COVID-19 disease and autoimmune disorders: A mutual pathway

Abstract

Coronavirus disease 2019 (COVID-19) is a real challenge for humanity with high morbidity and mortality. Despite being primarily a respiratory illness, COVID-19 can affect nearly every human body tissue, causing many diseases. After viral infection, the immune system can recognize the viral antigens presented by the immune cells. This immune response is usually controlled and terminated once the infection is aborted. Nevertheless, in some patients, the immune reaction becomes out of control with the development of autoimmune diseases. Several human tissue antigens showed a strong response with antibodies directed against many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins, such as SARS-CoV-2 S, N, and autoimmune target proteins. The immunogenic effects of SARS-CoV-2 are due to the sizeable viral RNA molecules with interrupted transcription increasing the pool of epitopes with increased chances of molecular mimicry and interaction with the host immune system, the overlap between some viral and human peptides, the viral induced-tissue damage, and the robust and complex binding between sACE-2 and SARS-CoV-2 S protein. Consequently, COVID-19 and its vaccine may trigger the development of many autoimmune diseases in a predisposed patient. This review discusses the mutual relation between COVID-19 and autoimmune diseases, their interactive effects on each other, the role of the COVID-19 vaccine in triggering autoimmune diseases, the factors affecting the severity of COVID-19 in patients suffering from autoimmune diseases, and the different ways to minimize the risk of COVID-19 in patients with autoimmune diseases.

Key Words: COVID-19, SARS-CoV-2, Autoimmune Diseases, Vaccines

Core Tip: There is a mutual relation between coronavirus disease 2019 (COVID-19) and autoimmune diseases. Patients with immune deficiencies or autoimmune disorders are at a higher risk for infection with COVID-19, as they are frequently treated with anti-cytokine, glucocorticoids, and immunosuppressive drugs. Meanwhile, COVID-19 and its vaccine could trigger the development of autoimmune diseases. Therefore, a multi-purpose comprehensive social and family program with exercise and psychological support is highly needed for patients with autoimmune disorders to lessen the harmful effects of social isolation impeded during the COVID-19.

INTRODUCTION

The coronavirus disease 2019 (COVID-19), with its global pandemic, which started with the first reported case in December 2019, is a real challenge for humanity. These challenges are due to the uncertainty about the origin of the virus, its rapid transmission, the difference in racial susceptibility, the wide variety of clinical presentations, the conflict in diagnosis, the rapid mutations that continuously elaborate, the disparity of the treatment regimens in the different parts of the world, and the high morbidity and mortality rates[1,2]. The virus that causes COVID-19, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the beta coronaviruses group. This group is a part of a Coronaviridae family with spherical, positive-sense, non-segmented, single-stranded, and large (100–160 nm) RNA viruses[1].

SARS-CoV-2 is a single-stranded RNA virus with a positive sense and a unique pleomorphic or spherical, non-segmented envelope with distinctive crown-shaped peplomers or spikes[3]. It has four main structural proteins: spike protein (S), small envelope glycoprotein (E), membrane glycoprotein (M), and nucleocapsid protein (N). Other several accessory proteins are present and have particular functions. S protein is a sizeable trimeric glycoprotein that facilitates viral binding to host cells through binding to angiotensin-converting enzyme II receptors with its two non-covalently associated subunits. The first subunit (S1) binds to angiotensin-converting enzyme II (ACE2) with its subunit receptor-binding domain (RBD). The second subunit (S2 subunit) controls the fusogenic ability of the virus-cell membrane and fixes the S protein to the cell membrane[4]. The E protein is a small envelope glycoprotein of three variants, participates in viral assembly and virion release, and plays a critical role in the virus pathogenesis. M glycoprotein shapes the viral envelope and is accountable for transmembrane nutrient transporting and bud release. N protein is formed from the matrix protein and is present near the viral nucleic acid material within a capsid to help pack the viral RNA genome inside the viral envelope. This process is a fundamental component of the self-assembly and replication of the virus[5,6]. The virus's genome encodes for the four essential structural proteins (S, M, E, and N), hemagglutinin esterase, and another six accessory genes occupying the main part of the viral genome (about two-thirds). There are three well-defined variants of SARS-CoV-2: A, B, and C, according to their genomic differences[7].

PATHOGENESIS AND IMMUNOGENICITY OF SARS-COV-2

Despite being primarily a respiratory illness, COVID-19 can affect nearly every human body tissue, causing a broad range of illnesses. Similar to SARS-CoV, SARS-CoV-2 uses ACE2 receptors to enter the host cells. It uses the surface S glycoprotein with its two domains (S1 and S2) to bind at the RBD with the ACE2 receptor and fuse the viral envelope membrane with the cell membrane. However, SARS-CoV-2 S proteins bind stronger with human ACE2 receptors than SARS[8]. These spike proteins have high antigenicity, as indicated by the elevated plasma anti-S neutralizing antibodies levels in convalescent patients[9].

The body localization and expression of ACE2 receptors could determine the potential target organs of SARS-CoV-2 infection and outline the disease progression and clinical consequences. ACE2 receptors were first reported in the heart, kidneys, and type-I and II alveolar cells. Then, recently high expression of ACE2 receptors was reported in the brain, eyes, nasal and oral mucosa, thyroid, esophageal epithelium, gastric mucosa, liver, cholangiocytes, pancreas, the smooth muscle cells, and enterocyte from the small intestine to the colon, skin, testis, ovary, uterus, vagina, and urinary bladder[10,11]. All these organs should be considered as a potential target for SARS-CoV-2 infection. ACE2 receptor expression may be absent in the bone marrow, lymph nodes, thymus, spleen, and numerous immune system cells[12]. The patients' differences in ACE2 receptor distribution and ACE2-SARS-CoV-2 mutual interactions could affect the disease pathophysiology, progression, and consequences. Many factors could affect ACE2 receptors distribution, including heritability, patient demographics, lifestyle, comorbidities, and drugs[13]. Meanwhile, soluble ACE-2 (sACE-2) is found in the serum or plasma due to shedding from the cell surface. These sACE-2 strongly interact with SARS-CoV-2 S protein and vasopressin to initiate receptor-mediated endocytosis, enabling SARS-CoV-2 to enter the host cells[14].

After viral entry into the body, it attaches to the mucosal cell, entering the cell either at the plasma membrane or the endosome through receptor-triggered endocytosis[15,16]. The receptor-dependent endocytosis starts by latching the RBD part of the S1 protein of the viral envelope to a pocket in the ACE2 receptor, fixing the virus to the cell membrane. Then, the transmembrane protease serine 2 present near ACE2 receptors cleaves a protein between the S1 and S2 units in a specific location, with the help of the Furin enzyme, which enables the viral entry into the cell after binding. The enzymatically induced cutting of S protein exposes previously hidden parts of the S protein, which undergo a series of remarkable conformational changes and more fixation into the cell membrane. Once inserted, S proteins pull back on themselves, pulling the membranes of the cell and the virus together to fuse. When the viral envelope starts to merge with the host cell membrane, it creates a fusion pore that allows the virus to release its genetic material into the cell cytoplasm of the infected cell[17,18].

After receptor engagement and viral replication inside the affected epithelial cells of the nasal cavity, there will be an initial asymptomatic phase for one to two days. During this phase, the virus continues to replicate and multiply without significant resistance by the innate cellular immunity. After this initial stage, the symptoms appear from 2-14 d. Once the SARS CoV-2 virus spreads to the lower respiratory tract, it stimulates a vigorous innate immune response with a more significant pro-inflammatory response that may progress to viral sepsis and other consequences of acute respiratory distress syndrome that may end with multisystem organ failures and even death[19].

Viral antigen presentation

After viral infection, T lymphocytes can recognize the viral antigens presented by major histocompatibility complex (MHC) class I on the surface of all the nucleated human cells and the platelets. This step is crucial for cytokine release and promotes CD8+ T cells cytotoxic activity. However, MHC class II can occasionally present the viral epitopes to CD4+ T cells[20,21]. The human leukocyte antigens (HLA) association is not very well-identified for SARS-CoV-2 infection, which could be crucial for preventing and treating COVID-19. However, a study by Tomita et al[22] showed that patients with HLA genotypes (HLA-A*11:01 or HLA-A*24:02) might efficiently produce T-cell-mediated immune responses to SARS-CoV-2 than patients with HLA-A*02:01. At the same time, reports documented the ability of SARS-CoV-2 to inhibit the expression of HLA-antigens. Giamarellos-Bourboulis et al[23] showed that the plasma-derived from patients with severe SARS-CoV-2 infection could inhibit the expression of HLA-DR on CD14+ monocytes, which could partially be reversed by Tocilizumab (IL-6 blocker), indicating the role of hyper-inflammation and the sustained cytokine production in inducing this immune dysregulation.

