Clinical Update on the Prevention and Management of Postoperative Crohn's Disease Recurrence.

PURPOSE OF REVIEW: Despite advances in therapeutics, a significant portion of patients with Crohn's disease still require surgical management. In this article, we present updates to the natural history, prognostication and postoperative monitoring, and novel therapeutics in the prevention and treatment of postoperative Crohn's disease recurrence. RECENT FINDINGS: Clinical risk factors have been associated with higher rates of postoperative recurrence (POR), and in recent studies demonstrate an increased cumulative risk with presence of additional risk factors. Additional novel clinical, histologic, and "-omic" risk factors for recurrence have recently been elucidated, including the role of the mesentery on recurrence and perioperative intraabdominal septic complications. High-risk patients benefit most from medical prophylaxis, including anti-TNF with or without immunomodulator therapy to prevent recurrence. New biologics such as vedolizumab and ustekinumab have emerging evidence in the use of prophylaxis, especially with recent REPREVIO trial data. Non-invasive disease monitoring, such as cross-sectional enterography, intestinal ultrasound, and fecal calprotectin, have been validated against ileocolonoscopy. Recent advances in the prediction, prevention, and monitoring algorithms of postoperative Crohn's disease may be leading to a reduction in postoperative recurrence. Ongoing trials will help determine optimal monitoring and management strategies for this at-risk population.

Anastomotic Configuration and Temporary Diverting Ileostomy Do Not Increase Risk of Anastomotic Stricture in Postoperative Crohn's Disease.

INTRODUCTION: Surgical management of Crohn's disease (CD) is common. Postoperative complications include anastomotic stricturing (AS). The natural history and risk factors for AS have not been elucidated. METHODS: A retrospective cohort study of patients with CD who underwent ileocolonic resection (ICR) with ≥1 postoperative ileocolonoscopy between 2009 and 2020. Postoperative ileocolonoscopies with corresponding cross-sectional imaging were evaluated for evidence of AS without neoterminal ileal extension. Severity of AS and endoscopic intervention at time of detection were collected. Primary outcome was development of AS. Secondary outcome was time to AS detection. RESULTS: A total of 602 adult patients with CD underwent ICR with postoperative ileocolonoscopy. Of these, 426 had primary anastomosis, and 136 had temporary diversion at time of ICR. Anastomotic configuration consisted of 308 side-to-side, 148 end-to-side, and 136 end-to-end. One hundred ten (18.3%) patients developed AS with median time of 3.2 years to AS detection. AS severity at time of detection was associated with need for repeat surgical resection for AS. On multivariable Cox proportional hazard regression, anastomotic configuration and temporary diversion were not associated with risk of or time to AS. Preoperative stricturing disease was associated with decreased time to AS (adjusted hazard ratio 1.8; P = 0.049). Endoscopic ileal recurrence before AS was not associated with subsequent AS detection. DISCUSSION: AS is a relatively common postoperative CD complication. Patients with previous stricturing disease behavior are at increased risk of AS. Anastomotic configuration, temporary diversion, and ileal CD recurrence do not increase risk of AS. Early detection and intervention for AS may help prevent progression to repeat ICR.

Change in Biologic Class Promotes Endoscopic Remission Following Endoscopic Postoperative Crohn's Disease Recurrence.

