Cytokine storm (CS) is a hyperinflammatory syndrome causing multiorgan dysfunction and high mortality, especially in patients with malignant hematologic neoplasms. Triggers include malignant neoplasm-associated hemophagocytic lymphohistiocytosis (MN-HLH), cytokine release syndrome from chimeric antigen receptor T-cell therapy (CAR-T CRS), and COVID-19, but the underlying mechanisms of inflammation and their impact on outcomes are poorly understood.

To delineate the inflammatory patterns characterizing different CS etiologies and their association with clinical outcomes.

This retrospective cohort study was conducted at the MD Anderson Cancer Center in Houston, Texas, between March 1, 2020, and November 20, 2022, using the software-as-a-service Syntropy Foundry Platform. Participants were patients with malignant hematologic neoplasms who developed CS from COVID-19 (COVID-CS), MN-HLH, or CAR-T CRS.

Diagnostic criteria for COVID-CS were developed based on surging inflammatory markers (interleukin-6, C-reactive protein, and ferritin), while diagnosis of MN-HLH and CAR-T CRS followed established guidelines.

The study compared cytokine levels, clinical characteristics, and survival outcomes across the 3 cohorts and focused on inflammatory markers, survival times, and key factors associated with survival identified through univariate and multivariable analyses.

A total of 671 patients met the inclusion criteria. Of those, 220 (33%) had CAR-T CRS, 227 (34%) had COVID-CS, and 224 (33%) had MN-HLH. Patients were predominantly male (435 [65%]), and 461 (69%) were White, with significant differences in median age (CAR-T CRS, 63 [IQR, 54-71] years; COVID-CS, 63 [IQR, 52-72] years; MN-HLH, 55 [IQR, 41-65] years; P < .001) as well as number of admission days and underlying cancer type across cohorts. Marked variations in cytokine levels and survival outcomes were observed, with the MN-HLH cohort exhibiting the highest levels of inflammatory markers (eg, median TNF-α, 105 pg/mL [IQR, 38-201 pg/mL] for MN-HLH vs 23 pg/mL [IQR, 17-42 pg/mL] for COVID-CS) and lowest fibrinogen and albumin levels. The cohort with CAR-T CRS showed substantially longer survival times compared with the cohort with COVID-CS (hazard ratio [HR], 2.93; 95% CI, 1.95-4.41) and the cohort with MN-HLH (HR, 8.12; 95% CI, 5.51-12.00). Clustering analysis showed overlapping patterns between COVID-CS and CAR-T CRS, while MN-HLH formed a distinct cluster.

This study of CS syndromes found distinct immune responses within each cohort. The distinct clinical patterns and outcomes associated with different CS etiologies emphasize the importance of early diagnosis and timely intervention.

SARS-CoV-2 infection affects both lipid metabolism and lung function. The severity of the disease has been associated with reduced levels of both high-density lipoprotein (HDL) and low-density lipoprotein cholesterol. Despite the crucial role that these nanoparticles play in SARS-CoV-2 infection, few studies have examined their structure during COVID-19 beyond HDL quantity. The study aimed to assess apolipoprotein levels in COVID-19 patients who either survived or died following ICU admission. In addition, ICU survivors and non-survivors were compared for HDL particle size and proteome.

Between February and April 2020, our study enrolled 37 COVID-19 patients upon their intensive care unit admission. Among them, 18 survived the disease, while 19 succumbed to it. We used mass spectrometry to assess plasma levels of 14 apolipoproteins and LCAT. Additionally, we analyzed HDL subpopulation distribution by utilizing native polyacrylamide gel electrophoresis. HDL particles were isolated from both surviving and non-surviving patients using ultracentrifugation, followed by characterization of their proteomes with NanoLC-MS/MS.

Plasma apolipoproteins, including Apo A-II, Apo Cs (I, II, III), Apo H, Apo J, Apo M, and LCAT, were decreased in patients who did not survive COVID-19. However, no alterations were noted in the distribution of HDL subpopulations in relation to mortality. HDL composition was further altered based on mortality, displaying a decline in Apo H and paraoxonase 3.

In conclusion, we have shown an alteration in plasma apolipoproteins and HDL composition between surviving COVID-19 patients and non-survivors. Some markers, such as Apo H, are more predictive than baseline lipid concentrations such as HDL-C. These markers appear to provide a more accurate indication of mortality during COVID-19 compared with baseline lipid concentrations such as HDL-C.

SARS-CoV-2 in patients who need Intensive Care (ICU) is associated with a mortality rate ranging from 10 to 40%-45%, with an increase in morbidity and mortality in presence of sepsis.

We assumed that immunoglobulin (Ig) M and IgA enriched IgG (IGAM) therapy may support SARS COV-2 sepsis-related phase improving patient outcome. We conducted a retrospective case-control study on all the patients admitted to our ICU during the three pandemic waves between February 2020 and April 2021. Upon ICU admission, patients received anticoagulants with the standard supportive treatment (ST) ± IGAM therapy. After matching for the baseline characteristics and treatments, the patients receiving IGAM therapy too (group A), were compared with those undergoing ST (group B) only.

85 patients were enrolled in group A, whereas 111 in group B. The mortality resulted lower in group A [37.6% versus 55.8%, OR: 0.7 (02-08), P = .01)]. A logistic regression analysis identified IGAM treatment as a survival predictor [OR: 0.35 (95%CI, 0.2-0.8)], whereas experiencing a super-infection [OR: 1.88 (95%CI, 1.5-4.9)] and a septic shock [OR: 1.92 (95%CI, 1.4-4.3)] as predictors of death. On day 7, the probability of dying was 3 times higher in patients treated with ST only. Variable life adjustment display (VLAD) was equal to 2.4 in group A, while - 2.2 group B (in terms of lives saved in relation with those expected, in according with Simplified Acute Physiology Score II (SAPS II) score.

The treatment based on IGAM infusion seems to give an advantage chance of survival in SARS-CoV-2 severe infection. Further prospective studies are warranted.

Bacterial coinfection in patients with SARS-CoV-2 infection is an important risk factor for death. This study investigated whether there were differences in levels of serum inflammatory markers in COVID-19 patients with bacterial coinfections compared with those without bacterial infection.