The innate immunity

The immune responses to SARS-CoV-2 start with the innate immune response by the interferon (IFN)-mediated pathways and the adaptive cellular and humeral immunity through the T lymphocyte and the antibody-mediated pathways. However, SARS CoV-2 can antagonize the IFN-mediated antiviral responses, allowing viral replication with a high early viral load and transmissibility[24]. The innate immune response to SARS-CoV-2 infection in the respiratory tract is mediated through alveolar macrophages and dendritic cells, inducing a cascade of inflammation to restrict virus replication effectively. This cascade of inflammation arises from the release of pro-inflammatory cytokines, particularly IL-18 and IL-1β, which explains the distinguished characteristic of neutrophilia and leukopenia commonly observed in patients with severe COVID-19[25]. The released inflammatory mediators recruit T lymphocytes and monocytes primarily, but not neutrophils, to the site of infection, which explains the lymphopenia and the raised neutrophil-lymphocyte ratio observed in most patients with COVID-19[26]. However, this induced inflammatory cascade plays a significant role in the pathogenesis of severe organ injury and adverse disease outcomes[27]. The differences in patients' susceptibility to coronavirus infection may be related to the differences in the Mannose-binding lectin (MBL) protein, which has a significant role in pattern-recognition molecules, one of the first-line host defense mechanisms against SARS-CoV-2 infections[28]. MBL pathway activates the complement pathway that promotes thrombosis and coagulopathy in severe COVID-19[29]. The viral RNA also activates Toll-Like Receptor 3, 7, 8, and 9, which accordingly activates the pathway including Nuclear Factor kappa B (NF-κB)[30].

This immune response is usually controlled and terminated once the infection is aborted. Nevertheless, in some patients, the immune reaction becomes out of control with excessive unwanted response ending with a cytokine storm with a low level of IFN in early-stage and high levels in late-stage, an excessive increase of interleukin (IL)-6, IL-2, IL-7, and IL-10, massive increase of granulocyte-macrophage colony-stimulating factor (GM-CSF), Macrophage Inflammatory Protein 1α (MIP-1α), Tumor Necrosis Factor-alpha (TNF-α), plasma-induced protein 10 (IP-10), monocyte chemotactic protein-1 (MCP-1), and Inflammatory Protein 1α (MIP-1α)[31-33]. This deviated immune response's exact mechanism is unknown but may be related to the antagonistic effects of viral N protein on the interferon signaling pathway. Interferons-mediated innate immunity is the first defense mechanism against viral infections, including COVID-19, through activating macrophages and natural killer (NK) cells, which destroy the virus-infected cells[26]. Interferon deficiency causes an elevation in pro-inflammatory cytokines, an inadequate antiviral response, ACE2 receptor upregulation, high viral load, and subsequent excessive inflammatory response[34,35]. Complement activity is essential in immunity modulation and can predict the clinical outcome of SARS-CoV-2 infection. Complement protein C3 activation occurs early in the course of COVID-19. It plays a significant role in enhancing prothrombotic and pro-inflammatory conditions with immune complex deposition in different organs that may proceed to extensive endothelial damage, acute respiratory distress syndrome, and even end-organ damage observed in severe cases of COVID-19[36,37]. Consumption of the complement proteins in the immune complexes explains the low levels of C3 and C4 observed in instances of severe COVID-19. Detection of low levels of C3 and C4 can be a warning sign of the need for additional management in patients admitted with COVID-19[38]. Immune complexes depositions induced-vascular injury and antibody-dependent enhancement increase viral replication in Fc-receptor expressing cells[39].

The adaptive immunity

The three main types of lymphocytes, B cells, T cells, and natural killer cells, play a vital role in clearing infections once they begin. Their plasma numbers correlate well with better survival. Lower leukocyte and lymphocyte numbers help the virus avoid the host immune response with a high viral load and transmission rate[40]. Once activated by SARS-CoV-2, natural killer T cells can prevent viral spread from the upper airways to the rest of the body and, consequently, determine the severity of the symptoms, the viral load, transmission to the community, and the disease outcome[41].

Although T and B lymphocytes do not express ACE2 receptors, some of them can still be infected by the SARS-CoV-2 virus, which indicates the presence of other receptors participating in the viral entry in some lymphocytes. After a few days from SARS-CoV-2 infection, naïve lymphocytes differentiate into Th2 and produce Th2 cell serum cytokines. The higher the levels of Th2 cell serum cytokines are, the worse the outcome is[42]. Some memory T cells can be primed by a previous animal or human coronavirus infections, so they can recognize some of the viral proteins, help clear SARS-CoV-2 and produce asymptomatic infections in many patients even in the absence of antibodies in their serum[43]. SARS-CoV-2 induces a direct cytotoxic effect on the lymphocytes to evade the immune system, resulting in lymphopenia, preventing cytokine storm, and diminishing the innate immune responses[44]. SARS-CoV-2 also upregulates many apoptosis-involved genes, including P53, which helps develop lymphopenia. This SARS-CoV-2-induced lymphopenia is prevalent in patients with old age or other comorbidities such as obesity, hypertension, or diabetes mellitus[45]. Lymphopenia could also result from increased leukocyte adhesion and extravasation due to SARS-CoV-2-induced endothelial dysfunction, particularly in old age and with comorbidities, augmenting the problem of lymphopenia[46]. Effector T cells are the leading players driving immune responses to achieve immune functions. These cells have both promoting and inhibitory regulatory functions of innate immunity. The maturation and differentiation of naïve-T cells to mature fully functioning effector cells are controlled by cytokines produced by activated cells of the innate and adaptive immune systems. SARS-CoV-2 induces enhanced inhibitory receptor expression on the surface of T cells due to cytokine activity or reduction of the regulatory T-cells. These inhibitory effects negatively exhaust the effector T cells and reduce the defense against SARS-CoV-2[47]. CD4+ T cells, CD8+ T cells, and B cells have a crucial protective role against SARS-CoV-2 infections. A decrease in CD4+ T cell number and function causes cytokine, neutralizing antibody production reduction, and reduced lymphocyte recruitment to lung tissue. These effects cause an increased risk of interstitial pneumonitis and delay the clearance of infection from the lungs. However, depletion of CD8+ T cells at the beginning of SARS-CoV-2 infection does not affect the viral clearance or replication[48].

B lymphocytes represent 15% of peripheral white blood cells and are responsible for the humoral immunity and protection against various pathogens through various immunologic functions, including antibody production. Specific immunoglobulin M (IgM) anti-SARS antibodies appear within two weeks after infection, reaching the peak in the third week, to gradually disappear until the end of the third month[49]. Immunoglobulin G (IgG) started to appear by the end of the second week, reaching the peak by the end of the fourth week, and persisted for longer but not for a long time [in SARS-CoV-1, Ig G lasts for about two years][50]. Consequently, antibody levels can be used to determine the stage of SARS-CoV-2 infection. The levels of anti-SARS-CoV-2 antibodies decrease by about 50% within 1-3 mo following the beginning of the infection[51]. However, some cases with agammaglobulinemia infected COVID-19 showed full recovery without functioning B-cells[52,53]. The antibody response may help inhibit viral replication through neutralization and blocking the viral entry, egress, or fusion with the host. However, enhancing antibodies may counteract the neutralizing antibodies. Antibodies can enhance viral infections and participate in COVID-19 pathogenesis via antibody-dependent enhancement. The level of enhancing antibodies is positively correlated with pro-inflammatory mediators levels and negatively correlated with anti-inflammatory mediators. Which has the upper hand, the neutralizing or enhancing antibodies depend on the dominant antibody type concentrations and affinity[54,55]. Abnormal B lymphocytes maturation and conversion to macrophage-like cells caused by the viral S protein impairs the immune system's humoral and cellular elements in responding to severe infection with SARS-CoV-2[56]. Table 1 shows the various factors that affect the severity of infection with COVID-19.

