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Obejectives: This study explored the immunomodulatory effects of a prebiotic formula consisting of 2'-fucosyllactose (2'-FL), galacto-oligosaccharides (GOSs), and fructo-oligosaccharides (FOSs) (hereinafter referred to as 2FGF) in cyclophosphamide (CTX)-induced immunosuppressed BALB/c mice and its underlying mechanisms. Methods: Sixty healthy female BALB/c mice were randomly divided into the following groups: normal control (NC) group; CTX treatment (CTX) group; 2FGF low-dose (2FGF-L) group; 2FGF medium-dose (2FGF-M) group; and 2FGF high-dose (2FGF-H) group. An immunosuppressed model was established in the 2FGF-H group by intraperitoneal injection of 80 mg/kg CTX. After 30 days of 2FGF intervention, peripheral blood, spleen tissue, thymus tissue, and intestinal tissue from the mice were collected and analyzed. The changes in weight and food intake of the mice were recorded weekly. Hematoxylin-eosin (HE) staining was used to observe the histological change of the spleen tissue. Enzyme-linked immunosorbent assay (ELISA) was employed to detect cytokine levels in peripheral blood. Flow cytometry was used to analyze T lymphocyte subgroup ratio of splenic lymphocytes. Western blot analysis was conducted on intestinal tissues to assess the expression of proteins involved in the tight junction, toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathways. Additionally, molecular techniques were used to analyze the intestinal microbiota. Results: The results showed that 2FGF restored CTX-induced splenic injury, increased the number of splenic T lymphocytes, and elevated serum cytokines such as interleukin-4 (IL-4) and IL-10. In the intestine, 2FGF upregulated the expression of intestinal epithelial tight junction proteins such as Claudin-1 and zonula occludens 1 (ZO-1), thereby enhancing intestinal barrier function and activating the MAPK and NF-κB pathways via TLR4. Furthermore, 2FGF elevated the α-diversity (Shannon and Simpson indices) of the gut microbiota in CTX-induced immunosuppressed mice, enriching bacteria species positively correlated with anti-inflammatory cytokines (e.g., IL-4) such as g_Streptomyces and g_Bacillus and negatively correlated with pro-inflammatory cytokines (e.g., IL-1β) such as g_Saccharomyces . The results suggest that 2FGF may enhance immunity via the gut-immune axis. Conclusions: The 2FGF prebiotic formula showed an immunomodulatory effect in CTX-induced immunosuppressed mice, and the mechanism of which might involve optimizing the gut flora, enhancing intestinal homeostasis, strengthening the intestinal barrier, and promoting the expression of immune factors by regulating the TLR-4/MAPK/NF-κB pathway.

Codonopsis pilosula, an important medicinal and edible plant in traditional Chinese medicine, is used widely as a tonifying herb for various immunodeficiency diseases. A neutral polysaccharide (CPPs-D1N1) was purified from C. pilosula, composed of fructose and glucose in a molar ratio of 97.28:2.72, with an average molecular weight of 5.985 kDa. Structural analysis revealed a backbone composed of →1)-β-D-Fruf-(2 → units with some β-D-Fruf-(2 → linkages. In a murine immunosuppression model induced by cyclophosphamide injection, oral treatment with C. pilosula polysaccharide was administered, investigating changes in gut microbiota during therapy. The polysaccharide modulated serum immunoglobulins (Ig-G, Ig-M), cytokines (IL-2, IL-6, TNFα), and spleen and thymus indices in immunodeficient mice. Additionally, functional gene primer sequencing enrichment methods revealed alterations in abundance, diversity, and structure of butyrate-producing bacterial populations in the gut, with primary differential genera identified as Butyribacter, Rumanococcus, Dysosmobacter, and Ruseburia. This study provides in vivo evidence supporting the beneficial effects of C. pilosula polysaccharide oral therapy in improving gut microbiota, particularly butyrate-producing bacteria, during treatment of immunosuppressive diseases., Competing Interests: Declaration of competing interest The authors declare that they do not have any conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Dietary fiber (DF) has a good application prospect in effectively restoring the integrity of the intestinal mucosal barrier. Ginseng-DF has good physicochemical properties and physiological activity and shows positive effects in enhancing immunity. The aim of this study was to investigate the protective effect of Ginseng-DF on intestinal mucosal barrier injury induced by cyclophosphamide (CTX) in immunosuppressed mice and its possible mechanism., Methods: The effects of Gginseng-DF on immune function in mice were studied by delayed-type hypersensitivy, lymphocyte proliferation assay and NK cytotoxicity assay, the T lymphocyte differentiation and intestinal barrier integrity were analyzed by flow cytometry and western blot., Results: Ginseng-DF (2.5% and 5%) could attenuate the inhibition of DTH response by CTX, promote the transformation and proliferation of lymphocytes, and stimulate NK effector cell activity. At the same time, Ginseng-DF could restore the proportion of CD4 + /CD8 + T lymphocytes induced by CTX to different extents, improved spleen tissue damage, promoted the secretion of immunoglobulin IgG, and enhanced body immunity. More importantly, Ginseng-DF could up-regulate the contents of TNF-α, IFN-γ, IL-6 and IL-1β in serum and intestine of immunosuppressed mice to maintain the balance between Th1/Th2 cytokines, and improve the permeability of intestinal mucosal barrier. Meanwhile, Ginseng-DF could reduce intestinal epithelial cell apoptosis and improve intestinal adaptive immunity in CTX-induced immunosuppressed mice by regulating MAPK/NF-κB signaling pathway., Conclusion: Ginseng-DF can be used as a safe dietary supplement to enhance body immunity and reduce intestinal mucosal injury caused by CTX., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitexin-2-O-rhamnoside (VR) is an important active substance in hawthorn, which is widely used as a food or functional food raw material; however, its immunomodulatory activities have not been extensively studied. In this study, BALB/c mice immunocompromised by cyclophosphamide (CY) were used as models to explore the effects of VR on the immunity and antioxidant capacity of mice. The results revealed that VR can restore weight to the immunosuppressed mice to varying degrees, improve spleen and thymus injury, and restore peripheral blood levels. Furthermore, it can effectively promote the proliferation of T and B lymphocytes, natural killer (NK) and cytotoxic T lymphocyte (CTL) cell activities, and the secretion and mRNA expression of cytokines IFN-γ, IL-2, IL-6, and IL-12 to 0.36, 0.34, 50.25%, 45.74%, 28.36 pg/mL or 0.68, 31.81 pg/mL or 0.74, 20.40 pg/mL or 0.75, and 19.81 pg/mL or 0.55, respectively. Moreover, it can upregulate the phosphorylation level of PI3K/Akt signaling pathway in mice immunosuppressed by CY, increase the activities of glutathione peroxidase (GSH-Px), chloramphenicol acetyltransferase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), and decrease the level of malondialdehyde (MDA). This study provides a theoretical and experimental basis for the research and development of health products with targeted efficacy, and the development of diversified products in the hawthorn deep-processing industry., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cancer patients with COVID-19 have reduced survival. While most cancer patients, like the general population, have an almost 100% rate of seroconversion after COVID-19 infection or vaccination, patients with haematological malignancies have lower seroconversion rates and are far less likely to gain adequate protection. This raises the concern that patients with haematological malignancies, especially those receiving immunosuppressive therapies, may still develop the fatal disease when infected with COVID-19 after vaccination. There is an urgent need to develop Guidelines to help direct vaccination schedules and protective measures in oncology patients, differentiating those with haematological malignancies and those in an immunocompromised state., (© 2022. The Author(s).)

