Advances in Bacterial Lysate Immunotherapy for Infectious Diseases and Cancer.

Antigenic cell fragments, pathogen-associated molecular patterns, and other immunostimulants in bacterial lysates or extracts may induce local and systemic immune responses in specific and nonspecific paradigms. Based on current knowledge, this review aimed to determine whether bacterial lysate has comparable functions in infectious diseases and cancer treatment. In infectious diseases, including respiratory and urinary tract infections, immune system activation by bacterial lysate can identify and combat pathogens. Commercially available bacterial lysates, including OM-85, Ismigen, Lantigen B, and LW 50020, were effective in children and adults in treating respiratory tract infections, chronic obstructive pulmonary disease, rhinitis, and rhinosinusitis with varying degrees of success. Moreover, OM-89, Uromune, Urovac, Urivac, and ExPEC4V showed therapeutic benefits in controlling urinary tract infections in adults, especially women. Bacterial lysate-based therapeutics are safe, well-tolerated, and have few side effects, making them a good alternative for infectious disease management. Furthermore, a nonspecific immunomodulation by bacterial lysates may stimulate innate immunity, benefiting cancer treatment. "Coley's vaccine" has been used to treat sarcomas, carcinomas, lymphomas, melanomas, and myelomas with varying outcomes. Later, several similar bacterial lysate-based therapeutics have been developed to treat cancers, including bladder cancer, non-small cell lung cancer, and myeloma; among them, BCG for in situ bladder cancer is well-known. Proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, may activate bacterial antigen-specific adaptive responses that could restore tumor antigen recognition and response by tumor-specific type 1 helper cells and cytotoxic T cells; therefore, bacterial lysates are worth investigating as a vaccination adjuvants or add-on therapies for several cancers.

Broncho-Vaxom Attenuates Lipopolysaccharide-Induced Inflammation in a Mouse Model of Acute Lung Injury.

Acute lung injury (ALI) is a condition associated with acute respiratory failure, resulting in significant morbidity and mortality. It involves cellular changes such as disruption of the alveolar-capillary membrane, excessive neutrophil migration, and release of inflammatory mediators. Broncho-Vaxom® (BV), a lyophilized product containing cell membrane components derived from eight bacteria commonly found in the respiratory tract, is known for its potential to reduce viral and bacterial lung infections. However, the specific effect of BV on ALI has not been clearly defined. This study explored the preventive effects of BV and its underlying mechanisms in a lipopolysaccharide (LPS)-induced ALI mouse model. Oral BV (1 mg/kg) gavage was administered one hour before the intratracheal injection of LPS to evaluate its preventive effect on the ALI model. The pre-administration of BV significantly mitigates inflammatory parameters, including the production of inflammatory mediators, macrophage infiltration, and NF-κB activation in lung tissue, and the increase in inflammatory cells in bronchoalveolar lavage fluid (BALF). Moreover, BV (3 µg/mL) pretreatment reduced the expression of M1 macrophage markers, interleukins (IL-1ß, IL-6), tumor necrosis factor α, and cyclooxygenase-2, which are activated by LPS, in both mouse alveolar macrophage MH-S cells and human macrophage THP-1 cells. These findings showed that BV exhibits anti-inflammatory effects by suppressing inflammatory mediators through the NF-κB pathway, suggesting its potential to attenuate bronchial and pulmonary inflammation.

A critical analysis of the effect of OM-85 for the prevention of recurrent respiratory tract infections or wheezing/asthma from systematic reviews with meta-analysis.

