Oxidation and "Unconventional” Approaches to Infection

Nonpharmacological approaches can be useful to control infectious diseases. Historically infection has been successfully managed with oxidation therapy methods that support the body's own innate defenses. Several modalities include ozone and hyperbaric oxygen therapy, ultraviolet blood irradiation (UBI), intravenous hydrogen peroxide, and ascorbate therapies. Oxidation therapies are virtually 100% safe, and repeatedly reported as highly and quickly effective in quelling infection (bacterial and viral) either as stand-alone therapies or adjunctive with drugs. They are directly and indirectly germicidal, and modulate the immune system via pro-oxidant signaling molecules. Oxidation therapies especially enhance oxygen delivery and metabolism, critical for all infection defenses. Ozone has remitted Ebola, COVID-19, and bacterial infections. UBI defeated most preantibiotic era infections in hospitals. Not being drug therapy, the effects of oxidation defenses, used by planetary animal life for millions of years, are not diminished by antibiotic-resistant organisms. Oxidation, depending on delivery method, can be very inexpensive and third world adaptable. This chapter summarizes the use of these key modalities, by exploring known published literature. © 2022 Elsevier Inc. All rights reserved.

Role of gut microbiota in infectious and inflammatory diseases.

Thousands of microorganisms compose the human gut microbiota, fighting pathogens in infectious diseases and inhibiting or inducing inflammation in different immunological contexts. The gut microbiome is a dynamic and complex ecosystem that helps in the proliferation, growth, and differentiation of epithelial and immune cells to maintain intestinal homeostasis. Disorders that cause alteration of this microbiota lead to an imbalance in the host's immune regulation. Growing evidence supports that the gut microbial community is associated with the development and progression of different infectious and inflammatory diseases. Therefore, understanding the interaction between intestinal microbiota and the modulation of the host's immune system is fundamental to understanding the mechanisms involved in different pathologies, as well as for the search of new treatments. Here we review the main gut bacteria capable of impacting the immune response in different pathologies and we discuss the mechanisms by which this interaction between the immune system and the microbiota can alter disease outcomes.

Antiviral Potential of Coconut (Cocos nucifera L.) Oil and COVID-19

Background: COVID-19 caused by the novel SARS Coronavirus-2 (SARS-CoV-2) is causing serious problems in the global public health sphere. In the absence of a powerful antiviral treatment, the exploration of plant-based products with antiviral potential has gained interest. Scope and Approach: This commentary presents the prospects of utilizing coconut oil directly or its derivatives such as monolaurin in treating COVID-19 with a special emphasis on their biochemical characteristics features. The potential pitfalls therein and way forward are also highlighted. Key findings and conclusions: There are enough research-backed evidences to demonstrate the antiviral capabilities of coconut oil and monolaurin. The possibility of developing a medium-chain fatty acidbased nasal spray as a prophylactic or therapeutic is also discussed. Nevertheless, the potential impediments in devising suitable therapeutic models to treat SARS-CoV-2, are presented.Copyright © 2021 Bentham Science Publishers.

Intermodulation of gut-lung axis microbiome and the implications of biotics to combat COVID-19.

The novel coronavirus disease pandemic caused by the COVID-19 virus has infected millions of people around the world with a surge in transmission and mortality rates. Although it is a respiratory viral infection that affects airway epithelial cells, a diverse set of complications, including cytokine storm, gastrointestinal disorders, neurological distress, and hyperactive immune responses have been reported. However, growing evidence indicates that the bidirectional crosstalk of the gut-lung axis can decipher the complexity of the disease. Though not much research has been focused on the gut-lung axis microbiome, there is a translocation of COVID-19 infection from the lung to the gut through the lymphatic system resulting in disruption of gut permeability and its integrity. It is believed that detailed elucidation of the gut-lung axis crosstalk and the role of microbiota can unravel the most significant insights on the discovery of diagnosis using microbiome-based-therapeutics for COVID-19. This review calls attention to relate the influence of dysbiosis caused by COVID-19 and the involvement of the gut-lung axis. It presents first of its kind details that concentrate on the momentousness of biotics in disease progression and restoration.Communicated by Ramaswamy H. Sarma.

First use of imlifidase desensitization in a highly sensitized lung transplant candidate: a case report.