Abstract: Immunodeficiency-associated lymphoproliferative disorders are associated with latent infection by Epstein-Barr virus (EBV). Most cases of EBV-positive immunodeficiency-associated lymphoproliferative disorders arise from B cells, although some are of T-cell or natural killer origin. Cutaneous involvement is unusual and sporadically reported in the literature. We describe a rare case of an EBV-positive T-cell lymphoma presenting in the skin of a 32-year-old woman using adalimumab for neurosarcoidosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In the present study, the purpose is to compare the effect of water extraction and alkali-assisted extraction on the structural characteristics and immunomodulatory activity of polysaccharides from Fuzhuan brick tea (FBTPs). The results indicated that water-extracted FBTPs (W-FBTPs) and alkali-extracted FBTPs (A-FBTPs) had similar molecular weights but different monosaccharide compositions, of which A-FBTPs had a higher yield and uronic acid groups corresponding to galacturonic acid (GalA). Moreover, A-FBTPs had stronger ability to promote phagocytic capacity, acid phosphatase activity and nitric oxide (NO) secretion in macrophages in vitro . In the in vivo study, A-FBTPs exhibited a promising effect to adjust the immune imbalance by enhancing the body features, antioxidant activities, immune response and intestinal mucosal barrier in cytoxan (CTX)-induced immunosuppressive mice. Besides, A-FBTP supplementation effectively improved CTX-induced gut microbiota dysbiosis, including promoting the abundance of beneficial bacteria ( e.g. , Lactobacillus ) and short chain fatty acid (SCFA)-producing bacteria ( e.g. , Lachnospiraceae, Prevotellaceae and Ruminococcaceae), along with reducing the growth of potentially pathogenic microbes ( e.g. , Desulfovibrionaceae and Helicobacter ). These findings suggested that alkaline extraction might be a promising way to obtain high-quality acidic polysaccharides from Fuzhuan brick tea (FBT), and A-FBTPs could be developed as novel potential prebiotics and immunomodulators for further application in food formulations.

Cancer immunotherapy can boost the immune response of patients to eliminate tumor cells and suppress tumor metastasis and recurrence. However, immunotherapy resistance and the occurrence of severe immune-related adverse effects are clinical challenges that remain to be addressed. The tumor microenvironment plays a crucial role in the therapeutic efficacy of cancer immunotherapy. Injectable hydrogels have emerged as powerful drug delivery platforms offering good biocompatibility and biodegradability, minimal invasion, convenient synthesis, versatility, high drug-loading capacity, controlled drug release, and low toxicity. In this review, we summarize the application of injectable hydrogels as a unique platform for targeting the immunosuppressive tumor microenvironment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Geng, Yue, Lo, Huang and Jin.)

Background & Aims: Regulatory T cell (Treg) depletion increases antitumor immunity. However, severe autoimmunity can occur following systemic loss of Tregs, which could be avoided by selectively depleting intratumoral Tregs. Herein, we aimed to investigate the role of tumor-infiltrating CCR4 + Tregs in hepatocellular carcinoma (HCC) and to provide a potential target strategy for immunotherapy., Methods: CCR4 + Tregs were analyzed by flow cytometry in murine models and clinical samples. The function of tumor-infiltrating and induced CCR4 + Tregs was interrogated by genetic and epigenetic approaches. To block CCR4 + Treg chemotaxis, we developed an N-terminus recombinant protein of CCR4 (N-CCR4-Fc) as a neutralizing pseudo-receptor that effectively bound to its ligand CCL22. The efficacy of CCR4 antagonism as an immunotherapeutic agent was evaluated by tumor weights, growth kinetics and survival curves., Results: CCR4 + Tregs were the predominant type of Tregs recruited to hepatitis B-associated HCC (HBV + HCC), correlating with sorafenib resistance and HBV load titers. Compared with CCR4 - Tregs, CCR4 + Tregs exhibited increased IL-10 and IL-35 expression, and enhanced functionality in suppressing CD8 + T cells. CCR4 + Tregs also displayed PD-1 + TCF1 + stem-like properties. ATAC-seq data revealed substantial chromatin remodeling between tumor-infiltrating Tregs (TIL-Tregs) and induced Tregs, suggesting that long-term chromatin reprogramming accounted for the acquisition of enhanced immunosuppressive stem-like specificity by CCR4 + TIL-Tregs. Treatment with a CCR4 antagonist or N-CCR4-Fc blocked intratumoral Treg accumulation, overcame sorafenib resistance, and sensitized tumors to PD-1 checkpoint blockade., Conclusions: Intratumoral stem-like CCR4 + Tregs orchestrated immunosuppressive resource cells in the tumor microenvironment. CCR4 could be targeted to enhance antitumor immunity by specifically blocking infiltration of Tregs into the tumor microenvironment and inhibiting maintenance of the TIL-Treg pool., Lay Summary: Targeting regulatory T cells is a promising approach in cancer immunotherapy; however, severe autoimmunity can occur following systemic regulatory T cell loss. This could be avoided by selectively depleting intratumoral regulatory T cells. Herein, targeting intratumoral stem-like CCR4 + regulatory T cells helped to overcome sorafenib resistance and sensitize tumors to immune checkpoint blockade in mouse models of liver cancer. This approach could have wide clinical applicability., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86 + cells, CD4 + and CD8 + T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3 + lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.