Acute respiratory tract infections (RTIs) are one of the most common causes of pediatric consultations/hospitalizations and a major trigger for asthma exacerbations. Some consensus statements have recommended the use of immunostimulants to boost natural defenses against severe or repeated infections. One of the most common immunostimulants is OM-85; while several randomized clinical trials (RCTs) have evaluated its efficacy in preventing acute RTIs and wheezing/asthma exacerbations, results have been conflicting. Similarly, various systematic reviews with meta-analyses (SRMs) on OM-85 have used different strategies, populations, and outcomes; moreover, SRM conclusions are limited when the original studies are highly heterogeneous or have a low quality, hindering the generalizability of the findings. Here we summarize the evidence on the effect of OM-85 to prevent acute RTIs, wheezing/asthma episodes, or loss of asthma control in children, by including and critically evaluating all SRMs published to date. We searched for SRMs on OM-85 in three publication databases and found nine SRMs (seven for RTI, and two for wheezing/asthma). Among those, one had a high confidence evaluation of quality (AMSTAR-2 tool) and found a reduction in the total number of acute RTIs among the OM-85 group. Overall, no strong recommendations can be derived from the existing literature, mainly due to the high heterogeneity among included RCTs and SRMs. Further, large, high-quality RCTs are needed to confirm the true efficacy of OM-85 for the prevention of acute RTIs, asthma development, and asthma exacerbations.

Preventive effects of prenatal administration of OM-85/BV on asthma and respiratory infection risk in the offspring: A review of animal models.

Asthma is the most common chronic disease in childhood affecting the daily lives of many patients despite current treatment regimens. Therefore, the need for new therapeutic approaches is evident, where a primary prevention strategy is the ultimate goal. Studies of children born to mothers in farming environments have shown a lower risk of respiratory infections and asthma development. Already at birth, these newborns have demonstrated accelerated maturation and upregulation of host defense immune functions suggesting a prenatal transplacental training of the innate immune system through maternal microbial exposure. This mechanism could possibly be utilized to help prevent both respiratory infections and asthma in young children. Human studies exploring the potential preventative effects of pregnancy bacterial lysate treatment on asthma and respiratory infections are lacking, however, this has been studied in experimental studies using mice through administrations of the bacterial lysate OM-85. This review will present the current literature on the immunomodulatory effects relevant for respiratory infections and asthma in the offspring of mice treated with OM-85 throughout pregnancy. Further, the review will discuss the cellular and molecular mechanisms behind these effects. In conclusion, we found promising results of an accelerated immune competence and improved resistance to airway challenges as a result of prenatal bacterial lysate treatment that may pave the way for implementing this in human trials to prevent asthma and respiratory infections.

Polyvalent Bacterial Lysate with Potential Use to Treatment and Control of Recurrent Urinary Tract Infections.

Overuse of antimicrobials has greatly contributed to the increase in the emergence of multidrug-resistant bacteria, a situation that hinders the control and treatment of infectious diseases. This is the case with urinary tract infections (UTIs), which represent a substantial percentage of worldwide public health problems, thus the need to look for alternatives for their control and treatment. Previous studies have shown the usefulness of autologous bacterial lysates as an alternative for the treatment and control of UTIs. However, a limitation is the high cost of producing individual immunogens. At the same time, an important aspect of vaccines is their immunogenic amplitude, which is the reason why they must be constituted of diverse antigenic components. In the case of UTIs, the etiology of the disease is associated with different bacteria, and even Escherichia coli, the main causal agent of the disease, is made up of several antigenic variants. In this work, we present results on the study of a bacterial lysate composed of 10 serotypes of Escherichia coli and by Klebsiella pneumoniae, Klebsiella aerogenes, Enterococcus faecalis, Proteus mirabilis, Citrobacter freundii, and Staphylococcus haemolyticus. The safety of the compound was tested on cells in culture and in an animal model, and its immunogenic capacity by analysing in vitro human and murine macrophages (cell line J774 A1). The results show that the polyvalent lysate did not cause damage to the cells in culture or alterations in the animal model used. The immunostimulatory activity assay showed that it activates the secretion of TNF-α and IL-6 in human macrophages and TNF-α in murine cells. The obtained results suggest that the polyvalent lysate evaluated can be an alternative for the treatment and control of chronic urinary tract infections, which will reduce the use of antimicrobials.