Lung transplant candidates who are highly sensitized against human leucocyte antigen present an ongoing challenge with regards to finding immunologically acceptable donors. Desensitization strategies aimed at reducing preformed donor-specific antibodies have a number of limitations. Imlifidase, an IgG-degrading enzyme derived from Streptococcus pyogenes, is a novel agent that has been used to convert positive crossmatches to negative in kidney transplant candidates, allowing transplantation to occur. We present the first case of imlifidase use for antibody depletion in a highly sensitized lung transplant candidate who went on to undergo a successful bilateral lung transplant.

The Association between Previous Antibiotic Consumption and SARS-CoV-2 Infection: A Population-Based Case-Control Study.

Background: The susceptibility to SARS-CoV-2 infection is complex and not yet fully elucidated, being related to many variables; these include human microbiome and immune status, which are both affected for a long period by antibiotic use. We therefore aimed to examine the association of previous antibiotic consumption and SARS-CoV-2 infection in a large-scale population-based study with control of known confounders. Methods: A matched case-control study was performed utilizing the electronic medical records of a large Health Maintenance Organization. Cases were subjects with confirmed SARS-CoV-2 infection (n = 31,260), matched individually (1:4 ratio) to controls without a positive SARS-CoV-2 test (n = 125,039). The possible association between previous antibiotic use and SARS-CoV-2 infection was determined by comparing antibiotic consumption in the previous 6 and 12 months between the cases and controls. For each antibiotic consumed we calculated the odds ratio (OR) for documented SARS-CoV-2 infection, 95% confidence interval (CI), and p-value using univariate and multivariate analyses. Results: The association between previous antibiotic consumption and SARS-CoV-2 infection was complex and bi-directional. In the multivariate analysis, phenoxymethylpenicillin was associated with increased rate of SARS-CoV-2 infection (OR 1.110, 95% CI: 1.036-1.191) while decreased rates were associated with previous consumption of trimethoprim-sulfonamides (OR 0.783, 95% CI: 0.632-0.971) and azithromycin (OR 0.882, 95% CI: 0.829-0.938). Fluroquinolones were associated with decreased rates (OR 0.923, 95% CI: 0.861-0.989) only in the univariate analysis. Previous consumption of other antibiotics had no significant association with SARS-CoV-2 infection. Conclusions: Previous consumption of certain antibiotic agents has an independent significant association with increased or decreased rates of SARS-CoV-2 infection. Plausible mechanisms, that should be further elucidated, are mainly antibiotic effects on the human microbiome and immune modulation.

Emerging immunomodulatory strategies for cell therapeutics.

Cellular therapies are poised to transform the field of medicine by restoring dysfunctional tissues and treating various diseases in a dynamic manner not achievable by conventional pharmaceutics. Spanning various therapeutic areas inclusive of cancer, regenerative medicine, and immune disorders, cellular therapies comprise stem or non-stem cells derived from various sources. Despite numerous clinical approvals or trials underway, the host immune response presents a critical impediment to the widespread adoption and success of cellular therapies. Here, we review current research and clinical advances in immunomodulatory strategies to mitigate immune rejection or promote immune tolerance to cellular therapies. We discuss the potential of these immunomodulatory interventions to accelerate translation or maximize the prospects of improving therapeutic outcomes of cellular therapies for clinical success.

Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System.

A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme activity could also have an impact on the immune system. Therefore, we performed a comprehensive study on the influence of elF4A inhibition with natural and synthetic rocaglates on various immune cells. The effect of the rocaglates zotatifin, silvestrol and CR-31-B (-), as well as the nonactive enantiomer CR-31-B (+), on the expression of surface markers, release of cytokines, proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdMs), monocyte-derived dendritic cells (MdDCs), T cells and B cells was assessed. The inhibition of elF4A reduced the inflammatory potential and energy metabolism of M1 MdMs, whereas in M2 MdMs, drug-specific and less target-specific effects were observed. Rocaglate treatment also reduced the inflammatory potential of activated MdDCs by altering cytokine release. In T cells, the inhibition of elF4A impaired their activation by reducing the proliferation rate, expression of CD25 and cytokine release. The inhibition of elF4A further reduced B-cell proliferation, plasma cell formation and the release of immune globulins. In conclusion, the inhibition of the elF4A RNA helicase with rocaglates suppressed the function of M1 MdMs, MdDCs, T cells and B cells. This suggests that rocaglates, while inhibiting viral replication, may also suppress bystander tissue injury by the host immune system. Thus, dosing of rocaglates would need to be adjusted to prevent excessive immune suppression without reducing their antiviral activity.