Background & Aims: Liver transplant (LT) recipients or other immunocompromised patients were not included in the registration trials studying the efficacy of vaccines against SARS-CoV-2. Although the clinical efficacy of COVID-19 vaccines in immunocompromised patients is unknown, many societies have recommended vaccination of this highly vulnerable patient population., Methods: In this prospective study, we determined antibody responses to spike protein, 4 weeks after the 2 nd dose of mRNA vaccines or after the single dose of Johnson & Johnson vaccine, in LT recipients and those with chronic liver disease (CLD) with and without cirrhosis., Results: Of the 233 patients enrolled so far, 62 were LT recipients, 79 had cirrhosis (10 decompensated) and 92 had CLD without cirrhosis. Antibody titers were defined as undetectable (<0.40 U/ml), suboptimal (0.40-250 U/ml) and adequate (>250 U/ml). Of the 62 patients who had LT, antibody levels were undetectable in 11 patients and suboptimal (median titer 17.6, range 0.47-212 U/ml) in 27 patients. Among 79 patients with cirrhosis, 3 had undetectable antibody levels and 15 had suboptimal (median titer 41.3, range 0.49-221 U/L) antibody responses. Of the 92 patients without cirrhosis, 4 had undetectable antibody levels and 19 had suboptimal (median titer 95.5, range 4.9-234 U/L) antibody responses. Liver transplantation, use of 2 or more immunosuppression medications and vaccination with a single dose of the Johnson & Johnson vaccine were associated with poor immune response on multivariable analysis. No patient had any serious adverse events., Conclusions: Poor antibody responses after SARS-CoV-2 vaccination were seen in 61% of LT recipients and 24% of those with CLD., Lay Summary: The clinical efficacy of COVID-19 vaccines in immunocompromised patients is unknown. We performed a prospective study to evaluate immune responses to COVID-19 vaccines (Moderna, Pfizer or Johnson & Johnson) in 62 liver transplant recipients, 79 patients with cirrhosis and 92 with chronic liver diseases without cirrhosis. We found that 17.8% of liver transplant recipients, 3.8% of those with cirrhosis and 4.3% of those with chronic liver diseases without cirrhosis had undetectable antibody levels. In total, 61.3% of liver transplant recipients and 24% of those with chronic liver diseases (with or without cirrhosis) had poor antibody responses (undetectable or suboptimal). Liver transplantation, use of immunosuppressive medications and vaccination with a single dose of Johnson & Johnson vaccine were associated with poor antibody responses when adjusted for other factors., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) has affected more than a hundred million individuals and caused more than three million deaths worldwide. Specific risk groups were defined for increased risk of mortality and morbidity in COVID-19, and renal transplant recipients are at a significantly increased risk regarding outcomes due to their immunosuppressed conditions. This study evaluated the general characteristics of kidney transplant recipients with COVID-19 infection. Among 1257 transplant cases, 56 had COVID-19 infection, and 23 (41%) were hospitalized during the 9-month study period. Among all COVID-19 cases, 58% were male with a mean age of 45.5 (±13.2, 19-71) years, and the most frequent comorbidities were hypertension (70.9%) and diabetes (23.6%). Hospitalized patients were older (p = 0.03) and had higher rates of hypertension (p = 0.008), diabetes (p = 0.002), and ischemic heart disease (p = 0.03). Therapeutic management included antimetabolite withdrawal and prednisolone increase in 71%, calcineurin inhibitor withdrawal in 8% and decrease in 58%, hydroxychloroquine in 17%, tocilizumab in 3%, and antivirals in 67% of patients. Acute kidney injury and respiratory failure developed in 34% and 85%, respectively. The mortality rate was 23%. These results emphasized that the COVID-19 infection in renal transplant recipients significantly increases the risk of morbidity and mortality. Therefore, these patients should be intervened earlier and monitored closely to prevent poor outcomes., (© 2021 Wiley Periodicals LLC.)

Introduction: Lung transplant patients are immunocompromised because of the medication they receive to prevent rejection, and as a consequence are susceptible to (respiratory) infections. Adequate vaccination strategies, including COVID-19 vaccination, are therefore needed to minimize infection risks., Areas Covered: The international vaccination guidelines for lung transplant patients are reviewed, including the data on immunogenicity and effectivity of the vaccines. The impact on response to vaccination of the various categories of immunosuppressive drugs, used in the posttransplant period, on response to vaccination is described. A number of immunosuppressive and/or anti-inflammatory drugs also is used for controlling the immunopathology of severe COVID-19. Current available COVID-19 vaccines, both mRNA or adenovirus based are recommended for lung transplant patients., Expert Opinion: In order to improve survival and quality of life, infections of lung transplant patients should be prevented by vaccination. When possible, vaccination should start already during the pre-transplantation period when the patient is on the waiting list. Booster vaccinations should be given post-transplantation, but only when immunosuppression has been tapered. Vaccine design based on mRNA technology could allow the design of an array of vaccines against other respiratory viruses, offering a better protection for lung transplant patients.

The effects of immunomodulatory activity of two types of carboxymethyl pachymaran (CMP-1 and CMP-2) on cyclophosphamide (CTX)-induced mice were investigated. Both CMP-1 and CMP-2 were found to restore the splenomegaly and alleviate the spleen lesions and the mRNA expressions of TLR4, MyD88, p65 and NF-κB in spleen were also increased. CMP-1 and CMP-2 could enhance the immunity by increasing the levels of TNF-α, IL-2, IL-6, IFN-γ, Ig-A and Ig-G in serum. In addition, CMP-1 could increase the relative abundance of Bacteroidetes and reduce the relative richness of Firmicutes at the phylum level. CMP-1 and CMP-2 could reduce the relative abundance Erysipelatoclostridum at the genus level. CMP-1 and CMP-2 might enhance the immune function of immunosuppression mice by regulating the gene expression in the TLR4/NF-κB signaling pathway and changing the composition and abundance of the intestinal microbiota. The results suggested that CMP-1 and CMP-2 would be as potential immunomodulatory agents in functional foods.

In this study, the immunomodulatory effect of sea buckthorn (SBT) pulp oil was elucidated in immunosuppressed Balb/c mice induced by cyclophosphamide (CTX). The results showed that SBT pulp oil could reverse the decreasing trend of body weight, thymus/spleen index and hematological parameters induced by CTX. Compared with immunosuppressive mice induced by CTX, SBT pulp oil could enhance NK cytotoxicity, macrophage phagocytosis, and T lymphocyte proliferation, and regulate the proportion of T cell subsets in mesenteric lymph nodes (MLN), and promote the production of secretory immunoglobulin A (sIgA), IFN-γ, IL-2, IL-4, IL-12 and TNF-α in the intestines. In addition, SBT pulp oil can promote the production of short fatty acids (SCFAs), increase the diversity of gut microbiota, improve the composition of intestinal flora, increase the abundance of Alistipes, Bacteroides, Anaerotruncus, Lactobacillus, ASF356, and Roseburia, while decreasing the abundance of Mucispirillum, Anaeroplasma, Pelagibacterium, Brevundimonas, Ochrobactrum, Acinetobacter, Ruminiclostridium, Blautia, Ruminiclostridium, Oscillibacter, and Faecalibaculum. This study shows that SBT pulp oil can regulate the diversity and composition of intestinal microflora in CTX-induced immunosuppressive Balb/c mice, thus enhancing the intestinal mucosa and systemic immune response. The results can provide a basis for understanding the function of SBT pulp oil and its application as a new probiotic and immunomodulator.

Introduction: Several vaccine candidates have been developed using different platforms, including nucleic acids (DNA and RNA), viral vectors (replicating and non-replicating), virus-like particles, peptide-based, recombinant proteins, live attenuated, and inactivated virus modalities. Although many of these vaccines are undergoing pre-clinical trials, several large clinical trials investigating the clinical efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines have produced promising findings., Areas Covered: In this review, we provide a status update on COVID-19 vaccines currently undergoing clinical trials and discuss issues of concern beyond vaccine efficacy and safety, including dosing regimens, the mixed vaccine strategy, prior severe acute respiratory syndrome coronavirus-2 infection, antibody levels, cellular immunity and protection, variants of concern, COVID-19 vaccine distribution, vaccination willingness, herd immunity, immunity passports, and vaccine indications., Expert Opinion: Four vaccines have obtained emergency use authorization, 87 are at the clinical development stage, and 186 are in pre-clinical development. While the knowledge and development of COVID-19 vaccines is rapidly expanding, the benefits of COVID-19 vaccines must outweigh the potential risks of adverse events. To combat the COVID-19 pandemic, clinicians should consistently update COVID-19-associated information, and healthcare authorities and manufacturers should work together to provide adequate and appropriate vaccinations for the prevention of COVID-19., Plain Language Summary: What is the context? Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic: the coronavirus disease 2019 (COVID-19) outbreak. The development and implementation of the COVID-19 vaccine could be an important measure to control the COVID-19 pandemic. What is new? Several phase 3 clinical trials have demonstrated the effectiveness and safety of COVID-19 vaccines for the prevention of SARS-CoV-2 infections. Several COVID-19 vaccines have obtained emergency use authorization and been implemented in many countries. Although concerns regarding unusual blood clots and low platelet counts have been raised, the benefits of COVID-19 vaccines outweigh the potential risks of adverse events. What is the impact? Except for children, the COVID-19 vaccine is recommended for all people, including those pregnant or immunocompromised. Healthcare authorities should advise people receiving the vaccine that they must seek medical attention if they have associated thromboembolism and thrombocytopenia symptoms. More studies are necessary to determine the appropriate vaccine dose and regimen strategy, as well as the effectiveness of COVID-19 vaccines against variants of concerns. A global effort must be made to achieve widespread vaccination and herd immunity.

