Real-world effectiveness of fecal microbiota transplantation for first or second Clostridioides difficile infection.

BACKGROUND AND AIMS: Clostridioides difficile infection (CDI) is associated with high mortality. Fecal microbiota transplantation (FMT) is an established treatment for recurrent CDI, but its use for first or second CDI remains experimental. We aimed to investigate the effectiveness of FMT for first or second CDI in a real-world clinical setting. METHODS: This multi-site Danish cohort study included patients with first or second CDI treated with FMT from June 2019 to February 2023. The primary outcome was cure of C. difficile-associated diarrhea (CDAD) eight weeks after the last FMT treatment. Secondary outcomes included CDAD cure one and eight weeks after the first FMT treatment and 90-day mortality following positive C. difficile test. RESULTS: We included 467 patients, with 187 (40%) having their first CDI. The median patient age was 73 years (interquartile range (IQR) 58-82 years). Notably, 167 (36%) had antibiotic-refractory CDI, 262 (56%) had severe CDI, and 89 (19%) suffered from fulminant CDI. Following the first FMT treatment, cure of CDAD was achieved in 353 patients (76%, 95% confidence interval (CI) 71-79%) at week one. At week eight, 255 patients (55%, 95% CI 50-59%) maintained sustained effect. In patients without initial effect, repeated FMT treatments led to an overall cure of CDAD in 367 patients (79%, 95% CI 75-82%). The 90-day mortality was 10% (95% CI 8-14%). CONCLUSION: Repeated FMT treatments demonstrate high effectiveness in managing patients with first or second CDI. Forwarding FMT in CDI treatment guidelines could improve patient survival.

Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection.

BACKGROUND & AIMS: Little is known about in utero exposure to and postnatal clearance of anti-tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. METHODS: We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected. RESULTS: The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94-1.49) and 1.97 for infliximab (95% CI, 1.50-2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9-5.0) and 7.3 months for infliximab (95% CI, 6.2-8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09-6.78; P = .02). CONCLUSIONS: In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.

Self-reported adherence to medical treatment, breastfeeding behaviour, and disease activity during the postpartum period in women with Crohn's disease.

OBJECTIVES: Adherence to medical treatment among women with Crohn's disease (CD) in the postpartum period has never been examined. The impact of breast-feeding on disease activity remains controversial. We aimed to assess rates of non-adherence to medical treatment among women with CD in the postpartum period. Further, to assess breast-feeding rates and the impact of breast-feeding on the risk of relapse. METHODS: Within a population of 1.6 million, we identified 154 women with CD who had given birth within a 6-year period. We combined questionnaire data, data from medical records and public register data. We used logistic regression to estimate prevalence odds ratios (POR) for non-adherence, relapse and breast-feeding according to different predictors. RESULTS: Among 105 (80%) respondents, 59 (56%) reported taking medication. Of these, 66.1% reported to be adherent to medical treatment. Fear of medication transmission to the breast milk was stated as the reason for non-adherence in 60%. Those who received counselling regarding medical treatment were less likely to be non-adherent (POR 0.55, 95% confidence interval [CI] 0.1-2.5). In total, 87.6% were breast-feeding. Breast-feeding rates did not vary by medical treatment. Predictors for relapse in CD were smoking (POR 1.85, 95% CI 0.62-5.54) and non-adherence among medical treated (POR 1.25, 95% CI 0.26-6.00). Breast-feeding seemed protective against relapse (POR 0.33, 95% CI 0.10-1.26). CONCLUSIONS: Adherence to medical treatment in the postpartum period was high, and counselling seemed to increase adherence. Relapse may be explained by non-adherence or smoking while breast-feeding seemed protective.

Influence of medical treatment, smoking and disease activity on pregnancy outcomes in Crohn's disease.

OBJECTIVE. Little is known about predictors for adverse pregnancy outcomes among women with Crohn's disease (CD). In this population-based study, we examined pregnancy outcomes in CD stratified by medical treatment and smoking status while accounting for disease activity. METHODS. In two Danish regions with a population of 1.6 million, we identified 154 CD women who had given birth within a 6-year period. We combined questionnaire data, prescription data, data from medical records and population-based medical databases. We used logistic regression to estimate prevalence odds ratios (POR) for adverse pregnancy outcomes by different predictors. RESULTS. Among 105 (80%) respondents, 55 (52%) reported taking medication during pregnancy. The majority (95%) were in disease remission. The children's mean birth weight did not differ by maternal medical treatment. As expected, smoking was a predictor of low birth weight. Mean birth weight in children of smokers in medical treatment was significantly reduced by 274 g compared with children of non-smokers who received medical treatment. In children of women without medical treatment, this difference was 126 g between smokers and non-smokers. Women in medical treatment did not have an increased risk of preterm delivery (POR 0.71; 95% confidence interval (CI) 0.18-2.79), congenital malformations (POR 0.60; 0.10-3.76) or cesarean section (POR 1.40; 0.63-3.08). CONCLUSIon. In CD, smoking was negatively associated with child birth weight. This association was most pronounced among women who received medical treatment. Maternal medical treatment for CD did not seem to be a risk factor for adverse pregnancy outcomes.