Pilot analysis of intravenous lipid infusion role in COVID-19 mortality.

INTRODUCTION: How to reduce the fatality of coronavirus disease (COVID-19) is still challenging. A proper nutritional support has been always a matter of attention in critically ill patients. MATERIAL AND METHODS: We assessed COVID-19 patients who had received intralipid infusion due to medical indications and compared them with those who did not receive it regarding fatality rate and prognosis. As a part of a data mining project using data of observational cohort of COVID-19 patients hospitalized in the educational centers of Iran University of Medical Sciences, Tehran, Iran, an inferential case series was performed. A total of 19 patients with SARS-CoV-2 infection were selected from the cohort. Briefly, 13 patients survived and 6 patients died, and 12 patients were admitted in intensive care unit (ICU). All dead cases were ICU admitted. The association of intralipid infusion and survival rate was examined using Fisher exact test. No association was observed between intralipid infusion and survival. CONCLUSIONS: No significant protecting effect was observed for patients who received intralipid for medical indications. Since intralipid was administered according to medical indications, surviving of all the non-ICU admitted patients despite having underlying diseases was remarkable. Despite the fact, due to several bias factors that could not be controlled in such a retrospective study, the results might be accidental. We suggest to assess such an effect retrospectively in other centers as well.

SARS-CoV-2 Variability in Patients and Wastewaters-Potential Immuno-Modulation during the Shift from Delta to Omicron.

The continuous emergence of SARS-CoV-2 variants favors potential co-infections and/or viral mutation events, leading to possible new biological properties. The aim of this work was to characterize SARS-CoV-2 genetic variability during the Delta-Omicron shift in patients and in a neighboring wastewater treatment plant (WWTP) in the same urban area. The surveillance of SARS-CoV-2 was performed by routine screening of positive samples by single nucleotide polymorphism analysis within the S gene. Moreover, additionally to national systematic whole genome sequencing (WGS) once a week in SARS-CoV-2-positive patients, WGS was also applied when mutational profiles were difficult to interpret by routine screening. Thus, WGS was performed on 414 respiratory samples and on four wastewater samples, northeastern France. This allowed us to report (i) the temporally concordant Delta to Omicron viral shift in patients and wastewaters; (ii) the characterization of 21J (Delta) and 21K (Omicron)/BA.1-21L (Omicron)/BA.2-BA.4 mixtures from humans or environmental samples; (iii) the mapping of composite mutations and the predicted impact on immune properties in the viral Spike protein.

Exosite binding modulates the specificity of the immunomodulatory enzyme ScpA, a C5a inactivating bacterial protease.

The C5a peptidase from Streptococcus pyogenes (ScpA) is a highly specific enzyme with potential therapeutic value. ScpA is a good model for studying determinants of specificity in the multidomain immunomodulatory enzymes (IMEs), which comprise a large family of bacterial surface proteases. The surface exposed region of ScpA has 5 main domains which includes 3 C-terminal Fn3-like domains (Fn1, Fn2 and Fn3) (Kagawa et al. 2009). Progressive deletion of the Fn3-like domains from the C-ter resulted in loss of enzyme activity and showed an important role for the Fn2 domain in enzyme function. Functional investigation of specific acidic residues on the Fn2 domain identified 3 residues 30-50 Å from the catalytic site (D783, E864 and D889) which impacted to differing degrees on binding and on catalysis, supporting the presence of an exosite on the Fn2. In particular, residue D783 was observed to impact on both substrate binding affinity and the activity of ScpA. A double mutant cycle analysis showed energetic coupling between the targeted ScpA residues and residues in the core portion (residues 1-67) of the C5a substrate. The data supports the presence of a communication network between the active site and the exosite on Fn2. These findings provide a basis for rational engineering of this important enzyme family to enhance stability, activity and/or specificity.

mTOR inhibitors, mycophenolates, and other immunosuppression regimens on antibody response to SARS-CoV-2 mRNA vaccines in solid organ transplant recipients.