Table 1 Factors affecting the severity of coronavirus disease 2019 infections.

Factor		Example
Viral-related factors		The viral load[24]; Mutation/virulence; Previous infections with other Coronaviruses e.g., SARS-CoV[43,59]
Host-related factors:	Demographic factors	Patients' age[61,62]
		Gender[80,182]
		Race/ethnic group
	Physiological	Pregnancy[215]; Personel differences in ACE2 receptors distribution[13]
	Pathological factors	Presence of comorbidities such as obesity, hypertension, tuberculosis, HIV, anemia, nutritional deficiencies, or diabetes mellitus[13,45,159,169,171,181]
	Immunological factors	The type of HLA-antigen[20-23]
		The plasma numbers of B cells, T cells, and natural killer lymphocytes[40,41]
		The hemoglobin and ferritin levels[216]
		The levels of C3 and C4[38]
		The differences in the MBL protein[28]
	Environmental factors	Socioeconomic status[217]
		Overcrowding[218]
		Smocking[205]
		Alcohol consumption[204]
		Particular occupations: Occupations that involve a higher degree of physical proximity to others over long periods[219]
	Pharmacological factors	Certain drugs increase the severity (e.g., rituximab, high-dose corticosteroid)[140,187,191]. Certain drugs decrease the severity (e.g., ubiquinone, ezetimibe, flecainide, rosuvastatin, artificial tears, licorice)[214]
		Vaccination status of the patients

ACE2: Angiotensin-converting enzyme II; HLA: Human leukocyte antigens; HIV: Human immunodeficiency virus; MBL: Mannose-binding lectin; SARS-CoV: Severe acute respiratory syndrome coronavirus 2.

AUTOIMMUNITY AND CROSS REACTIVITY OF SARS-COV-2

In antigenic or molecular mimicry, common antigenic sites are shared between microorganisms and the host tissue. The microorganism-triggered immune response is directed against the microorganism and the host cells with the common antigenic determinant. This deviated autoimmune response is responsible for developing many autoimmune disorders in humans. Recently, it has been observed that several human tissue antigens showed a strong reaction with antibodies directed against SARS-Cov-2. This antigenic mimicry was observed for many SARS-CoV-2 proteins, including but not limited to SARS-CoV-2 S, N, and autoimmune target proteins[57]. These induced antibodies can react with a wide variety of human tissues and proteins such as skin, respiratory, digestive, cardiac, and nervous tissues, producing a wide array of autoimmune disorders with extensive cellular, tissue, and organ damage observed in severe COVID-19 cases[58]. The cross-reactivity of SARS-CoV-2 is not limited to the human body. SARS-CoV-2 also has cross-reactivity with SARS-CoV, as patients with COVID-19 can produce IgG and IgM antibodies able to react with SARS-CoV. This observation is fundamental as it helps understand that some patients may have mild or aggressive COVID-19. Previous infection with SARS-CoV with pre-exciting antibodies that can cross-react with SARS-CoV-2 may explain this variation in the clinical presentation in patients with COVID-19. However, recovery from SARS-CoV infection might not protect against SARS-CoV-2 and vice versa[59]. Cross-reactivity between SARS-CoV-2 and other human coronaviruses, especially beta coronaviruses (particularly SARS-CoV and MERS-CoV), may explain numerous phenomena. The increased pathogenicity and severity of SARS-CoV-2 infection in areas with common pre-existing SARS-CoV infection is due to the possible presence of enhancing cross-reactive antibodies against those common coronaviruses[60]. Enhancing cross-reactive antibodies to SARS-CoV-2 in patients previously exposed to SARS-CoV can explain the early response with higher titers in older age and the milder symptoms in the pediatric age[61,62]. However, the lower prevalence of COVID-19 in the pediatric age is multifactorial and could be related to the age-dependent immaturity of ACE2 receptors in children[63]. The tissue damage induced by the cross-reactive autoantibody induces the release of more self-antigens, activating more autoreactive T-cells, producing more self epitopes, and sparking autoimmunity[64]. Cross-reactive antibodies also raise a question about using convalescent plasma to treat patients with SARS-CoV-2 infection to neutralize SARS-CoV-2. However, convalescent plasma may lack effectiveness and, on the other hand, may induce endothelial damage due to the transmission of cross-reactive enhancing antibodies[65]. Cross-reactivity is also of paramount importance in the vaccination industry, considering SARS-CoV-2 cross-enhancing or neutralizing epitopes to minimize the vaccine side effects and vaccine-induced autoimmunity[66].

SARS-COV-2 INDUCED AUTOIMMUNE AND AUTO-INFLAMMATORY CONDITIONS

A variety of factors may trigger autoimmunity by generating a hyperstimulated immune system. The terms exposome, infectomes, and autoinfectomes are recently introduced in autoimmunity. Exposome describes all the environmental triggers (exogenous or endogenous) that the host could expose to it. Infectomes are all infectious microbes that the host can be exposed to during his/her life. In the same way, autoinfectomes are all infectious agents that can trigger autoimmunity upon exposure[67]. The ability of SARS-CoV-2 to initiate autoimmune and autoinflammatory responses is related to many factors. The SARS-CoV-2 can induce a state of the hyperstimulated immune system with changes in the circulating leukocyte and an extensive increase in the levels of the pro-inflammatory cytokines, known as "cytokine release syndrome" in patients with variable degrees of COVID-19[32]. The large RNA with 30,000 nucleotides and the complex transcriptome with the interrupted transcription and recombination activities increase the chance of interaction with the host immune system[68]. The interrupted RNA transcription and recombination produce a wide variability of protein sequences with a powerful resource of epitopes with molecular mimicry, another reason for stimulating the immune system and inducing autoimmunity associated with COVID-19[69]. There is an overlap between some viral and human peptides, so that if altered or mutated could initiate autoimmunity. From these human peptides; cerebellum-2 (which protects against multiple sclerosis), follistatin-related protein 1 (which has anti-hypoxia-induced pulmonary hypertension), Solute carrier family 12 member 6 (responsible for electroneutral potassium-chloride cotransport), and olfactory receptor 7D4 (responsible for the sense of smell)[70]. Tissue damage may result from the viral infection causing cell death and the release of self-proteins to be identified by the host immune system as foreign material and spark the process of autoimmunity[71]. At the same time, there is a hypothesis that sACE-2, which usually binds strongly with SARS-CoV-2 S protein, forms a complex, stimulating the production of anti-ACE2 antibodies and triggering type II and III hypersensitivity reactions and Type IV cellular immune reactions against the viral particles attached to sACE-2, and autoimmunity cascade. The virus-activated T cells could injure the self-tissues by initiating an inflammatory milieu or directly damaging the cells[72]. Table 2 summarizes the causes of the increased immunogenic effect of SARS-CoV-2.

Table 2 Factors that increase the rate of autoimmunity in coronavirus disease 2019.

The ability of the virus to infect nearly all the human body tissues

Large RNA with interrupted transcription increases the pool of epitopes with increased chances of molecular mimicry and interaction with the host immune system

The overlap between some viral and human peptides

The viral-induced tissue damage increases the chance of deviated immune system

The immunogenic effect of the robust and complex binding between sACE-2 and SARS-CoV-2 S protein

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Infection with SARS-CoV-2 can serve as infectome induce a range of autoimmune and auto-inflammatory conditions such as Multisystem Inflammatory Syndrome in Adults (MIS-A), Multisystem Inflammatory Syndrome in Children (MIS-C), and various autoimmune/rheumatic manifestations with a proposed link between the autoimmune and autoinflammatory sequelae of SARS-CoV-2 infection[73]. MIS-C may include Kawasaki-like disease, toxic shock syndrome, Kawasaki disease (KD) shock syndrome, macrophage activation syndrome, and myocarditis. MIS-A, contrary to MIS-C, is not well defined with a hyperinflammatory state and inconsistent features of KD[74]. Although children usually encounter a milder COVID-19 than adults, the severe MIS-C that followed the disease in some children brought several unanswered questions to the scientific community[75].