Risk of Helicobacter pylori transmission by faecal microbiota transplantation via oral capsules.

OBJECTIVES: The aim was to determine if Helicobacter pylori is transmitted from donors to recipients by faecal microbiota transplantation (FMT) via oral capsules. METHODS: In a cohort of faeces donors not primarily screened for H. pylori, consecutive stool samples were retrospectively analysed by the H. pylori stool antigen test (SAT). Subsequently, we analysed recipient stool samples collected before and after receiving faeces donated by H. pylori SAT-positive donors, and we recorded recipient use of antibiotics and proton pump inhibitors. All stool samples were frozen upon collection and stored at -80°C until use. RESULTS: Thirteen out of 40 faeces donors (33%; 95% CI, 20-48%) were H. pylori SAT-positive. Among those positive, five donors donated faeces for 28 capsule-based FMTs performed in 26 recipients with stool samples collected before and after FMT. At a median of 59 days (range, 7-84 days) after FMT, no recipients (0%; 95% CI, 0-11%) were H. pylori SAT-positive. DISCUSSION: We found no occurrence of H. pylori transmission from healthy, asymptomatic donors to recipients by oral capsule-based FMT, although with a wide CI.

Donor, patient age and exposure to antibiotics are associated with the outcome of faecal microbiota transplantation for recurrent Clostridioides difficile infection: A prospective cohort study.

BACKGROUND: Faecal microbiota transplantation (FMT) is effective for recurrent Clostridioides difficile infection (rCDI), but its effect varies inexplicably. AIMS: To optimise the effectiveness of FMT for rCDI and validate determinants for effect METHODS: We conducted a cohort study, including all patients treated with FMT for rCDI between October 2018 and June 2020. Statistical process control was used to evaluate the impact of prospective quality improvement on the effect of single FMT treatments per 10-11 patients. Targeting an 80% effect, optimisations included changes to processing procedures, preparation and clinical application of FMT. The primary outcome was the resolution of Clostridioides difficile-associated diarrhoea at week 8. If CDI recurred, FMT was repeated. All patients were followed for 8 weeks after their latest FMT. RESULTS: 183 patients with rCDI received 290 FMT treatments. A single FMT achieved resolution at week 8 in 127 (69%, 95% CI: 62%-76%), while repeated FMT cumulatively achieved resolution in 167/183 (91%, 95% CI: 86%-95%). The single FMT effect varied between 36% and 100% over time. In a mixed-effect model, patient age above 65 years, non-rCDI antibiotics at week 1 post-FMT, and donor were associated with effect. Neither increasing the dosages of faecal microbes nor standardising the processing improved outcomes. CONCLUSION: FMT has a high cumulative effectiveness in patients with rCDI following multiple administrations, but the single FMT effect is variable and may be optimised using statistical process control. Optimising FMT by considering patient age, post-FMT antibiotics, donor and multiple administrations may improve the treatment outcomes. CLINICALTRIALS: gov (Study identifier: NCT03712722).

Low-dose Methotrexate Therapy Does Not Affect Semen Parameters and Sperm DNA.

BACKGROUND: Methotrexate is widely used in inflammatory diseases during the patients' reproductive years. The effect on male fertility and sperm DNA integrity is largely unknown. We evaluated sperm DNA integrity and basic semen parameters according to the World Health Organization (WHO) in male patients with inflammatory diseases treated with methotrexate. METHODS: Semen samples from 14 patients on low-dose maintenance methotrexate were compared with samples from 40 healthy volunteers. Further, 5 patients delivered samples on and off methotrexate therapy for paired comparison. Sperm DNA fragmentation index (DFI), concentration, motility, and morphology were evaluated. Blood sex hormones and methotrexate levels were measured in blood and semen. RESULTS: DNA fragmentation index in methotrexate-treated patients was comparable with that in healthy volunteers (DFI, 11.5 vs 15.0; P = .06), and DFI did not change significantly on and off methotrexate in the paired samples (DFI, 12.0 vs 14.0; P = 0.35). Sperm concentration, motility, and morphology did not differ between men treated with methotrexate and healthy volunteers. Sperm progressive motility increased off therapy compared with on therapy (65.0% vs 45.0%, P = .04), but all fluctuations in progressive motility were within the WHO reference interval. All methotrexate polyglutamates1-5 were detected in blood, but only methotrexate polyglutamate1 in semen. Serum testosterone was unaffected by methotrexate therapy. CONCLUSIONS: Patients treated with low-dose methotrexate have a sperm quality comparable with that of healthy volunteers, and methotrexate treatment does not increase sperm DNA fragmentation. This study does not support cryopreservation of semen before treatment initiation nor a 3-month methotrexate-free interval prior to conception.

Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children.

BACKGROUND AND AIMS: For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. METHODS: We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. RESULTS: Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. CONCLUSIONS: Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.

Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study.

BACKGROUND: Little is known about the consequences of intrauterine exposure to, and the post-natal clearance of, vedolizumab. AIMS: To investigate the levels of vedolizumab in umbilical cord blood of newborns and rates of clearance after birth, as well as how these correlated with maternal drug levels, risk of infection and developmental milestones during the first year of life METHODS: Vedolizumab-treated pregnant women with inflammatory bowel disease were prospectively recruited from 12 hospitals in Denmark and Canada in 2016-2020. Demographics were collected from medical records. Infant developmental milestones were evaluated by the Ages and Stages Questionnaire (ASQ-3). Vedolizumab levels were measured at delivery and, in infants, every third month until clearance. Non-linear regression analysis was applied to estimate clearance. RESULTS: In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes. Median infant:mother vedolizumab ratio at birth was 0.44 (95% confidence interval [CI], 0.32-0.56). The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4). No infant had detectable levels of vedolizumab at 6 months of age. Developmental milestones at 12 months were normal or above average. Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring. CONCLUSIONS: Neonatal vedolizumab clearance following intrauterine exposure is rapid. Infant vedolizumab levels did not correlate with the risk of infections during the first year of life. Continuation of vedolizumab throughout pregnancy is safe.

Faecal Microbiota Transplantation Eradicated Extended-Spectrum Beta-Lactamase-Producing Klebsiella pneumoniae from a Renal Transplant Recipient with Recurrent Urinary Tract Infections.

Renal transplant recipients (RTRs) are highly susceptible to infections, and antimicrobial resistance is an increasing problem with limited treatment options. Faecal microbiota transplantation (FMT) is effective for recurrent Clostridium difficile infection and may be used for patients with intestinal carriage of multidrug-resistant (MDR) microorganisms. We present a RTR who suffered from recurrent urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase-producing (ESBL+) Klebsiella pneumoniae. Blood and urinary isolates revealed the same antibiotic susceptibility pattern, and whole-genome sequencing confirmed identical isolates in blood and urine. Despite several treatments with meropenem, the patient experienced recurrent infections that caused hospitalisation. ESBL+ K. pneumoniae was isolated in faeces. In an attempt to decolonise the gut, FMT was performed. A few days after nasojejunal infusion of donor faeces, the patient experienced a single relapse of UTI. During the subsequent 12 months, no further episodes of UTI occurred. Absence of ESBL+ K. pneumoniae in urine and faeces was demonstrated during follow-up. We conclude that FMT may be an effective treatment in RTRs with recurrent UTIs caused by intestinal colonisation with MDR organisms.

Sperm DNA Integrity is Unaffected by Thiopurine Treatment in Men With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Sperm DNA integrity, concentration, and motility are suspected to be altered by thiopurines (azathioprine [AZA] and 6-mercaptopurine [6-MP]). We investigated the impact of thiopurines on semen quality in men with inflammatory bowel disease [IBD], by a comprehensive panel of semen analyses. METHODS: Semen from 40 men with IBD, in remission on AZA/6-MP therapy, was prospectively collected and compared with samples from 40 healthy volunteers. Paired samples [off and on AZA/6-MP] were obtained from a subset of IBD patients, and blood and semen were collected to determine 6-MP transmission to the ejaculate. Sperm DNA fragmentation was evaluated via sperm chromatin structure assay [SCSA] and Comet analysis. Conventional World Health Organization [WHO] parameters, i.e. semen volume and sperm concentration, motility, and morphology, were assessed. Additionally, we measured thioguanine nucleotide [TGN] incorporation in sperm cell DNA. RESULTS: Sperm DNA fragmentation levels did not differ between men with IBD on AZA/6-MP and healthy volunteers when evaluated by SCSA [p = 0.23] and Comet analysis [p = 0.72]. IBD patients on AZA/6-MP had significantly lower total and progressive sperm motility than healthy volunteers [48.5% versus 64.5%, p = 0.0003; 27.4% versus 43.3%, p = 0.0004; respectively], with no differences in concentration, volume, or morphology. The same trend was observed in the 10 paired samples. TGN incorporation was not detectable in sperm DNA, but 6-MP was detected in seminal plasma and correlated to blood levels [rs = 0.79, p = 0.02]. CONCLUSIONS: Thiopurines do not increase sperm DNA fragmentation but may impair sperm motility in this IBD cohort. Our findings support existing epidemiological data that thiopurine therapy is safe during preconception and should not be abandoned.