A total of 235 inpatients with SARS-CoV-2 infection admitted to Qingdao Central Hospital from December 7, 2022, to August 7, 2024, were included. Patients were divided into a bacteria-positive group (115 cases) and a bacteria-negative group (120 cases) according to whether they had bacterial coinfections. PCT, CRP, and 12 kinds of cytokines were compared between groups, and the distribution of bacterial species in the positive group was statistically analyzed.

The serum levels of CRP (Z = 8.94, p < 0.001), PCT (Z = 5.59, p < 0.001), IL-1β (t = 4.863, p < 0.001), IL-2 (t = 5.810, p < 0.001), IL-5 (t = 3.837, p < 0.001), IL-6 (t = 4.910, p < 0.001), IL-8 (t = 3.325, p < 0.001), ILIL-12p70 (t = 4.722, p < 0.001), IL-17 (t = 3.315, p = 0.001) and TNF-α (t = 4.251, p < 0.001) between the two groups were significantly different. IL-4, IL-10, IFN-α, and IFN-γ were not statistically significant (p > 0.05). Among the 115 bacteria-positive patients, 56 patients were positive for one species and 59 patients were multiple infections. Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae were common species.

Serum PCT and CRP levels in COVID-19 patients with bacterial coinfection are higher than those without bacterial infection. Cytokines such as IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12p70, IL-17, and TNF-α may be involved in the progression of COVID-19 combined with bacterial infection. They can be used as potential markers to evaluate the disease condition and prognosis.

In the context of the cytokine storm the takes place in severe COVID-19 patients, the Interleukin 6 (IL6) pathway emerges as one of the key pathways involved in the pathogenesis of this hyperinflammatory state. The strategy of blocking the inflammatory storm by targeting the IL6 is a promising therapy to mitigate mortality. The use of Tocilizumab was recommended by the World Health Organization (WHO) to treat severe COVID-19 patients. However, the efficacy of Tocilizumab is variable. We hypothesize that the genetic background could be behind the efficacy of Tocilizumab in terms of mortality.

We performed a targeted-next generation sequencing of 287 genes, of which 264 belong to a community panel of ThermoFisher for the study of genetic causes of primary immunodeficiency disorders, and 23 additional genes mostly related to inflammation, not included in the original community panel. This panel was sequenced in an initial cohort of 425 COVID-19 patients, of which 232 were treated with Tocilizumab and standard therapy, and 193 with standard therapy only. Selected genetic variants were genotyped by single base extension in additional 245 patients (95 treated with Tocilizumab and 150 non-treated with Tocilizumab). Appropriate statistical analyses and internal validation, including logistic regression models, with the interaction between Tocilizumab and genetic variants, were applied to assess the impact of these genetic variants in the efficacy of Tocilizumab in terms of mortality.

Age (p < 0.001) and cardiovascular disease (p < 0.001) are risk factors for mortality in COVID-19 patients. The presence of GG and TT genotypes at IL10Rβ (rs2834167) and IL1β (rs1143633) genes significantly associates with a reduced risk of mortality in patients treated with Tocilizumab (OR = 0.111; 95%CI = 0.015-0.829; p = 0.010 and OR = 0.378; 95%CI = 0.154-0.924; p = 0.028 respectively). The presence of CC genotype at IL1RN (rs2234679) significantly associates with an increased risk of mortality, but only in patients not treated with Tocilizumab (OR = 3.200; 95%CI = 1.512-6.771; p = 0.002). Exhaustive internal validation using a bootstrap method (B = 500 replicates) validated the accuracy of the predictive models.

We developed a series of predictive models based on three genotypes in genes with a strong implication in the etiopathogenesis of COVID-19 disease capable of predicting the risk of mortality in patients treated with Tocilizumab.

Inflammation-associated diseases are very common clinically with a high incidence; however, there is still a lack of effective treatments. Cell-biomimetic nanoplatforms have led to many breakthroughs in the field of biomedicine, significantly improving the efficiency of drug delivery and its therapeutic implications especially for inflammation-associated diseases. Macrophages are an important component of immune cells and play a critical role in the occurrence and progression of inflammation-associated diseases while simultaneously maintaining homeostasis and modulating immune responses. Therefore, macrophage-biomimetic nanoplatforms not only inherit the functions of macrophages including the inflammation tropism effect for targeted delivery of drugs and the neutralization effect of pro-inflammatory cytokines and toxins via membrane surface receptors or proteins, but also maintain the functions of the inner nanoparticles. Macrophage-biomimetic nanoplatforms are shown to have remarkable therapeutic efficacy and excellent application potential in inflammation-associated diseases. In this review, inflammation-associated diseases, the physiological functions of macrophages, and the classification and construction of macrophage-biomimetic nanoplatforms are first introduced. Next, the latest applications of different macrophage-biomimetic nanoplatforms for the treatment of inflammation-associated diseases are summarized. Finally, challenges and opportunities for future biomedical applications are discussed. It is hoped that the review will provide new ideas for the further development of macrophage-biomimetic nanoplatforms.

As an antibody-based therapy, plasma therapy has been used as an emergency therapeutic strategy against severe acute respiratory syndrome coronavirus type 2 infection. Due to the critical role of macrophages in coronavirus disease-19 (COVID-19)-associated hyperinflammation, the main objective of this study was to assess the effect of plasma transfusion on the expression levels of the inflammatory biomarkers involved in activation and pulmonary infiltration of macrophages. The target population included 50 severe hospitalized COVID-19 patients who were randomly assigned into 2 groups, including intervention and control. Serum levels of chemokine (C-C motif) ligand (CCL)-2, CCL-3, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. Moreover, quantitative real-time polymerase chain reaction (PCR) was carried out to assess the relative expression of nuclear factor (NF)-κB1, NF-κB2, nuclear factor erythroid 2 p45-related factor 2 (NRF-2), and thioredoxin-interacting protein genes. Sampling was done at baseline and 72 h after receiving plasma. The intervention group demonstrated significantly lower serum levels of IL-6, TNF-α, and CCL-3. In addition, real-time PCR data analyses showed that the relative expression of NF-κB2 was significantly declined in the patients who received plasma. The use of convalescent plasma probably has a significant inhibitory effect on the cytokines, chemokines, and inflammatory genes related to macrophage activation, which are closely associated with the worsening of clinical outcomes in severe COVID-19.