In vitro anti-inflammatory and antibiofilm activities of bacterial lysates from lactobacilli against oral pathogenic bacteria.

Postbiotics are functional biological compounds, such as bacterial lysates (BLs) released from probiotic bacteria. Although postbiotics exert various bioactivities, the anti-inflammatory and antibiofilm activities of BLs against oral pathogenic bacteria have not been investigated. In the present study, pretreatment with BLs extracted from Lactobacillus plantarum and L. rhamnosus GG suppressed the mRNA and protein expression levels of inflammatory mediators induced by the lipopolysaccharide (LPS) of Porphyromonas gingivalis in RAW 264.7 cells. Both BLs attenuated P. gingivalis LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) and activation of nuclear factor-κB (NF-κB), suggesting that BLs inhibit periodontal inflammatory responses by regulating the MAPK and NF-κB signaling pathways. Moreover, both BLs interfered with biofilm formation by Streptococcus mutans; however, they did not eradicate the established S. mutans biofilm. Furthermore, both BLs downregulated gtfB, gtfC, and gtfD responsible for biofilm formation by S. mutans, suggesting that BLs reduce the synthesis of extracellular polysaccharide and thereby reduce S. mutans biofilm. Taken together, these results suggest that BLs of L. plantarum and L. rhamnosus GG can attenuate periodontal inflammation and dental caries and thus contribute to the improvement of oral health.

The Monkey Head Mushroom and Memory Enhancement in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, and no effective treatments are available to treat this disorder. Therefore, researchers have been investigating Hericium erinaceus, or the monkey head mushroom, an edible medicinal mushroom, as a possible treatment for AD. In this narrative review, we evaluated six preclinical and three clinical studies of the therapeutic effects of Hericium erinaceus on AD. Preclinical trials have successfully demonstrated that extracts and bioactive compounds of Hericium erinaceus have potential beneficial effects in ameliorating cognitive functioning and behavioral deficits in animal models of AD. A limited number of clinical studies have been conducted and several clinical trials are ongoing, which have thus far shown analogous outcomes to the preclinical studies. Nonetheless, future research on Hericium erinaceus needs to focus on elucidating the specific neuroprotective mechanisms and the target sites in AD. Additionally, standardized treatment parameters and universal regulatory systems need to be established to further ensure treatment safety and efficacy. In conclusion, Hericium erinaceus has therapeutic potential and may facilitate memory enhancement in patients with AD.

Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation.

BACKGROUND: The prevalence of osteoarthritis (OA) is increasing, yet clinically effective and economical treatments are unavailable. We have previously proposed a cell-free fat extract (CEFFE) containing multiple cytokines, which possessed antiapoptotic, anti-oxidative, and proliferation promotion functions, as a "cell-free" strategy. In this study, we aimed to evaluate the therapeutic effect of CEFFE in vivo and in vitro. METHODS: In vivo study, sodium iodoacetate-induced OA rats were treated with CEFFE by intra-articular injections for 8 weeks. Behavioral experiments were performed every two weeks. Histological analyses, anti-type II collagen, and toluidine staining provided structural evaluation. Macrophage infiltration was assessed by anti-CD68 and anti-CD206 staining. In vitro study, the effect of CEFFE on macrophage polarization and secretory factors was evaluated by flow cytometry, immunofluorescence, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of CEFFE on cartilage regeneration was accessed by cell counting kit-8 assay and qRT-PCR. The generation of reactive oxygen species (ROS) and levels of ROS-related enzymes were investigated by qRT-PCR and western blotting. RESULTS: In rat models with sodium iodoacetate (MIA)-induced OA, CEFFE increased claw retraction pressure while decreasing bipedal pressure in a dose-dependent manner. Moreover, CEFFE promoted cartilage structure restoration and increased the proportion of CD206+ macrophages in the synovium. In vitro, CEFFE decreased the proportion of CD86+ cells and reduced the expression of pro-inflammatory factors in LPS + IFN-γ induced Raw 264.7. In addition, CEFFE decreased the expression of interleukin-6 and ADAMTs-5 and promoted the expression of SOX-9 in mouse primary chondrocytes. Besides, CEFFE reduced the intracellular levels of reactive oxygen species in both in vitro models through regulating ROS-related enzymes. CONCLUSIONS: CEFFE inhibits the progression of OA by promoting cartilage regeneration and limiting low-grade joint inflammation.

Sustained release of Lactobacillus casei cell wall extract can induce a continuous and stable IgA deposition model.

Mucosal immune regulation is considered a key aspect of immunopathogenesis of IgA nephropathy (IgAN). Direct experimental evidence clarifying the role of intestinal mucosa attributes in IgAN is lacking. In this study, a mouse model was established via multiple low-dose intraperitoneal injections of Lactobacillus casei cell wall extract (LCWE) emulsified with Complete Freund's Adjuvant (CFA). We found continuous and stable deposition of IgA in glomerular mesangial areas, accompanying high circulating levels of IgA and IgA-IgG complexes. Expression of the key extracellular matrix components collagen IV and fibronectin also increased in the mesangial areas of LCWE-induced mice. IgA+ B220+ B-cell proportion increased in the small intestine (SI), Peyer's patches, inguinal lymph nodes, spleen, and bone marrow. The intestinal barrier was dysfunctional in the LCWE-induced mice, and consistent with this, higher levels of serum zonulin (namely prehaptoglobin-2), a regulator of epithelial and endothelial barrier function, were observed in patients with IgAN. Hematoxylin and eosin staining results indicated that immune tissues such as liver, spleen, and lymph nodes showed an inflammatory response and focal lesions. Glucocorticoid methylprednisolone treatment could alleviate serum IgA and IgA-IgG complex levels and mesangial IgA deposition. Taken together, our results indicate that we have successfully constructed a mouse model with IgA deposition in the mesangial areas of the glomeruli and provide evidence for the connection between the intestinal barrier and elevated circulating IgA and IgA-IgG in IgAN. © 2022 The Pathological Society of Great Britain and Ireland.

Bacterial lysates (OM-85 BV): a cost-effective proposal in order to contrast antibiotic resistance.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is one of the most frequent pathologies in which antibiotics are used because 50% of the exacerbations are attributable to a bacterial infection. The aims of our study were: i) to perform a meta-analysis on the efficacy of the bacterial lysate OM-85 BV in preventing acute exacerbations in patients with COPD; ii) to evaluate whether this preventive treatment can lead to significant savings for the National Health Service (NHS). METHODS: A systematic research was conducted in the electronic database MEDLINE (PubMed) in June 2017-July 2020, collecting evidences without time restrictions. Only randomized controlled trials (RCTs) were included. The keywords used were "OM 85 BV AND chronic bronchitis" and "OM 85 BV AND COPD". A cost-effectiveness analysis (CEA) was performed considering the costs for a treatment with OM-8BV, the costs for the treatment of an acute exacerbation and the number of prevented exacerbations. RESULTS: 59 publications were found, but the meta-analysis was conducted on 13 studies that met the inclusion criteria. OM-85 BV is responsible of a statistically significant reduction in the mean number of COPD exacerbations (p < 0.01; WMD = -0.86; CI 95%: -1.38, -0.34) and in the days of antibiotic therapy (p < 0.01; WMD = -9.49; CI 95%: -11.93, -7.05). The cost-effectiveness ratio with a negative value is in favor to treatment. CONCLUSIONS: OM-85 BV is effective in reducing exacerbations, and could lead to significant savings for the NHS. Moreover, reducing the number of exacerbations it could avoid an over-use of antibiotics and the consequent antibiotic resistance.

Bacterial lysate add-on therapy to reduce exacerbations in severe asthma: A double-blind placebo-controlled trial.

