Prognostic factors affecting outcomes in fistulating perianal Crohn's disease: a systematic review.

BACKGROUND: One in three patients with Crohn's disease will develop a perianal fistulae, and one third of these will achieve long-term healing or closure. A barrier to conducting well-designed clinical trials for these patients is a lack of understanding of prognostic factors. This systematic review sets out to identify factors associated with prognosis of perianal Crohn's fistulae. METHODS: This review was registered on the PROSPERO database (CRD42016050316) and conducted in line with PRISMA guidelines along a predefined protocol. English-language studies assessing baseline factors related to outcomes of fistulae treatment in adult patients were included. Searches were performed on MEDLINE and Embase databases. Screening of abstracts and full texts for eligibility was performed prior to extraction of data into predesigned forms. Bias was assessed using the QUIPS tool. RESULTS: Searches identified 997 papers. Following removal of duplicates and secondary searches, 923 were screened for inclusion. Forty-seven papers were reviewed at full-text level and 13, 2 of which were randomised trials, were included in the final qualitative review. Two studies reported distribution of Crohn's disease as a prognostic factor for healing. Two studies found that CARD15 mutations decreased response of fistulae to antibiotics. Complexity of fistulae anatomy was implicated in prognosis by 4 studies. CONCLUSIONS: This systematic review has identified potential prognostic markers, including genetic factors and disease behaviour. We cannot, however, draw robust conclusions from this heterogeneous group of studies; therefore, we recommend that a prospective cohort study of well-characterised patients with Crohn's perianal fistulae is undertaken

Developing a core outcome set for fistulising perianal Crohn's disease

OBJECTIVE: Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn's disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. DESIGN: Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback fromtheir panel(in the second round) andall participants(in the third round) to allow refinement of their scores. RESULTS: A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study.The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). CONCLUSION: A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care

A systematic review of classification systems for pilonidal sinus

Background Pilonidal sinus disease (PSD) is a simple chronic inflammatory condition resulting from loose hairs forcibly inserted into vulnerable tissue in the natal cleft. It is an acquired disease with a slight familial tendency. There is no agreement on optimum treatment and the multitude of therapeutic options cannot be compared due to the lack of a universally adopted classification of the disease. The aim of our study was to perform a systematic review of the literature to determine how presentations of PSD are classified and reported. Methods A systematic review of the English language literature was undertaken searching studies published after 1980. Results Eight classification systems of PSD were identified. Most classification systems were based on anatomical pathology hypotheses. The location and number of sinuses were the main factors defining classification systems. No articles were retrieved that assessed the validity and/or reliability of the classification system employed. Furthermore, there was no evidence to suggest a correlation between prognosis outcome and subgroup. Conclusions Based on the evidence available from the literature reviewed we have no recommendations regarding the use of the current classification of PSD. A well-recognised and practical classification system to guide clinical practice is required

Protocol for the ORION trial (RadiO fRequency ablatION for haemorrhoids): a randomised controlled trial

Background Haemorrhoids are common and can significantly impact the personal and working lives of individuals. Those with more severe symptoms and those not responding to conservative management may require surgery. Current surgical techniques are associated with a degree of postoperative discomfort which may delay return to normal activity. Recurrence is lower in more radical procedures but resulting pain is higher. Radiofrequency ablation (RFA) is a new technique that is gaining popularity and has several hypothesised benefits, including reduced pain and recurrence. However, available evidence is limited. A recent overview from the National Institute for Health and Clinical Excellence recommended more research, in the form of randomised controlled trials, be carried out before further investment is made by national health services. Our aim is to assess whether RFA is at least as good in terms of recurrence as existing surgical interventions, but superior in terms of pain, for patients with symptomatic grade II and III haemorrhoids. Methods The RadiO fRequency ablatION for haemorrhoids (ORION) trial will be a pragmatic multicentre patient/assessorblind parallel group-controlled trial with economic evaluation. The target sample size is 376 participants (188 per arm) and is based on two co-primary endpoints: (i) a non-inferiority design for recurrence and (ii) superiority design for pain at seven days. Participants with grade II or III haemorrhoids will be recruited in 16 National Health Service hospitals and randomised (1:1) to either RFA or surgeon’s choice of surgery. Conclusions Results will inform future practice for the treatment of grade II–III haemorrhoids and provide evidence for national health services on future investments in RFA