GOALS: Assess the outcomes of various therapeutic regimens to treat initial endoscopic postoperative recurrence despite biologic prophylaxis. BACKGROUND: Postoperative biologic prophylaxis reduces postoperative Crohn's disease (CD) recurrence rates. Optimal treatment strategies for endoscopic recurrence have not been elucidated. STUDY: Retrospective cohort study of adult CD patients who underwent ileocolonic resection between 2009 and 2020. Patients with endoscopic postoperative recurrence despite prophylactic biologic therapy and ≥1 subsequent colonoscopy were included. Treatment changes after recurrence were categorized as (1) therapy optimization or continuation or (2) new biologic class. The primary outcome was composite endoscopic or surgical recurrence at the time of or prior to subsequent follow-up colonoscopy. RESULTS: Eighty-one CD patients with endoscopic recurrence (54.3% i2b, 22.2% i3, and 23.5% i4) despite biologic prophylaxis (86.4% anti-tumor necrosis factor, 8.6% vedolizumab, 4.9% ustekinumab) were included. Most patients received therapy optimization or continuation (76.3%, n=61) following recurrence compared to being started on a new biologic class. Sixty patients (N=48 therapy optimization; N=12 new biologic class) experienced composite recurrence (78.3% endoscopic, 21.7% surgical). On multivariable modeling, initiation of a new biologic class was associated with reduced risk for composite recurrence compared to therapy optimization or continuation (aOR: 0.26; P=0.04). Additionally, initiation of a new biologic class was associated with endoscopic improvement when adjusting for endoscopic severity at the time of recurrence (aOR: 3.4; P=0.05). On sensitivity analysis, a new biologic class was associated or trended with improved rates of endoscopic healing and composite recurrence when directly compared to therapy optimization or continuation. CONCLUSION: In patients with CD who experience endoscopic recurrence despite biologic prophylaxis, changing the mechanism of biologic action may promote endoscopic improvement.

Test Characteristics of Cross-sectional Imaging and Concordance With Endoscopy in Postoperative Crohn's Disease.

BACKGROUND & AIMS: Postoperative Crohn's disease (CD) surveillance relies on endoscopic monitoring. The role of cross-sectional imaging is less clear. We evaluated the concordance of cross-sectional enterography with endoscopic recurrence and the predictive ability of radiography for future CD postoperative recurrence. METHODS: We performed a multi-institution retrospective cohort study of postoperative adult patients with CD who underwent ileocolonoscopy and cross-sectional enterography within 90 days of each other following ileocecal resection. Imaging studies were interpreted by blinded, expert CD radiologists. Patients were categorized by presence of endoscopic postoperative recurrence (E+) (modified Rutgeerts' score ≥i2b) or radiographic disease activity (R+) and grouped by concordance status. RESULTS: A total of 216 patients with CD with paired ileocolonoscopy and imaging were included. A majority (54.2%) exhibited concordance (34.7% E+/R+; 19.4% E-/R-) between studies. The plurality (41.7%; n = 90) were E-/R+ discordant. Imaging was highly sensitive (89.3%), with low specificity (31.8%), in detecting endoscopic postoperative recurrence. Intestinal wall thickening, luminal narrowing, mural hyper-enhancement, and length of disease on imaging were associated with endoscopic recurrence (all P < .01). Radiographic disease severity was associated with increasing Rutgeerts' score (P < .001). E-/R+ patients experienced more rapid subsequent endoscopic recurrence (hazard ratio, 4.16; P = .033) and increased rates of subsequent endoscopic (43.8% vs 22.7%) and surgical recurrence (20% vs 9.5%) than E-/R- patients (median follow-up, 4.5 years). CONCLUSIONS: Cross-sectional imaging is highly sensitive, but poorly specific, in detecting endoscopic disease activity and postoperative recurrence. Advanced radiographic disease correlates with endoscopic severity. Patients with radiographic activity in the absence of endoscopic recurrence may be at increased risk for future recurrence, and closer monitoring should be considered.

Dimensions and Morphologic Variability of the Retro-Orbicularis Oculi and Frontalis Muscle Fat Pad.

PURPOSE: To quantify the complete dimensions of the retro-orbicularis oculi fat (ROOF) pad and to determine its relationship to other fat compartments of the forehead. METHODS: The entire forehead of 14 hemifaces of seven fresh frozen human cadavers (four female, three male) was dissected in the subcutaneous and submuscular planes. For each plane, a ruler was placed at the facial midline, and images of the dissection plane were taken at 90° and 45°. Images were analyzed for vertical height, horizontal length, the distance to midline from the point of maximal height, and area for each hemiface of the ROOF and for the entire fat compartment contiguous with the ROOF. A two-tailed t test was conducted between ROOF and ROOF plus the extended fat plane across all measurements. A Wilcoxon nonparametric signed rank test was performed to determine equivalent fat distribution of the extended fat plane over each cadaver's respective eye. RESULTS: The deep fat originating from the ROOF consistently extended laterally and superiorly in each specimen, distinctly separated via septae from the deep central, deep lateral, and the deep temporal fat compartments. The color, composition, and distribution of this contiguous deep fat did not differ phenotypically from the traditional ROOF. The extended deep fat plane possessed an average vertical height of 3.09 ± 0.68 cm, average distance to midline from point of maximal height of 3.56 ± 0.53 cm, an average horizontal length of 5.37 ± 0.82 cm, and an average area of 13.40 ± 2.69 cm. The extended deep fat demonstrated a statistically significant increase in maximal height, length, and total area compared with the ROOF. A Wilcoxon nonparametric signed rank test was nonsignificant (α = 0.01) across all measurements, demonstrating that the extended fat plane was similarly distributed over each eye. CONCLUSIONS: A layer of deep fat originating from the traditionally defined ROOF extends superiorly and laterally beneath the frontalis muscle, separate from the deep lateral, deep central, and deep temporal fat pads. This is the first study to clearly demonstrate a contiguous superficial musculoaponeurotic system layer of fat extending under both the orbicularis oculi and frontalis muscles. This plane of fat is more appropriately described as the retro-orbicularis oculi and frontalis fat.