BACKGROUND: Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune-modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown. AIMS: To reduce asthma exacerbations by add-on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune-modulatory effects of this treatment. METHODS: Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year were included. The intervention regimen consisted of OM-85/placebo for 10 consecutive days per month for 6 months during two winter seasons. Primary end-point was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent. RESULTS: Seventy-five participants were included (38 OM-85; 37 placebo). Exacerbation frequencies were not different between the groups after 18 months (incidence rate ratio 1.07, 95%CI [0.68-1.69], p = 0.77). With the use of OM-85, FEV1% increased by 3.81% (p = 0.04) compared with placebo. Nasopharyngeal swabs taken during RTIs detected a virus less frequently in patients using OM-85 compared to placebo (30.5% vs. 48.0%, p = 0.02). In subjects with type 2 inflammation adherent to the protocol (22 OM-85; 20 placebo), a non-statistically significant decrease in exacerbations in the OM-85 group was observed (IRR = 0.71, 95%CI [0.39-1.26], p = 0.25). Immune-modulatory effects included an increase in several plasma cytokines in the OM-85 group, especially IL-10 and interferons. Peripheral blood T- and B cell subtyping, including regulatory T cells, did not show differences between the groups. CONCLUSION: Although OM-85 may have immune-modulatory effects, it did not reduce asthma exacerbations in this heterogeneous severe adult asthma group. Post hoc analysis showed a potential clinical benefit in patients with type 2 inflammation.

Bacterial lysate treatment in allergic disease: A systematic review and meta-analysis.

OBJECTIVE: The aim of this review was to assess the efficacy of bacterial lysate treatment in patients with allergic disease. METHOD: Randomized controlled trials (RCTs) of bacterial lysate therapy for patients with allergic diseases (asthma, atopic dermatitis, and allergic rhinitis) were searched using PubMed, EMBASE, Cochrane, China National Knowledge Infrastructure, Chinese Biomedical literature, and Wanfang databases up to March 2020. Based on the guidelines of the Cochrane collaboration, risk of bias was assessed. RESULTS: This meta-analysis based on 19 studies comparing bacterial lysate-treated patients with a control group showed a 24% (RR: 1.24, 95% CI [1.19, 1.30]) increase in improvement of allergy symptom control. In addition, the improvement of asthma symptom control was 22% (RR: 1.22, 95% CI [1.14, 1.26]) higher in the bacterial lysate treatment group. Moreover, the levels of immunoglobulin (IgA and IgG), T lymphocyte subtype (CD3+, CD4+, CD4+/CD8+, Th1), and cytokines (IFN-γ, IL-2, and IL-12) were increased in the treated group compared with controls. There was no significant difference in adverse event rate between the two groups. CONCLUSION: Treatment with bacterial lysate improves symptom control in patients with allergic diseases on the basis of routine therapy. No adverse risk was found in this meta-analysis.

Investigation into antibacterial and wound healing properties of platelets lysate against Acinetobacter baumannii and Klebsiella pneumoniae burn wound infections.

BACKGROUND AND AIM: Treatment of burn wound infections has become a global challenge due to the spread of multidrug-resistant bacteria; therefore, the development of new treatment options for the mentioned infections is essential. Platelets have drawn much attention for this purpose because they are a safe and cost-effective source of different antimicrobial peptides and growth factors. The present study evaluated antibacterial effects and wound healing properties of Platelet-derived Biomaterial (PdB) against Acinetobacter baumannii and Klebsiella pneumoniae burn wound infections. METHODS: PdB was prepared through the freezing and thawing process and then, in vitro antibacterial effect was determined by disk diffusion and broth microdilution methods. Afterward, burn wound was inflicted on 56 rats, infected with both bacteria, and topical administration was performed to evaluate antibacterial effects and wound healing properties of PdB. RESULTS: In vitro results showed that PdB inhibited the growth of A. baumannii in the highest dose (0.5), while we did not detect any inhibitory effects against K. pneumoniae. By contrast, PdB significantly inhibited the growth of bacteria in treated animal wounds compared to the control groups (P value < 0.05). Macroscopic assessments pointed to the significant enhancement of wound closure in the treated animals. In addition, histopathological examination demonstrated that treatment of rats with PdB led to a considerable increase in re-epithelialization and attenuated the formation of granulation tissue (P value < 0.05). CONCLUSION: The use of topical PdB is an attractive strategy for treating A. baumannii and K. pneumoniae burn wound infections because it inhibits bacterial growth and promotes wound healing properties.

Intraoperative Stromal Vascular Fraction Therapy Improves Histomorphometric and Vascular Outcomes in Irradiated Mandibular Fracture Repair.

BACKGROUND: Cell-based treatments have demonstrated the capacity to enhance reconstructive outcomes in recent decades but are hindered in clinical utility by regulatory hurdles surrounding cell culture. This investigation examines the ability of a noncultured stromal vascular fraction derived from lipoaspirate to enhance bone healing during fracture repair to further the development of translatable cell therapies that may improve outcomes in irradiated reconstruction. METHODS: Isogenic male Lewis rats were divided into three groups: fracture, irradiated fracture, and irradiated fracture with stromal vascular fraction treatment. Irradiated groups received a fractioned dose of 35 Gy before mandibular osteotomy. Stromal vascular fraction was harvested from the inguinal fat of isogenic donors, centrifuged, and placed intraoperatively into the osteotomy site. All mandibles were evaluated for bony union and vascularity using micro-computed tomography before histologic analysis. RESULTS: Union rates were significantly improved in the irradiated fracture with stromal vascular fraction treatment group (82 percent) compared to the irradiated fracture group (25 percent) and were not statistically different from the fracture group (100 percent). Stromal vascular fraction therapy significantly improved all metrics of bone vascularization compared to the irradiated fracture group and was not statistically different from fracture. Osteocyte proliferation and mature bone formation were significantly reduced in the irradiated fracture group. Bone cellularity and maturity were restored to nonirradiated levels in the irradiated fracture with stromal vascular fraction treatment group despite preoperative irradiation. CONCLUSIONS: Vascular and cellular depletion represent principal obstacles in the reconstruction of irradiated bone. This study demonstrates the efficacy of stromal vascular fraction therapy in remediating these damaging effects and provides a promising foundation for future studies aimed at developing noncultured, cell-based therapies for clinical implementation.

Photosynthetically Controlled Spirulina, but Not Solar Spirulina, Inhibits TNF-α Secretion: Potential Implications for COVID-19-Related Cytokine Storm Therapy.

An array of infections, including the novel coronavirus (SARS-CoV-2), trigger macrophage activation syndrome (MAS) and subsequently hypercytokinemia, commonly referred to as a cytokine storm (CS). It is postulated that CS is mainly responsible for critical COVID-19 cases, including acute respiratory distress syndrome (ARDS). Recognizing the therapeutic potential of Spirulina blue-green algae (Arthrospira platensis), in this in vitro stimulation study, LPS-activated macrophages and monocytes were treated with aqueous extracts of Spirulina, cultivated in either natural or controlled light conditions. We report that an extract of photosynthetically controlled Spirulina (LED Spirulina), at a concentration of 0.1 µg/mL, decreases macrophage and monocyte-induced TNF-α secretion levels by over 70% and 40%, respectively. We propose prompt in vivo studies in animal models and human subjects to determine the putative effectiveness of a natural, algae-based treatment for viral CS and ARDS, and explore the potential of a novel anti-TNF-α therapy.

Epithelial dysfunction, respiratory infections and asthma: the importance of immunomodulation. A focus on OM-85.

