NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.

COronaVIrus Disease-2019 (COVID-19) is associated with a hypercoagulable state. Intracardiac thrombosis is a potentially serious complication but has seldom been evaluated in COVID-19 patients. We assessed the incidence, associated factors, and outcomes of COVID-19 patients with intracardiac thrombosis. In 2020, COVID-19 inpatients were identified from the National Inpatient Sample (NIS) database. Data on clinical characteristics, intracardiac thrombosis, and adverse outcomes were collected. Multivariable logistic regression was used to identify factors associated with intracardiac thrombosis, in-hospital mortality, and morbidities. In 2020, 1,683,785 COVID-19 inpatients (mean age 63.8 years, 32.2% females) were studied. Intracardiac thrombosis occurred in 0.10% (1830) of cases. In-hospital outcomes included 13.2% all-cause mortality, 3.5% cardiovascular mortality, 2.6% cardiac arrest, 4.4% acute coronary syndrome (ACS), 16.1% heart failure, 1.3% stroke, and 28.3% acute kidney injury (AKI). Key factors for intracardiac thrombosis were congestive heart failure history and coagulopathy. Intracardiac thrombosis independently linked to higher risks of all-cause mortality (odds ratio [OR]: 3.32 (2.42-4.54)), cardiovascular mortality (OR: 2.95 (1.96-4.44)), cardiac arrest (OR: 2.04 (1.22-3.43)), ACS (OR: 1.62 (1.17-2.22)), stroke (OR: 3.10 (2.11-4.56)), and AKI (OR: 2.13 (1.68-2.69)), but not heart failure. While rare, intracardiac thrombosis in COVID-19 patients independently raised in-hospital mortality and morbidity risks.

Thrombophilia, characterized by an imbalance between fibrinolysis and coagulation leading to inappropriate blood clotting, is a significant medical condition. The CDC has designated it as an underdiagnosed, serious, and potentially preventable disorder, contributing to an estimated 600,000-900,000 cases and 100,000 deaths annually in the United States. These figures surpass the combined annual mortality of AIDS, breast cancer, and motor vehicle accidents. The pathogenesis of thrombophilia involves complex interactions between genetic predispositions, such as mutations in Factor V Leiden, Factor II, MTHFR, and Serpine-1, and environmental factors, including unhealthy lifestyles, prolonged hospitalization, obesity, and cancer. Prevalence of specific genetic mutations varies across populations. Additional risk factors include age, family history, and pregnancy, with recent attention to increased susceptibility in SARS-CoV-2 infection. While molecular diagnostic techniques are available, there remains a need for robust, cost-effective, and accurate screening methods for large populations. This systematic review provides an updated overview of thrombophilia, encompassing pathophysiology, epidemiology, genetic and environmental risk factors, coagulation cascade, population-specific mutation prevalence, and diagnostic approaches. By synthesizing clinical and molecular evidence, this review aims to guide researchers, hematologists, and clinicians in the diagnosis and management of thrombophilia.

The antibody-mediated immune response is crucial for the development of protective immunity against SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Understanding the interaction between SARS-CoV-2 and the immune system is critical because new variants emerge as a result of the virus's ongoing evolution. Understanding the function of B cells in the SARS-CoV-2 infection process is critical for developing effective and long-lasting vaccines against this virus. Triggered by the innate immune response, B cells transform into memory B cells (MBCs). It is fascinating to observe how MBCs provide enduring immune defence, not only eradicating the infection but also safeguarding against future reinfection. If there is a lack of B cell activation or if the B cells are not functioning properly, it can lead to a serious manifestation of the disease and make immunisation less effective. Individuals with disruptions in the B cells have shown increased production of cytokines and chemokines, resulting in a poor prognosis for the disease. Therefore, we have developed an updated review article to gain insight into the involvement of B cells in SARS-CoV-2 infection. The discussion has covered the generation, functioning, and dynamics of neutralising antibodies (nAbs). Furthermore, we have emphasised immunotherapeutics that rely on nAbs.

The emergence of catastrophic antiphospholipid syndrome (CAPS) alongside coronavirus disease 2019 (COVID-19) is of great concern, because of its high mortality and unclear mechanism. This severe disease, characterized by multiple thrombi and multisystem disorder, has notably diverse clinical presentations, which complicates its diagnosis in clinical practice. Now, we report a rare case of CAPS in a patient with COVID-19.

A 64-year-old patient who mainly presented with pain and swelling 2 months ago progressed gradually into multiple thrombi, including pulmonary embolism, renal embolism, and deep vein thrombosis; transient ischemic attack; multiple organ dysfunction with acute kidney injury; and necrosis of both lower limbs, left upper extremity, both ears, and penile gangrene.

He was diagnosed as CAPS with COVID-19 by positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) testing and high-titer immunoglobulin (Ig) A anti-β2-glycoprotein I antibody (anti-β2GPI).

Active rescue treatments such as anticoagulants, plasmapheresis, glucocorticoid pulse therapy, antibiotics, and multi-organ functional support alleviated the disease effectively.

Although his clinical symptoms were successfully controlled, we could not save the necrotic tissue. The patient refused to undergo limb amputation and died of necrotic tissue infection.

CAPS in patients with COVID-19 is an extremely serious disease with a high mortality rate. A delay in diagnosis and treatment can result in potentially devastating consequences. Therefore, physicians should be alert to the possibility of CAPS in patients with multiple thrombi and COVID-19. Furthermore, this case serves as a foundation upon which future studies can build to investigate the possible mechanisms of IgA anti-β2GPI-positive CAPS in patients with COVID-19, which may guide the exploration of potential therapeutic strategies to prevent the disease's progression.

Long COVID (LC) is a novel condition that is characterized by persistent symptoms that last from months to years following a SARS-CoV-2 infection. While LC symptoms vary widely, neuropathy is one of the most prevalent symptoms and drastically affects patients' quality of life. However, the underlying pathophysiology of LC neuropathy remains poorly understood. Here, we investigated the prevalence and potential mechanisms of LC neuropathy in the largest LC neuropathy cohort to date.

We conducted an observational study of 977 adults with LC at Dell Medical School. Participants underwent clinical assessments, skin punch biopsy, and comprehensive metabolic, endocrine and immunological profiling. A subset of patients received treatment with intravenous immunoglobulin (IVIG).

Neuropathic symptoms were reported by 55% (534/977) participants, with skin biopsy confirming small fiber neuropathy in 56.5% (48/85) cases, affecting both epidermal and autonomic nerve fibers. Common risk factors for neuropathy, including metabolic and endocrine disorders, did not fully explain neuropathic symptoms. While general immunological markers (lymphocyte, T cell, and B cell count and C reactive protein were unremarkable, unexpectedly, we detected anti-ganglioside antibodies (AGAs) in 25% of patients with LC neuropathy, a comparable rate to other AGA-associated neuropathies. Longitudinal testing revealed persistent AGA positivity, and multiple elevated AGAs in a subset of patients. In a pilot treatment cohort of eight patients, IVIG treatment resulted in improvement of patient reported neuropathic symptoms.

Our findings reveal a high prevalence of small fiber neuropathy in LC, with evidence suggesting an autoimmune mechanism involving AGAs in one in four LC neuropathy patients. The therapeutic response to IVIG further supports an autoimmune pathophysiology, suggesting potential benefits of immunomodulation in LC neuropathy patients.

In some reports, antiphospholipid antibodies (aPL) prevalence is higher in COVID-19 patients. This study intended to compare aPL prevalence between COVID-19 patients and healthy controls, and differences in aPL types using meta-analysis.

This work retrieved published literature about association between COVID-19 and aPL from Embase, Web of Science, PubMed, and The Cochrane Library databases. The observation group was COVID-19 patients, and the control group was healthy individuals. Outcome measures contained any of following aPLs: classic aPL: anti-cardiolipin antibodies (aCL) and anti-β2-glycoprotein-1 antibodies (Anti-β2GP1); other non-criteria aPL: anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and anti-annexin-V antibodies (AnV). Meta-analysis was done on Review Manager 5.4.

10 studies involving 2288 patients were deemed eligible for inclusion. The results of the meta-analysis showed that the prevalence of Classic aPL and Any aPL in the COVID-19 group was significantly higher than in the healthy group (Classic aPL, RR = 2.55, 95 % CI = 1.83-3.55, P < 0.00001; Any aPL, RR = 2.34, 95 % CI = 1.46-3.77, P = 0.0005). Anti-β2GP1 IgA antibodies were the most common aPL in COVID-19 patients, with a significantly higher prevalence than in the healthy group (RR = 4.26, 95 % CI = 2.84-6.40, P < 0.00001). The prevalence of the four types of IgM aPL was significantly higher in the COVID-19 group compared to the healthy group, while there was no significant difference in aPL IgG between the two groups.

The prevalence of aPL in COVID-19 patients was significantly higher than in the healthy control group. IgM aPL was more easily detectable in the early stages of COVID-19 infection, while IgG aPL may be of more concern in the later time points of the immune epidemiology following SARS-CoV-2 infection.

Antiphospholipid syndrome (APS) is a well-established cause of recurrent pregnancy loss (RPL). If coronavirus disease 2019 (COVID-19) infection or vaccination induces antiphospholipid antibody (aPL) production, it may lead to miscarriage in subsequent pregnancies. We investigated the association between COVID-19 infection and vaccination history with aPL positivity in women with RPL. This study included 424 women with RPL. We found no difference in the positivity rate for aPL according to the presence or absence of a history of COVID-19 infection. The positivity rate was significantly higher in patients infected during the omicron period (27.9 %, 43/154) than in those infected during the delta period (8.7 %, 2/23) of the COVID-19 pandemic (P = 0.0351). Of the 416 patients with a detailed vaccination history, 365 (87.7 %) had received at least one vaccination. The aPL positivity rate did not significantly differ according to the history of vaccination or number of vaccinations. Our results suggest that mild COVID-19 infection and vaccination are unlikely to stimulate aPL production and, therefore, are unlikely to increase miscarriage due to APS.

The SARS-CoV-2 pandemic, while subsiding, continues to plague the world as new variants emerge. Millions have died, and millions more battle with the debilitating symptoms of a clinical entity known as long Covid. The biggest challenge remains combating an ever-changing variant landscape that threatens immune evasion from vaccine and prior infection-generated immunity. In addition, the sequelae of symptoms associated with long Covid almost certainly point to multiple pathologies that range from direct damage to organs during infection to a potential role for infection-induced autoreactive antibodies in promoting autoimmune-like conditions in these patients. In this study, a peptide scan of the SARS-CoV-2 spike protein was done to detect novel, highly conserved linear epitopes that do not elicit autoantibodies. We identified eight predicted linear epitopes capable of eliciting anti-spike IgG antibodies. Immunizations alternating peptide conjugated to KLH with the full trimer yielded the highest antibody levels, but homologous immunization with some of the peptides also yielded high levels when an additional immunization step was added. Of all regions tested, the stem helix adjacent to the heptad repeat 2 (HR2) region also elicited high levels of autoreactive antibodies to known autoantigens in common systemic autoimmune disorders such as lupus and scleroderma and may contribute to the long Covid syndrome seen in some patients. Implications to vaccine design are discussed.