A recent study concluded that SARS-CoV-2 mRNA vaccine responses were improved among transplant patients taking mTOR inhibitors (mTORi). This could have profound implications for vaccine strategies in transplant patients; however, limitations in the study design raise concerns about the conclusions. To address this issue more robustly, in a large cohort with appropriate adjustment for confounders, we conducted various regression- and machine learning-based analyses to compare antibody responses by immunosuppressive agents in a national cohort (n = 1037). MMF was associated with significantly lower odds of positive antibody response (aOR = 0.09 0.130.18 ). Consistent with the recent mTORi study, the odds tended to be higher with mTORi (aOR = 1.00 1.452.13 ); however, importantly, this seemingly protective tendency disappeared (aOR = 0.47 0.731.12 ) after adjusting for MMF. We repeated this comparison by combinations of immunosuppression agents. Compared to MMF + tacrolimus, MMF-free regimens were associated with higher odds of positive antibody response (aOR = 2.39 4.267.92 for mTORi+tacrolimus; 2.34 5.5415.32 for mTORi-only; and 6.78 10.2515.93 for tacrolimus-only), whereas MMF-including regimens were not, regardless of mTORi use (aOR = 0.81 1.542.98 for MMF + mTORi; and 0.81 1.512.87 for MMF-only). We repeated these analyses in an independent cohort (n = 512) and found similar results. Our study demonstrates that the recently reported findings were confounded by MMF, and that mTORi is not independently associated with improved vaccine responses.

A pilot randomized controlled trial of de novo belatacept-based immunosuppression following anti-thymocyte globulin induction in lung transplantation.

The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a two-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after three participants in the Belatacept arm died compared to none in the Control arm. Subsequently, two additional participants in the Belatacept arm died for a total of five deaths compared to none in the Control arm (log rank p = .016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the two groups. We conclude that the investigational regimen used in this study is associated with increased mortality after lung transplantation.

Beneficial Immune Regulation by Biological Response Modifier Glucans in COVID-19 and Their Envisaged Potentials in the Management of Sepsis.

Sepsis is a life-threatening condition caused by an abnormal immune response induced by infection with no approved or specific therapeutic options. We present our perspectives for the therapeutic management of sepsis through a four-way approach: (1) infection control through immune enhancement; (2) immune suppression during the initial hyper-inflammatory phase; (3) balanced immune-modulation to counter the later immune-paralysis phase; and (4) advantageous effects on metabolic and coagulation parameters throughout. COVID-19 is a virus-triggered, accelerated sepsis-like reaction that is associated with the rapid progress of an inflammatory cascade involving a cytokine storm and multiorgan failure. Here, we discuss the potential of the biological response modifiers, ß-glucans (BRMGs), in the management of sepsis based on their beneficial effects on inflammatory-immune events in COVID-19 clinical studies. In COVID-19 patients, apart from metabolic regulation, BRMGs, derived from a black yeast, Aureobasidium pullulans strain AFO-202, have been reported to stimulate immune responses. BRMGs, produced by another strain (N-163) of A. pullulans, have been implicated in the beneficial regulation of inflammatory markers and immunity, namely IL-6, C-reactive protein (CRP), D-Dimer, ferritin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCR), leucocyte-to-C-reactive protein ratio (LeCR), and leukocyte-to-IL-6 ratio (LeIR). Agents such as these ß-glucans, which are safe as they have been widely consumed by humans for decades, have potential as adjuncts for the prevention and management of sepsis as they exert their beneficial effects across the spectrum of processes and factors involved in sepsis pathology, including, but not limited to, metabolism, infection, inflammation, immune modulation, immune enhancement, and gut microbiota.

Effect of Urinary Trypsin Inhibitor (Ulinastatin) Therapy in COVID-19.

Purpose: End-organ damage in coronavirus disease-2019 (COVID-19) is linked to "cytokine storm" and excessive release of inflammatory mediators. Various novel therapies have been used in COVID-19 including urinary trypsin inhibitor therapy. This study explores the efficacy of ulinastatin in COVID-19. Materials and methods: We retrieved the medical records of patients admitted during one month and did a propensity score analysis to create matched treatment and control groups. We analyzed these groups and the outcomes were presented with appropriate statistics. Survival curve was prepared to compare the survival effect of ulinastatin therapy at the end of hospitalization, among both the groups. Results: A total of 736 patients were admitted, and after adjusting the data with propensity score matching, 55 cases were selected by the system. On the final outcome analysis, we found that intensive care unit (ICU) length of stay [median (interquartile range) days 3 (3.5-7.8) vs 2 (0-4); p-value 0.28] in control vs intervention groups, and in hospital mortality (odds ratio: 0.491, CI 95%: 0.099-2.44, p-value 0.435) were not statistically different among the groups. In survival plot analysis also, there was no statistical difference (p-value 0.414) among both the groups.Conclusion: In this retrospective study, we conclude that the final outcome of the ICU length of stay, and overall, in hospital mortality were not different among both the groups. Hence, adequately powered randomized control trials are urgently required to confirm any benefit of ulinastatin therapy in COVID-19 treatment. How to cite this article: Jain A, Kasliwal R, Jain SS, Jain R, Gupta D, Gupta P, et al. Effect of Urinary Trypsin Inhibitor (Ulinastatin) Therapy in COVID-19. Indian J Crit Care Med 2022;26(6):696-703.