Vagus Nerve Stimulation and Other Neuromodulation Methods for Treatment of Traumatic Brain Injury.

The objective of this paper is to review the current literature regarding the use of vagus nerve stimulation (VNS) in preclinical models of traumatic brain injury (TBI) as well as discuss the potential role of VNS along with alternative neuromodulation approaches in the treatment of human TBI. Data from previous studies have demonstrated VNS-mediated improvement following TBI in animal models. In these cases, VNS was observed to enhance motor and cognitive recovery, attenuate cerebral edema and inflammation, reduce blood brain barrier breakdown, and confer neuroprotective effects. Yet, the underlying mechanisms by which VNS enhances recovery following TBI remain to be fully elucidated. Several hypotheses have been offered including: a noradrenergic mechanism, reduction in post-TBI seizures and hyper-excitability, anti-inflammatory effects, attenuation of blood-brain barrier breakdown, and cerebral edema. We present other potential mechanisms by which VNS acts including enhancement of synaptic plasticity and recruitment of endogenous neural stem cells, stabilization of intracranial pressure, and interaction with the ghrelin system. In addition, alternative methods for the treatment of TBI including deep brain stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, and focused ultrasound stimulation are discussed. Although the primary source data show that VNS improves TBI outcomes, it remains to be determined if these findings can be translated to clinical settings.

Application of Tauroursodeoxycholic Acid for Treatment of Neurological and Non-neurological Diseases: Is There a Potential for Treating Traumatic Brain Injury?

The objective of this review was to evaluate the potential of tauroursodeoxycholic acid (TUDCA) for neuroprotection in traumatic brain injury (TBI) patients in the neurocritical care setting. Specifically, we surveyed preclinical studies describing the neuroprotective and systemic effects of TUDCA, and the potential therapeutic application of TUDCA. Preclinical studies have provided promising data supporting its use in neurological disease characterized by apoptosis-induced neuronal loss. TUDCA inhibits multiple proteins involved in apoptosis and upregulates cell survival pathways. In addition, TUDCA exhibits anti-inflammatory effects in models of neuroinflammation and attenuates neuronal loss in chronic neurodegenerative diseases. This may be applicable to TBI, which also triggers inflammatory and apoptotic processes. Additionally, preliminary data support the use of pharmacological therapies that reduce apoptosis and inflammation associated with TBI. The anti-apoptotic and anti-inflammatory mechanisms of TUDCA could prove promising in the treatment of TBI. Currently, there are no published data supporting improvement in clinical outcomes of TBI by treatment with TUDCA, but future studies should be considered.

Postoperative Crohn's Disease Recurrence Risk and Optimal Biologic Timing After Temporary Diversion Following Ileocolic Resection.