Introduction: The classification of antiphospholipid syndrome (APS) comprises clinical criteria (vascular thrombosis or obstetric complications throughout life) and laboratory criteria (antiphospholipid antibodies (aPLs) positivity, confirmed at least twice at 12-week interval). Methods: In 100 patients admitted to the hospital with COVID-19 pneumonia, thrombosis and pregnancy complications were recorded during the hospital stay and in personal medical history. They were tested for nine types of aPLs at four time points (admission, deterioration, discharge, and 3-month follow-up): anticardiolipin (aCL), anti-β2-glycoproteinI (anti-β2GPI), and antiphosphatidylserine/prothrombin (aPS/PT) isotypes IgM/IgG/IgA. Results: During hospitalization, aPLs were detected at least once in 51% of patients. All 7% of deceased patients tested negative for aPLs upon admission, and only one patient became aCL IgG positive as his condition worsened. In 83.3% of patients, intrahospital thrombosis was not related to aPLs. One patient with pulmonary artery and cerebral artery thrombosis was given an APS diagnosis (triple aPLs positivity on admission, double on follow-up). Personal anamnesis (PA) for thromboembolism was verified in 10 patients, all of whom tested negative for aPLs at admission; however, transition to aPLs positivity at discharge (as the disease subsided) was seen in 60% of patients: three of six with arterial thrombosis (at follow-up, two did not appear, and one was negativized) and three of four with deep vein thrombosis (one was confirmed at follow-up and diagnosed with APS, one was negativized, and one did not appear). At admission, the majority of the aPLs were of the aCL IgG class (58.8%). Unexpectedly, as the COVID-19 disease decreased, anti-β2GPI IgG antibodies (linked with thromboses) became newly positive at discharge (14.9%), as confirmed at follow-up (20.8%). Conclusion: The incidence of APS in our cohort was 2.0%, whereas in the general population, it ranges from 0.001% to 0.002%. The incidence might have increased even more if the four aPLs-positive patients with intrahospital thrombosis/history of thrombosis had attended follow-up. Recommendation: All patients with severe COVID-19 or post-COVID syndrome should be evaluated for current/previous thrombosis and tested for aPLs at least twice: at admission to the hospital and at discharge, then retested 3 months later in positive cases in order to be given the appropriate therapy.

Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG oligodeoxynucleotide-treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

Testing of antiphospholipid antibodies (aPLs) has attracted increasing attention for its association with thrombosis and pregnancy loss. However, few studies reported long-term monitoring outcomes of patients who experienced pregnancy loss and exhibited positivity for aPLs.

We investigated the causes of fetal death in five cases with positive aPLs and traced the patients for changes in aPLs, subsequent pregnancy outcomes, and thrombotic events.

This is a report of five typical cases from a prospective cohort study on the diagnosis of antiphospholipid syndrome (APS) in patients who were hospitalized for fetal death in Xining, China. Long-term follow-up was conducted and repeat aPL testing was recommended when the patients were confirmed or suspect APS.

All five patients had subsequent pregnancies that resulted in term livebirths. None of the patients experienced thrombotic events. One showed progression of aPL serostatus from alone IgM of aβ2GP-1 to both IgM and IgG of aβ2GP-1, two exhibited fluctuation of aPL serostatus, and one had negative conversion, and the other one had not retested aPLs and did not receive any intervention with uneventful subsequent pregnancy.

The aPLs of a patient with APS may develop or may disappear, so long-term monitoring cannot be discounted. Also, a woman who has experienced fetal death and exhibits positivity for aPLs may not necessarily be a patient with APS, as there are a variety of conditions in which aPLs appear.

The impact of Coronavirus disease 2019 (COVID-19) on clinical outcomes in pulmonary embolism (PE) patients receiving extended anticoagulation therapy is not fully understood. The study aimed to investigate the impact of the Omicron outbreak on patients with PE receiving extended anticoagulation therapy.

This prospective multicenter cohort study was conducted during the Omicron pandemic. Patients diagnosed with PE between January 1, 2016, and September 1, 2022, who were on extended anticoagulation therapy, were recruited. The study compared VTE recurrence and bleeding events between COVID-19 and non-COVID-19 patients, using the propensity score weighting with overlap weights (PSOW) method for the final analysis.

A total of 521 patients with PE receiving extended anticoagulation therapy were enrolled. Patients suffering from COVID-19 had significantly higher bleeding rates (10.5 % vs 2.1 %, p = 0.001), with consistent results after PSOW (OR = 4.79, 95%CI [1.04-22.21], p = 0.045). No significant differences in VTE recurrence were observed between these two groups before and after weighting. During follow-up, 31 % of patients developed long COVID, with higher bleeding rates (14.6 % vs 3.5 %, p < 0.001). After PSOW, there was a significantly increased bleeding risk in patients with long COVID (HR = 3.29, 95%CI [1.28, 8.49]); Log-Rank test p < 0.001). Furthermore, a prior history of active malignancy (OR = 9.3; 95%CI [1.38, 59.98]), chronic kidney disease (OR = 13.98; 95%CI [1.59, 122.27]) and bleeding occurred during the acute phase of COVID-19 (OR = 23.73; 95%CI [5.20, 108.35]) were independent predictors of bleeding in patients with long COVID.

COVID-19 and long COVID are associated with an increased bleeding risk in PE patients undergoing extended anticoagulation therapy. This study emphasizes the need for close monitoring and optimization of anticoagulation strategies in PE patients.

As the COVID-19 pandemic transitions, understanding the intricate dynamics of the disease becomes paramount. This systematic review explores the role of antiphospholipid antibodies in COVID-19, focusing on their potential clinical implications.