More than 3 years after the start of SARS-CoV-2 pandemic, the molecular mechanisms behind the viral pathogenesis are still not completely understood. Long non-coding RNAs (lncRNAs), well-known players in viral infections, can represent prime candidates for patients' risk stratification. The purpose of the current study was to investigate the lncRNA profile in a family cluster of COVID-19 cases with different disease progression, during the initial wave of the pandemic and to evaluate their potential as biomarkers for COVID-19 evolution. LncRNA expression was investigated in nasopharyngeal swabs routinely collected for diagnosis. Distinct expression patterns of five lncRNAs (HOTAIR, HOTAIRM1, TMEVPG1, NDM29 and snaR) were identified in all the investigated cases, and they were associated with disease severity. Additionally, a significant increase in the expression of GAS5-family and ZFAS1 lncRNAs, which target factors involved in the inflammatory response, was observed in the sample collected from the patient with the most severe disease progression. An lncRNA prognostic signature was defined, opening up novel research avenues in understanding the interactions between lncRNAs and SARS-CoV-2.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the "Cytokine Storm" (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.

Respiratory syncytial virus (RSV) infection has been identified to serve as the primary cause of acute lower respiratory infectious diseases in children under the age of one and a significant risk factor for the emergence and development of pediatric recurrent wheezing and asthma, though the exact mechanism is still unknown.

In this study, we discuss the key routes that lead to recurrent wheezing and bronchial asthma following RSV infection. It is interesting to note that following the coronavirus disease 2019 (COVID-19) epidemic, the prevalence of RSV changes significantly. This presents us with a rare opportunity to better understand the associated mechanism for RSV infection, its effects on the respiratory system, and the immunological response to RSV following the COVID-19 epidemic. To better understand the associated mechanisms in the occurrence and progression of pediatric asthma, we thoroughly described how the RSV infection directly destroys the physical barrier of airway epithelial tissue, promotes inflammatory responses, enhances airway hyper-responsiveness, and ultimately causes the airway remodeling. More critically, extensive discussion was also conducted regarding the potential impact of RSV infection on host pulmonary immune response.

In conclusion, this study offers a comprehensive perspective to better understand how the RSV infection interacts in the control of the host's pulmonary immune system, causing recurrent wheezing and the development of asthma, and it sheds fresh light on potential avenues for pharmaceutical therapy in the future.

Starting in 2019, coronavirus disease 2019 (COVID-19) caused an epidemic that was growing rapidly and has harmed millions of people globally. It has been demonstrated that survivin regulates lymphocyte survival, a main route involved in COVID-19 pathogenesis. Survivin belongs to the inhibitor of apoptosis protein (IAP) family, and its primary functions comprise regulating mitosis and inhibiting apoptosis. Since lower survivin expression has been shown to increase the sensitivity of lymphocytes to apoptotic induction, we looked into the function of survivin and its corresponding pathways in COVID-19 pathogenesis.

The expression of survivin, X-linked inhibitor of apoptosis protein (XIAP), caspases 3, 7, 9, and poly (ADP-ribose) polymerase (PARP) was evaluated at both mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) derived from healthy donors and patients with severe and moderate COVID-19 by qRT-PCR and Western blotting, respectively. Then, we enforced apoptosis to COVID-19 patient-derived lymphocytes, and the percent was assessed by flow cytometry.

Survivin and XIAP were less expressed in PBMCs derived from COVID-19 patients as apoptosis inhibitors than PARP, cleaved-PARP, caspase 9, and cleaved caspases 3 and 7, according to the results of real-time PCR and Western blot analysis. Additionally, according to the flow cytometry results, the down-regulation of survivin served as a potential factor in the lymphocyte depletion observed in patients with COVID-19.

The role of survivin and its related pathway was first discovered in the development of COVID-19 and may serve as a potential prognostic and therapeutic target.

The COVID-19 pandemic propelled immunology into global news and social media, resulting in the potential for misinterpreting and misusing complex scientific concepts.

To study the extent to which immunology is discussed in news articles and YouTube videos in English and Italian, and if related scientific concepts are used to support specific political or ideological narratives in the context of COVID-19.

In English and Italian we searched the period 11/09/2019 to 11/09/2022 on YouTube, using the software Mozdeh, for videos mentioning COVID-19 and one of nine immunological concepts: antibody-dependent enhancement, anergy, cytokine storm, herd immunity, hygiene hypothesis, immunity debt, original antigenic sin, oxidative stress and viral interference. We repeated this using MediaCloud for news articles.Four samples of 200 articles/videos were obtained from the randomised data gathered and analysed for mentions of concepts, stance on vaccines, masks, lockdown, social distancing, and political signifiers.

Vaccine-negative information was higher in videos than news (8-fold in English, 6-fold in Italian) and higher in Italian than English (4-fold in news, 3-fold in videos). We also observed the existence of information bubbles, where a negative stance towards one intervention was associated with a negative stance to other linked ideas. Some immunological concepts (immunity debt, viral interference, anergy and original antigenic sin) were associated with anti-vaccine or anti-NPI (non-pharmacological intervention) views. Videos in English mentioned politics more frequently than those in Italian and, in all media and languages, politics was more frequently mentioned in anti-guidelines and anti-vaccine media by a factor of 3 in video and of 3-5 in news.

There is evidence that some immunological concepts are used to provide credibility to specific narratives and ideological views. The existence of information bubbles supports the concept of the "rabbit hole" effect, where interest in unconventional views/media leads to ever more extreme algorithmic recommendations.

Little is known about the impact of the COVID-19 pandemic on patients with Parkinson's disease (PD) at different stages of the pandemic. This study aims to assess the lives and disease status of PD patients during the zero-COVID policy period and after ending the zero-COVID policy.

This multicenter cross-sectional study included two online surveys among PD patients in China, from May 30 to June 30 in 2022 and from January 1 to February 28 in 2023, respectively. The survey questionnaires contained four sections: (1) status of COVID-19 infection; (2) impact on motor and non-motor symptoms; (3) impact on daily and social lives; and (4) impact on PD disease management.

A total of 1764 PD patients participated in the first online survey, with 200 patients having lockdown experience and 3 being COVID-19-positive (0.17%). In addition, 537 patients participated in the second online survey, with 467 patients having COVID-19 infection (86.96%). (1) During zero-COVID, all of the COVID-19-positive patients had mild symptoms of COVID-19 and no death was reported. After zero-COVID, 83.51% of the COVID-19-positive patients had mild symptoms. The overall death rate and inpatient mortality rate of COVID-19-positive PD patients were 3.21% and 30.00%, respectively. (2) During zero-COVID, 49.43% of PD patients reported worsening of PD-related symptoms (lockdown vs. unlockdown, 60.50% vs. 48.02%, P = 0.0009). After zero-COVID, 54.93% of PD patients reported worsening of PD-related symptoms (COVID-19 positive vs. COVID-19 negative, 59.31% vs. 25.71%, P < 0.0001). (3) During zero-COVID, 62.36% of patients felt worried, and 'limited outdoor activities' (55.39%) was the top reason for mental health problems. After zero-COVID, 59.03% of patients felt worried, with 'poor health' (58.10%) being the top reason. The PD patients tended to change their daily activities from offline to online, and their economic and caregiver burdens increased both during and after zero-COVID. (4) Most PD patients would like to choose online rehabilitation during (69.56%) and after zero-COVID (69.27%). The demand for online medication purchasing also increased during (47.00%) and after zero-COVID (26.63%).

The COVID-19 pandemic aggravated the motor and non-motor symptoms of PD patients either during or after the zero-COVID policy period. The PD patients also experienced prominent mental health problems, changes in daily activities, and increases in economic and caregiver burdens. The COVID-19 pandemic has changed ways of PD management with increasing demands for online medication purchasing and rehabilitation.

The use of natural compounds, such as curcumin, to treat infections caused by bacteria, viruses, fungi, parasites, inflammatory diseases, and various types of cancer is an active and dynamic area of research. Curcumin has a long history of use in the food industry, and there is currently a growing interest in its therapeutic applications. Numerous clinical trials have consistently shown that curcumin, a polyphenolic compound, is safe and well-tolerated even at high doses. There is no toxicity limit. However, the clinical efficacy of curcumin has been limited by its constraints. However, scientific evidence indicates that the use of adjuvants and carriers, such as nanoparticles, exosomes, micelles, and liposomes, can help overcome this limitation. The properties, functions, and human benefits of using nanocurcumin are well-supported by scientific research. Recent evidence suggests that nanocurcumin may be a beneficial therapeutic modality due to its potential to decrease gene expression and secretion of specific inflammatory biomarkers involved in the cytokinestorm seen in severe COVID-19, as well as increase lymphocyte counts. Nanocurcumin has demonstrated the ability to improve clinical manifestations and modulate immune response and inflammation in various autoinflammatory diseases. Additionally, its efficacy, affordability, and safety make it a promising replacement for residual cancer cells after tumor removal. However, further studies are necessary to evaluate the safety and efficacy of nanocurcumin as a new therapeutic in clinical trials, including appropriate dosage, frequency, and duration.

The stability of the core can significantly impact the therapeutic effectiveness of liposome-based drugs. While the spherical nucleic acid (SNA) architecture has elevated liposomal stability to increase therapeutic efficacy, the chemistry used to anchor the DNA to the liposome core is an underexplored design parameter with a potentially widespread biological impact. Herein, we explore the impact of SNA anchoring chemistry on immunotherapeutic function by systematically studying the importance of hydrophobic dodecane anchoring groups in attaching DNA strands to the liposome core. By deliberately modulating the size of the oligomer that defines the anchor, a library of structures has been established. These structures, combined with in vitro and in vivo immune stimulation analyses, elucidate the relationships between and importance of anchoring strength and dissociation of DNA from the SNA shell on its biological properties. Importantly, the most stable dodecane anchor, (C12)9, is superior to the n = 4-8 and 10 structures and quadruples immune stimulation compared to conventional cholesterol-anchored SNAs. When the OVA1 peptide antigen is encapsulated by the (C12)9 SNA and used as a therapeutic vaccine in an E.G7-OVA tumor model, 50% of the mice survived the initial tumor, and all of those survived tumor rechallenge. Importantly, the strong innate immune stimulation does not cause a cytokine storm compared to linear immunostimulatory DNA. Moreover, a (C12)9 SNA that encapsulates a peptide targeting SARS-CoV-2 generates a robust T cell response; T cells raised from SNA treatment kill >40% of target cells pulsed with the same peptide and ca. 45% of target cells expressing the entire spike protein. This work highlights the importance of using anchor chemistry to elevate SNA stability to achieve more potent and safer immunotherapeutics in the context of both cancer and infectious disease.

Low-carbohydrate, high-fat (LCHF) nutrition therapy is characterized by carbohydrates comprising <26% of the daily caloric intake and a higher proportion of fat. LCHF therapies reduce exogenous glucose load, improve glycemic control, decrease inflammation, and improve clinical outcomes such as respiratory function. Given the altered metabolism in critically ill patients, LCHF nutrition therapy may be especially beneficial as it enables the conservation of protein and glucose for metabolic roles beyond energy use. In critical illness, LCHF diets have the potential to reduce hyperglycemia, improve ventilation, decrease hospital length of stay and reduce hospital costs. The purpose of this commentary piece is to describe LCHF nutrition therapy, summarize its impact on health outcomes, and discuss its role in the intensive care unit (ICU). Additional research on the effects of LCHF nutrition therapy on critically ill patients is warranted, including a focus on COVID-19.

Inflammatory cytokine storms (CS) in COVID-19 patients are associated with elevated levels of 13 specific cytokines, potentially impacting male fertility by causing testicular cell damage and disrupting the immune microenvironment. Some patients present with scrotal discomfort and orchitis. However, few studies have explored cytokine expression in testicular cells and their role in cell-to-cell communication. In this study, we integrated single-cell sequencing data sets of testicular cells, annotating 20 cell clusters using marker genes and the Human Cell Landscape database. We constructed cell pseudo-chronological trajectories, hub genes, and analyzed the cytokine interaction network between sperm cells using CellChat. Our findings identified 12 types of testicular cells, with four cytokines (IL8, CCL2, CCL3, and TNF) potentially involved in immune processes. Pseudo-chronological trajectory analysis indicated IL8 and CCL3's essential roles in testicular macrophages and endothelial cell development, affecting the immune microenvironment. We determined eight key cytokines (IL1, IL2, IL4, IL6, CCL, CSF3, TNF, and IFN-II) functions in cell interaction networks. Network analysis of exogenous cytokines directly acting on testicular cells showed IL2 potentially affecting all testicular cells, suggesting a vital role in cell communication. This research offers valuable insights into CSs effects on testicular cells and their potential impact on male fertility during COVID-19 infection.

All severe cases of SARS-CoV-2 infections are characterized by a high risk of disease progression towards ARDS, leading to a bad outcome. Respiratory symptoms in COVID-19 patients often do not correspond to disease's worsening. In our sample, median age was 74 years (72-75) and 54% were men. The median period of hospitalization was 9 days. Firstly, we observed a significant asynchronous trend of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) in 764 selected among 963 patients, who were consecutively recruited in two hospitals (Cannizzaro, S. Marco) in Catania, Italy. NLR values in deceased patients showed an increase from baseline over time. By contrast, CRP tended to fall from baseline to median day of hospitalization in all three subgroups, but steeply increased at the end of hospitalization only in ICU-admitted patients. Then, we evaluated the relationships between NLR and CRP as continuous variables with PaO₂/FiO₂ ratio (P/F). NLR was an independent predictor of mortality (HR: 1.77, p < 0.0001), while ICU admission was more significantly associated with CRP (HR: 1.70, p < 0.0001). Finally, age, neutrophils, CRP, and lymphocytes are significantly and directly linked to P/F, while the influence of inflammation on P/F, reflected by CRP, was also mediated by neutrophils.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress syndrome. Patients with chronic liver disease have been frequently affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes may be a risk factor for disease progression, even in the absence of underlying liver disease. While the respiratory tract is a primary target of SARS-CoV-2, it has become evident that COVID-19 is a multisystemic infectious disease. The hepatobiliary system might be influenced during COVID-19 infection, ranging from a mild elevation of aminotransferases to the development of autoimmune hepatitis and secondary sclerosing cholangitis. Furthermore, the virus can promote existing chronic liver diseases to liver failure and activate the autoimmune liver disease. Whether the direct cytopathic effects of the virus, host reaction, hypoxia, drugs, vaccination, or all these risk factors cause liver injury has not been clarified to a large extent in COVID-19. This review article discussed the molecular and cellular mechanisms involved in the pathogenesis of SARS-CoV-2 virus-associated liver injury and highlighted the emerging role of liver sinusoidal epithelial cells (LSECs) in virus-related liver damage.

Severe coronavirus disease 2019 (COVID-19) is associated with systemic hyper-inflammation. An adaptive interaction between gut microbiota and host immune systems is important for intestinal homeostasis and systemic immune regulation. The association of gut microbial composition and functions with COVID-19 disease severity is sparse, especially in India. We analysed faecal microbial diversity and abundances in a cohort of Indian COVID-19 patients to identify key signatures in the gut microbial ecology in patients with severe COVID-19 disease as well as in response to different therapies. The composition of the gut microbiome was characterized using 16Sr RNA gene sequences of genomic DNA extracted from faecal samples of 52 COVID-19 patients. Metabolic pathways across the groups were predicted using PICRUSt2. All statistical analyses were done using Vegan in the R environment. Plasma cytokine abundance at recruitment was measured in a multiplex assay.

The gut microbiome composition of mild and severe patients was found to be significantly different. Immunomodulatory commensals, viz. Lachnospiraceae family members and Bifidobacteria producing butyrate and short-chain fatty acids (SCFAs), were under represented in patients with severe COVID-19, with an increased abundance of opportunistic pathogens like Eggerthella. The higher abundance of Lachnoclostridium in severe disease was reduced in response to convalescent plasma therapy. Specific microbial genera showed distinctive trends in enriched metabolic pathways, strong correlations with blood plasma cytokine levels, and associative link to disease outcomes.

Our study indicates that, along with SARS-CoV-2, a dysbiotic gut microbial community may also play an important role in COVID-19 severity through modulation of host immune responses.

Nonbiological artificial liver (NBAL) is frequently used as a first-line treatment for hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). This study aimed to compare the therapeutic efficacy and cost-effectiveness ratio (CER) of comprehensive medical treatment, plasma exchange (PE), and double plasma molecular adsorption system (DPMAS) plus half-dose PE (DPMAS+PE) in patients with HBV-ACLF.

A total of 186 patients with HBV-ACLF randomly received comprehensive medical treatment, PE, or DPMAS+PE and were prospectively evaluated. Patients were divided into four subgroups based on the pretreatment prothrombin activity (PTA): Group I (PTA>40%), group II (PTA 30-40%), group III (PTA 20-30%), and group IV (PTA<20%). The main outcome measures were 28 day effectiveness; 90 day liver transplantation-free survival; change of biochemical parameters; and CER.

DPMAS+PE treatment was associated with significantly higher 28 day effectiveness and 90 day liver transplantation-free survival compared with PE treatment in patients with group I liver failure. Clearance of serum total bilirubin (TBIL), AST, and creatinine (Cr) were significantly higher in the DPMAS+PE group than in the PE group. For subjects with group I liver failure, DPMAS+PE treatment had advantages of lower CER values and better cost-effectiveness.

Compared with comprehensive medical treatment and PE alone, DPMAS with half-dose sequential PE treatment more effectively improved TBIL, AST, and Cr in HBV-ACLF patients, improved 28 day effectiveness and 90 day survival rates in patients with group I liver failure, and was more cost effective. DPMAS+PE is a viable NBAL approach for treatment of HBV-ACLF.

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by SARS-CoV-2 infection. Patients with severe COVID-19 exhibit robust induction of proinflammatory cytokines, which are closely associated with the development of acute respiratory distress syndrome. However, the underlying mechanisms of the NF-κB activation mediated by SARS-CoV-2 infection remain poorly understood. Here, we screened SARS-CoV-2 genes and found that ORF3a induces proinflammatory cytokines by activating the NF-κB pathway. Moreover, we found that ORF3a interacts with IKKβ and NEMO and enhances the interaction of IKKβ-NEMO, thereby positively regulating NF-κB activity. Together, these results suggest ORF3a may play pivotal roles in the pathogenesis of SARS-CoV-2 and provide novel insights into the interaction between host immune responses and SARS-CoV-2 infection.

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A₂ that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A₂ IIA (sPLA₂-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA₂-IIA levels together with eicosanoids in the sera of COVID patients. sPLA₂ could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A₂, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA₂-IIA in COVID-19-associated coagulopathy (CAC).