COVID-19 vaccination is recommended for multiple sclerosis patients. Disease-modifying therapies can influence the safety and efficacy of COVID-19 vaccines. RNA, DNA, protein, and inactivated vaccines are likely safe for multiple sclerosis patients. A few incidences of central demyelination were reported with viral vector vaccines, but their benefits likely outweigh their risks if alternatives are unavailable. Live-attenuated vaccines should be avoided whenever possible in treated patients. Interferon-beta, glatiramer acetate, teriflunomide, fumarates, and natalizumab are not expected to impact vaccine efficacy, while cell-depleting agents (ocrelizumab, rituximab, ofatumumab, alemtuzumab, and cladribine) and sphingosine-1-phosphate modulators will likely attenuate vaccine responses. Coordinating vaccine timing with dosing regimens for some therapies may optimize vaccine efficacy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes., Methods: Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event]., Results: In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death., Conclusions: During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Severe acute respiratory syndrome coronavirus 2 infected patients, receiving background anti-CD20 therapy, were treated with convalescent plasma or plasma-based products. Eight patients were included in the study, presenting with prolonged disease course and delayed viral clearance. CP/plasma-based products were offered as an add-on therapy to standard medical treatment. All patients showed remarkable clinical and laboratory improvement. In addition, polymerase chain reaction from nasopharyngeal swabs rapidly converted to negative following plasma administration. This study emphasizes the therapeutic efficacy of convalescent plasma and plasma-based products in a subgroup of immunocompromised patients with iatrogenic B-cell depletion., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this study, we evaluated the immune-enhancing activity of kimchi-derived Lactobacillus plantarum 200655 on immune suppression by cyclophosphamide (CP) in ICR mice. Animals were fed distilled water or 1×10 9 colony-forming unit/kg B.W. 200655 or Lactobacillus rhamnosus GG as a positive control for 14 days. An in vivo model of immunosuppression was induced using CP 150 and 100 mg/kg B.W. at 7 and 10 days, respectively. Body weight, spleen index, spleen weight, and gene expression were measured to estimate the immune-enhancing effects. The dead 200655 (D-200655) group showed an increased spleen weight compared to the sham control (SC) group. Similarly, the spleen index was significantly higher than that in the CP-treated group. The live 200655 (L-200655) group showed an increased mRNA expression of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in splenocytes. Also, the iNOS and COX-2 mRNA expression was upregulated in the L-200655 group compared to the CP-only (SC) group. The phosphorylation of ERK and MAPK was also upmodulated in the L-200655 group. These results indicate that L. plantarum 200655 ameliorated CP-induced immune suppression, suggesting that L. plantarum 200655 may have the potential to enhance the immune system.

Myelosuppression is the major dose-limiting toxicity of cancer chemotherapy. There have been many attempts to find new strategies that reduce myelosuppression. The dietary supplementation with lactic acid bacteria (LAB) improved respiratory innate immune response and the resistance against respiratory pathogens in immunosupressed hosts. Although LAB viability is an important factor in achieving optimal protective effects, non-viable LAB are capable of stimulating immunity. In this work, we studied the ability of oral preventive administration of viable and non-viable Lactobacillus rhamnosus CRL1505 or L. plantarum CRL1506 (Lr05, Lr05NV, Lp06V or Lp06NV, respectively) to minimize myelosuppressive and immunosuppressive effects derived from chemotherapy. Cyclophosphamide (Cy) impaired steady-state myelopoiesis in lactobacilli-treated and untreated control mice. Lr05V, Lr05NV and Lp06V treatments were the most effective to induce the early recovery of bone marrow (BM) tissue architecture, leukocytes, myeloid, pool mitotic and post-mitotic, peroxidase positive, and Gr-1 Low/High cells in BM. We selected the CRL1505 strain for being the one capable of maintaining its myelopoiesis-enhancing properties in its non-viable form. Although the CRL1505 treatments do not modify the Cy ability to induce apoptosis, both increased the incorporation of BrdU in BM cells. Consequently, Lr05NV and Lr05V treatments were able to promote early recovery of LSK cells (Lin - Sca-1 + c-Kit + cells), multipotent progenitors (Lin - Sca-1 + c-Kit + CD34 + cells), and myeloid cells (Gr-1 + Ly6G + Ly6C - cells) with respect to the untreated Cy control. In addition, these treatments were able to increase the frequency of IL17A-producing innate lymphoid cells in the intestinal lamina propria (IL-17A + RORγt + CD4 - NKp46 + cells) after Cy injection. These results were correlated with an increase in the IL-17A serum levels, a GM-CSF high expression and a CXCL12 lower expression in BM. Therefore, both Lr05V and Lr05NV treatments are able to activate beneficially the IL-17A/GM-CSF axis and accelerate the recovery of Cy-induced immunosuppression by increasing BM myeloid precursors. We demonstrated for the first time the beneficial effect of CRL1505 strain on myelopoiesis affected by a chemotherapeutic drug. Furthermore, Lr05NV could be a good and safe resource for reducing chemotherapy-induced leukopenia. The results are a starting point for future research and open up broad prospects for future applications of the immunobiotics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gramajo Lopez, Gutiérrez, Saavedra, Hebert, Alvarez and Salva.)

Background: Bacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae., Methods: Three days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9) -/- mice received an intraperitoneal injection of 100 μg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed., Results: Pre-treatment with 100 μg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9 -/- mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection., Conclusions: Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.

Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not receiving high-dose steroids, a prerequisite for optimal T-cell function, practically excluding the most susceptible to infections patients from the benefits of AI. To address this issue, we here rapidly generated, clinical doses of a steroid-resistant T-cell product, simultaneously targeting four viruses (adenovirus, cytomegalovirus, Epstein Barr virus, and BK virus) and the fungus Aspergillus fumigatus , by genetic disruption of the glucocorticoid receptor (GR) gene using CRISPR/CAS9 ribonucleoprotein delivery. The product, "Cerberus" T cells (Cb-STs), was called after the monstrous three-headed dog of Greek mythology, due to its triple potential; specificity against viruses, specificity against fungi and resistance to glucocorticoids. Following efficient on-target GR disruption and minimal off-target editing, the generated Cb-STs maintained the characteristics of pentavalent-STs, their unedited counterparts, including polyclonality, memory immunophenotype, specificity, and cytotoxicity while they presented functional resistance to dexamethasone. Cb-STs may become a powerful, one-time treatment for severely immunosuppressed patients under glucocorticoids who suffer from multiple, life-threatening infections post-transplant, and for whom therapeutic choices are limited., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Koukoulias, Papayanni, Georgakopoulou, Alvanou, Laidou, Kouimtzidis, Pantazi, Gkoliou, Vyzantiadis, Spyridonidis, Makris, Chatzidimitriou, Psatha, Anagnostopoulos, Yannaki and Papadopoulou.)