This systematic review, following PRISMA guidelines, assesses studies exploring the link between antiphospholipid antibodies and COVID-19. PubMed/Medline, Embase, and Scopus were searched for relevant studies published up to December 22, 2024. Inclusion criteria comprised studies involving patients diagnosed with COVID-19 and reporting on the presence of antiphospholipid antibodies. The risk of bias in individual studies was evaluated using the Joanna Briggs Institute appraisal tool.

Our Study includes 59 records involving a total of 28,489 COVID-19 patients. Antiphospholipid antibodies were tested in 14,498 COVID-19 patients. It was observed that 50.84% of patients tested positive for antiphospholipid antibodies. Various types of antiphospholipid antibodies, including Anticardiolipin, Anti beta2 glycoproteins, and Lupus anticoagulant antibody, displayed prevalence rates in the patients with thrombosis. The overall frequency of antiphospholipid antibodies in thrombosis patients was 38.55%.

The presence of antiphospholipid antibodies in a significant proportion of COVID-19 patients underscores the need for a detailed investigation into their role in thrombotic events. Our study highlights potential avenues for targeted interventions. However, the evolving nature of COVID-19 necessitates continued research efforts to clarify clinical implications and optimize management strategies in this complex landscape of thrombosis and immunology. The review reveals some limitations, such as variability in study designs and demographics and inherent differences in methodologies among included studies. Future studies should address these limitations with standardized methodologies for more conclusive findings.

Few pathogens have historically been subjected to as intense scientific and clinical scrutiny as SARS-CoV-2. The genetic, immunological, and environmental factors influencing disease severity and post-infection clinical outcomes, known as correlates of immunity, remain largely undefined. Clinical outcomes of SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to those with life-threatening COVID-19 symptoms. While most infected individuals return to their former health and fitness within a few weeks, some develop debilitating chronic symptoms, referred to as long-COVID. Autoimmune responses have been proposed as one of the factors influencing long-COVID and the severity of SARS-CoV-2 infection. The association between viral infections and autoimmune pathologies is not new. Viruses such as Epstein-Barr virus and cytomegalovirus, among others, have been shown to induce the production of autoantibodies and the onset of autoimmune conditions. Given the extensive literature on SARS-CoV-2, here we review current evidence on SARS-CoV-2-induced autoimmune pathologies, with a focus on autoantibodies. We closely examine mechanisms driving autoantibody production, particularly their connection with disease severity and long-COVID.

The factors contributing to the development of severe coronavirus disease 2019 (COVID-19) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. Although the presence of immune complexes (ICs), formed between antibodies and their antigens, has been linked to COVID-19 severity, their role requires further investigation, and the antigens within these ICs are yet to be characterized.

Here, a C1q enzyme-liked immunosorbent assay and immune complexome analysis were used to determine IC concentrations and characterize IC antigens, respectively, in the sera of 64 unvaccinated COVID-19 patients with PCR-confirmed SARS-CoV-2 infection, enrolled at seven participating centers in 2020. For the analysis, the patients were split into the severe (n = 35) and non-severe (n = 28) groups on the basis of their COVID-19 symptoms.

We found that neither serum IC concentration nor IC antigen number was associated with COVID-19 severity. However, we identified six IC antigens, which were significantly enriched in the severe versus non-severe group. These IC antigens were all derived from human proteins, namely haptoglobin, the serum amyloid A-2 protein, the serum amyloid A-1 protein, clusterin, and lipopolysaccharide-binding protein, and complement-factor-H-related protein 3. Meanwhile, we found no association between COVID-19 severity and IC antigens derived from SARS-CoV-2 proteins. Collectively, the six IC antigens predicted COVID-19 severity with a moderate degree of accuracy (area under the receiver operating characteristic curve = 0.90, sensitivity = 94 %, specificity = 79 %).

The IC antigen signature identified in this study may have important implications for the diagnosis and treatment of severe COVID-19.

CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19.

Using banked samples (n = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies.

Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%, P = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (P = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69-5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)].

We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.

It has been more than three years since COVID-19 impacted the lives of millions of people, many of whom suffer from long-term effects known as long-haulers. Notwithstanding multiorgan complaints in long-haulers, signs and symptoms associated with cognitive characteristics commonly known as "brain fog" occur in COVID patients over 50, women, obesity, and asthma at excessive. Brain fog is a set of symptoms that include cognitive impairment, inability to concentrate and multitask, and short-term and long-term memory loss. Of course, brain fog contributes to high levels of anxiety and stress, necessitating an empathetic response to this group of COVID patients. Although the etiology of brain fog in COVID-19 is currently unknown, regarding the mechanisms of pathogenesis, the following hypotheses exist: activation of astrocytes and microglia to release pro-inflammatory cytokines, aggregation of tau protein, and COVID-19 entry in the brain can trigger an autoimmune reaction. There are currently no specific tests to detect brain fog or any specific cognitive rehabilitation methods. However, a healthy lifestyle can help reduce symptoms to some extent, and symptom-based clinical management is also well suited to minimize brain fog side effects in COVID-19 patients. Therefore, this review discusses mechanisms of SARS-CoV-2 pathogenesis that may contribute to brain fog, as well as some approaches to providing therapies that may help COVID-19 patients avoid annoying brain fog symptoms.

