The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines.

The first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics.

Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial.

BACKGROUND: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. METHODS: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. DISCUSSION: Transplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08-02-2022).

Ten-Year Follow-Up of Patients Treated with Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection from a Randomized Controlled Trial and Review of the Literature.

Fecal microbiota transplantation (FMT) has become a well-established treatment for recurrent Clostridioides difficile infection (rCDI). While short-term outcomes and adverse events relating to FMT have been well documented, there still is a paucity of data with regard to long-term safety. In this report, we describe the long-term follow-up of the prospective cohort of the first randomized controlled trial of FMT for rCDI, and review the existing literature. A total of 34 patients were treated with FMT for rCDI. Seven patients were still alive after a follow-up of more than 10 years and three patients were lost to follow-up. None of the 34 patients had experienced a new-onset autoimmune, gastrointestinal, or malignant disorder during follow-up. We did not find any deterioration or amelioration of pre-existing medical conditions. Furthermore, no deaths directly attributable to FMT could be identified. These findings are in accordance with the data in available literature. In conclusion, no long-term adverse events or complications directly attributable to FMT were found in our prospective cohort. Review of the available literature does not point to long-term risks associated with FMT in this elderly population, provided that carefully screened fecal suspensions are being used. No firm conclusion on the long-term safety of FMT in younger patients could be drawn.

Clinical Application and Potential of Fecal Microbiota Transplantation.

Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent Clostridioides difficile infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to C. difficile infection. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug-resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed.

Update of treatment algorithms for Clostridium difficile infection.

BACKGROUND: Clostridium difficile is the leading cause of antibiotic-associated diarrhoea, both in healthcare facilities and in the community. The recurrence rate of C. difficile infection (CDI) remains high, up to 20%. Since the publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve higher sustained clinical cure in CDI. AIM: To review novel treatments and approaches for CDI, except probiotics and vaccines. We focused on new antibiotics, antibiotic inactivators, monoclonal antibodies and gut microbiota modulating therapies. SOURCES: A literature review was performed for clinical trials published in PubMed, Embase or Cochrane Library between January 2013 and November 2017. CONTENT: We analysed 28 clinical trials and identified 14 novel agents. Completed phase 2 studies were found for cadazolid, LFF571, ridinilazole and nontoxigenic C. difficile strains. Four phase 3 active comparator studies comparing vancomycin with bezlotoxumab, surotomycin (n = 2) and rifaximin have been published. Seven clinical trials for treatment of multiple recurrent CDI with faecal microbiota transplantation were analysed, describing faecal microbiota transplantation by upper or lower gastrointestinal route (n = 5) or by capsules (n = 2). IMPLICATIONS: Metronidazole is mentioned in the ESCMID guideline as first-line therapy, but we propose that oral vancomycin will become the first choice when antibiotic treatment for CDI is necessary. Fidaxomicin is a good alternative, especially in patients at risk of relapse. Vancomycin combined with faecal microbiota transplantation remains the primary therapy for multiple recurrent CDI. We anticipate that new medication that protects the gut microbiota will be further developed and tested to prevent CDI during antibiotic therapy.

[Faecal microbiota transplantation: indications in perspective]. / Fecestransplantatie: wanneer wel en wanneer niet?

- As yet, with cure rates around 85%, recurrent Clostridium difficile infection is the only definite indication for faecal microbiota transplantation.- Faecal microbiota transplantation induces clinical remission and endoscopic improvements in 24-30% of patients with ulcerative colitis, compared to 5% (water) to 20% (autologous faeces) in placebo-treated patients. Current research focuses on the identification of 'super donors', and subgroups of patients in which faecal microbiota transplantation is effective.- In patients with metabolic syndrome, faecal microbiota transplantation may increase insulin sensitivity. Weight, body mass index, and energy metabolism are not affected by faecal microbiota transplantation in humans.- In addition to the aforementioned indications, faecal microbiota transplantation is an emerging treatment modality for patients with Crohn's disease, irritable bowel syndrome, graft-versus-host-disease, and carriage of multidrug-resistant micro-organisms. Randomized controlled trials, comparing faecal microbiota transplantation with placebo treatment, are required to determine the effectiveness of faecal microbiota transplantation in these patient groups.