Cadmium (Cd) is one of the most toxic environmental heavy metals to which the general population is exposed mainly via the oral route. Owing to its immunomodulatory potential, orally acquired Cd affects antimicrobial immune defense in several organs, including the lungs. While there are data concerning Cd and viral and bacterial pulmonary infections, effects on fungal infections are not studied yet. In the present study, the effect of the Cd (5 mg/L for 30 days, in drinking water, the average daily Cd intake 0.641 ± 0.089 mg/kg) on the immune response of rats to pulmonary A. fumigatus infection was examined. Data obtained showed that orally acquired cadmium does not affect the elimination of the fungus in immunocompetent rats owing to the preservation of some aspects of innate immune responses (lung leukocyte infiltration and NBT reduction) and an increase in other (increased numbers of mucus-producing goblet cells, MPO release). Cd does not affect an IFN-γ response in lung leukocytes during the infection (despite suppression of cytokine production in cells of lung-draining lymph nodes), while it stimulates IL-17 and suppresses IL-10 response to the fungus. As a result, the elimination of the fungus occurs in a milieu with the prevailing proinflammatory response in Cd-exposed animals that preserved fungal elimination from the lungs, though with more intense injury to the lung tissue. Therefore, the proinflammatory microenvironment in the lungs created by Cd that sustains inflammatory/immune response to the fungus to which humans are exposed for a lifetime, raises a concern of orally acquired Cd as a risk factor for the development of chronic low-grade pulmonary inflammation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection with high mortality rate usually seen in the context of immunosuppression. Although cases have been reported largely in patients with HIV/AIDS, following the use of monoclonal antibodies and occasionally in haematological malignancies, there is no review to date of patients with smouldering or treated myeloma who developed PML. Here, we conducted a literature search of PML cases in patients with multiple myeloma (MM), analyse patient and disease characteristics and describe the possible mechanisms that could lead to the development of PML. The lack of data and case reports until 2010 may indicate that PML in MM is underdiagnosed. Simultaneously, with an expanding field of new therapeutic options, patients with MM live longer, albeit continually immunosuppressed, and at risk of opportunistic infections. Emerging new treatments for PML in the horizon render the need to look out for this complication mandatory, and more case reports are needed to enrich our knowledge in this field.

A sulfated Chinese yam polysaccharide (S-CYP) was obtained from non-starch Chinese yam polysaccharide (CYP) by chlorosulfonic acid-pyridine (CSA-Pyr) method. The physicochemical characteristics and immunological activity of S-CYP were evaluated in this study. Results showed that sulfated modification changed the physicochemical properties of Chinese yam polysaccharide. Body weights and thymus index of the mice in polysaccharides group were increased compared with the cyclophosphamide (Cy)-induced immunosuppressed mice in model group, and could restore the splenomegaly that caused by Cy. It also showed that S-CYP could enhance the immunomodulatory activity on splenic lymphocytes since it could increase the proliferation of splenic lymphocytes and effectively cooperate with ConA to induce splenic lymphocytes differentiation into T lymphocytes. Meanwhile, the number of CD3 + CD4 + and CD3 + CD8 + T lymphocytes was elevated, the CD4+/CD8+ ratio was restored in polysaccharides group. The levels of splenic lymphocytes cytokines (interleukin (IL)-1β, tumor necrosis (TNF)-α), and the levels of immunoglobulin (IgG and IgM) secretion in serum were also increased by S-CYP significantly. These findings demonstrate that CYP and S-CYP can serve as a promising immunomodulator with potential application in functional food and nutraceutical industry., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

There is an accumulating body of literature surrounding the impact of COVID-19 infection in solid organ transplant recipients. The aim of this review was to summarize the existing literature specifically in kidney transplant (KTx) recipients, with an emphasis on the epidemiology, clinical presentation, laboratory findings, post-operative outcomes, and therapeutic strategies currently employed. We identified thirty-seven studies published between January 1, 2020, and June 10, 2020, that were included in our analysis. As is reported in the general population, there is a wide variation in COVID-19 presentation among KTx patients, ranging from asymptomatic to life-threatening end-organ failure. The most common symptoms are predominantly respiratory and associated with fever. On laboratory evaluation, many patients present with lymphopenia and increased CRP, which are both associated with inferior outcomes. The majority of patients with severe symptoms have been managed with reduction of immunosuppression, including decreased doses of CNIs and withdrawal of MMF. Lastly, although there are no high-level data supporting the use of immunomodulatory drugs, such as IL-6 inhibitors, early experiences have suggested these drugs may improve outcomes in KTx patients with severe COVID-19., (© 2020 Wiley Periodicals LLC.)

Background: In late December 2019, a novel coronavirus SARS-CoV-2 started to spread around the world in different populations. Its clinical and laboratory characteristics and outcome in kidney transplant recipients are little known. Therefore, we describe 22 kidney transplant recipients with SARS-CoV-2-induced pneumonia., Methods: All kidney transplant recipients who referred to the Razi Hospital of Rasht with a diagnosis of SARS-CoV-2 infection from February 20 to 19th of April 2020 have been included in this observational study., Results: We present 22 cases of COVID-19 in kidney transplant recipients (median age 52 years [interquartile range 40.75-62.75 years]) and baseline eGFR 60 (mL/min/1.73 m 2 ) (44.75-86.75). Patients complained of cough (72.7%), dyspnea (63.6%), fever (68.2%), and chill (72.7%) with greater prevalence. We decreased the dose of immunosuppression and started stress dose of intravenous hydrocortisone or equivalent oral prednisolone. Each patient received antiviral therapy based on the latest updated version of local protocol at the time of admission. CT scan findings in 90.9% of patients showed bilateral multifocal lesions. Acute kidney injury (AKI) was observed in 12 patients during hospitalization. Six patients died after a median of 12 days from admission (IQR, 1-21)., Conclusions: In this small observational study, we observed high AKI occurrence and mortality rate in kidney transplant recipients with COVID-19., (© 2020 Wiley Periodicals LLC.)

Background: Concerns about the safety and efficacy of vaccines in patients with autoimmune diseases (AID) have led to contradictions and low vaccination coverage in this population, who are at a higher risk of infections, including by human papillomavirus (HPV). Although HPV vaccines have been recommended for immunocompromised patients, there is still a lack of data to support its use for AID patients, such as juvenile dermatomyositis (JDM) patients. The aim of this study was to assess the safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in a cohort of JDM patients., Methods: JDM patients aged from 9 to 20 years and healthy controls (HC) were enrolled to receive a 3-dose schedule of qHPV vaccine from March/2014 to March/2016. Study visits were performed before the first dose, 1 month after the second and third doses, and 6 months after the third dose. Participants completed a diary of possible adverse events for 14 days following each dose of vaccination (AEFV). Disease activity and current therapy were analyzed at each visit for JDM patients. In addition, serum samples from all participants were collected to test antibody concentrations against HPV16 and 18 at each visit. Participant recruitment was conducted in ten Brazilian centres. From 47 eligible JDM patients and 41 HC, 42 and 35, respectively, completed the 3-dose schedule of the vaccine, given that five JDM patients and two HC had received doses prior to their inclusion in the study., Results: The AEFVs presented by the participants were mild and in general did not differ between JDM and HC groups. No severe AEFVs were related to the vaccination. Disease activity was stable, or even improved during the follow-up. One month after the third dose of the vaccine the JDM group presented seropositivity of 100% for HPV16 and 97% for HPV18, similarly to the HC group, who presented 100% for both serotypes (p = 1.000). Six months after the third dose the seropositivity for the patient group was 94% for both HPV types., Conclusions: The HPV vaccination in this cohort of JDM patients was safe and immunogenic. Since the seropositivity against HPV16 and 18 was very high after the 3-dose schedule, this regimen should be recommended for JDM patients., Trial Registration: Brazilian Clinical Trials Registry, number: RBR-9ypbtf . Registered 20 March 2018 - Retrospectively registered.