Patients with COVID-19 may develop a wide variety of autoimmune disorders such as arthritis, antiphospholipid antibody syndrome (APS), MIS-A/C, Kawasaki and Kawasaki-like disease, antiphospholipid syndrome, systemic vasculitis, systemic lupus erythematosus (SLE), hemophagocytic lymphohistiocytosis, autoimmune blood disorders (such as idiopathic thrombocytopenic purpura, autoimmune thrombotic thrombocytopenic purpura, and autoimmune hemolytic anemia), neurological autoimmune disorders (such as encephalitis, cranial neuropathies, Guliian Barre syndrome, myelitis, and optic neuritis, acute disseminated encephalomyelitis {ADEM}, and multiple sclerosis), interstitial lung disease, autoimmune ocular disorders (Retinal vein vasculitic occlusion), renal disorders (Crescentic glomerulonephritis, Goodpasture syndrome), inflammatory bowel disease, and autoimmune endocrine disorders (such as diabetes mellitus and subacute thyroiditis)[76].

Risk factors increasing the likelihood of autoimmune diseases in patients with COVID-19

Infections with SARS-CoV-2 increase the likelihood of autoimmune disease development as about 50% of the patients have autoantibodies in their blood, even with mild disease, and the risk increases with increasing severity. Severe disease is usually associated with a higher viral load with robust immune stimulation and higher antibody levels. There is a strong association between immune hyperactivation and excessive cytokine release in patients with severe COVID-19. However, mild COVID-19 or even asymptomatic infection may also trigger autoimmune disorders[77]. Demographic features such as female gender, old age, overweight, or obesity generally increase the risk of developing autoimmune diseases, particularly with COVID-19. Aging causes functional impairment of the immune with potentially higher autoreactive antibody levels[78]. Although females usually have milder diseases than males with higher recovery rates, they have more chance of autoimmune disorders. The risk difference of autoimmune disorders between males and females is related to sex hormone differences as androgens like testosterone are immunosuppressive, while estrogen may enhance or reduce immune response[79]. Particular ethnic populations are more genetically predisposed to have autoimmune disorders following SARS-CoV-2 infection, such as Caribbean descent, sub-Saharan, Asian, Black, and mixed ethnicity[80]. Nucleic acid vaccine administration may increase the risk of autoinflammatory and autoimmune disorders, especially in young females. In addition, a pre-existing autoimmune disorder is a risk factor for another autoimmune disorder or more severe symptoms following COVID-19[81]. Gut dysbiosis is a risk factor for both COVID-19 and autoimmune diseases. Ivermectin, a commonly used drug in managing COVID-19 in certain countries, induces significant alteration of gut microbiota, which may increase the risk of autoimmune disorders. However, more studies are needed to confirm this hypothesis[63,82].

Common autoantibodies with SARS-CoV-2 infection

Patients with COVID-19 may develop multiple categories of autoantibodies and autoimmune diseases. However, the clinical significance of these antibodies needs more elaboration. From these antibodies are anti-nuclear antibodies (ANA), antiphospholipid antibodies (as lupus anticoagulant, Anti-β2 glycoprotein 1, and anticardiolipin), anti-Interferon-gamma (Anti-IFN-ɣ) antibodies, anti-melanoma differentiation-associated gene 5 (Anti-MDA5) antibodies, and anti-ACE2 autoantibodies[83]. ANA antibodies are found in 4-50% of patients with COVID-19, especially with old age, even without autoimmune disease. Presence of ANA antibodies in patients with COVID-19 increases the incidence of neurologic and thrombotic complications and unfavorable outcomes[76]. Anti-type-I interferon (IFN) antibodies are present in 10.2% of patients presented with severe COVID-19 pneumonia[84]. Antiphospholipid antibodies (anticardiolipin and/or anti-β2 glycoprotein 1) are present in a significant portion of critically ill patients with COVID-19. These antibodies and elevated factor VIII may contribute to hypercoagulopathy in severe cases of COVID-19[85]. Anti-MDA5 antibodies are associated with the rare disease amyopathic dermatomyositis. They are also present in more than 40% of patients with severe COCID-19. Higher titers of Anti-MDA5 antibodies are associated with more severe disease and a higher risk of death[86]. Anti-ACE2 antibodies are present in many patients with COVID-19 and are associated with low plasma levels of sACE-2 and increasing angiotensin II levels, which triggers a pro-inflammatory state that causes symptoms of post-SARS-CoV-2 Acute Sequelae[87]. The SARS-CoV-2 virus causes damage to the human brain via complex indirect processes and stimulates autoantibody formation, predominantly against brain-based antigens (autoantibodies against contactin-associated protein 2, ganglioside GD1b, and myelin oligodendrocyte glycoprotein), inducing a wide variety of COVID-19-triggered neurological complications[64].

COVID-19-INDUCED AUTOIMMUNE DISEASES

Multisystem inflammatory syndromes (MIS-A, MIS-C, and MIS-A/C)

Multisystem inflammatory syndrome (MIS) is a rare acute and non-chronic but seriously complicates COVID-19 in adults and children. It is currently a distinct phenomenon of severe COVID-19 due to the frequent absence of respiratory involvement. The MIS pathogenesis is unclear but primarily due to the autoimmune process. MIS-A associated with COVID-19 infection usually occurs in adults aged 35-54. Clinical recognition of MIS-A is confused with other hyperinflammatory manifestations of COVID-19, which makes MIS-A challenging to distinguish from acute biphasic COVID-19 and post-acute sequelae of SARS-CoV-2 infection[88]. To its name, MIS-A involves multiple organs and systems with at least one or more extrapulmonary organs (an average of 4-5 organs). The most affected organs are hematologic, cardiovascular (myocarditis, pericardial effusion, hypotension, cardiac dysfunction, heart failure, arterial or venous thrombosis, and cardiogenic shock), gastrointestinal tract (diarrhea), acute liver injury, respiratory system (dyspnea), skin manifestations (polymorphic rashes and other mucocutaneous manifestations), renal, and nervous system (severe mononeuritis multiplex[89-91].

It can be diagnosed according to the CDC criteria for defining MIS-A. It should occur in adults aged 21 years or older, with manifestations that need hospitalization for more than 24 h, as determined by clinical and laboratory criteria. Clinical criteria include fever (≥ 38.0 °C) for ≥ 24 h before hospitalization or within the first three hospitalization days plus three or more of the following clinical criteria; one of them at least should be from the primary criteria. Primary clinical criteria include severe cardiac involvement, skin rash, and non-purulent conjunctivitis. Secondary clinical criteria include; new-onset neurologic manifestations, non-medication-related hypotension or shock, abdominal manifestations (abdominal pain, vomiting, or diarrhea), and thrombocytopenia. Laboratory criteria include evidence of recent SARS-CoV-2 infection (positive PCR, antigen, or antibody) and elevated at least two inflammatory markers from the following: erythrocyte sedimentation rate, C-reactive protein, IL-6, ferritin, and procalcitonin[92]. MIS-A should be differentiated from meningitis, intra-abdominal sepsis, KD, drug reaction, and haemophagocytic lymphohistiocytosis. It is treated with corticosteroids, anticoagulants (e.g., heparin, enoxaparin, aspirin), immune modulators such as Infliximab (TNF inhibitors), Tocilizumab (IL-6 receptor inhibitor), Anakinra (IL-1 receptor antagonist), and intravenous immunoglobulin (IVIG). Patients who develop shock/hypotension require intensive care unit admission, vasoactive medications, and respiratory support with mechanical ventilation[93].

MIS-C occurs in people younger than 21, a few weeks after infection with SARS-CoV-2. The affected children have a fever with clinical evidence of severe disease requires hospitalization and multisystem (more than two) organ involvement (heart, kidneys, respiratory, gastrointestinal, hematologic, skin, and/or nervous system) without other possible reasons explaining the manifestations, evidence of recent infection with SARS-CoV-2 (positive PCR, antigen or antibody), and presence of markers of systemic inflammation (high ferritin, fibrinogen, procalcitonin, lactic acid dehydrogenase, C-reactive protein, erythrocyte sedimentation rate, D-dimer, lactic acid dehydrogenase, or interleukin 6, reduced lymphocytes, elevated neutrophils, and low albumin)[94,95]. As MIS-C frequently affects the heart, we may need to perform B-type natriuretic peptide, cardiac enzymes and Troponin I or T, electrocardiogram, and echocardiography. According to the organs affected, other laboratory tests may be needed[96]. MIS-C is primarily treated with supportive care, fluid resuscitation, and inotropic support as a cardiogenic shock is one of the most severe presentations. Respiratory support is indicated with impending respiratory failure. Extracorporeal membranous oxygenation is rarely required. IVIG, steroids, other anti-inflammatories, and anticoagulants are frequently used. Antibiotics may be used with suspected sepsis. Aspirin is commonly prescribed due to the frequent involvement of coronary arteries[97,98].