COVID-19 may induce a state of hypercoagulability, particularly in critically ill patients, for reasons that remain unknown. Numerous studies have identified the presence of antiphospholipid antibodies in patients with COVID-19; however, the definitive diagnosis of antiphospholipid syndrome continues to pose challenges. Here, we present the case of a patient infected with SARS-CoV-2 who developed life-threatening severe thrombocytopenia, profound anaemia, acute pulmonary hypertension, right ventricular failure, and renal insufficiency. Laboratory investigations revealed significantly elevated levels of antiphospholipid antibodies. We conducted a one-year follow-up study with blood sampling performed every 12 weeks. The patient exhibited persistent high titres of antiphospholipid antibodies and ongoing renal dysfunction necessitating daily oral warfarin antithrombotic therapy. Antiphospholipid syndrome is a complex clinical condition that poses challenges for clinicians, particularly in critically ill patients, and is often associated with delayed and inaccurate diagnosis and treatment. Therefore, we extensively reviewed the literature and international guidelines to conduct a comprehensive analysis of the aetiology, pathogenesis, and treatment strategies of APS. We hope this work will provide a valuable reference for health care professionals.

Acute ischemic stroke (AIS) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to explore neurovascular imaging patterns in patients with SARS-CoV-2-related AIS.

We retrospectively analyzed clinical and radiological data of patients hospitalized with AIS and a positive PCR test for SARS-CoV-2 prior to AIS onset. The control group comprised of AIS patients from a pre-COVID-19 pandemic period matched for gender and age.

Thirty-five SARS-CoV-2-related stroke patients, and 35 controls were included. Fifty-seven percent of SARS-CoV-2 patients had either mild or asymptomatic disease. A distinctive imaging pattern of floating arterial mural thrombus was detected in 5 patients of the SARS-CoV-2 group. In 4 patients thrombus was attached to a stenotic atherosclerotic plaque in the proximal internal carotid artery. In the 5th patient a cardiac CTA showed multiple floating thrombi in the descending aorta. In the control group, floating thrombus was only detected in one patient. Treatment with dual antiplatelet therapy was associated with thrombus dissolution and good clinical outcome. Patients with floating thrombi had a longer time from SARS-CoV-2 diagnosis to stroke onset (mean 7.4 versus 3.4 days).

Floating arterial mural thrombi attached to atherosclerotic plaques are unique characteristic source of AIS in SARS-CoV-2 patients. They may lead to ischemic stroke in patients with mild or asymptomatic infection up to 1-2 weeks from SARS-CoV-2 diagnosis. Patients with embolic AIS and SARS-CoV-2 diagnosis should perform high resolution cranio-cervical vascular imaging to evaluate floating thrombi as a potential embolic source.

Understanding the pathobiology of critical illness is essential for patients' prognosis. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. As part of the host response, procoagulant responses, one of the most primitive reactions in biology, start at the very beginning of diseases and can be monitored throughout the process. Currently, we can achieve near-complete monitoring of the coagulation process, and procoagulant responses serve as indicators of the severity of host response in critically ill patients. However, the rapid interpretation of the complex results of various biomarkers remains a challenge for many clinicians. The indicators commonly used for coagulation assessment are complex, typically divided into three categories for clarity: process index, functional index, and outcome index. Monitoring and understanding these indicators can help manage procoagulant responses. The intervention of procoagulant response should be part of the bundle therapy, alongside the treatment for primary disease, management for hemodynamics, and controlling for host response. Early intervention for procoagulant response mainly includes anti-inflammation, antiplatelet and anticoagulant therapy, as well as management of primary disease. In this review, we systemically introduce the onset, assessment and intervention of procoagulant response.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), causes post-acute infection syndrome in a surprisingly large number of cases worldwide. This condition, also known as long COVID or post-acute sequelae of COVID-19, is characterized by extremely complex symptoms and pathology. There is a growing consensus that this condition is a consequence of virus-induced immune activation and the inflammatory cascade, with its prolonged duration caused by a persistent virus reservoir.

In this cross-sectional study, we analyzed the SARS-CoV-2-specific T cell response against the spike, nucleocapsid, and membrane proteins, as well as the levels of spike-specific IgG antibodies in 51 healthcare workers, categorized into long COVID or convalescent control groups based on the presence or absence of post-acute symptoms. Additionally, we compared the levels of autoantibodies previously identified during acute or critical COVID-19, including anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-neutrophil cytoplasmic antibodies, and anti-thyroid peroxidase (anti-TPO). Furthermore, we analyzed the antibody levels targeting six nuclear antigens within the ENA-6 S panel, as positivity for certain anti-nuclear antibodies has recently been shown to associate not only with acute COVID-19 but also with long COVID. Finally, we examined the frequency of diabetes in both groups. Our investigations were conducted at an average of 18.2 months (convalescent control group) and 23.1 months (long COVID group) after confirmed acute COVID-19 infection, and an average of 21 months after booster vaccination.

Our results showed significant differences between the two groups regarding the occurrence of acute infection relative to administering the individual vaccine doses, the frequency of acute symptoms, and the T cell response against all structural SARS-CoV-2 proteins. A statistical association was observed between the incidence of long COVID symptoms and highly elevated anti-TPO antibodies based on Pearson's chi-squared test. Although patients with long COVID showed moderately elevated anti-SARS-CoV-2 spike IgG serum antibody levels compared to control participants, and further differences were found regarding the positivity for anti-nuclear antibodies, anti-dsDNA, and HbA1c levels between the two groups, these differences were not statistically significant.

This study highlights the need for close monitoring of long COVID development in patients with elevated anti-TPO titers, which can be indicated by strongly elevated SARS-CoV-2-specific T cell response and moderately raised anti-spike IgG levels even long after the acute infection. However, our results do not exclude the possibility of new-onset thyroid autoimmunity after COVID-19, and further investigations are required to clarify the etiological link between highly elevated anti-TPO titers and long COVID.