During the COVID-19 pandemic caused by the SARS-CoV-2 virus patients with compromised immune systems may be particularly vulnerable. Aside from known causes of immunocompromised states one cause which may have not received due attention is consumption of adulterated recreational drugs. Levamisole-adulterated cocaine poses a particular concern given that documented risk of agranulocytosis and severe neutropenia that may put those exposed at risk of bacterial superinfections and other complications as well as potentially increasing exposure. While oustanding questions remain these risks may warrant inclusion into patient counseling activities by clinicians.

Background: Development of long-term immunologic memory relies upon humoral and cellular immune responses. Vaccinations aim to stimulate these responses against pathogens. Several studies have evaluated the impact of multiple sclerosis disease-modifying therapies on immune response to vaccines. Findings from these studies have important implications for people with multiple sclerosis who require vaccination and are using disease-modifying therapies., Methods: Searches using PubMed and other engines were conducted in May 2020 to collect studies evaluating the impact of various disease-modifying therapies on immune responses to vaccination., Results: Several studies demonstrated preserved immune responses in people treated with beta-interferons to multiple vaccine types. Limited data suggest vaccine responses to be preserved with dimethyl fumarate treatment, as well. Vaccine responses were reduced to varying degrees in those treated with glatiramer acetate, teriflunomide, sphingosine-1-phosphate receptor modulators, and natalizumab. The timing of vaccination played an important role in those treated with alemtuzumab. Humoral vaccine responses were significantly impaired by B cell depleting anti-CD20 monoclonal antibody therapies, particularly to a neoantigen. Data are lacking on vaccine responses in patients with multiple sclerosis taking cladribine and high-dose corticosteroids. Notably, the majority of these studies have focused on humoral responses, with few examining cellular immune responses to vaccination., Conclusions: Prior investigations into the effects of individual disease-modifying therapies on immune responses to existing vaccines can serve as a guide to expected responses to a SARS-CoV-2 vaccine. Responses to any vaccination depend on the vaccine type, the type of response (recall versus response to a novel antigen), and the impact of the individual disease-modifying therapy on humoral and cellular immunity in response to that vaccine type. When considering a given therapy, clinicians should weigh its efficacy against MS for the individual patient versus potential impact on responses to vaccinations that may be needed in the future., Competing Interests: Declaration of Competing Interest John R. Ciotti has received funding from the Biogen MS Clinical Fellowship Program. Manouela V. Valtcheva has nothing to disclose. Anne H. Cross is funded by the Manny & Rosalyn Rosenthal – Dr. John L. Trotter MS Center Chair in Neuroimmunology. She has also received consulting and/or speaking fees from Biogen, Celgene, EMD Serono, Genentech/Roche, Novartis and Race to Erase MS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Candida spp. are opportunistic fungi that can cause severe infections especially in immunocompromised patients. Candidiasis is currently the most frequent fungal disease affecting humans globally. This rise is attributed to the vast increase in resistance to antifungal agents. In recent years, the epidemiological and clinical relevance of fungal infections caused by Candida species have attracted a lot of interest with increasing reports of intrinsic and acquired resistance among Candida species. Thus, the formulation of novel, and efficient therapy for Candida infection persists as a critical challenge in modern medicine. The use of nanoparticle as a potential biomaterial to achieve this feat has gained global attention. Nanoparticles have shown promising antifungal activity, and thus, could be seen as the next generation antifungal agents. This review concisely discussed Candida infection with emphasis on anti-candida resistance mechanisms and the use of nanoparticles as potential therapeutic agents against Candida species. Moreover, the mechanisms of activity of nanoparticles against Candida species, recent findings on the anti-candida potentials of nanoparticles and future perspectives are also presented.

Liposomal amphotericin B (L-AMB) is a broad-spectrum antifungal drug that is used to treat fungal infections. However, clinical evidence of its use in patients with renal failure is limited. Here, we aimed to identify factors associated with acute kidney injury (AKI) in patients administered L-AMB. We retrospectively utilized a combination of Diagnosis Procedure Combination data and laboratory data obtained from hospitals throughout Japan between April 2008 and January 2018. In total, 507 patients administered L-AMB were identified. After L-AMB treatment initiation, AKI, which was defined as a ≥ 1.5-fold increase within 7 days or ≥ 0.3 mg/dL increase within 2 days in serum creatinine according to the KDIGO criteria, was recognized in 37% of the total patients (189/507). The stages of AKI were stage 1 in 20%, stage 2 in 11%, and stage 3 in 7%. Five factors were associated with AKI of all stages: prior treatment with angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers or carbapenem; concomitant administration of catecholamines or immunosuppressants; and ≥ 3.52 mg/kg/day of L-AMB dosing. Serum potassium < 3.5 mEq/L before L-AMB therapy was associated with severe AKI of stage 2 and 3. Altogether, these factors should be carefully considered to reduce the occurrence of AKI in patients administered L-AMB.

Background: Severe critical illness-induced immune suppression, termed immunoparalysis, is associated with longer duration of organ dysfunction in septic children. mRNA studies have suggested differential benefit of hydrocortisone in septic children based on their immune phenotype, but this has not been shown using a functional readout of the immune response. This study represents a secondary analysis of a prospectively conducted immunophenotyping study of pediatric severe sepsis to test the hypothesis that hydrocortisone will be differentially associated with clinical outcomes in children with or without immunoparalysis., Methods: Children with severe sepsis/septic shock underwent blood sampling within 48 h of sepsis onset. Immune function was measured by quantifying whole blood ex vivo LPS-induced TNFα production capacity, with a TNFα response < 200 pg/ml being diagnostic of immunoparalysis. The primary outcome measure was number of days in 14 with MODS. Univariate and multivariable negative binomial regression models were used to examine associations between hydrocortisone use, immune function, and duration of MODS., Results: One hundred two children were enrolled (age 75 [6-160] months, 60% male). Thirty-one subjects received hydrocortisone and were more likely to be older (106 [52-184] vs 38 [3-153] months, p = 0.04), to have baseline immunocompromise (32 vs 8%, p = 0.006), to have higher PRISM III (13 [8-18] vs 7 [5-13], p = 0.0003) and vasoactive inotrope scores (20 [10-35] vs 10 [3-15], p = 0.0002) scores, and to have more MODS days (3 [1-9] vs 1 [0-3], p = 0.002). Thirty-three subjects had immunoparalysis (TNFα response 78 [52-141] vs 641 [418-1047] pg/ml, p < 0.0001). Hydrocortisone use was associated with longer duration of MODS in children with immunoparalysis after adjusting for covariables (aRR 3.7 [1.8-7.9], p = 0.0006) whereas no association with MODS duration was seen in children without immunoparalysis (aRR 1.2 [0.6-2.3], p = 0.67)., Conclusion: Hydrocortisone use was independently associated with longer duration of MODS in septic children with immunoparalysis but not in those with more robust immune function. Prospective clinical trials using a priori immunophenotyping are needed to understand optimal hydrocortisone strategies in this population.

