Pediatric inflammatory bowel diseases (IBD) are similar to the adult-onset type in many aspects, including the necessity of high-quality randomized controlled trials. However, recruiting children ...into clinical trials is conceptually more challenging than in adults. Furthermore, the long delay between adult and pediatric approval of new drugs leads not only to the unbearable extensive use of these drugs as off-label without appropriate dosing and safety data but also to more challenges when eventually the pediatric trial is performed. This review offers possible solutions to age-specific pitfalls in performing trials in pediatric IBD. Many of the challenges could be adequately addressed by accepting full extrapolation of efficacy from adult trials. This is advisable if small pharmacokinetics/ pharmacodynamics (PK/PD) studies show similarity to adult data. Then, pediatric trials can focus on dosing and safety while avoiding the controversial use of placebo. Judicious use of non-invasive activity scores and biomarkers, providing immediate and effective treatment in active disease and ensuring equipoise of treatments both within and outside the trial are the mainstay of a feasible trial in children. The recent trend of including adolescents in adult phase-3 trials addresses some obstacles but introduces others. Acknowledging and addressing these age-specific challenges would facilitate pediatric drug development in IBD.
Abstract
Despite compelling evidence pointing to a critical role of gut microflora in inflammatory bowel disease (IBD) pathogenesis, the role of antibiotics in clinical practice remains limited, ...largely due to heterogeneous trials with often conflicting evidence. In this review, we revisit previous randomized controlled trials and high-quality uncontrolled studies in an effort to better elucidate the role of antibiotics in contemporary treatment algorithms. The most established role of antibiotics is in perianal Crohn's disease (CD), utilizing ciprofloxacin with or without metronidazole often as an adjunct to biological therapy. Evidence also points to a likely modest role of various antibiotic classes in mild to moderate luminal CD, including ciprofloxacin, metronidazole, azithromycin, and rifaximin. The benefit of metronidazole in preventing postoperative recurrence in CD is well reported; however, the long-term benefit of this intervention remains uncertain. The use of antibiotics in ulcerative colitis (UC) is even more controversial, but studies using broad-spectrum oral antibiotic cocktails have reported a possible role in acute severe colitis and chronic persistent UC. Similarly, the role of oral vancomycin and gentamicin in very early-onset IBD has interesting preliminary results. Adverse events of antibiotics, the resulting alterations in the microbiome with its associated unknown long-term sequela, and the emergence of antibiotic-resistant strains must be carefully balanced. Therefore, although antibiotics may be underused in the treatment of IBD, their integration into clinical practice must be approached judiciously and individually.
Two SARS-CoV-2 mRNA vaccines were approved to prevent COVID-19 infection, with reported vaccine efficacy of 95%. Liver transplant (LT) recipients are at risk of lower vaccine immunogenicity and were ...not included in the registration trials. We assessed vaccine immunogenicity and safety in this special population.
LT recipients followed at the Tel-Aviv Sourasky Medical Center and healthy volunteers were tested for SARS-CoV-2 IgG antibodies directed against the Spike-protein (S) and Nucleocapsid-protein (N) 10–20 days after receiving the second Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine dose. Information regarding vaccine side effects and clinical data was collected from patients and medical records.
Eighty LT recipients were enrolled. Mean age was 60 years and 30% were female. Twenty-five healthy volunteer controls were younger (mean age 52.7 years, p = 0.013) and mostly female (68%, p = 0.002). All participants were negative for IgG N-protein serology, indicating immunity did not result from prior COVID-19 infection. All controls were positive for IgG S-protein serology. Immunogenicity among LT recipients was significantly lower with positive serology in only 47.5% (p <0.001). Antibody titer was also significantly lower in this group (mean 95.41 AU/ml vs. 200.5 AU/ml in controls, p <0.001). Predictors for negative response among LT recipients were older age, lower estimated glomerular filtration rate, and treatment with high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group.
LT recipients developed substantially lower immunological response to the Pfizer-BioNTech SARS-CoV-2 mRNA-based vaccine. Factors influencing serological antibody responses include age, renal function and immunosuppressive medications. The findings require re-evaluation of vaccine regimens in this population.
The Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine elicited substantially inferior immunity in liver transplant recipients. Less than half of the patients developed sufficient levels of antibodies against the virus, and in those who were positive, average antibody levels were 2x less compared to healthy controls. Factors predicting non-response were older age, renal function and immunosuppressive medications.
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•Liver transplant recipients exhibited reduced response to the SARS-CoV-2 mRNA-based vaccine.•Neutralizing antibody was detected in only 47.5% of patients following vaccination.•Antibody titers were significantly lower compared to the control group.•Age, renal function and immunosuppression were associated with lower immunological response.