Coronavirus disease 2019 (Covid-19) is caused by a novel severe acute respiratory syndrome coronavirus virus type 2 (SARS-CoV-2) leading to the global pandemic worldwide. Systemic complications in Covid-19 are mainly related to the direct SARS-CoV-2 cytopathic effects, associated hyperinflammation, hypercytokinemia, and the development of cytokine storm (CS). As well, Covid-19 complications are developed due to the propagation of oxidative and thrombotic events which may progress to a severe state called oxidative storm and thrombotic storm (TS), respectively. In addition, inflammatory and lipid storms are also developed in Covid-19 due to the activation of inflammatory cells and the release of bioactive lipids correspondingly. Therefore, the present narrative review aimed to elucidate the interrelated relationship between different storm types in Covid-19 and the development of the mixed storm (MS). In conclusion, SARS-CoV-2 infection induces various storm types including CS, inflammatory storm, lipid storm, TS and oxidative storm. These storms are not developing alone since there is a close relationship between them. Therefore, the MS seems to be more appropriate to be related to severe Covid-19 than CS, since it develops in Covid-19 due to the intricate interface between reactive oxygen species, proinflammatory cytokines, complement activation, coagulation disorders, and activated inflammatory signaling pathway.

Hospitalized patients have an increased risk of developing hospital-acquired sacral pressure injury (HASPI). However, it is unknown whether SARS-CoV-2 infection affects HASPI development. To explore the role of SARS-CoV-2 infection in HASPI development, we conducted a single institution, multi-hospital, retrospective study of all patients hospitalized for ≥5 days from March 1, 2020 to December 31, 2020. Patient demographics, hospitalization information, ulcer characteristics, and 30-day-related morbidity were collected for all patients with HASPIs, and intact skin was collected from HASPI borders in a patient subset. We determined the incidence, disease course, and short-term morbidity of HASPIs in COVID-19(+) patients, and characterized the skin histopathology and tissue gene signatures associated with HASPIs in COVID-19 disease. COVID-19(+) patients had a 63% increased HASPI incidence rate, HASPIs of more severe ulcer stage (OR 2.0, p<0.001), and HASPIs more likely to require debridement (OR 3.1, p=0.04) compared to COVID-19(-) patients. Furthermore, COVID-19(+) patients with HASPIs had 2.2x increased odds of a more severe hospitalization course compared to COVID-19(+) patients without HASPIs. HASPI skin histology from COVID-19(+) patients predominantly showed thrombotic vasculopathy, with the number of thrombosed vessels being significantly greater than HASPIs from COVID-19(-) patients. Transcriptional signatures of a COVID-19(+) sample subset were enriched for innate immune responses, thrombosis, and neutrophil activation genes. Overall, our results suggest that immunologic dysregulation secondary to SARS-CoV-2 infection, including neutrophil dysfunction and abnormal thrombosis, may play a pathogenic role in development of HASPIs in patients with severe COVID-19.

Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can contribute to the pathogenesis of airway diseases. NETs are known to be directly cytotoxic to the lung epithelium and endothelium, highly involved in acute lung injury, and implicated in disease severity and exacerbation. This review describes the role of NET formation in airway diseases, including chronic rhinosinusitis, and suggests that targeting NETs could be a therapeutic strategy for airway diseases.

The ongoing COVID-19 pandemic caused by SARS-CoV-2 infections has quickly developed into a global public health threat. COVID-19 patients show distinct clinical features, and in some cases, during the severe stage of the condition, the disease severity leads to an acute respiratory disorder. In spite of several pieces of research in this area, the molecular mechanisms behind the development of disease severity are still not clearly understood. Recent studies demonstrated that SARS-CoV-2 alters the host cell splicing and transcriptional response to overcome the host immune response that provides the virus with favorable conditions to replicate efficiently within the host cells. In several disease conditions, aberrant splicing could lead to the development of novel chimeric transcripts that could promote the functional alternations of the cell. As severe SARS-CoV-2 infection was reported to cause abnormal splicing in the infected cells, we could expect the generation and expression of novel chimeric transcripts. However, no study so far has attempted to check whether novel chimeric transcripts are expressed in severe SARS-CoV-2 infections. In this study, we analyzed several publicly available blood transcriptome datasets of severe COVID-19, mild COVID-19, other severe respiratory viral infected patients, and healthy individuals. We identified 424 severe COVID-19 -specific chimeric transcripts, 42 of which were recurrent. Further, we detected 189 chimeric transcripts common to severe COVID-19 and multiple severe respiratory viral infections. Pathway and gene enrichment analysis of the parental genes of these two subsets of chimeric transcripts reveals that these are potentially involved in immune-related processes, interferon signaling, and inflammatory responses, which signify their potential association with immune dysfunction leading to the development of disease severity. Our study provides the first detailed expression landscape of chimeric transcripts in severe COVID-19 and other severe respiratory viral infections.

Natural killer (NK) cells are among the most important innate immunity members, which are the first cells that fight against infected cells. The function of these cells is impaired in patients with COVID-19 and they are not able to prevent the spread of the disease or destroy the infected cells. Few studies have evaluated the effects of COVID-19 vaccines on NK cells, though it has been demonstrated that DNA vaccines and BNT162b2 can affect NK cell response. In the present paper, the effects of SARS-CoV-2 on the NK cells during infection, the effect of vaccination on NK cells, and the NK cell-based therapies were reviewed.

The impact of coronavirus disease 2019 (COVID-19) pandemic on patients with neurodegenerative diseases and the specific neurological manifestations of COVID-19 have aroused great interest. However, there are still many issues of concern to be clarified. Therefore, we review the current literature on the complex relationship between COVID-19 and neurodegenerative diseases with an emphasis on Parkinson's disease (PD) and Alzheimer's disease (AD). We summarize the impact of COVID-19 infection on symptom severity, disease progression, and mortality rate of PD and AD, and discuss whether COVID-19 infection could trigger PD and AD. In addition, the susceptibility to and the prognosis of COVID-19 in PD patients and AD patients are also included. In order to achieve better management of PD and AD patients, modifications of care strategies, specific drug therapies, and vaccines during the pandemic are also listed. At last, mechanisms underlying the link of COVID-19 with PD and AD are reviewed.