How to: Establish and run a stool bank.

BACKGROUND: Since 2013, several stool banks have been developed following publications reporting on clinical success of 'faecal microbiota transplantation' (FMT) for recurrent Clostridium difficile infections (CDI). However, protocols for donor screening, faecal suspension preparation, and transfer of the faecal suspension differ between countries and institutions. Moreover, no European consensus exists regarding the legislative aspects of the faecal suspension product. Internationally standardized recommendations about the above mentioned aspects have not yet been established. OBJECTIVE: In 2015, the Netherlands Donor Feces Bank (NDFB) was founded with the primary aim of providing a standardized product for the treatment of patients with recurrent CDI in the Netherlands. Standard operation procedures for donor recruitment, donor selection, donor screening, and production, storage, and distribution of frozen faecal suspensions for FMT were formulated. RESULTS AND DISCUSSION: Our experience summarized in this review addresses current donor recruitment and screening, preparation of the faecal suspension, transfer of the faecal microbiota suspension, and the experiences and follow-up of the patients treated with donor faeces from the NDFB.

[Fecal microbiota transplantation, a novel therapy for recurrent Clostridium difficile infection]. / Fecale microbiota transplantatie: een nieuwe behandeling voor recidiverende Clostridium difficile-infectie.

Clostridium difficile infection is caused by a disturbance of the gut microbiota, often resulting from the use of antibiotics. Among a sub group of patients with this disorder, treatment with antibiotics is not effective. They develop a chronic, recurrent infection. Such patients can be treated with a fecal microbiota transplantation (FMT), or fecal transplantation. The crucial steps for safe application of fecal transplantation are central donor selection and screening. To optimise safety and to guarantee the availability of donor feces for fecal transplantation, the Nederlandse Donor Feces Bank (Dutch Donor Feces Bank) was established. At this facility, ready-to-use, screened donor feces can be ordered for patients with (recurrent) Clostridium difficile infections, who can then be treated at their own hospital.

A nation-wide population-based study of inguinal hernia repair incidence and age-stratified recurrence in an Asian population.

PURPOSE: It has been estimated in the UK that 27 % of men and 3 % of women will undergo an inguinal hernia repair (IHR) during their lifetimes. However, no epidemiologic study investigating IHR has been performed to date in an Asian population. The present study explored the incidence and recurrence of IHR in an Asian population using a nation-wide population-based dataset in Taiwan. METHODS: Based on the National Health Insurance Database, we identified 5806 patients who underwent an IHR between 2000 and 2010 and followed them until they had a recurrence, died during hospitalization, left the program, or the study ended. We calculated the age-stratified recurrence rates and used Cox proportional hazards to explore the influence of demographic and clinical factors on recurrence. We also plotted IHR occurrence over the study period. RESULTS: Among the 5806 sampled subjects who had an IHR, 565 (9.73 %) had an IHR recurrence yielding an overall incidence of 18.23 per 1000 person-years. The hazard ratios for recurrence increased with age, and were greater among men and blue collar workers. The incidence of IHR decreased from 168.21 to 92.10 per 100,000 person-years over the study period. Surgical complication rates ranged between 0.16 and 2.57 %. CONCLUSIONS: On account of the increased risk of recurrence with age, young hernia patients may not want to delay surgery. This study detected a decreasing trend in initial IHR rates, confirming similar trends reported in Western countries. However, the incidence of initial IHR is lower in Taiwan than it is in the West.

Treatment of recurrent and severe Clostridium difficile infection.

Clostridium difficile infection (CDI) is a serious complication of hospitalization and antibiotic use with a high mortality and very high costs. Despite appropriate treatment, a subset of patients develop chronic recurrent CDI. Some other patients develop severe and life-threatening colitis. The risk factors, pathogenesis, and treatment of recurrent CDI and severe CDI are discussed in this review. In particular, fecal microbiota transplantation (FMT) as a treatment strategy is outlined and a treatment algorithm incorporating FMT is described.