Long COVID, a type of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC) defined by medically unexplained symptoms following infection with SARS-CoV-2, is a newly recognized infection-associated chronic condition that causes disability in some people. Substantial progress has been made in defining its epidemiology, biology, and pathophysiology. However, there is no cure for the tens of millions of people believed to be experiencing long COVID, and industry engagement in developing therapeutics has been limited. Here, we review the current state of knowledge regarding the biology and pathophysiology of long COVID, focusing on how the proposed mechanisms explain the physiology of the syndrome and how they provide a rationale for the implementation of a broad experimental medicine and clinical trials agenda. Progress toward preventing and curing long COVID and other infection-associated chronic conditions will require deep and sustained investment by funders and industry.

Multiple concerning reports have emerged of cardiovascular complications, particularly thrombosis, following mRNA vaccination against the SARS-CoV-2 pathogen. The presence of serologically persistent anti-phospholipid antibodies is a characteristic of antiphospholipid syndrome, which presents with clinical manifestations including thrombosis or pregnancy morbidity. Anti-SARS-CoV-2 mRNA vaccines pose a theoretical risk of cross-reactivity between the SARS-CoV-2 spike protein and phospholipids in host tissues. In this study, serum anti-phospholipid antibody titers before and after SARS-CoV-2 mRNA vaccination were compared among 184 hospital staff members. Although no significant differences were found in terms of antibody titers targeting cardiolipin and β2-glycoprotein I, post-vaccination antibody titers targeting phosphatidylethanolamine were found to be significantly increased compared to pre-vaccination levels (p = 0.008). Anti-phosphatidylethanolamine antibodies are the most common anti-phospholipid antibodies detected in patients with recurrent miscarriages at < 10 weeks of gestation. However, the association between vaccination and these types of adverse events remains unknown, thus warranting further investigation.

Despite the growing interest in gender medicine, the influence of sex and gender on human diseases, including stroke, continues to be underestimated and understudied. The COVID-19 pandemic has overall impacted not only the occurrence and management of stroke but has also exacerbated sex and gender disparities among both patients and healthcare providers. This paper aims to provide an updated overview on the influence of sex and gender in stroke pathophysiology and care during COVID-19 pandemic, through biological, clinical, psychosocial and research perspectives. Gender equity and awareness of the importance of sexual differences are sorely needed, especially in times of health crisis but have not yet been achieved to date. To this purpose, the sudden yet worldwide diffusion of COVID-19 represents a unique learning experience that highlights critical unmet needs also in gender medicine. The failures of this recent past should be kept as food for thought to inspire proper strategies reducing inequalities and to address women's health and wellbeing issues, particularly in case of future pandemics.

In addition to the respiratory symptoms associated with COVID-19, the disease has consistently been linked to many autoimmune diseases such as systemic lupus erythematous and antiphospholipid syndrome (APS). APS in particular was of paramount significance due to its devastating clinical sequela. In fact, the hypercoagulable state seen in patients with acute COVID-19 and the critical role of anticoagulant treatment in affected individuals shed light on the possible relatedness between APS and COVID-19. Moreover, the role of autoimmunity in the assumed association is not less important especially with the accumulated data available regarding the autoimmunity-triggering effect of SARS-CoV-2 infection. This is furtherly strengthened at the time patients with COVID-19 manifested antiphospholipid antibodies of different types following infection. Additionally, the severe form of the APS spectrum, catastrophic APS (CAPS), was shown to have overlapping characteristics with severe COVID-19 such as cytokine storm and multi-organ failure. Interestingly, COVID vaccine-induced autoimmune phenomena described in the medical literature have pointed to an association with APS. Whether the antiphospholipid antibodies were present or de novo, COVID vaccine-induced vascular thrombosis in certain individuals necessitates further investigations regarding the possible mechanisms involved. In our current paper, we aimed to focus on the associations mentioned, their implications, importance, and consequences.

COVID-19 may predispose patients to cardiac injuries but whether COVID-19 infection affects the morphological features of coronary plaques to potentially influence the outcome of patients with coronary artery disease (CAD) remains unknown. By using optical coherence tomography (OCT), this study compared the characteristics of coronary plaque in patients with CAD with/without COVID-19 infection. The 206 patients were divided into 2 groups. The COVID-19 group had 113 patients between December 7, 2022, and March 31, 2023, who received OCT assessment after China decided to lift the restriction on COVID-19 and had a history of COVID-19 infection. The non-COVID-19 group had 93 patients without COVID-19 infection who underwent OCT before December 7, 2022. The COVID-19 group demonstrated a higher incidence of plaque ruptures (53.1% vs 38.7%, p = 0.039), erosions (28.3% vs 11.8%, p = 0.004), fibrous (96.5% vs 89.2%, p = 0.041) and diffuse lesions (73.5% vs 50.5%, p <0.001) compared with the non-COVID-19 group, whereas non-COVID-19 group exhibited a higher frequency of cholesterol crystals (83.9% vs 70.8%, p = 0.027), deep calcifications (65.6% vs 51.3%, p = 0.039) and solitary lesions (57.0% vs 34.5%, p = 0.001). Kaplan-Meier survival analysis revealed a significantly lower major adverse cardiac events-free probability in the COVID-19 group (91.6% vs 95.5%, p = 0.006) than in the non-COVID-19 group. In conclusion, OCT demonstrated that COVID-19 infection is associated with coronary pathological changes such as more plaque ruptures, erosions, fibrosis, and diffuse lesions. Further, COVID-19 infection is associated with a higher propensity for acute coronary events and a higher risk of major adverse cardiac events in patients with CAD.