Invasive fungal infections are a potentially life-threatening complication in immunocompromised patients. The aim of this study was to assess the efficacy and safety of posaconazole as compared with other antifungal agents for preventing invasive fungal infections in immunocompromised patients. Embase, CENTRAL, and MEDLINE were searched for randomized conweekmonthtrolled trials (RCTs) up to June 2020. A systematic review with meta-analysis of RCTs was performed using random-effects model. Trial sequential analysis (TSA) was conducted for the primary outcome to assess random errors. A total of five RCTs with 1,617 participants were included. Posaconazole prophylaxis was associated with a significantly lower risk of IFIs (RR, 0.43 [95% CI 0.28 to 0.66, p = 0.0001]) as compared to other antifungal agents. No heterogeneity was identified between studies (I 2  = 0%). No significant associations were observed for the secondary outcomes measured, including risk reduction of invasive aspergillosis and candidiasis, clinical failure, all-cause mortality, and treatment-related adverse events, except for infection-related mortality (RR, 0.31 [95% CI 0.15 to 0.64, p = 0.0001]). Subgroup analysis favoured posaconazole over fluconazole for the prevention of IFIs (RR, 0.44 [95% CI 0.28 to 0.70, p = 0.0004]). TSA confirmed the prophylactic benefit of posaconazole against IFIs. Posaconazole is effective in preventing IFIs among immunocompromised patients, particularly those with hematologic malignancies and recipients of allogenic hematopoietic stem cell transplantation.

Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor. Ceftolozane-tazobactam has been approved for treatment of complicated urinary tract infections and acute pyelonephritis, for complicated intra-abdominal infections (with metronidazole) in adults, and for hospital-acquired bacterial pneumonia including ventilator-associated bacterial pneumonia. This study analyzed gram-negative pathogen susceptibility in US and European patients who are considered at risk for infections caused by pathogens resistant to commonly used antimicrobials: patients in the intensive care unit (ICU), patients on the hematology/oncology or transplant service who may be immunocompromised, and patients >65 years old (yo). ICU patients had the lowest susceptibility for Enterobacterales and PSA. The susceptibility for isolates from the immunocompromised and >65 yo groups was similar. Ceftolozane-tazobactam was the most active agent against PSA, with ≥90%S for >65 yo and immunocompromised, and >80%S for ICU. Meropenem and ceftolozane-tazobactam were the most active agents against Enterobacterales., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Pneumocystis pneumonia (PCP) has a high mortality rate in HIV-negative immunocompromised patients, but is preventable with antimicrobial prophylaxis. We aimed to determine the incidence of PCP in three hospitals in Auckland, New Zealand that would have been potentially preventable if patients had been prescribed prophylaxis according to commonly proposed indications., Methods: We conducted a retrospective study of HIV-negative adults with PCP who were admitted to Middlemore, North Shore or Waitakere Hospitals between January 2011 and June 2017. We classified their PCP as potentially preventable if they had not been prescribed prophylaxis despite having a commonly proposed indication for this., Results: Of the 108 patients with PCP, 33/108 (30.6%) had potentially preventable infection. Of these, 14/33 (42.4%) died within 30 days of diagnosis of PCP. Most potentially preventable infections occurred in patients with solid organ or haematologic malignancies who were receiving high-dose corticosteroids for >4 weeks. We estimate that 28 cases of PCP and 12 deaths could have been prevented over the study duration if prophylaxis was prescribed to those with commonly proposed indications., Conclusion: There is a substantial incidence of potentially preventable PCP and PCP-related mortality in the Auckland region. This could be reduced by greater clinician familiarity with commonly proposed indications for PCP prophylaxis, particularly for clinicians prescribing prolonged corticosteroid courses to patients with malignancies., Competing Interests: Nil.

The holistic approach of the human immune system is based on the study of its components collectively driving a functional response to an immunogenic stimulus. To appreciate a specific immune dysfunction, a condition is mimicked ex vivo and the immune response induced is assessed. The application field of such assays are broad and expanding, from the diagnosis of primary and secondary immunodeficiencies, immunotherapy for cancer to the management of patients at-risk for infections and vaccination. These assays are immune monitoring tools that may contribute to a personalised and precision medicine. The purpose of this review is to describe immune functional assays available in the setting of non-HIV acquired immune deficiency. First, we will address the use of theses assays in the diagnosis of opportunistic infections such as viral reactivation. Secondly, we will report the usefulness of these assays to assess vaccine efficacy and to manage immunosuppressive therapies., (Copyright © 2020. Published by Elsevier Masson SAS.)

Background: Malakoplakia is an uncommon, tumor-like inflammatory disease characterized by impaired histiocytes that are unable to completely digest phagocytized bacteria. The genitourinary tract is the most common site of involvement, however, cases have also been described in the gastrointestinal tract, suggesting that it is the second most common site of involvement. This study investigates the clinical and histologic features of malakoplakia in the gastrointestinal tract., Case Presentation: For 23 gastrointestinal specimens (biopsies and resections) from patients with a pathologic diagnosis of malakoplakia, we recorded the gender, age, location, primary diagnosis, endoscopic or surgical indication, endoscopic/gross impression and immune status (immunocompromised vs. immunocompetent)., Conclusion: Malakoplakia occurred throughout the length of the gastrointestinal tract with most of the cases located in the sigmoid colon and rectum (n = 10); other sites included the transverse and descending colon (n = 4), stomach/gastroesophageal junction (n = 4), appendix (n = 2), cecum (n = 1), small bowel (n = 1), and the peri-anal area (n = 1). Endoscopically, these lesions most commonly appeared as polyps (n = 10) or masses (n = 5), other clinical endoscopic impressions varied from a thickened area/fibrosis to mucosal erythema. Most patients were immunocompromised due to a disease state (e.g. organ transplantation, cancer diagnosis, autoimmune condition) and/or medication effect. Eight patients with malakoplakia were on immunosuppressive medications (8/23, 35%). Common immunosuppressed disease states included cancer (n = 9), autoimmune disease (n = 5), status post organ transplantation (n = 4), diabetes (n = 5), infection/sepsis (n = 3), and HIV/AIDS (n = 1). Some patients had multiple co-morbidities (i.e. diabetes and organ transplant). Twenty-one patients with malakoplakia were in an immunosuppressive state (21/23, 91%).