Association between osteoporosis and urinary calculus: evidence from a population-based study.

SUMMARY: This population-based case-control analysis investigated the association between osteoporosis and prior urinary calculus (UC) in Taiwan. We succeeded in detecting an association between osteoporosis and prior UC (adjusted odds ratio = 1.66). This association was consistent and significant regardless of stone location. INTRODUCTION: UC has been demonstrated to be a risk factor for osteoporotic fractures, but no studies to date have directly investigated the association between UC and osteoporosis. This case-control analysis aimed to investigate the association of osteoporosis with prior UC using a population-based dataset in Taiwan. METHODS: We first identified 39,840 cases ≥40 years who received their first-time diagnosis of osteoporosis between 2002 and 2009 and then randomly selected 79,680 controls. We used conditional logistic regression analyses to compute the odds ratio (OR) and the corresponding 95 % confidence interval (CI) for having been previously diagnosed with UC between cases and controls. RESULTS: The OR of having been previously diagnosed with UC for patients with osteoporosis was 1.66 (95 % CI = 1.59-1.73) when compared to controls after adjusting for geographic location, urbanization level, type I diabetes mellitus, coronary heart disease, hyperlipidemia, rheumatoid arthritis, stroke, renal disease, Parkinson's disease, hyperthyroidism, chronic hepatopathy, Cushing's syndrome, malabsorption, gastrectomy, obesity, and alcohol abuse/alcohol dependence syndrome. The results consistently showed that osteoporosis was significantly associated with a previous diagnosis of UC regardless of stone location; the adjusted ORs of prior kidney calculus, ureter calculus, bladder calculus, and unspecified calculus when compared to controls were 1.71 (95 % CI = 1.61-1.81), 1.60 (95 % CI = 1.47-1.74), 1.59 (95 % CI = 1.23-2.04), and 1.69 (95 % CI = 1.59-1.80), respectively. CONCLUSIONS: This study succeeded in detecting an association between osteoporosis and prior UC. In addition, our findings were consistent and significant regardless of stone location.

Increased risk of psoriasis following chronic rhinosinusitis without nasal polyps: a population-based matched-cohort study.

BACKGROUND: Although chronic rhinosinusitis without nasal polyps (CRSsNP) and psoriasis both share immunological disturbances as pathological factors, no prior study has investigated the risk for psoriasis among patients with CRSsNP. OBJECTIVES: To investigate the subsequent risk for psoriasis following a diagnosis of CRSsNP by utilizing a cohort study design and a population-based dataset in Taiwan. METHODS: In total, 13 242 subjects with CRSsNP were included in the study cohort and 39 726 subjects were randomly extracted for the comparison cohort. We individually tracked each individual in this study (n = 52 968) for a 5-year period following their index date to identify those subjects who received a subsequent diagnosis of psoriasis. Cox proportional hazards regression analysis was conducted to calculate the 5-year risk of subsequent psoriasis following a diagnosis of CRS among the sampled subjects. RESULTS: The incidence rate of psoriasis during the 5-year follow-up period was 1·41 [95% confidence interval (CI) 1·14-1·71] per 1000 person-years and 0·69 (95% CI 0·59-0·81) per 1000 person-years for the study and comparison cohort, respectively. Stratified Cox proportional hazards regression revealed that the hazard ratio for psoriasis during the 5-year follow-up period for subjects with CRSsNP compared with the control group was 2·01 (95% CI 1·54-2·62) after adjusting for monthly income, geographical region, hypertension, diabetes, coronary heart disease and hyperlipidaemia, and censoring the cases who died during the 5-year follow-up period. CONCLUSION: This study detected an increased risk for psoriasis among patients with CRSsNP.

Risk of infections subsequent to pyogenic liver abscess: a nationwide population-based study.