KD-COVID-19

COVID-19 is usually milder, less frequent, and has less mortality in children than adults due to less maturity and function of ACE2 receptors. Since the early beginning of 2020, there has been an increased reporting of children presented with fever, signs, and features of systemic inflammation common with KD[99]. KD is an acute, usually self-limited systemic inflammatory disease of medium- and small-sized vessels. It mainly involves children under five years of age with higher frequency in children from Asian countries like Japan, where it was first described in 1967[100]. It is usually preceded by upper respiratory tract infections, particularly with RNA viral infection of the upper respiratory tract, as viruses were usually isolated from the mucous obtained from the bronchial epithelium[101]. Despite being a self-limited disease, hemodynamic instability and shock may occur in some cases, known as KD shock syndrome. About 20%–25% of untreated patients of KD develop changes in the coronary arteries, ranging from asymptomatic dilatation or aneurysms to massive aneurysmal dilatation of the coronary artery with thrombosis and myocardial infarction that could progress to sudden death[102].

Symptoms of COVID-19-associated MIS-C may have the standard features of KD. Therefore, it is essential to differentiate between classical KD and COVID-19 (KD-COVID-19). The table shows the differences between the classic KD and KD-COVID-19 [also known as pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2 infection' (PIMS-TS) in Europe and 'multisystem inflammatory syndrome in children (MIS-C)] in the United States. KD-COVID-19 usually occurs in older children, higher incidence of myocarditis and cardiac involvement, more gastrointestinal and meningeal manifestations, shock, hemodynamic failure, manifestations of macrophage activation syndrome, frequent leukopenia, significant lymphopenia, thrombocytopenia, high ferritin, procalcitonin, cardiac enzymes, and troponins than classic KD[103]. Recent or current evidence of SARS-CoV-2 infection is needed to diagnose KD-COVID-19. Patients with KD-COVID-19 have more severe diseases than those with classic KD and frequently need hospitalization and intensive care support[104]. Early diagnosis of COVID-19, recognition of KD-COVID-19, and rapid therapy initiation are vital for effective management, recovery, and prevention of end-organ damage and mortality[105]. IVIG therapy is usually effective in KD-COVID-19, but the resistance rate is more common than in children with classic KD, and steroid therapy is generally needed. In refractory cases to IVIG, pulse intravenous methylprednisolone therapy and aspirin are used, especially when a suspected cardiac injury is present[106]. Hydrogen gas inhalation treats KD-COVID-19 as a stable and efficient antioxidant that positively affects oxidative damage, improves inflammation and cell apoptosis, and antagonizes abnormal blood vessel inflammation[107]. Table 3 summarises the differences between the classic Kawasaki Disease and Kawasaki Disease -COVID-19.

Table 3 Differences between the classic Kawasaki disease and Kawasaki disease - coronavirus disease 2019.

	Classic KD	KD-COVID-19
Age	Children < 5 yr of age	Older age
General condition	Less ill than in KD-COVID-19	More severely ill
Gastrointestinal & meningeal signs	Less common	More common
CBC	Leucocytosis, anemia, & thrombocytosis. Thrombocytopenia may occur	Leukopenia with marked lymphopenia, thrombocytopenia
Ferritin	Increased	Markedly increased
Incidence of myocarditis	Subclinical myocarditis is nearly present in all patients. However, clinically evident myocarditis is uncommon.	Very high, up to 60.4% in patients with KD-like multisystemic disease.
Response to IV gamma globulins	Well-responding	Resistance to IVIG therapy is common.
Adjunct steroids	May be needed	Usually needed

COVID-19: Coronavirus disease 2019; CBC: blood cell count; KD: Kawasaki disease; IVIG: Intravenous immunoglobulin.

APS

There is a high prevalence of venous thrombosis and embolism in patients with COVID-19, especially in severe cases (about 25% to 31% of those without thromboprophylaxis). Consequently, researchers investigated the possible underlying predisposing factors such as hypoxia, immobilization, or disseminated coagulopathy[108]. Serum antiphospholipid antibodies (aPLs), the whole mark of APS, are found in 1%-5% of the healthy population, and their titer increases with age. These rates are comparable to patients with COVID-19 (from 2.7% to 13.4%), which decreases the possibility of recognizable association with thrombosis[109,110]. Another study showed that serum antiphospholipid antibodies might be found transiently in up to 12% of young, healthy subjects, increased to 18% in older adults with chronic diseases[111]. The presence of aPL is not enough to develop APS; a second hit such as aging, critical illnesses, or infections is needed to trigger the development of APS. APS is characterized by documented thrombotic and/or pregnancy-related morbidity in the presence of persistent medium to a high titer of aPLs. To diagnose APS according to Sydney criteria, we need to have persistent high titers of lupus anticoagulant, anticardiolipin antibodies IgG or IgM, or anti-β2glycoprotein-1 IgG and/or IgM for at least 12 wk[112]. However, these criteria need to be modified to limit testing to lupus anticoagulant and anti-β2glycoprotein-1 IgG and to omit anticardiolipin antibodies and anti-β2glycoprotein-1 IgM from laboratory testing. Lupus anticoagulants and anti-β2glycoprotein-1 IgG are associated with a higher risk of thrombosis, particularly lupus anticoagulants[113].

Some studies elucidated high levels of lupus anticoagulants in patients with COVID-19. However, it is unknown whether lupus anticoagulant was newly produced with COVID-19 or increased in a previously present titer[114]. Another study by Xiao et al[115] showed that aPLs were present in 47% of critically ill patients due to COVID-19. They also analyzed the risk of developing cerebral infarction by the type of aPLs, with IgA anti-β2glycoprotein-1 being the aPL antibody associated with the highest infarction risk, followed by IgA anticardiolipin antibodies and IgG anti-β2glycoprotein-1. The study also showed that these antibodies need to appear five to six weeks after the disease onset, indicating that a long disease course increases the risk of developing APS and, consequently, thrombotic complications. A severe fatal form of APS (Catastrophic APS) was recorded in some patients with COVID-19. However, there is no current strong evidence of CAPS association with COVID-19. CAPS presented with acute multiorgan involvement (three or more organs, systems, and/or tissues), proof of widespread vascular occlusions, intense hypercoagulable state, and elevated titers of aPLs. Lupus anticoagulant, anticardiolipin IgG, and anticardiolipin IgM were seen in 83%, 81%, and 49% of patients with CAPS[116]. Some factors usually trigger CAPS, such as viral infections, including COVID-19, especially pulmonary infections. SARS-CoV-2 may aggravate the pathogenic effects of APS, initiating inflammatory and prothrombotic cascades. The positive tropism of SARS-CoV-2 towards the vascular endothelium may also alter the COVID-19 clinical presentation in susceptible patients and initiate flaring up of underlying vascular diseases. As CAPS has a high mortality rate, approaching 50%, timely identification and management are vital[117]. It responds to plasmapheresis or plasma exchange. However, it poorly responds to anticoagulant therapy with high mortality risk[118].