COVID‐19 is associated with increased morbidity and mortality in transplant recipients. There are no efficacy data available regarding these patients with any of the available SARS‐CoV‐2 vaccines. We ...analyzed the humoral response following full vaccination with the BNT162b2 (Pfizer‐BioNTech) in 136 kidney transplant recipients, and compared it to 25 controls. In order to exclude prior exposure to the virus, only participants with negative serology to SARS‐CoV‐2 nucleocapsid protein were included. All controls developed a positive response to spike protein, while only 51 of 136 transplant recipients (37.5%) had positive serology (p < .001). Mean IgG anti‐spike level was higher in the controls (31.05 41.8 vs. 200.5 65.1 AU/mL, study vs. control, respectively, p < .001). Variables associated with null humoral response were older age (odds ratio 1.66 95% confidence interval 1.17–2.69), high‐dose corticosteroids in the last 12 months (1.3 1.09–1.86), maintenance with triple immunosuppression (1.43 1.06–2.15), and regimen that includes mycophenolate (1.47 1.26–2.27). There was a similar rate of side effects between controls and recipients, and no correlation was found between the presence of symptoms and seroconversion. Our findings suggest that most kidney transplant recipients remain at high risk for COVID‐19 despite vaccination. Further studies regarding possible measures to increase recipient's response to vaccination are required.
Most kidney transplant recipients do not mount an appreciable anti‐spike antibody response to the BNT162b2 (Pfizer‐BioNTech) SARS‐CoV‐2 vaccine.
The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment ...targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD.
Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale.
In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn’s disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth.
STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.
This year, the European Society for Gastroenterology Hepatology and Nutrition (ESPGHAN) joined forces with the European Federation of Crohn’s & Colitis Associations (EFCCA) to drive awareness of the ...hidden costs of paediatric inflammatory bowel diseases (IBD) and make the invisible visible. This feature puts the hidden cost of paediatric IBD in the spotlight and the author makes the case for policy makers to recognise the invisible cost of paediatric IBD. He pledges to take four key steps to reduce the burden of the diseases on society and improve the lives of children and their families.
Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early ...childhood, along with endoscopic or histological features of Crohn’s disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.
ABSTRACT
Background:
The diagnosis of pediatric‐onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its ...different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete.
Methods:
We aimed to revise the original Porto criteria using an evidence‐based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm.
Results:
The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD‐unclassified (IBD‐U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy.
Conclusions:
These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up‐to‐date guidelines for the definition and diagnosis of the IBD spectrum.
HIV-infected men who have sex with men (MSM) who use recreational drugs (RD) or excessive alcohol (EA) may be involved in risky sexual behaviours, including unprotected anal intercourse (UAI). This ...study describes the prevalence RD/EA-use among HIV-infected MSM, and compares those who used RD/EA with those who did not.
This cross-sectional study included HIV-infected MSM who were recruited in a convenient sample from two AIDS-treatment centres and events for HIV-infected MSM in Israel in 2016. Participants completed anonymous questionnaires including RD/EA-use and their sexual behaviours. RD/EA-use was defined as consumption of any psychoactive stimulants or dissociative anaesthetics, or an uptake of alcohol until drunkenness before or during sex.
Of all 276 HIV-infected MSM, 202 (73.2%) used RD/EA. Those who used RD/EA were younger, reported earlier sexual debut, had more sexual partners, were more likely to perform UAI with casual partners, more commonly involved in paid sex, used psychiatric medications and more likely to be unsatisfied with their health-status compared to those who did not use RD/EA. HIV-infected MSM who used RD/EA reported a lower CD4-count and higher viral-load than those who did not. In a multivariate analysis, being younger, reported earlier sexual debut and been prescribed psychiatric drugs were associated with RD/EA-use among HIV-infected MSM.
A large proportion of HIV-infected MSM used RD/EA and also engaged in risky sexual behaviours. A subset of HIV-infected MSM can benefit from mental support during their routine treatment at the AIDS treatment centres and should also receive harm reduction intervention by their providers in order to minimize potential risks pertaining to RD/EA-use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite the growing use of medical salvage therapy,colectomy has remained a cornerstone in managing acute severe ulcerative colitis（ASC） both in children and in adults.Colectomy should be regarded as ...a life saving procedure in ASC,and must be seriously considered in any steroid-refractory patient.However,colectomy is not a cure for the disease but rather the substitution of a large problem with smaller problems,including fecal incontinence,pouchitis,irritable pouch syndrome,cuffitis,anastomotic ulcer and stenosis,missed or de-novo Crohn＇s disease and,in young females,reduced fecundity.This notion has led to the widespread practice of offering medical salvage therapy before colectomy in most patients without surgical abdomen or toxic megacolon.Medical salvage therapies which have proved effective in the clinical trial setting include cyclosporine,tacrolimus and infliximab,which seem equally effective in the short term.Validated predictive rules can identify a subset of patients who will eventually fail corticosteroid therapy after only 3-5 d of steroid therapy with an accuracy of 85%-95%.This accuracy is sufficiently high for initiat-ing medical therapy,but usually not colectomy,early in the admission without delaying colectomy if required.This approach has reduced the colectomy rate in ASC from 30%-70% in the past to 10%-20% nowadays,and the mortality rate from over 70% in the 1930s to about 1%.In general,restorative proctocolectomy（ileoanal pouch or ileal pouch-anal anastomosis）,especially the J-pouch,is preferred over straight pullthrough（ileo-anal） or ileo-rectal anastomosis,which may still be considered in young females concerned about infertility.Colectomy in the acute severe colitis setting,is usually performed in three steps due to the severity of the inflammation,concurrent steroid treatment and the generally reduced clinical condition.The first surgical step involves colectomy and constructing an ileal stoma,the second-constructing the pouch and the third-closing the stoma.This review focuses on the role of surgical treatment in ulcerative colitis in the era of medical rescue therapy.
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