This nationwide study aimed to provide risk estimates for a panel of infections subsequent to pyogenic liver abscesses (PLA) in Taiwan. In this study, we selected 12 050 patients diagnosed with PLA as our study cohort and 60 250 non-PLA patients as our comparison cohort. We individually tracked each subject for a 1-year period beginning with their index date to identify those who were subsequently diagnosed with any of the following infections: pneumonia, endophthalmitis, septic pulmonary embolism, pulmonary abscess, pleural empyema, meningitis, abscess of prostate, renal and perinephric abscess, epidural spinal abscess, osteomyelitis, necrotizing fasciitis, splenic abscess, psoas abscess and infectious endocarditis. We found that during the 1-year follow-up period, the subjects with PLA had a consistently higher incidence of all types of infections than comparison subjects. In particular, compared with subjects without PLA, the adjusted hazard ratios (HR) of pulmonary abscess, pleural empyema, renal and perinephric abscess, epidural spinal abscess and splenic abscess were 26.71, 18.56, 43.21, 51.32 and 126.51, respectively. We further analysed the HR of extra-hepatic Klebsiella pneumoniae infections among patients with PLA caused by K. pneumoniae. We found that the HR was higher for 12 of the 15 analysed extra-hepatic infections after restricting the analysis to only infections with K. pneumoniae aetiologies.

Bisphosphonates reduced the risk of acute myocardial infarction: a 2-year follow-up study.

UNLABELLED: This population-based matched cohort analysis explored the effects of bisphosphonate treatment on acute myocardial infarction (AMI). We found that patients who received bisphosphonate therapy had a lower risk of AMI during a 2-year follow-up period (hazard ratio (HR) = 0.35). Our data support that bisphosphonates may provide protective effects against cardiovascular events. INTRODUCTION: Although bisphosphonates have been suggested to have anti-atherosclerotic effects in animal models, evidence in human subjects is still conflicting. Therefore, this study aimed to explore the effects of bisphosphonate treatment on AMI using a population-based cohort study. METHODS: We identified 1,548 patients who received bisphosphonate therapy for osteoporotic fractures and randomly extracted 4,644 subjects with vertebral or hip fractures as a comparison cohort. Each patient was individually tracked for 2 years to identify those who subsequently suffered an AMI. Stratified Cox proportional hazards regressions were performed to assess the effect of bisphosphonate treatment on the risk of AMI. RESULTS: Six (0.4 %) of the patients who received bisphosphonate therapy and 49 (1.1 %) of the comparison subjects suffered an AMI during the 2-year follow-up period. The incidence rate of AMI was 1.94 (95 % CI = 0.79-4.03) per 1,000 person-years in patients who received bisphosphonate therapy and 5.28 (95 % CI = 3.95-6.92) per 1,000 person-years in comparison patients. Regression analysis revealed that patients who received bisphosphonate therapy had a lower hazard of AMI during the 2-year follow-up period than comparison patients (HR = 0.37, 95 % CI = 0.16-0.85, p = 0.020). After censoring cases that died from non-AMI causes and adjusting for both demographic and risk factors, the HR of AMI for patients who received bisphosphonate therapy was 0.35 (95 % CI = 0.14-0.84, p = 0.020) than that of comparison patients. CONCLUSIONS: Patients who received bisphosphonate therapy had a lower risk of AMI during the 2-year follow-up period. Our data support that bisphosphonates may provide protective effects against cardiovascular events.

Association between osteoporosis and psoriasis: results from the Longitudinal Health Insurance Database in Taiwan.