The Possible Role of Prion-Like Viral Protein Domains on the Emergence of Novel Viruses as SARS-CoV-2.

Self-replicating proteins or prions deviate from the central dogma of replication. The discovery of prion-like domains in coronavirus SARS-CoV-2 suggests their possible role in viral evolution. Here, we have outlined the possible role of self-replicating protein-like domains in the emergence of novel viruses. Further studies are needed to understand the function of these viral self-replicating protein-like domains and whether they could be antiviral target(s) for the development of effective antiviral agents in the future.

Neutralizing antibody response against the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants after a third mRNA SARS-CoV-2 vaccine dose in kidney transplant recipients.

Seroconversion after COVID-19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants pose an increasing threat to these patients. In this observational cohort study, we measured anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies three weeks after a third mRNA vaccine dose in 49 kidney transplant recipients and compared results to 25 age-matched healthy controls. In addition, vaccine-induced neutralization of SARS-CoV-2 wild-type, the B.1.617.2 (delta), and the B.1.1.529 (omicron) variants was assessed using a live-virus assay. After a third vaccine dose, anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies were significantly lower in kidney transplant recipients compared to healthy controls. Only 29/49 (59%) sera of kidney transplant recipients contained neutralizing antibodies against the SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant and neutralization titers were significantly reduced compared to healthy controls (p < 0.001). Vaccine-induced cross-neutralization of the B.1.1.529 (omicron) variants was detectable in 15/35 (43%) kidney transplant recipients with seropositivity for anti-S1 IgG, surrogate neutralizing, and/or anti-RBD antibodies. Neutralization of the B.1.1.529 (omicron) variants was significantly reduced compared to neutralization of SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant for both, kidney transplant recipients and healthy controls (p < .001 for all).

Inflammation and the role of infection: Complications and treatment options following neurotrauma.

Traumatic brain injury can have devastating consequences for patients and extended hospital stays and recovery course. Recent data indicate that the initial insult causes profound changes to the immune system and leads to a pro-inflammatory state. This alteration in homeostasis predisposes patients to an increased risk of infection and underlying autoimmune conditions. Increased emphasis has been placed on understanding this process both in the clinical and preclinical literature. This review highlights the intrinsic inflammatory conditions that can occur within the initial hospital stay, discusses long-term immune consequences, highlights emerging treatment options, and delves into important pathways currently being investigated with preclinical models.

Controlled modulation of all the arms of the immunity including innate immunity by biological response modifier glucans, a simple yet potential nutritional supplement strategy to fight COVID-19.

Immune modulation, being one of the potential strategies to combat COVID-19 infection, emphasis has been laid on enhancing the innate immune response in a balanced manner. Beta (ß)-glucans have been suggested as nonspecific immunostimulatory adjuvants to beneficially boost protective antiviral immunity. Through this article, we wish to emphasize that ß-glucans not only enhance the innate immunity but also possess the capability to modulate all the arms of the immunity viz., innate, adaptive, TRIM at different sites including those postulated to be the entry site of the SARS-CoV2. Other than immune modulation capabilities, the beneficial metabolic- and coagulation-related effects of ß-glucans, a simple nutritional supplementation strategy, make them be considered for larger clinical studies to validate their prophylactic vaccine adjuvant and nutritional-based therapeutic supplement activities to effectively fight the COVID-19 pandemic. PRACTICAL APPLICATIONS: A 360° wholesome protection from viral infections is possible only when all the arms of the immune system function in a balanced and effective manner which is especially important in COVID-19. Nutritional supplementation using biological response modifier beta (ß)-glucans (BRMGs) is worth considering for large-scale clinical studies based on their track record of safety and their beneficial regulation of all the arms of the immune system.