BACKGROUND: Postoperative recurrence of Crohn's disease (CD) is common. While most patients undergo resection with undiverted anastomosis (UA), some individuals also have creation of an intended temporary diversion (ITD) with an ileostomy followed by ostomy takedown (OT) due to increased risk of anastomotic complications. We assessed the association of diversion with subsequent CD recurrence risk and the influence of biologic prophylaxis timing to prevent recurrence in this population. METHODS: This was a retrospective cohort study of CD patients who underwent ileocolic resection between 2009 and 2020 at a large quaternary health system. Patients were grouped by continuity status after index resection (primary anastomosis or ITD). The outcomes of the study were radiographic, endoscopic, and surgical recurrence as well as composite recurrence postoperatively (after OT in the ITD group). Propensity score-weighted matching was performed based on risk factors for diversion and recurrence. Multivariable regression and a Cox proportional hazards model adjusting for recurrence risk factors were used to assess association with outcomes. Subgroup analysis in the ITD group was performed to assess the impact of biologic timing relative to OT (no biologic, biologic before OT, after OT) on composite recurrence. RESULTS: A total of 793 CD patients were included (mean age 38 years, body mass index 23.7 kg/m2, 52% female, 23% active smoker, 50% penetrating disease). Primary anastomosis was performed in 67.5% (n = 535) and ITD in 32.5% (n = 258; 79% loop, 21% end) of patients. Diverted patients were more likely to have been males and to have had penetrating and perianal disease, prior biologic use, lower body mass index, and lower preoperative hemoglobin and albumin (all P < .01). After a median follow-up of 44 months, postoperative recurrence was identified in 83.3% patients (radiographic 40.4%, endoscopic 39.5%, surgical 13.3%). After propensity score matching and adjusting for recurrence risk factors, no significant differences were seen between continuity groups in radiographic (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 0.91-1.91) or endoscopic recurrence (aHR, 1.196; 95% CI, 0.84-1.73), but an increased risk of surgical recurrence was noted in the ITD group (aHR, 1.61; 95% CI, 1.02-2.54). Most (56.1%) ITD patients started biologic prophylaxis after OT, 11.4% before OT, and 32.4% had no postoperative biologic prophylaxis. Biologic prophylaxis in ITD was associated with younger age (P < .001), perianal disease (P = .04), and prior biologic use (P < .001) but not in recurrence (P = .12). Despite higher rates of objective disease activity identified before OT, biologic exposure before OT was not associated with a significant reduction in composite post-OT recurrence compared with starting a biologic after OT (52% vs 70.7%; P = 0.09). CONCLUSIONS: Diversion of an ileocolic resection is not consistently associated with a risk of postoperative recurrence and should be performed when clinically appropriate. Patients requiring diversion at time of ileocolic resection are at high risk for recurrence, and biologic initiation prior to stoma reversal may be considered.

Diversion of an ileocolic resection is not consistently associated with a risk of postoperative recurrence and should be performed when clinically appropriate. Patients requiring diversion at time of ileocolic resection are high risk for recurrence, and biologic initiation prior to stoma reversal may be considered.

The impact of the COVID-19 pandemic on Clostridioides difficile infection and utilization of fecal microbiota transplantation.

Previous research has demonstrated that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains cell entry through the angiotensin-converting enzyme 2 receptor, which is abundantly found throughout the gastrointestinal (GI) tract, resulting in a wide array of GI manifestations of coronavirus disease 2019 (COVID-19). By gaining entry into the intestinal epithelial and stromal cells, SARS-CoV-2 has been observed to cause intestinal inflammation and gut dysbiosis. Alterations in gut microbiota are known to be involved in the pathophysiology of Clostridioides difficile infection (CDI). During the initial stages of the COVID-19 pandemic, rates of CDI were similar to historical data despite the increased use of antibiotics. This may be due to increased emphasis on hygiene and protective equipment and reduced C. difficile testing as diarrhea was presumed to be COVID-19 related. Studies also demonstrated additional risk factors for CDI in COVID-19 patients, including length of hospitalization and new abdominal pain during admission. Although not associated with increased mortality, CDI was associated with increased length of hospital stay among patients admitted with COVID-19. Due to fecal viral shedding and concern of oral-fecal transmission of SARS-CoV-2, increased safety regulations were introduced to fecal microbiota transplantation (FMT) leading to reduced rates of this procedure during the COVID-19 pandemic. FMT for recurrent CDI during the COVID-19 pandemic remained highly effective without any reports of SARS-CoV-2 transmission. In addition, limited data show that FMT may be effective in treating COVID-19 and restoring healthy gut microbiota. The goal of this article is to review the impact that the COVID-19 pandemic has had on hospital-acquired CDI and the utilization of FMT.