Background: The pathogenesis of the abnormality of the immune system is still not clear at present. Chemosynthetic drugs, human or animal immune products and microbiological drugs are used as the main drugs in clinics currently, but these drugs have different side effects. So researchers turned to safer natural products in order to find immunomodulatory active substances from natural products and their extracts., Methods: Immunosuppressed mice were induced by cyclophosphamide and administered with Cordyceps militaris polypeptide (CMP) for the study on the effect of CMP on the immune function of mice and its mechanism. Based on the 1748 differential gene sets selected in our previous work, the transcription factors and their corresponding target genes were screened by integrating the TRED (Transcriptional Regulatory Element Database), a transcriptional factor-target gene regulatory network was constructed, then the role of transcription factors in the regulatory network was elucidated by statistically analyzing the key nodes, and finally, the correlation of network genes with diseases was analyzed by using the DAVID database., Results: The results of animal experiments showed that CMP could increase the immune organ indexes, the number of white blood cells, the degree of delayed allergy and the content of hemolysin in the serum of mice. CMP was found to be involved in the regulation of immune function in mice through genes Kdr, Spp1, Ptgs2, Rel, and Smad3, and transcription factors Ets1, E2f2 and E2f1. E2F2 and E2F1 are members of the E2F family, so we speculated that the E2F family might play an important role, and its main regulatory pathways were the PI3K-Akt signaling pathway and TNF signaling pathway., Conclusion: CMP can improve the immunity of mice. CMP can regulate the immune function of mice through multiple genes and transcription factors, and may also play a role in immune-related diseases, such as cancer.

Immunocompromised patients are predisposed to chronically infected wounds. Especially ulcers in the dorsal region often experience secondary polymicrobial infections. However, current wound infection models mostly use single-strain bacteria. To mimic clinically occurring infections caused by fecal contamination in immunocompromised/immobile patients, which differ significantly from single-strain infections, the present study aimed at the establishment of a new mouse model using infection by fecal bacteria. Dorsal circular excision wounds in immunosuppressed mice were infected with fecal slurry solution in several dilutions up to 1:8,000. Impact of immunosuppressor, bacterial load and timing on development of wound infections was investigated. Wounds were analyzed by scoring, 3D imaging and swab analyses. Autofluorescence imaging was not successful. Dose-finding of cyclophosphamide-induced immunosuppression was necessary for establishment of bacterial wound infections. Infection with fecal slurry diluted 1:166 to 1:400 induced significantly delayed wound healing (p < 0.05) without systemic reactions. Swab analyses post-infection matched the initial polymicrobial suspension. The customized wound score confirmed significant differences between the groups (p < 0.05). Here we report the establishment of a simple, new mouse model for clinically occurring wound infections by fecal bacteria and the evaluation of appropriate wound analysis methods. In the future, this model will provide a suitable tool for the investigation of complex microbiological interactions and evaluation of new therapeutic approaches.

Selective suppression of graft rejection while maintaining anti-pathogen responses has been elusive. Thus far, the most successful strategies to induce suppression of graft rejection relies on inhibition of T-cell activation. However, the very same mechanisms that induce allograft-specific T-cell suppression are also important for immunity against microbial pathogens as well as oncogenically transformed cells, resulting in significant immunosuppression-associated comorbidities. Therefore, defining the pathways that differentially regulate anti-graft versus antimicrobial T-cell responses may allow the development of regimen to induce allograft-specific tolerance. Recent work has defined a molecular pathway driven by the immunoregulatory protein coronin 1 that regulates the phosphodiesterase/cyclic adenosine monophosphate pathway and modulates T cell responses. Interestingly, disruption of coronin 1 promotes allograft tolerance while immunity towards a range of pathogenic microbes is maintained. Here, we briefly review the work leading up to these findings as well as their possible implications for transplantation medicine.

Camellia sinensis L., its fresh leaves and buds are used to make tea, is an important industrial crop with a long history. However, less attention has been paid to tea flowers. Indeed, tea flower extract (TFE) is a rich source of functional molecules, but its nutritional value remains unclear. This study, from the perspective of "whole food", aimed to investigate the composition of TFE and further explore its possible health-promoting effects on cyclophosphamide-induced mice. It was found that TFE was mainly composed of carbohydrates (34.02 ± 1.42%), phenolic compounds (11.57 ± 0.14%), crude proteins (27.72 ± 3.07%) and saponins (2.81 ± 0.00%). Supplementation of TFE at 200 mg/kg·BW/d regulated intestinal homeostasis by improving the intestinal barrier, alleviating dysbacteriosis (reverse 44 of 68 disordered genera), stimulated immunoreactions with significant enhancement of serum TNF-α, IFN-γ, IL-1β, IL-2 and IL-6. Furthermore, TFE could improve the liver function through decreasing the hepatic malondialdehyde and aminotransferase levels and increasing the levels of catalase, myeloperoxidase, superoxide dismutase and reduced glutathione. Notably, the ameliorating effects of TFE on cyclophosphamide-induced immunosuppression and the hepatic injury were associated with its modulation of gut microbiota. The results provide the evidence for the application of tea flower as potential functional food., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To review the use of antibiotic stewardship interventions in the adult oncology and hematopoietic cell transplantation (HCT) populations. Data Sources: A literature search of PubMed was performed from inception to October 31, 2019. The general search terms used were oncology, cancer, hematologic malignancy, antimicrobial stewardship, antibiotic stewardship, febrile neutropenia, neutropenic fever, de-escalation, discontinuation, prophylaxis, practice guidelines, clinical pathway, rapid diagnostics, Filmarray, Verigene, MALDI-TOF, antibiotic allergy , and antimicrobial resistance . Study Selection and Data Extraction: Relevant English-language studies describing interventions supported by the Infectious Diseases Society of America guidelines on "Implementing an Antibiotic Stewardship Program" were included. Data Synthesis: Antibiotic stewardship publications in the oncology population have increased in recent years. Studies have described the impact of stewardship interventions, including preauthorization, prospective audit and feedback, implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN) prior to neutrophil recovery, allergy assessments, and use of rapid diagnostic testing. Many of these interventions have been shown to decrease antibiotic use without increased negative consequences, such as affecting length of stay or mortality. Relevance to Patient Care and Clinical Practice: This review synthesizes available evidence for implementing antibiotic stewardship interventions, particularly de-escalation of antibiotics for FN and implementation of clinical pathways for FN and sepsis, in oncology patients and HCT recipients. Summary tables highlight studies and specific research needs for clinicians. Conclusions: Immunocompromised populations, including oncology patients, have often been excluded from stewardship studies. Antibiotic stewardship is effective in reducing antibiotic consumption and improving outcomes in this patient population, although more quality data are needed.

Background: Histoplasma capsulatum is the most common endemic mycosis in the United States and frequently presents as an opportunistic infection in immunocompromised hosts. Though liver involvement is common in disseminated histoplasmosis, primary gastrointestinal histoplasmosis of the liver in absence of lung involvement is rare. Similarly, cholestatic granulomatous hepatitis in liver histoplasmosis is rarely seen., Case Presentation: We present a rare case of primary gastrointestinal histoplasmosis manifesting with acute granulomatous hepatitis and cholestasis in a 48-year-old female with psoriatic arthritis, receiving methotrexate and infliximab. The epidemiology, risk factors, clinical presentation, diagnosis, and treatment of histoplasmosis is discussed. Furthermore, we review the published cases of biopsy-proven disseminated histoplasmosis with cholestatic jaundice to highlight histoplasmosis involvement in the liver., Conclusion: Histoplasmosis should be considered in immunosuppressed patients with fever, chills, abdominal pain and cholestasis with progressive jaundice, particularly in subjects without evidence of biliary obstruction. Future studies are needed to accurately assess the risk of this fungal infection, specifically in patients on immunomodulatory therapy for autoimmune disease.