Autoantibodies are immune system-produced antibodies that wrongly target the body's cells and tissues for attack. The COVID-19 pandemic has made it possible to link autoantibodies to both the severity of pathogenic infection and the emergence of several autoimmune diseases after recovery from the infection. An overview of autoimmune disorders and the function of autoantibodies in COVID-19 and other infectious diseases are discussed in this review article. We also investigated the different categories of autoantibodies found in COVID-19 and other infectious diseases including the potential pathways by which they contribute to the severity of the illness. Additionally, it also highlights the probable connection between vaccine-induced autoantibodies and their adverse outcomes. The review also discusses the therapeutic perspectives of autoantibodies. This paper advances our knowledge about the intricate interaction between autoantibodies and COVID-19 by thoroughly assessing the most recent findings.

To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19.

This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-β2-Glycoprotein-I (aβ2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)].

Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies.

These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.

In 2024, over 775 million cases of COVID-19 were recorded, including approximately 7 million deaths, indicating its widespread and dangerous nature. The disease is caused by the SARS-CoV-2 virus, which can manifest a wide spectrum of symptoms, from mild infection to respiratory failure and even death. Neurological symptoms, such as headaches, confusion, and impaired consciousness, have also been reported in some COVID-19 patients. These observations suggest the potential of SARS-CoV-2 to invade the central nervous system and induce neuroinflammation during infection. This review specifically explores the relationship between SARS-CoV-2 infection and selected neurological diseases such as multiple sclerosis (MS), ischemic stroke (IS), and Alzheimer's disease (AD). It has been observed that the SARS-CoV-2 virus increases the production of cytokines whose action can cause the destruction of the myelin sheaths of nerve cells. Subsequently, the body may synthesize autoantibodies that attack nerve cells, resulting in damage to the brain's anatomical elements, potentially contributing to the onset of multiple sclerosis. Additionally, SARS-CoV-2 exacerbates inflammation, worsening the clinical condition in individuals already suffering from MS. Moreover, the secretion of pro-inflammatory cytokines may lead to an escalation in blood clot formation, which can result in thrombosis, obstructing blood flow to the brain and precipitating an ischemic stroke. AD is characterized by intense inflammation and heightened oxidative stress, both of which are exacerbated during SARS-CoV-2 infection. It has been observed that the SARS-CoV-2 demonstrates enhanced cell entry in the presence of both the ACE2 receptor, which is already elevated in AD and the ApoE ε4 allele. Consequently, the condition worsens and progresses more rapidly, increasing the mortality rate among AD patients. The above information underscores the numerous connections between SARS-CoV-2 infection and neurological diseases.

COVID-19 has prominent effects on the nervous system with important manifestations on neuroimaging. In this review, we discuss the neuroimaging appearance of acute COVID-19 that became evident during the early stages of the pandemic. We highlight the underlying pathophysiology mediating nervous system effects and neuroimaging appearances including systemic inflammatory response such as cytokine storm, coagulopathy, and para/post-infections immune mediated phenomena. We also discuss the nervous system manifestations of COVID-19 and the role of imaging as the pandemic has evolved over time, including related to the development of vaccines and the emergence of post-acute sequalae such as long COVID.

Testing for lupus anticoagulant (LA) is not recommended in case of inflammation as C-reactive protein (CRP) can interfere in vitro with the phospholipids present in the activated partial thromboplastin time test used to detect an LA. However, the potential interference of an acute phase protein (ie, CRP) in LA testing using the dilute Russell's viper venom (DRVV) test is poorly studied.

To study the effect of inflammation, as evidenced by increased CRP levels, on DRVV tests.

First, a retrospective analysis (2013-2023) was performed: data on all LA workups were retrieved, and the association between CRP levels and DRVV screen, mix, and confirm clotting times was studied. Second, data on DRVV panels and CRP levels were extracted from 2 prospective studies involving intensive care unit patients to study the association between both variables. Third, CRP was added to normal pooled plasma at 6 relevant concentrations (up to 416 mg/L) to study the association between CRP itself and DRVV coagulation times.

In the retrospective analysis, DRVV screen and confirm clotting times significantly increased as CRP increased (increase of 0.11 seconds and 0.03 seconds per 1 mg/L increase of CRP level, respectively). In the prospective analysis, only DRVV screen was prolonged with high CRP levels (increase of 0.06 seconds for a 1 mg/L increase in CRP level); DRVV screen/confirm ratio was also increased with high CRP levels. In vitro, the addition of CRP did not significantly increase any DRVV clotting times.

LA testing should be performed with much caution in the presence of inflammation as it may be associated with prolongation of both activated partial thromboplastin time and DRVV clotting times.

Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post-acute sequelae of COVID-19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS-CoV-2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS-CoV-2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection. This continuous self-stimulation of neutrophils leads, in turn, to systemic inflammation, micro-thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications.

A hallmark of COVID-19 is the variety of complications that follow SARS-CoV-2 infection in some patients, and that target multiple organs and tissues. Also remarkable are the associations with several auto-inflammatory disorders and the presence of autoantibodies directed to a vast array of antigens. The processes underlying autoantibody production in COVID-19 have not been completed deciphered. Here, we review mechanisms involved in autoantibody production in COVID-19, multisystem inflammatory syndrome in children, and post-acute sequelae of COVID19. We critically discuss how genomic integrity, loss of B cell tolerance to self, superantigen effects of the virus, and extrafollicular B cell activation could underly autoantibody proaction in COVID-19. We also offer models that may account for the pathogenic roles of autoantibodies in the promotion of inflammatory cascades, thromboembolic phenomena, and endothelial and vascular deregulations.