SLE

SLE is a chronic multisystem autoimmune disease with varied relapsing or remitting clinical manifestations. It is more common in females and certain ethnic groups, such as African Americans and Hispanics. Due to the aberrant immune system activity in SLE, immune complexes and autoimmune antibodies are significantly produced against cytoplasmic and nuclear antigens[119]. Few patients reports documented newly diagnosed SLE in patients with COVID-19. There is a wide variation in the clinical presentation in the reported cases. It presented with manifestations of serositis (pericardial and pleural effusion), renal manifestations (nephritis, proteinuria), skin manifestations (varicella-like rash), cardiac dysfunctions (pericardial tamponade, ventricular dysfunction), secondary APS, neurological complications (neuropsychiatric symptoms, cerebral hemorrhage), hematological disorders (anemia, positive direct Coombs, hemolytic anemia, lymphopenia, thrombocytopenia,), finger vasculitis, low complement, and presence of autoantibodies (aPL, ANA, and anti- dsDNA). Patients with COVID-19-associated SLE had a high mortality rate reaching 50%. Hence appropriate and prompt diagnosis and management are highly indicated to decrease morbidity and mortality. Renal involvement carries the worst prognostic predictor with the highest mortality rate. The treatment should be individualized and may involve glucocorticoids, plasma exchange, hydroxychloroquine, anticoagulation, tocilizumab, and intravenous immunoglobulins[120-123].

Autoimmune-like neurologic disease

SARS-CoV-2-triggered inflammatory and autoimmune cascades may affect the nervous system, producing various neurological complications. About 60% of patients with COVID-19 suffer from anosmia (loss of smelling) and ageusia (loss of taste sensation), which verifies the hypothesis of its neurovirulence[48]. This high percentage of anosmia and ageusia observed with SARS-CoV-2 infection indicates the high viral neurotropism with the olfactory nerve serves as a portal of brain entry. However, anosmia and ageusia can be the first or only symptoms present in some patients with COVID-19[124]. Another portal of brain entry is through retrograde axonal transport via peripheral and cranial nerves. An example of this portal of entry is SARS-CoV-2-associated Guillain-Barre syndrome, an acute inflammatory, demyelinating, sensorimotor polyradiculoneuropathies frequently reported in patients with COVID-19. It results from the autoantibodies production that cross-react with myelin components gangliosides and glycolipids present in the peripheral nerves due to molecular mimicry. These autoantibodies cause peripheral nerve demyelination and axonal damage in a progressive ascending pattern[125]. It occurs primarily secondary to SARS-CoV-2-induced immune reaction, as the virus was not detected in the cerebrospinal fluid of any patient suffering from GBS[126].

Miller Fisher syndrome (MFS) and polyneuritis cranialis were rarely reported as autoimmune neurological complications of SARS-CoV-2 infection. They are other examples of the virus's neurotropism and its ability to rapidly spread to the different brain areas, including the thalamus and the brain stem. MFS is classically present with acute onset of a triad composed of external ophthalmoplegia, loss of tendon reflexes, and ataxia[127]. Polyneuritis cranialis is a rare, gradual, and slowly progressive disorder involving multiple cranial nerves (usually IV, V, VI, and VII). Viral infection often preceded these disorders, which triggered an immune-mediated mechanism. Few reported cases followed SARS-CoV-2 infection. CSF showed albuminocytological dissociation, and the patients had a significant elevation of inflammatory mediators, such as the interleukin-8. It can be successfully treated with IVIG[128]. Other reported neurological disorders related to COVID-19 aberrant immune response include acute motor-sensory axonal neuropathy, acute transverse myelitis, acute necrotizing encephalopathy, acute necrotizing myelitis, and acute disseminated encephalomyelitis[129].

Post-COVID-19 pneumonia lung fibrosis

Progressive pulmonary fibrosis following COVID-19 pneumonia is one of the severe complications of SARS-CoV-2 infections that could be associated with irreversible lung dysfunction. Post-COVID-19 pulmonary fibrosis is multifactorial, with many theories explaining the potential causes of post-COVID pulmonary fibrosis. One theory is the cytokine storm caused by an aberrant immune mechanism that triggers pulmonary fibrosis[130]. IL-6 is a pro-inflammatory cytokine with a pro-fibrotic activity that activates the neutrophils and their accumulation at the injury site. Neutrophil accumulation causes proteases and oxygen-free radical release causing pulmonary interstitial edema and acute inflammation[131]. Annexin A2 is crucial to protect against pulmonary fibrosis as it is essential to activate endogenous tissue plasminogen activator to lyse clots and promote fibrin clearance and pulmonary fibrinolysis[132]. Anti-Annexin A2 antibodies are associated with systemic thrombosis, cell death, and non-cardiogenic pulmonary edema. Annexin A2 inhibition can induce diffuse alveolar damage and pulmonary fibrosis in patients with severe COVID-19[133].

Arthritis

Arthritis was reported early in COVID-19 or lately after the resolution of the disease. Different types of arthritis were reported in patients with COVID-19; viral arthritis, reactive arthritis, chronic arthritis, and rheumatoid arthritis[134]. López-González et al[135] reported joint pain in some patients with COVID-19; some did not have other signs of arthritis. They also reported crystal-induced arthritis (gouty with monosodium urate and pseudogouty with calcium pyrophosphate) in some patients. Ono et al[136] reported the occurrence of reactive arthritis three weeks later in a patient who developed severe COVID-19 pneumonia. The patient improved with anti-Inflammatory non-steroidal drugs and intra-articular corticosteroid injection. Reactive arthritis generally develops one to three weeks after the infection. The precise mechanisms of COVID-19-induced arthritis are not entirely identified. It could be related to viral-induced macrophage activation with subsequent release of cytokines and chemokines in high amounts, sparking the inflammatory process[82]. Although viremia is expected in reactive arthritis, SARS-CoV-2 was detected only in the blood in 15% of cases with COVID-19. Consequently, molecular mimicry may explain arthritis pathogenesis[137]. Inflammatory mediators such as Interleukin 17 A are present in patients with reactive arthritis, spondyloarthritis, and COVID-19 -induced hyperinflammatory state[138].

COVID-19-induced vasculitis

SARS-COV-2 can directly infect the vascular endothelium causing endotheliopathy. Indirect damage to the vascular endothelium can also be induced by the inflammatory mediators triggered by COVID-19[139]. Few case reports are documenting the development of COVID-19-associated vasculitis with positive anti-neutrophil cytoplasmic antibodies (ANCA). Uppal et al[140] described two cases of pauci-immune glomerulonephritis with high perinuclear-ANCA titer during SARS-CoV-2 infection. They clinically improved with the treatment of COVID-19 and the use of rituximab. Hussein et al[141] described a female patient who developed granulomatosis with polyangiitis and alveolar hemorrhage during COVID-19 infection. She was treated successfully with pulse steroid therapy, plasmapheresis, and IVIG. These reported cases clarify the importance of vascular endothelium in the pathophysiology and clinical course of COVID-19 and the need for a better understanding of the endothelial biology in patients with COVID-19[142].

Skin autoimmune disorders

Cutaneous manifestations of COVID-19 are common and may involve erythematous, maculopapular, urticarial petechial skin rashes, or diffuse disseminated erythema. The rashes may appear with the onset of the disease and may not correlate with the disease severity[143]. Pityriasis rosea-like rashes were reported in one patient with mild COVID-19[144]. Various reports described acral chilblain lesions due to vacuolar interface dermatitis with superficial and deep perivascular and periadnexal lymphohistiocytic infiltration[145,146]. Violaceous papules and digital swelling occur due to diffuse perivascular dense lymphoid infiltration of the dermis and hypodermis[147]. Desquamation of the peripheral digits may occur in younger children with severe disease or as a sign of KD-COVID-19[148]. Daneshgaran et al[149] showed that underlying mechanisms of skin involvement in patients with COVID-19 are related to cytokine release syndrome, coagulation and complement systems activation, or direct virus-induced skin damage with endothelial damage of the dermal vasculatures.

POST-VACCINATION AUTOIMMUNE DISORDERS

The vaccines work by provoking an immune response against specific antigens in the target organism that causes the disease with a long-lasting memory T-cell response. Vaccine adjuvants are used to enhance the immune response against the vaccine. However, these adjuvants can trigger autoimmune responses[150]. Vaccines have been involved in triggering autoimmune diseases for a long time. GBS was reported with Flu and Human Papilloma vaccines, and idiopathic thrombocytopenia occurred in some patients receiving the Measles-Mumps-Rubella vaccine[151]. COVID-19 vaccines can trigger a wide range of skin reactions; from non-specific local injection-site reactions to Type-I hypersensitivity reactions (e.g., urticarial rashes, angioneurotic edema, and even anaphylaxis) to Type-IV delayed hypersensitivity reactions (including delayed large skin lesions ("COVID arm") at the injection site, inflammatory reactions in a previous skin lesion, and more frequently erythema multiforme-like and morbilliform rashes[152]. COVID-19 vaccination-induced autoimmune skin disorders include immune thrombocytopenia, leukocytoclastic vasculitis, and lupus erythematosus[153].