UNLABELLED: This population-based analysis explored the association between osteoporosis and a previous diagnosis of psoriasis. We found that the adjusted odds ratio (OR) of having been previously diagnosed with psoriasis for subjects with osteoporosis was 1.65 (95 % confidence interval [CI], 1.42-1.94) when compared to controls. INTRODUCTION: Although previous studies have investigated this association between psoriasis and osteoporosis, significant controversy remains regarding its presence. Therefore, this study set out to explore the association between osteoporosis and a previous diagnosis of psoriasis through a population-based case-control study in Taiwan. METHODS: We identified 17,507 cases with a diagnosis of osteoporosis and randomly extracted 52,521 controls without a history of osteoporosis. We used conditional logistic regression analyses to calculate the OR for having been previously diagnosed with psoriasis. RESULTS: Subjects with osteoporosis had a significantly higher prevalence of previously diagnosed psoriasis (1.50 % vs. 0.87 %, p < 0.001) compared to controls. Conditional logistic regression analysis revealed that the OR of having been previously diagnosed with psoriasis for subjects with osteoporosis was 1.65 (95 % CI, 1.42-1.94) when compared to controls after adjusting for monthly income, hypertension, diabetes, coronary heart disease, hyperlipidemia, rheumatoid arthritis, stroke, renal disease, Parkinson's disease, hyperthyroidism, chronic hepatopathy, Cushing's syndrome, malabsorption, tobacco use disorder, obesity, alcohol abuse/alcohol dependence syndrome, the use of SSRIs, and the use of systemic glucocorticoids. Furthermore, osteoporosis was significantly associated with a previous diagnosis of psoriasis in both sexes; the adjusted OR of prior psoriasis for cases when compared to controls was 1.52 (95 % CI, 1.16-1.99) and 1.73 (95 % CI, 1.44-2.13) for males and females, respectively. We also found that the adjusted OR of prior severe psoriasis for cases was 1.96 (95 % CI, 1.37-2.81) that of controls. CONCLUSIONS: This investigation succeeded in detecting an association between osteoporosis and prior psoriasis among both men and women.

Haemorrhoids are associated with erectile dysfunction: a population-based study.

Haemorrhoids are associated with regional vascular abnormalities and rectal pain, which are hypothesized to increase the risk of erectile dysfunction (ED); however, few studies have investigated the association between ED and haemorrhoids. This case-control study aimed to estimate the association between haemorrhoids and ED by using a population-based data in Taiwan. We identified 6,310 patients with ED as cases and randomly selected 31,550 controls. Conditional logistic regression was performed to compute the odds ratio (OR) for having been previously diagnosed with haemorrhoids between cases and controls. The results show that haemorrhoids were found to be present among 1,572 (24.9%) cases and 4,491 (14.20%) controls. The OR for prior haemorrhoids among cases was 1.90 (95% CI = 1.78-2.03) when compared with controls after adjusting for monthly income, geographical location, hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity and alcohol abuse/alcohol dependence syndrome. Younger cases demonstrated a higher risk for prior haemorrhoids when compared with controls. In particular, the adjusted OR among cases <30 years old was 3.71 (95% CI = 2.74-5.02) when compared with controls. We concluded that there was an association between ED and a prior diagnosis of haemorrhoids.

The effects of chronic periodontitis and its treatment on the subsequent risk of psoriasis.

BACKGROUND: Although psoriasis and chronic periodontitis (CP) may share an underlying immune dysregulation as part of their pathologies, to date only one small-scale cross-sectional pilot study has investigated the potential association between CP and psoriasis. OBJECTIVES: This study aimed to investigate the subsequent risk for psoriasis following a diagnosis of CP by utilizing a cohort study design and population-based dataset in Taiwan. METHODS: In total, 115 365 patients with CP were included in the study cohort and 115 365 patients without CP were included in the comparison cohort. We individually tracked each patient for a 5-year period to identify those who had subsequently received a diagnosis of psoriasis. A Cox proportional hazards regression was performed to compute the 5-year risk of subsequent psoriasis following a diagnosis of CP. RESULTS: We found that the incidence rate of psoriasis during the 5-year follow-up period was 1·88 [95% confidence interval (CI) 1·77-1·99] per 1000 person-years in patients with CP and 1·22 (95% CI 1·14-1·32) per 1000 person-years in comparison patients. After censoring those who died during the follow-up period, and adjusting for monthly income and geographical region, compared with comparison patients, the hazard ratio (HR) of psoriasis for patients with CP was 1·52 (95% CI 1·38-1·70). Furthermore, the study subjects who had undergone a gingivectomy or periodontal flap operation had only a slightly higher adjusted risk of psoriasis than comparison patients (HR 1·26). CONCLUSIONS: This study detected an increased risk for psoriasis among patients with CP. Treatment for CP attenuated, but did not nullify, the risk for subsequent psoriasis.