The strikingly rapidly mutating nature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome has been a constant challenge during the coronavirus disease 2019 (COVID-19) pandemic. In this study, various techniques, including reverse transcription-quantitative polymerase chain reaction, antigen-detection rapid diagnostic tests, and high-throughput sequencing were analyzed under different scenarios and spectra for the etiological diagnosis of COVID-19 at the population scale. This study aimed to summarize the latest research progress and provide up-to-date understanding of the methodology used for the evaluation of the immunoprotection conditions against future variants of SARS-CoV-2. Our novel work reviewed the current methods for the evaluation of the immunoprotection status of a specific population (endogenous antibodies) before and after vaccine inoculation (administered with biopharmaceutical antibody products). The present knowledge of the immunoprotection status regarding the COVID-19 complications was also discussed. Knowledge on the immunoprotection status of specific populations can help guide the design of pharmaceutical antibody products, inform practice guidelines, and develop national regulations with respect to the timing of and need for extra rounds of vaccine boosters.

A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis-associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS-CoV-2-induced ARDS at the infective and post-infective stages. In this minireview, we examine drugs targeting IL-1β, IL-4/IL-13, IL-6 and TNF-α tested in COVID-19 patients.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a major public health threat to all countries worldwide. SARS-CoV-2 interactions with its receptor are the first step in the invasion of the host cell. The coronavirus spike protein (S) is crucial in binding to receptors on host cells. Additionally, targeting the SARS-CoV-2 viral receptors is considered a therapeutic option in this regard. In this review of literature, we summarized five potential host cell receptors, as host-cell surface bindings, including angiotensin-converting enzyme 2 (ACE2), neuropilin 1 (NRP-1), dipeptidyl peptidase 4 (DPP4), glucose regulated protein-78 (GRP78), and cluster of differentiation 147 (CD147) related to the SARS-CoV-2 infection. Among these targets, ACE2 was recognized as the main SARS-CoV-2 receptor, expressed at a low/moderate level in the human respiratory system, which is also involved in SARS-CoV-2 entrance, so the virus may utilize other secondary receptors. Besides ACE2, CD147 was discovered as a novel SARS-CoV-2 receptor, CD147 appears to be an alternate receptor for SARSCoV- 2 infection. NRP-1, as a single-transmembrane glycoprotein, has been recently found to operate as an entrance factor and enhance SARS Coronavirus 2 (SARS-CoV-2) infection under in-vitro. DPP4, which was discovered as the first gene clustered with ACE2, may serve as a potential SARS-CoV-2 spike protein binding target. GRP78 could be recognized as a secondary receptor for SARS-CoV-2 because it is widely expressed at substantially greater levels, rather than ACE2, in bronchial epithelial cells and the respiratory mucosa. This review highlights recent literature on this topic.

Severe acute respiratory syndrome coronavirus 2 is a virus that can still infect individuals and whose deadly effects continue despite the current vaccines and drugs. Since 2019, many studies on the pathogenesis of the disease have been completed and continue to be done. In addition to the diagnosis and treatment of the disease, many molecules that can be markers of the disease have been investigated. In the early stages of the pandemic, many nonspecific and infection-related laboratory findings and chest computed tomography were used to obtain information about the diagnosis of the disease. The more individual molecules became associated with the disease yet. The purpose of this review is to summarize the impact and role of many molecules associated with coronavirus disease-2019 infection that have been previously used and newly revealed. Numerous studies are summarized in this review. The obtained data show that previously used laboratory findings and new potential biomarkers are not specific to the disease. New potential biomarkers have been associated with the severity of the disease itself, as can be seen with lung imaging and even with routine laboratory findings. One of the important points that are seen frequently in studies is that the effectiveness of these molecules has been shown not only in coronavirus disease-2019 infection but also in many other diseases. This removes the pathogenesis of the disease from being a unique mechanism created by the Severe acute respiratory syndrome coronavirus 2 and provides a general perspective formed by viral or bacterial infections. However, there are still many molecular changes that need to be investigated. Future studies will continue to update themselves with the mutations of the virus.

SARS-CoV-2 is the causative virus for the CoVID-19 pandemic that has frequently mutated to continue to infect and resist available vaccines. Emerging new variants of the virus have complicated notions of immunity conferred by vaccines versus immunity that results from infection. While we continue to progress from epidemic to endemic as a result of this collective immunity, the pandemic remains a morbid and mortal problem.

The SARS-CoV-2 virus has a very complex manner of replication. The spike protein, one of the four structural proteins of the encapsulated virus, is central to the ability of the virus to penetrate cells to replicate. The objective of this review is to summarize these complex features of viral replication.

A review of the recent literature was performed on the biology of SARS-CoV-2 infection from published work from PubMed and works reported to preprint servers, e.g., bioRxiv and medRxiv.

The complex molecular and cellular biology involved in SARS-CoV-2 replication and the origination of >30 proteins from a single open reading frame (ORF) have been summarized, as well as the structural biology of spike protein, a critical factor in the cellular entry of the virus, which is a necessary feature for it to replicate and cause disease.

Purpose: COVID-19, a novel infection, presented with several complications, including socioeconomical and reproductive health challenges such as erectile dysfunction (ED). The present review summarizes the available shreds of evidence on the impact of COVID-19 on ED.Materials and methods: All published peer-reviewed articles from the onset of the COVID-19 outbreak to date, relating to ED, were reviewed. Results: Available pieces of evidence that ED is a consequence of COVID-19 are convincing. COVID-19 and ED share common risk factors such as disruption of vascular integrity, cardiovascular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD). COVID-19 also induces impaired pulmonary haemodynamics, increased ang II, testicular damage and low serum testosterone, and reduced arginine-dependent NO bioavailability that promotes reactive oxygen species (ROS) generation and endothelial dysfunction, resulting in ED. In addition, COVID-19 triggers psychological/mental stress and suppresses testosterone-dependent dopamine concentration, which contributes to incident ED.Conclusions: In conclusion, COVID-19 exerts a detrimental effect on male reproductive function, including erectile function. This involves a cascade of events from multiple pathways. As the pandemic dwindles, identifying the long-term effects of COVID-19-induced ED, and proffering adequate and effective measures in militating against COVID-19-induced ED remains pertinent.