Severe anaphylaxis was reported with Pfizer-BioNTech and Moderna vaccines. Consequently, the CDC recommends that prefilled epinephrine syringes be available in vaccination centers and observe the vaccinees for 15 or 30 min[154]. Delayed-type or T-cell mediated hypersensitivity adverse reactions were reported in 0.8% of the vaccinees near the injection site[155]. SARS-CoV-2 vaccination may also be complicated by autoimmune diseases that involve the skin, such as lupus erythematosus (LE), bullous pemphigoid, vitiligo, alopecia areata, and leukocytoclastic vasculitis[156,157]. Akinosoglou et al[159] reported bilateral elbow itchy annular granulomatous rash due to cutaneous small cell vasculitis after the first dose of the Pfizer-BioNTech vaccine. The rashes spontaneously resolved without medications within three to four days[158]. These vaccine-related adverse effects could be related to a pre-existing dysregulated immune status that could enhance polyclonal B-cell expansion with increased immune complex formation resulting in clinically significant vasculitis in genetically susceptible individuals[159].

MIS-A was reported in three patients within three to fourteen days after COVID-19 vaccination; one of them presented with shock. The three patients had underlying comorbidities such as asthma, depression, and hyperlipidemia[160]. Mild myocarditis was reported in six male patients between 16 and 49 years from Israel following BNT162b2 mRNA COVID-19 vaccination. Five presented one to three days after the second dose, while only one presented after 16 days from the first dose. All of them completely recovered within 4-8 d[161]. Autoimmune thyroid diseases (subacute thyroiditis and Graves' disease) were reported in a few persons following SARS-CoV-2 vaccinations, which could be a form of adjuvants-induced autoimmune/inflammatory syndrome (ASIA). Subacute thyroiditis and Graves' disease had developed in the reported cases within a few days following SARS-CoV-2 vaccination. ASIA was the underlying mechanism for several autoimmune endocrinopathies that developed after vaccination[150,162,163]. An et al[164] reported reactive arthritis in the left knee in a 23-year female; three days following the first and second doses of Sinovac-CoronaVac COVID-19 (inactivated whole virus) vaccine. She has a history of a similar condition two years before following a common cold which may indicate the genetic susceptibility of this patient.

Autoimmune hematological disorders were also observed following COVID-19 vaccination. Lee et al[165] reported that twenty patients between 22 and 73 years old developed immune thrombocytopenia and bleeding without thrombosis following Pfizer and Moderna SARS-CoV-2 (mRNA) vaccination. These patients tested positive for anti-platelet antibodies; some have other autoimmune conditions such as Crohn's disease or autoimmune hypothyroidism. Meanwhile, Cines et al[166] analyzed three independent reports describing 39 persons who developed immune thrombotic thrombocytopenia following the AstraZeneca COVID-19 vaccine (vaccine with modified recombinant adenovirus to encode SARS-CoV-2 S protein). Most patients had high antibody titer against platelet factor 4–polyanion complexes. Fourty% of the patients died from a cerebral hemorrhage, infarction, or both. Fatima et al[167] reported a 66-year-old woman who developed IgG-mediated autoimmune hemolytic anemia after Moderna COVID-19 (mRNA) vaccine. The patient had a history of psoriasis for five years before the vaccination.

Gaignard et al[168] also reported 77-year- males without previous comorbidities who developed autoimmune hemolytic anemia due to warm antibodies following Moderna COVID-19 (mRNA) vaccine. Brito et al[169] reported severe autoimmune hemolytic anemia in an 88-year-old Caucasian woman two days after the second dose of the COVID-19 mRNA vaccine. She had very high levels of anti-erythrocyte IgG and anti-C3d autoantibodies but without cold agglutinins. Murdych also reported severe autoimmune hemolytic anemia in an 84-year-old man with multiple comorbidities after the first dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. The patient tested positive for direct antiglobulin, anti-IgG, direct antiglobulin, polyspecific antihuman globulin, and negative anti-C3[170]. There are several other reports of autoimmune hepatitis following mRNA or viral vector COVID-19 vaccines. Drug-induced hepatitis was also reported following the inactivated whole virus vaccine[171].

Neurological side effects of the COVID-19 vaccine are usually mild. However, severe adverse autoimmune neurological sequelae were reported. Waheed et al[172] reported GBS in an 82-year-old highly functional woman without significant comorbidities 14 d after the first shot of the Pfizer COVID-19 vaccine. She was successfully treated with IVIG. Other neurological complications such as Bell's palsy, acute transverse myelitis, acute demyelinating polyneuropathy, and transverse myelitis were reported, especially with mRNA vaccine[173]. Cerebral venous sinus thrombosis was also described in women of childbearing age, especially with adenovector-based vaccination[174]. The importance of developing vaccine-related autoimmune reactions or diseases is related to their impact on the intake of second dose vaccination and the morbidity rate. However, being cautious is preferable until reliable data and a more extended experience are established[175]. It is also essential to be highly suspicious when reporting vaccine-related side effects and rule out actual SARS-CoV-2 infection.

EFFECTS OF AUTOIMMUNE DISEASES ON THE COURSE OF COVID-19

Patients with immune deficiencies or autoimmune disorders are at a higher risk for infection with COVID-19, as they are frequently treated with anti-cytokine, glucocorticoids, and/or immunosuppressive drugs. The infection rate with COVID-19 among people with immune diseases is twice that of the general population[176]. The data derived from international registries of patients with rheumatic diseases (C19-GRA3) who encountered COVID-19 showed poor outcomes depending on their medications[177]. For example, patients treated with antitumor necrosis factor (TNF) showed decreased hospitalization risk, indicating the protective effects of anti-TNF monotherapy against severe COVID-19. Antimalarial drugs (such as hydroxychloroquine), non-steroidal anti-inflammatory drugs, and biologic therapies were not related to increasing the risk of hospitalization due to COVID-19. In contrast, patients who received moderate to high dose glucocorticoids had poor prognoses and clinical outcomes[177,178]. However, other factors may also play a role in the clinical outcome that need more studies.

Meanwhile, the study by Gianfrancesco et al[179] showed that most patients with autoimmune disorders who encountered COVID-19 had entirely recovered from the infection, which could help assure these patients. A meta-analysis by Akiyama et al[176] showed that while patients with autoimmune disorders have an increased prevalence of COVID-19, their prognosis and clinical outcome were not significantly worse than individuals without autoimmune diseases. They related the higher rate of COVID-19 in patients with an autoimmune disorder to the increased rate of glucocorticoid use. A recent study by Malek Mahdavi et al[180] showed that the presence of other comorbidities (female gender, obesity, hypertension, cardiac disease, diabetes mellitus, pulmonary disease, and chronic renal disease) in patients with rheumatoid arthritis in addition to treatment with prednisolone > five mg/day and TNFα inhibitors were independent predictors of COVID-19 outcome. They also observed that symptoms such as anosmia, dyspnea, and taste loss were more common than in the general population. When comparing the effects of COVID-19 with influenza on patients with autoimmune diseases, Tan et al[181] found that the hospitalized patients due to COVID-19 had poor outcomes and higher mortality rates than with influenza. However, this study had many limitations, so we can not generalize their findings. Both autoimmune disease and COVID-19 are known to increase the risk of venous thromboembolism. Consequently, the co-occurrence of COVID-19 in patients with autoimmune diseases may heighten this risk. D'Silva et al[182] found that patients with autoimmune disorders had a higher risk of venous thromboembolism when infected with SARS-CoV-2 than the general population, independent of comorbidities.