INTRODUCTION: Damage to the respiratory epithelium, is often a multifactorial phenomenon. The risk for developing a damage in respiratory epithelium and recurrent respiratory infections may vary among individuals. Preventive measures are based on strengthening the immune function, thus increasing the natural response to pathogens. Immunomodulatory agents are: i. synthetic molecules; ii. Probiotics, prebiotics, symbiotics; iii. Lysates, bacterial extracts immunomodulators: OM-85, RU 41740, D53; iv. Trace elements, vitamins. OM-85 is used for the prevention of recurrent respiratory tract infections and/or exacerbations both in adults and children, showing a good efficacy and safety profile. Its active principle, an extract of bacterial lysates isolated from 21 known respiratory pathogenic strains, shows protection against airway infections of bacterial and viral origin. AREAS COVERED: This non-systematic review focuses on bacterial lysates and in particular on OM-85 and its effects on respiratory epithelium function and activity in asthma respiratory infections. Studies were selected by PubMed search of "bacterial lysate" or "OM-85" and "respiratory epithelium" or "respiratory infections", from 1993 to 2019. EXPERT OPINION: Results highlight the ability of OM-85 to trigger immunomodulatory and protective immune responses against different pathogens in vivo, including influenza and respiratory syncytial virus as well bacterial superinfection following influenza.

Immunoactive preparations and regulatory responses in the respiratory tract: potential for clinical application in chronic inflammatory airway diseases.

Introduction: The prevalence of chronic inflammatory airway diseases is rising. Their treatment with corticosteroids increases infection risk, while overuse of antimicrobial agents may increase morbidity and antimicrobial resistance. Nonspecific immunomodulatory compounds alter immune responses to both infectious and atopic challenges. These compounds may offer an alternative approach for symptom reduction and prophylaxis against both infections and exacerbations in chronic inflammatory airway disease.Areas covered: We assessed the available data on the efficacy of nonspecific immunomodulators including bacterial lysates, synthetic compounds, and vaccines in chronic rhinosinusitis (CRS); allergic and non-allergic rhinitis; chronic obstructive pulmonary disease (COPD), and asthma. A search of PubMed was carried out using the 'Clinical Trials' filter for each condition and immunomodulatory product detailed below, where available, data from meta-analyses were reported.Expert opinion: Pre-clinical data has revealed a coherent mechanistic path of action for oral immunomodulators on the respiratory immune system, principally via the gut-lung immune axis. In patients with asthma, allergic rhinitis, CRS, and COPD immunomodulatory therapy reduces symptoms, exacerbations, hospitalizations, and drug consumption. However, data are heterogeneous, and study quality remains limited. A lack of high-quality recent trials remains the major unmet research need in the field.

OM-85 BV for primary prevention of recurrent airway infections: a pilot randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the frequency of respiratory tract infections in children treated with OM-85 BV and placebo during the 3-month therapy period, and observation for a further 3 months after treatment. METHODS: A randomized, double-blind, placebo-controlled trial was conducted with 54 children (6 months to 5 years old) with no past history of recurrent respiratory infections attending daycare center. Family members were instructed to administer one capsule per day for 10 consecutive days, for 3 months of OM-85 BV or placebo. Telephone interviews were conducted every 30 days. RESULTS: There was no significant difference in the number of respiratory infections between the groups. The mean number of respiratory tract infection in the OM-85 BV Group in the first 3 months was 0.92±0.87, and in the Placebo Group was 0.74±1.02, and at 6 months it was 1.62±1.47 and 1.03±1.34, respectively. CONCLUSION: OM-85 BV was not effective in the primary prevention of respiratory tract infections. Although most authors recommend the use of this immunostimulant in children with a history of recurrent respiratory infections, more studies are needed to define its usefulness in the primary prevention of respiratory infections in healthy children exposed to few risk factors.

Embryonic stem cell extracts improve wound healing in diabetic mice.

AIMS/HYPOTHESIS: Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. METHODS: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. RESULTS: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. CONCLUSIONS: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.