Limited recent observational data have suggested that there may be a protective effect of oestrogen on the severity of COVID-19 disease. Our aim was to investigate the association between hormone replacement therapy (HRT) or combined oral contraceptive pill (COCP) use and the likelihood of death in women with COVID-19.

We undertook a retrospective cohort study using routinely collected computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. We identified a cohort of 1,863,478 women over 18 years of age from 465 general practices in England. Mixed-effects logistic regression models were used to quantify the association between HRT or COCP use and all-cause mortality among women diagnosed with confirmed or suspected COVID-19 in unadjusted and adjusted models.

There were 5,451 COVID-19 cases within the cohort. HRT was associated with a reduction in all-cause mortality in COVID-19 (adjusted OR 0.22, 95% CI 0.05 to 0.94). There were no reported events for all-cause mortality in women prescribed COCPs. This prevented further examination of the impact of COCP.

We found that HRT prescription within 6 months of a recorded diagnosis of COVID-19 infection was associated with a reduction in all-cause mortality. Further work is needed in larger cohorts to examine the association of COCP in COVID-19, and to further investigate the hypothesis that oestrogens may contribute a protective effect against COVID-19 severity.

Coronavirus disease 2019 (COVID-19) has been a global pandemic, caused by a novel coronavirus strain with strong infectivity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the in-depth research, the close relationship between COVID-19 and immune system has been dug out. During the infection, macrophages, dendritic cells, natural killer cells, CD8⁺ T cells, Th1, Th17, Tfh cells and effector B cells are all involved in the anti-SARS-CoV-2 responses, however, the dysfunctional immune responses will ultimately lead to the excessive inflammation, acute lung injury, even other organ failure. Thus, a detailed understanding of pertinent immune response during COVID-19 will provide insights in predicting disease outcomes and developing appropriate therapeutic approaches. In this review, we mainly clarify the role of immune cells in COVID-19 and the target-vaccine development and treatment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can produce a wide range of clinical manifestations from asymptomatic to life-threatening. Various researchers have worked to elucidate the pathogenic mechanisms underlying these variable presentations. Differences in individual responses to systemic inflammation and coagulopathy appear to be modulated by several factors, including sex steroid hormones. Transgender men or non-binary individuals who undergo gender-affirming hormone therapy (GAHT) are a unique population of interest for exploring the androgen-mediated coronavirus disease 2019 (COVID-19) hypothesis. As the search for reliable and effective COVID-19 treatments continues, understanding the risks and benefits of GAHT may mitigate COVID-19 related morbidity and mortality in this patient population.

To investigate the potential role of GAHT in the development of COVID-19 infections and complications.

This systematic review implemented an algorithmic approach using PRISMA guidelines. PubMed, Scopus, Google Scholar top 100 results, and archives of Plastic and Reconstructive Surgery was on January 12, 2022 using the key words "gender" AND "hormone" AND "therapy" AND "COVID-19" as well as associated terms. Non-English articles, articles published prior to 2019 (prior to COVID-19), and manuscripts in the form of reviews, commentaries, or letters were excluded. References of the selected publications were screened as well.

The database search resulted in the final inclusion of 14 studies related to GAHT COVID-19. Of the included studies, only two studies directly involved and reported on COVID-19 in transgender patients. Several clinical trials looked at the relationship between testosterone, estrogen, and progesterone in COVID-19 infected cis-gender men and women. It has been proposed that androgens may facilitate initial COVID-19 infection, however, once this occurs, testosterone may have a protective effect. Multiple clinical studies have shown that low baseline testosterone levels in men with COVID-19 are associated with worsening outcomes. The role of female sex hormones, including estrogen and progesterone have also been proposed as potential protective factors in COVID-19 infection. This was exemplified in multiple studies investigating different outcomes in pre- and post-menopausal women as well as those taking hormone replacement therapy. Two studies related specifically to transgender patients and GAHT found that estrogen and progesterone could help protect men against COVID-19, and that testosterone hormone therapy may increase the risk of contracting COVID-19.

Few studies were found related to the role of GAHT in COVID-19 infections. Additional research is necessary to enhance our understanding of this relationship and provide better care for transgender patients.

Optic perineuritis (OPN) is a previously undescribed sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here we present a case of OPN that developed several weeks after initial confirmation of the presence of novel coronavirus RNA in the nasopharynx by polymerase chain reaction assay and subsequent confirmation of SARS-CoV-2 IgG seropositivity in the absence of other systemic inflammatory or infectious markers.

An asymptomatic 71-year-old man with noninsulin-dependent diabetes mellitus (NIDDM) tested RNA positive for SARS-CoV-2 during a routine screening of patients at a skilled nursing facility. ~3 weeks after the positive SARS-CoV-2 polymerase chain reaction test, the patient developed subacute ophthalmoparesis of the left eye, horizontal diplopia, retro-orbital pain, and frontal headache. An urgent magnetic resonance imaging of the head and orbits suggested OPN. Cerebrospinal fluid studies were without evidence of other infectious, inflammatory, neoplastic, or paraneoplastic processes. He was started on a 5-day course of high-dose intravenous steroids and later transitioned to oral steroid therapy. Sixteen days after the initiation of steroid therapy, the patient had no headache or retro-orbital pain and demonstrated a marked improvement in horizontal gaze.

SARS-CoV-2-associated neurological sequelae have been increasingly recognized during the current coronavirus disease 2019 pandemic. The present case suggests that patients with confirmed SARS-CoV-2 positivity, even without pulmonary or other classic manifestations of active infection, may manifest diverse clinical presentations including postinfectious OPN that could be related to an underlying autoimmune reactive inflammatory response.

The pandemic of severe acute respiratory syndrome coronavirus-2 infection has prompted the urgent need for novel therapeutic approaches, especially for patients in critically severe conditions. To date, the pathogenesis of COVID-19 is not completely understood, and finding an effective new drug is still inconclusive. Mesenchymal stromal cell-derived extracellular vesicles contain large amounts of proteins, messenger RNA, and microRNAs that act as vehicles that transfer the cargo between cells. These nanotherapeutic materials exert anti-inflammatory effects on the immune system, which are necessary for subsidence of acute inflammation and promotion of tissue repair and regeneration. Therefore, the consideration of mesenchymal stromal cell-derived extracellular vesicles as a new, safe, and effective therapeutic approach in the treatment of COVID-19 pneumonia is suggested.