Factors affecting the severity Of COVID-19 in patients with autoimmune diseases

Table 4 summarises the factors that affect the severity of COVID-19 in patients with autoimmune disorders. The male sex and old age worsen the prognosis in patients with autoimmune diseases, similar to what is observed in the general population[183]. Freites Nuñez et al[184] indicated that age over fifty is an independent risk factor for hospitalization due to COVID-19 in patients with autoimmune diseases. Peach et al[185] found that the COVID-19-related mortality risk is higher in patients with autoimmune diseases with age equal to or higher than 35 years. They also showed that women with autoimmune diseases have a higher COVID-19-related mortality rate than men, contrary to the previous studies. The type of autoimmune disease can affect the severity of infection with SARS-CoV-2. For example, patients with SLE are at higher risk of severe COVID-19 than patients with rheumatoid arthritis. Patients with SLE may have a high rate of hypomethylation and ACE2 overexpression that may ease the viral entry into the cell[186].

Table 4 Factors that affect the severity of coronavirus disease 2019 in patients with autoimmune diseases.

The age and sex of the patients

The type of the autoimmune disease

The severity of the autoimmune disease.

Presence of comorbidities

The type of medication used

Disruption of the medical care continuity

Lack of medication adherence

Other factors that increase COVID-19 severity in the general population

COVID-19: Coronavirus disease 2019.

On the other hand, Ayala Gutiérrez et al[183] found that patients with rheumatoid arthritis, polymyalgia rheumatica, vasculitis, and spondyloarthropathies had a worse prognosis; In comparison, patients with primary Sjögren syndrome and systemic sclerosis had a better prognosis. The presence of medical comorbidities (such as diabetes, hypertension, and obesity) in patients with autoimmune disorders increases the probability of hospitalization, intensive care unit (ICU) admission, and acute renal failure when they encounter SARS-CoV-2 infection[182]. The type of medication used can alleviate or worsen the course of COVID-19. Some drugs used to treat autoimmune diseases (such as Tocilizumab, Anakinra, Baricitinib, or hydroxychloroquine) might have a preventive effect in patients with severe COVID-19 infections. This finding may illustrate the underlying pathogenetic relationship between COVID-19 and autoimmune diseases[187]. Patients with autoimmune diseases treated with rituximab may be at greater risk of severe SARS-CoV-2-induced pneumonia than the general population[188]. Disruption of the medical care continuity and lack of medication adherence due to the restrictions during the pandemic may make the patient prone to flare-up and worsen the associated autoimmune disease activity[189].

CONCERN ABOUT COVID-19 VACCINATION IN PATIENTS WITH AUTOIMMUNE DISORDERS

The immunogenicity and safety data of COVID-19 vaccines are still limited because patients with chronic diseases, including autoimmune diseases and immunosuppressed patients, were excluded from most experimental vaccine studies. Patients with autoimmune diseases are more liable for a more severe and complicated course of COVID-19 than the general population. Hence, the vaccination benefits far outweigh the risks[190]. According to the general vaccination guidelines in patients with immune deficiency or autoimmune diseases, giving these patients non-live vaccines (including mRNA vaccines) is recommended, providing adequate cellular and humoral immune response. It is preferable to give these patients the immunization during the disease's remission and without concurrent infections[191].

Patients on high doses of corticosteroids or Rituximab may avoid the vaccination. Preferably, COVID-19 vaccinations should be given before initiating any biological disease-modifying agents. Patients may receive the COVID-19 vaccine one month before or at least six months after the last Rituximab infusion, as Rituximab impairs the antibody responses for at least six months after administration[192]. Patients with autoimmune diseases or immune deficiency should receive annual influenza and Streptococcus pneumonia vaccination. COVID-19 vaccine should be given alone and at least two weeks before or after other vaccines. Coordinating timing with dosing regimens of COVID-19 vaccines may optimize the vaccine safety and efficacy, especially in patients with autoimmune diseases[193].

WAYS TO MINIMIZE THE RISK OF COVID-19 IN PATIENTS WITH AUTOIMMUNE DISEASES

Patients with autoimmune diseases are more liable to nutritional inadequacy due to the effects of the disease itself or related to the medications used. The nutritional inadequacy may increase the susceptibility to infection, especially to COVID-19, and permit infections to be more serious, even fatal[194]. Immune-regulator micronutrients such as vitamin A, D, and zinc are essential for immune cell metabolism and may provide antibacterial or anti-viral effects. Other micronutrients such as arginine may be needed as substrates for immune-active metabolites production, such as nitric oxide, one of the most crucial players in immunity[195]. Vitamin D decreases the risk of respiratory tract infections and other respiratory disorders. It is better to be taken daily to obtain maximum effects[196,197]. Vitamin E, Vitamin C, selenium, zinc, plant polyphenols, and long-chain omega-3 fatty acids have anti-oxidative effects and protect against inflammatory stress[198]. Adequate nutrition is essential for healthy gut microbiota, which plays a fundamental role in immunity modulation[199]. Several studies showed the efficacy of probiotics in gut microbial modification, improving gastrointestinal manifestation, and reducing multiorgan inflammation in different autoimmune diseases[200,201]. Licorice is a traditional herb used as a drink in Egypt for many centuries. It has many beneficial effects, such as anti-inflammatory, antitussive, antibacterial, immunomodulatory, and detoxifying agents for many disorders, especially respiratory diseases. It has a solid potential to be an effective adjuvant to prevent and treat COVID-19 with significant anti-inflammatory, anti-ACE2, and the ability to alleviate the clinical symptoms of the disease such as dry cough, shortness of breath, and fever[63].

Gut microbiota is an essential determinant of immunity. COVID-19 causes disruption of the intestinal flora and microbiota dysbiosis, which induces Th17 cell polarization in the small intestine with excessive interleukin (IL)-17A production, recruitment of neutrophils, and more intestinal mucosal immune damage[202]. Several studies highlighted the pathogenetic prole of the microbiome in the development of autoimmune diseases, especially in systemic lupus erythematosus. Peng et al[203] showed that probiotics successfully adjunctive therapy in SARS-CoV-2 infection[204]. Consequently, improving the host nutrition and general condition increases the ability to fight infection and enhances the vaccination response. Alcohol consumption and smoking should be avoided during the COVID-19 pandemic, particularly in patients with autoimmune diseases. Alcohol exacerbates intestinal inflammation, alters intestinal microbiota's composition and function, increases intestinal permeability, and disturbs intestinal immune homeostasi[205]. Cigarette smoking impairs various body functions such as cardiovascular, respiratory, and immune systems and exacerbates autoimmune diseases and allergies. Smoking impairs the nuclear factor-kappaB (NFκB), mitogen-activated protein kinases, and histone modification. It also impairs innate and adaptive immunity and makes the smoker more prone to infection[206].

Sleep hygiene has a direct impact on immunity upkeep and immunological response. Disordered Circadian rhythm, due to physical, social, or psychological disorders encountered during the COVID-19 pandemic, compromises the sleep quality and hence the immune system. Good sleep quality improves the response to vaccination and increases the resistance to infectious diseases[207]. Poor sleep quality is associated with increased pro-inflammatory interleukin levels (IL-1β, TNF-α, and IL-6)[208]. Exercise during the COVID-19 pandemic promotes health, improves host immunity, and should be encouraged. Acute and chronic exercise of moderate intensity can control excessive respiratory inflammation through multiple pathways. It also enhances and regulates the immune defense mechanism, particularly innate immunity, and improves metabolic health[209].

The enforced social isolation and stress during the pandemic negatively affect individual health, especially in children and the elderly[210,211]. Social isolation and anxiety disturb the various biological systems and the circulating stress hormones, glutamate, and immune system components[212]. Social isolation also triggers neuroinflammation and microglia overactivation and disturbs gut microbiota, inducing various neurological and autoimmune disorders. Therefore, a multi-purpose comprehensive social and family program with exercise and psychological support is highly needed for patients with autoimmune diseases to lessen the harmful effects of social isolation impeded during the COVID-19[213-219].

CONCLUSION

Mutual relations exist between COVID-19 and autoimmune diseases. Patients with autoimmune disorders are at an increased risk for COVID-19, and COVID-19 or its vaccine can trigger autoimmune diseases. Patients with autoimmune diseases should continue their medication but could be modified according to their clinical condition. Vaccination with non-living viruses, including mRNA, is safe and could prevent serious COVID-19. However, the COVID-19 vaccination could also trigger autoimmune disease. Consequently, precautions and strict follow-up are needed for these patients.

ACKNOWLEDGEMENTS

We thank the anonymous referees and editors for their valuable suggestions.