Real-world practice and outcomes in pilonidal surgery: pilonidal sinus treatment studying the options (PITSTOP) cohort

Background Numerous surgical approaches exist for the treatment of pilonidal disease. Current literature on treatment is of poor quality, limiting the ability to define optimal intervention. The aim of this study was to provide real-world data on current surgical practice and report patient and risk-adjusted outcomes, informing future trial design. Methods This UK-wide multicentre prospective cohort study, including patients (aged over 16 years) who had definitive treatment for symptomatic pilonidal disease, was conducted between May 2019 and March 2022. Patient and disease characteristics, and intervention details were analysed. Data on patient-reported outcomes, including pain, complications, treatment failure, wound issues, and quality of life, were gathered at various time points up to 6 months after surgery. Strategies were implemented to adjust for risk influencing different treatment choices and outcomes. Results Of the 667 participants consenting, 574 (86.1%) were followed up to the study end. Twelve interventions were observed. Broadly, 59.5% underwent major excisional surgery and 40.5% minimally invasive surgery. Complications occurred in 45.1% of the cohort. Those who had minimally invasive procedures had better quality of life and, after risk adjustment, less pain (score on day 1: mean difference 1.58, 95% c.i. 1.14 to 2.01), fewer complications (difference 17.5 (95% c.i. 9.1 to 25.9)%), more rapid return to normal activities (mean difference 25.9 (18.4 to 33.4) days) but a rate of higher treatment failure (difference 9.6 (95% c.i. 17.3 to 1.9)%). At study end, 25% reported an unhealed wound and 10% had not returned to normal activities. Conclusion The burden after surgery for pilonidal disease is high and treatment failure is common. Minimally invasive techniques may improve outcomes at the expense of a 10% higher risk of treatment failure

Development of a core descriptor set for Crohn's anal fistula

AIM: Crohn's anal fistula (CAF) is a complex condition, with no agreement on which patient characteristics should be routinely reported in studies. The aim of this study was to develop a core descriptor set of key patient characteristics for reporting in all CAF research. METHOD: Candidate descriptors were generated from published literature and stakeholder suggestions. Colorectal surgeons, gastroenterologists and specialist nurses in inflammatory bowel disease took part in three rounds of an international modified Delphi process using nine-point Likert scales to rank the importance of descriptors. Feedback was provided between rounds to allow refinement of the next ratings. Patterns in descriptor voting were assessed using principal component analysis (PCA). Resulting PCA groups were used to organize items in rounds two and three. Consensus descriptors were submitted to a patient panel for feedback. Items meeting predetermined thresholds were included in the final set and ratified at the consensus meeting. RESULTS: One hundred and thirty three respondents from 22 countries completed round one, of whom 67.0% completed round three. Ninety seven descriptors were rated across three rounds in 11 PCA-based groups. Forty descriptors were shortlisted. The consensus meeting ratified a core descriptor set of 37 descriptors within six domains: fistula anatomy, current disease activity and phenotype, risk factors, medical interventions for CAF, surgical interventions for CAF, and patient symptoms and impact on quality of life. CONCLUSION: The core descriptor set proposed for all future CAF research reflects characteristics important to gastroenterologists and surgeons. This might aid transparent reporting in future studies

Association of Forced Vital Capacity with the Developmental Gene NCOR2

Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered as suggestive evidence. For SNPs with evidence of replication, effects on the expression levels of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium), with further functional investigation performed using public epigenomic profiling data (ENCODE). Results NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional enhancer element in lung fibroblasts, but its eQTL effects could not be tested due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated at nominal level only in adults (p = 0.026). The eQTL analyses showed association of WNT16-rs2707469 with expression levels of the nearby gene CPED1.We found no statistically significant eQTL effects for SERPINE2-rs6754561. Conclusions We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a role of Vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2, a COPD gene with weak previous evidence of association with FVC, and suggest WNT16 as a further promising candidate

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials