Efficacy of probiotic treatment as post-exposure prophylaxis for COVID-19: A double-blind, Placebo-Controlled Randomized trial.

BACKGROUND & AIMS: The COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, additional strategies to mitigate the spread/severity of COVID-19 continue to be needed. Emerging evidence suggests susceptibility to respiratory tract infections in healthy subjects can be reduced by probiotic interventions; thus, probiotics may be a low-risk, low-cost, and easily implementable modality to reduce risk of COVID-19. METHODS: In this initial study, we conducted a randomized, double-blind, placebo-controlled trial across the United States testing probiotic Lacticaseibacillus rhamnosus GG (LGG) as postexposure prophylaxis for COVID-19 in 182 participants who had household exposure to someone with confirmed COVID-19 diagnosed within ≤7 days. Participants were randomized to receive oral LGG or placebo for 28 days. The primary outcome was development of illness symptoms within 28 days of COVID-19 exposure. Stool was collected to evaluate microbiome changes. RESULTS: Intention-to-treat analysis showed LGG treatment led to a lower likelihood of developing illness symptoms versus placebo (26.4 % vs. 42.9 %, p = 0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank, p = 0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis did not significantly differ between LGG and placebo groups (8.8 % vs. 15.4 %, p = 0.17). CONCLUSIONS: This data suggests LGG is associated with prolonged time to COVID-19 infection, reduced incidence of illness symptoms, and gut microbiome changes when used as prophylaxis ≤7 days post-COVID-19 exposure, but not overall incidence. This initial work may inform future COVID-19 prevention studies worldwide, particularly in developing nations where Lacticaseibacillus probiotics have previously been utilized to reduce other non-COVID infectious-morbidity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04399252, Date: 22/05/2020. https://clinicaltrials.gov/ct2/show/NCT04399252.

Ruminococcus gnavus and Limosilactobacillus reuteri Regulate Reg3γ Expression through Multiple Pathways.

Epithelium-derived antimicrobial peptides represent an evolutionarily ancient defense mechanism against pathogens. Regenerating islet-derived protein 3 γ (Reg3γ), the archetypal intestinal antimicrobial peptide, is critical for maintaining host-microbe interactions. Expression of Reg3γ is known to be regulated by the microbiota through two different pathways, although it remains unknown whether specific Reg3γ-inducing bacteria act via one or both of these pathways. In recent work, we identified Ruminococcus gnavus and Limosilactobacillus reuteri as commensal bacteria able to induce Reg3g expression. In this study, we show these bacteria require myeloid differentiation primary response protein 88 and group 3 innate lymphoid cells for induction of Reg3γ in mice. Interestingly, we find that R. gnavus and L. reuteri suppress Reg3γ in the absence of either myeloid differentiation primary response protein 88 or group 3 innate lymphoid cells. In addition, we demonstrate that colonization by these bacteria is not required for induction of Reg3γ, which occurs several days after transient exposure to the organisms. Taken together, our findings highlight the complex mechanisms underlying microbial regulation of Reg3γ.

Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial

STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSThe COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, supplemental strategies to mitigate the spread and severity of COVID-19 are urgently needed. Emerging evidence suggests susceptibility to infections, including respiratory tract infections, may be reduced by probiotic interventions; therefore, probiotics may be a low-risk, widely implementable modality to mitigate risk of COVID-19 disease, particularly in areas with low vaccine availability and/or uptake. ObjectiveTo determine whether daily probiotic Lactobacillus rhamnosus GG (LGG) is effective in preventing development of symptoms of illness within 28 days of COVID-19 exposure. DesignThis randomized, double-blind, placebo-controlled trial across the United States (PROTECT-EHC) enrolled in 2020-2021. Participants were followed for 60 days. SettingDescribe the study setting to assist readers to determine the applicability of the report to other circumstances, for example, multicenter, population-based, primary care or referral center(s), etc. ParticipantsParticipants included individuals [≥] 1 year of age with a household contact with a recent ([≤] 7 days) diagnosis of COVID-19. 182 participants were enrolled and randomized during the study period. InterventionParticipants were randomized to receive daily oral LGG or microcrystalline cellulose placebo for 28 days. Main Outcomes and MeasuresThe primary outcome was development of symptoms within 28 days of exposure to a COVID-19-infected household contact. Stool was collected to evaluate for changes in microbiome structure. Results182 participants were enrolled and randomized during the study period. Intention-to-treat analysis showed that participants randomized to LGG were less likely to develop symptoms versus those randomized to placebo (26.4% vs. 42.9%, p=0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank p=0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis did not significantly differ between LGG and placebo groups (8.8% vs. 15.4%, p=0.17). LGG was well-tolerated with no increased side effects versus placebo. Placebo recipients were more likely to stop the study product, temporarily or permanently, due to symptoms attributed to the study product (5.5% vs. 0%, p = 0.02). Conclusions and RelevanceOur study suggests that LGG is well-tolerated and is associated with prolonged time to development of COVID-19 infection, reduced incidence of symptoms, and changes to gut microbiome structure when used as post-exposure prophylaxis within 7 days after exposure. This preliminary work may inform the approach to prevention of COVID-19, particularly in underdeveloped nations where Lactobacillus probiotics have already been utilized to reduce non-COVID sepsis and infectious-morbidity. This study was limited by its remote format, which necessitated a primary endpoint of self-reported symptoms rather than laboratory-confirmed infection; further laboratory-based studies are needed to further define the efficacy of LGG in preventing COVID-19 infection, especially in larger populations and including comparison of pre-exposure vs. post-exposure prophylaxis. Trial registrationClinicalTrials.gov, NCT04399252, https://clinicaltrials.gov/ct2/show/NCT04399252 KEY POINTSO_ST_ABSQuestionC_ST_ABSIs daily probiotic Lactobacillus rhamnosus GG (LGG) effective in preventing development of symptoms of illness compatible with COVID-19 within 28 days of COVID-19 exposure compared to placebo? FindingsIn this randomized clinical trial that included 182 participants, the proportion who developed symptoms was 26.4% with LGG versus 42.9% with placebo, a significant difference. MeaningLGG probiotic may protect against the development of symptoms when used as post-exposure prophylaxis within 7 days after COVID-19 exposure.

A Modern-World View of Host-Microbiota-Pathogen Interactions.

The microbiota-the diverse set of commensal microbes that normally colonize humans-represents the first line of defense against infectious diseases. In this review, we summarize the direct and indirect mechanisms by which the microbiota modulates susceptibility to, and severity of, infections, with a focus on immunological mechanisms. Moreover, we highlight some of the ways that modern-world lifestyles have influenced the structure-function relationship between the microbiota and infectious diseases. Ultimately, understanding how the microbiota influences infectious risks will facilitate development of microbiota-derived therapeutics that bolster host defenses.

Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer.

Interleukin (IL)-10 is expressed in many solid tumours and plays an ambiguous role in controlling cancer growth and metastasis. In order to determine whether IL-10 is involved in tumour progression and prognosis in nonsmall cell lung cancer (NSCLC), IL-10 expression in tumour cells and tumour-associated macrophages (TAMs) and its associations, if any, with clinicopathological features were investigated. Paraffin-embedded sections of surgical specimens obtained from 50 patients who had undergone surgery for NSCLC were immunostained with an antibody directed against IL-10. TAMs and tumour cells positive for IL-10 were subsequently quantified. IL-10-positive TAM percentage was higher in patients with stage II, III and IV NSCLC, and in those with lymph node metastases compared with patients with stage I NSCLC. High IL-10 expression by TAMs was a significant independent predictor of advanced tumour stage, and thus was associated with worse overall survival. Conversely, IL-10 expression by tumour cells did not differ between stages II, III and IV and stage I NSCLC. In conclusion, interleukin-10 expression by tumour-associated macrophages, but not by tumour cells, may play a role in the progression and prognosis of nonsmall cell lung cancer. These results may be useful in the development of novel approaches for anticancer treatments.

CC ligand 2 levels are increased in LPS-stimulated peripheral monocytes of patients with non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) shows a particular aggressive behaviour. Tumour associated macrophages (TAMs) play an important role in tumour growth and progression and CC ligand 2 (CCL2)/CCR2 axis is markedly involved in their recruitment in the tumour mass from the circulation. The aim of this study was to determine the plasma levels of CCL2 and the expression of CCR2 in the peripheral blood mononuclear cells (PBMCs) of 18 smokers with NSCLC, eight healthy smokers and nine non-smokers. Then, we investigated CCL2 levels in the supernatants of unstimulated and LPS-stimulated PBMC cultures of the same groups of patients. CCL2 levels in plasma and supernatants of PBMC cultures were determined by ELISA. CCR2 expression in PBMC cytospins was assessed by immunocytochemistry. CCL2 plasma levels and CCR2 expression by PBMCs were similar in patients with NSCLC, healthy smokers and non-smokers. In the supernatants of unstimulated PBMC cultures, CCL2 content was not different between the three groups of subjects. Supernatants of LPS-stimulated PBMCs of NSCLC patients showed a higher content of CCL2 as compared to supernatants of non-smokers (p<0.005). CCL2 content increased 28.5-fold vs baseline production in the group of NSCLC patients, 15-fold in healthy smokers and 13-fold in the group of non-smokers. In conclusion, after LPS stimulation, PBMCs of patients with NSCLC release higher levels of CCL2 as compared to those of non-smokers, supporting the hypothesis of a CCL2 involvement in NSCLC biology.

Association between markers of emphysema and more severe chronic obstructive pulmonary disease.

BACKGROUND: The predominant emphysema phenotype is associated with more severe airflow limitation in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate whether COPD patients, with or without emphysema quantitatively confirmed by high resolution computed tomography (HRCT), have different COPD severity as assessed by the BODE index (body mass index, airflow obstruction, dyspnoea, exercise performance) and inspiratory capacity to total lung capacity ratio (IC/TLC), and by different biological markers of lung parenchymal destruction. METHODS: Twenty six outpatients with COPD and eight healthy non-smokers were examined. Each subject underwent HRCT scanning, pulmonary function tests, cell counts, and measurements of neutrophil elastase, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in induced sputum, as well as measurement of desmosine, a marker of elastin degradation in urine, plasma and sputum. RESULTS: Patients with HRCT confirmed emphysema had a higher BODE index and lower IC/TLC ratio than subjects without HRCT confirmed emphysema and controls. Forced expiratory volume in 1 second (FEV(1)), FEV(1)/forced vital capacity ratio, and carbon monoxide transfer coefficient were lower, whereas the number of eosinophils, MMP-9, and the MMP-9/TIMP-1 ratio in sputum were higher in patients with emphysema. In COPD patients the number of sputum eosinophils was the biological variable that correlated positively with the HRCT score of emphysema (p = 0.04). CONCLUSIONS: These results suggest that COPD associated with HRCT confirmed emphysema is characterised by more severe lung function impairment, more intense airway inflammation and, possibly, more serious systemic dysfunction than COPD not associated with HRCT confirmed emphysema.

[Occupational exposure to respiratory irritants and chronic obstructive pulmonary disease]. / Esposizione professionale ad agenti irritanti e sviluppo di broncopneumopatia cronica ostruttiva (BPCO).

Cigarette smoking and occupational exposure to respiratory irritants are the major riskfactors for chronic obstructive pulmonary disease (COPD), which is characterized by small-airway obstruction and destruction of pulmonary parenchyma: emphysema. We studied two groups of subjects: one exposed and the other one not-exposed to respiratory irritants, to investigate the relationship, if any, between occupational exposure and COPD. Subjects underwent high-resolution computed tomography-density mask of the chest to quantify pulmonary emphysema, pulmonary function tests, sputum induction and analysis for cell counts and measurements of metalloproteinase (MMP)-9 and its tissue inhibitor TIMP-1. Subjects with occupational exposure to respiratory irritants had higher residual volume and functional residual capacity, higher total inflammatory cells and neutrophils in induced sputum. By contrast, sputum levels of MMP-9, TIMP-1 and MMP-91TIMP-1 ratio did not differ between the 2 groups. We conclude that sputum induction and analysis could be a useful and non-invasive tool to study and follow subjects with occupational exposure to respiratory irritants.

Vasoactive intestinal peptide receptors in the airways of smokers with chronic bronchitis.

Vasoactive intestinal peptide (VIP) is a neuropeptide involved in the regulation of airway mucus secretion. The biological functions of VIP are mediated through two receptors, the vasoactive intestinal peptide receptor type 1 (VPAC1R) and type 2 (VPAC2R). The aim of this study was to quantify the expression of both VPAC1R and VPAC2R in the central airways of smokers with chronic bronchitis. Surgical specimens were obtained from 33 smokers undergoing thoracotomy for localised pulmonary lesions: 23 smokers with symptoms of chronic bronchitis and 10 asymptomatic smokers with normal lung function. By using immunohistochemical and microscopic analysis, an increased expression of VPAC1R, but not VPAC2R, was found in bronchial epithelium, bronchial glands and vessels of smokers with symptoms of chronic bronchitis compared with asymptomatic smokers. Smokers with symptoms of chronic bronchitis also had an increased number of mononuclear cells positive for both VPAC1R and VPAC2R in the bronchial submucosa. In conclusion, the expression of type 1 and type 2 vasoactive intestinal peptide receptors is increased in the central airways of smokers with chronic bronchitis, suggesting their possible involvement in the pathogenesis of chronic bronchitis.