Semen Quality and Sperm DNA Integrity in Patients With Severe Active Inflammatory Bowel Disease and Effects of Tumour Necrosis Factor-alpha Inhibitors.

BACKGROUND AND AIMS: The impact of severe inflammation on semen quality, including sperm DNA integrity, in men with inflammatory bowel disease [IBD] is unknown, as are the potential effects of anti-tumour necrosis factor-alpha [TNF-alpha] therapy. We investigated the influence of severe active IBD and anti-TNF-alpha treatment on semen quality. METHODS: We prospectively included 20 patients admitted with severe active IBD. Further, 19 patients who initiated and 17 who stopped anti-TNF-alpha therapy were included. Semen samples were obtained during active disease, and on/off treatment. For paired comparisons, samples were collected not less than 3 months after achieving remission, after treatment initiation, or after treatment cessation. Sperm DNA Fragmentation Index [DFI], concentration, morphology, and motility were evaluated. Sex hormones and seminal plasma anti-TNF-alpha drug levels were measured. RESULTS: In patients with severe disease, progressive sperm motility was impaired and increased significantly [from 28.4% to 37.4%, p = 0.045] during remission. There was no difference in DFI [12.5% versus 12.0%, p = 0.55], concentration [55.0 mill/ml versus 70.0 mill/ml, p = 0.39], or normal morphology [4.7% versus 5.1%, p = 0.51] in these patients. During active disease, testosterone was decreased, and normalised after obtaining remission. Patients who started anti-TNF-alpha therapy had a statistically significant, but clinically irrelevant, reduction in DFI after treatment initiation [12.8% versus 10.0%, p = 0.02]. All other semen parameters were unaffected by therapy. Anti-TNF-alpha drugs were excreted in negligible amounts in semen. CONCLUSIONS: Severe active IBD reduces progressive sperm motility and testosterone levels, but sperm DNA integrity is unaffected by active disease. Anti-TNF-alpha therapy does not impair sperm quality.

The Influence of Methotrexate Treatment on Male Fertility and Pregnancy Outcome After Paternal Exposure.

BACKGROUND: Inflammatory bowel disease incidence peaks during the reproductive years. Methotrexate (MTX) is frequently used for inflammatory bowel disease, but its use during pregnancy is contraindicated in women because of teratogenic effects. The aim of this review is to investigate the influence of MTX on male fertility and pregnancy outcomes after paternal MTX exposure. METHODS: A systematic literature search was performed by applying 2 focus areas, "methotrexate" and "male fertility or pregnancy outcome." Terms and keywords were used both as MeSH terms and free-text searches. Pertinent articles were searched for additional relevant references. RESULTS: In animal studies, MTX induces aberrations in sperm DNA that have not been identified in humans. The effects of MTX on human sperm quality have only been described in case reports. A transient adverse effect on sperm quality with low-dose MTX has been reported, but several other cases have not found harmful effects of MTX. MTX has not been measured in human sperm ejaculates; yet, the risk of a direct toxic effect on the fetus through MTX-contaminated seminal plasma seems negligible. Until now, 284 pregnancies with paternal MTX exposure have been reported. The outcomes were 248 live births and a total of 13 malformations, with no overt indication of MTX embryopathy. CONCLUSIONS: This review reveals the lack of studies on the safety of MTX with regard to male reproduction. It is not clear whether MTX transiently influences male fertility and sperm DNA integrity, and more studies are needed. Comparative cohort studies found no increased risk of adverse pregnancy outcomes.

Normal Sperm DNA Integrity in Patients With Inflammatory Bowel Disease on Ustekinumab Maintenance Therapy.

We demonstrate that ustekinumab does not adversely affect semen quality or sex hormones in male patients. Ustekinumab is not detectable in semen and poses no risk to partners. Our observations support a recommendation to continue ustekinumab therapy in patients wishing to conceive.

[Pompe disease is a differential diagnosis in case of reduced physical capacity and abnormal muscular fatigue].

Late-onset Pompe disease is an inherited metabolic myopathy with low activity of alpha glucosidase and variable clinical symptoms. In this case report we describe a woman with long standing muscular fatigue and malaise with the diagnosis initially established by pathologic findings in the muscle biopsy. Enzyme replacement therapy is now a treatment option, and a prompt diagnosis is therefore relevant. This disease should be considered in patients with unexplained fatigue and reduced physical capacity, especially in case of concurrent elevated levels of creatine kinase and liver enzymes.