During the coronavirus disease 2019 (COVID-19) pandemic, the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presented quite a diverse symptomatology, in addition to respiratory symptoms, while other clinical signs such as thrombosis, postoperative hemorrhages, acute kidney or liver failure, digestive disorders (vomiting and diarrheal stools) were also reported. We present the case of a patient diagnosed with transverse colon neoplasm and asymptomatic SARS-CoV-2 infection, who presented to the Emergency Room (ER) of the Emergency County Clinical Hospital, Craiova, Romania, with a clinical picture of low intestinal occlusion. Surgery was decided and a right hemicolectomy extended to the left, with terminal ileostomy performed. The postoperative evolution was favorable, with the resumption of intestinal transit and discharge on the third postoperative day. The patient returned to the ER Department on the fifth day after surgery, with diffuse abdominal pain, absence of intestinal transit and flatulence. Clinical examination of the abdomen revealed the presence of bloating sounds on palpation. Emergency laparotomy was again performed with the suspicion of postoperative occlusion and five perforations were found in the small bowel, associated with fecaloid peritonitis and mechanic-inflammatory occlusion. The perforations were without any obvious lesion substrate, four of them being located on the jejunum and one on the terminal ileum. The histopathological examination revealed hemorrhage and recent transmural thrombosis on the intestinal wall, most likely caused by COVID-19. Without any respiratory symptoms, the COVID-19 infection caused multiple intestinal lesions, leading to peritonitis and septic shock, followed by the patient's death.

Research on the relationship between mild COVID-19 and the subsequent development of isolated optic neuritis (ON) with antibodies specific to myelin oligodendrocyte glycoprotein (MOG-ON) and aquaporin 4 (AQP4-ON) is limited, particularly case-control studies that directly compare these conditions within the same affected population.

A retrospective analysis of initial MOG-ON and AQP4-ON cases during the COVID-19 peak and subsequent months. Patients were classified as possible COVID-19 related ON (PCRON) or non-COVID-19 related ON (NCRON). The study compared epidemiology, comorbidities, and clinical features between these groups.

Patients with MOG-ON tended to develop ON symptoms closer in time to a mild COVID-19 infection compared to those with AQP4-ON (6.87 ± 6.25 weeks vs. 11.06 ± 5.84 weeks; p = 0.038), a significantly higher proportion of patients with MON-ON developing symptoms within 6 weeks after COVID-19 compared to those with AQP4-ON (15/23 [65.2%] vs. 5/17 [29.4%]; p = 0.025). Comparing MOG-ON and AQP4-ON patients, MOG-ON patients were more likely to have a recent infection before ON onset (73.1% vs. 30%; p = 0.007) and had better peak and post-treatment visual acuity (p = 0.01; p < 0.001). In contrast, AQP4-ON patients frequently showed comorbid connective tissue diseases (30.0% vs. 0%, p = 0.004) and antinuclear antibody abnormalities (40.0% vs. 7.7%, p = 0.012). Among MOG-ON patients, PCRON had increased rates of atherosclerotic vascular diseases (AVDs) (53.3% vs. 9.1%, p = 0.036), phospholipid antibody abnormalities (60.0% vs. 18.2%, p = 0.04), and bilateral visual impairment (66.7% vs. 9.1%, p = 0.005). Multivariate analysis pinpointed AVDs (OR = 15.21, p = 0.043) and bilateral involvement (OR = 25.15, p = 0.015) as independent factors related to COVID-19 associated MOG-ON, with both being good discriminators for PCRON (AUC = 0.879). No differences were found between the PCRON and NCRON groups in AQP4-ON patients.

Mild COVID-19 is more likely associated with MOG-ON than AQP4-ON. MOG-ON that develops within 6 weeks following a COVID-19 infection may be associated with the COVID-19 infection. AVDs may have a synergistic effect on MOG-ON in patients with COVID-19, which warrants further investigation. COVID-19 related MOG-ON often affects both eyes, and acute visual function damage can be severe, but generally has a good prognosis.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 with staggering economic fallout and human suffering. The unique structure of SARS-CoV-2 and its underlying pathogenic mechanism were responsible for the global pandemic. In addition to the direct damage caused by the virus, SARS-CoV-2 triggers an abnormal immune response leading to a cytokine storm, culminating in acute respiratory distress syndrome and other fatal diseases that pose a significant challenge to clinicians. Therefore, potential treatments should focus not only on eliminating the virus but also on alleviating or controlling acute immune/inflammatory responses. Current management strategies for COVID-19 include preventative measures and supportive care, while the role of the host immune/inflammatory response in disease progression has largely been overlooked. Understanding the interaction between SARS-CoV-2 and its receptors, as well as the underlying pathogenesis, has proven to be helpful for disease prevention, early recognition of disease progression, vaccine development, and interventions aimed at reducing immunopathology have been shown to reduce adverse clinical outcomes and improve prognosis. Moreover, several key mutations in the SARS-CoV-2 genome sequence result in an enhanced binding affinity to the host cell receptor, or produce immune escape, leading to either increased virus transmissibility or virulence of variants that carry these mutations. This review characterizes the structural features of SARS-CoV-2, its variants, and their interaction with the immune system, emphasizing the role of dysfunctional immune responses and cytokine storm in disease progression. Additionally, potential therapeutic options are reviewed, providing critical insights into disease management, exploring effective approaches to deal with the public health crises caused by SARS-CoV-2.

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 patients with autoimmune diseases, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted patients with multiple sclerosis (MS) were associated with higher CD8 T cell responses. By contrast, patients taking mycophenolate mofetil (MMF) exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low anti-spike IgG response included B cell depletion within the last year, fingolimod, and combination treatment with MMF and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of preexisting anti-type I IFN antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.