroids in moderate to severe cases of COVID-19 .
Possible protective mechanisms against severe COVID-19 infection within CVID individuals
Because immunosuppressive therapies have been shown beneficial in the inflammatory phase of COVID-19, the question that arises is whether certain underlying immune defects identified in CVID can actually be protective?
Limited susceptibility to viral infections
Patients with predominant antibody immunodeficiency are particularly vulnerable to encapsulated bacterial infections, less prone to viral infections. Patients with agammaglobulinemia are susceptible to a limited number of viral infections (norovirus and enterovirus)while CVID patients are susceptible to rhinoviruses, noroviruses and herpesviruses .
Deficient B Lymphocyte responses
Patients with agammaglobulinemia lack B lymphocytes completely while patients with CVID have variable numbers of dysfunctional B lymphocytes with a marked reduction of mature CD27+ B lymphocytes. Thus we postulate that the lack of appropriate B cell response leads to decreased cytokine release. It has been demonstrated that mature B cells produce IL-6 to drive germinal center formation . COVID-19 treatments might consider the possibility of not only blocking produced cytokines but dampening the inflammatory functions of B lymphocytes and inhibiting cytokine production by monocytes and dendritic cells .
Loss of IL-6 receptor
Recently, a number of cases with primary immunodeficiency were found to have genetic defects in various components of the IL-6 pathway. Spencer et al.  and Nahum et al  reported cases with IL-6 receptor loss of function defects. Although these patients lack expression of a function IL-6R chain, it was hypothesized that cells should retain responsiveness to IL-6 through trans-signaling by binding gp130 co-receptor, however this was not the case, resulting in complete loss of IL-6 responsiveness in these patients . Thus, even if IL-6 is produced by immune cells as a response to infection, a subset of patients with primary immune deficiency demonstrate a complete loss of responsiveness to IL-6. An accessible measure to demonstrate lack of physiological IL-6 activity can be a disproportionate level of low CRP (normally synthesized by hepatocytes response to IL-6) as opposed to high serum IL-6 .
Impaired Toll-like Receptor pathway activation
The Toll-like receptors (TLR) are a family pattern recognition receptors that are essential in the innate immune response, being activated by different types of pathogen ligands in order to clear infections . TRLs which detect viral nucleic acids (TLR3, 7, 8 and 9) are expressed on intracellular endosome membranes. TLR7 responds to single-stranded ribonucleic acid (ssRNA) viruses , such as SARS-CoV-2. TLR7 is intrinsically expressed on the membranes of endosomes in plasmacytoid dendritic cells and B lymphocytes, which are abundantly present in lung tissue . Signaling in human immune cells by TLR7 has been well-known to trigger production of pro-inflammatory cytokines including TNF-a, IL-6, IL-1b, IL-12 and IFT-a . Thus, it is plausible to assume that the well documented cytokine storm partially responsible for severe forms of SARS-CoV-2 infection could also be a result of exaggerated TLR7 activation in lung residing immune cells. It has been demonstrated that certain TLR pathway activation is impaired in CVID, particularly TLR 7 and TLR9 involved in anti-viral innate immune response [2, 3].
High dose Immunoglobulin therapy
Immunoglobulin replacement therapy is the only therapeutic option for CVID and agammaglobulinemia. High does intravenous immunoglobulin (IVIG) was used in all reported cases of COVID-19 in CVID patients with great results. IVIG could also be potentially useful in treating severe COVID-19 patients due to it’s immunomodulatory and anti-inflammatory effects but also possibly due to it’s content of antibodies to other coronaviruses that cross react with SARS-CoV-2 .