The authors investigated the effects of tumor necrosis factor superfamily member 14 (TNFSF14, also called LIGHT) on fibroblasts in EoE.
Key findings:
LIGHT was up-regulated in the esophageal tissues from patients with EoE, compared with control individuals
Stimulation of esophageal fibroblasts with LIGHT induced inflammatory gene transcription
My take: The authors show that patients with EoE had proinflammatory fibroblasts in the epithelium. Further, they show that eosinophil-fibroblast interaction was dependent on intact LIGHT signaling.
“The committee strongly recommends that adults with moderate‐to‐severe CVS receive a tricyclic antidepressant (TCA) such as amitriptyline, as a first‐line prophylactic medication. “
Topiramate, Aprepitant, “Zonisamide or levetiracetam and mitochondrial supplements (Coenzyme Q10, L‐carnitine, and riboflavin) are conditionally recommended as alternate prophylactic medications, either alone or concurrently with other prophylactic medications.”
“For acute attacks, the committee conditionally recommends using serotonin antagonists such as ondansetron, and/or triptans such as sumatriptan or newer agents such as aprepitant (NK1 receptor antagonist) to abort symptoms.”
Evidence, dosing regimens, and algorithms are detailed in article
Sample ED CVS Protocol (for Adults):
____[name]____________ has an established diagnosis of Cyclic Vomiting Syndrome
Operational definition
* A recurring pattern of discrete episodes of severe vomiting, accompanied by profound nausea and/or severe abdominal pain * Patient returns to usual health status between episodes (may have inter‐episodic nausea and or dyspepsia) * In some patients, CVS episodes resemble a migraine attack * Patients may be restless, anxious, and distressed * Patients are not customarily dehydrated until late in the episode
Therapeutic goal
Rapid recognition and intervention may decrease severity of the attack and promote prompt resolution of symptoms
ED management
1. Clinical assessment: Pulse/Temp/BP/Weight, consciousness, and hydration 2. Laboratories/evaluation: CBC, urea, creatinine, LFT’s, lipase, glucose, and electrolytes EKG Urine analysis Diagnostic imaging at discretion of attending physician
Treatment
1. Intravenous fluids a. IV saline bolus if clinically dehydrated b. IV D5NS at 100%‐150% maintenance (suggested rate is 200 cc/h for a 70 kg adult.) 2. For vomiting and nausea a. IV ondansetron 8 mg IV × 1—may repeat q 4‐6 h if ondansetron is ineffective b. Consider diphenhydramine 50 mg IV and metoclopramide 10 mg IV c. Consider IV fosaprepitant 150 mg if available 3. For sedation a. IV lorazepam 1‐2 mg and b. IV diphenhydramine 50 mg for additional sedation 4. For migraine‐like presentation a. Sumatriptan nasal 20 mg (head forward technique) or b. Sumatriptan subcutaneous injection 6 mg/0.5 mL 5. For pain a. IV ketorolac 30 mg if > 60 minutes from onset; may repeat 15 mg q 6 h x 2 (maximum 60 mg/d) b. Opioids may be considered as part of an ongoing treatment plan in refractory patientsa
Reassess
1. Treatment failure—intensify treatment as indicated above or admit patient 2. Positive treatment response—discharge a. Continue ondansetron (soluble tablets) q 6‐8 h × 24‐48 h if initially effective b. Continue lorazepam × 24‐48 h if initially effective c. Continue NSAIDs for pain as needed
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition
A recent review article (E Sararino et al. Am J Gastroenterol 2020; 115: 1786-06. Use of the Functional Lumen Imaging Probe in Clinical Esophagology) is a terrific article for understanding Functional Lumen Imaging Probe (FLIP) techonology and uses. Thanks to Ben Gold for this reference.
The FLIP “measures luminal cross sectional area (CSA) and pressure in the esophagus using impedance planimetry and serves as an adjunct to existing esophageal investigative tests. A distensible balloon encasing a catheter with multiple pairs of impedance electrodes is used, and the balloon is distended with fluid of known conductivity and volume.”
FLIP can be done at time of endoscopy.
Distensibility index (DI). This is the ratio of EGJ cross sectional area to intraballoon pressure is generally considered the most useful FLIP metric. Normal DI values in adults range from 3.1 to 9.0 m3/mm Hg. Lower values indicated reduced EGJ opening.
FLIP can complement the diagnosis of achalasia when manometry and barium studies are inconclusive or negative in patients with typical symptoms.
FLIP can be used to assess fibrostenotic remodeling of the esophagus in eosinophilic esophagitis.
Lumen diameter measured using FLIP in complex strictures can potentially guide management.
This review has several helpful figures to illustrate the type of visual data available. It also provides a standard protocol for using FLIP. The current limitations for FLIP include the lack of real-time software analysis of the data which hinders reporting, and limited data supporting use.
Methods: Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given budesonide orodispersible tablet (BOT) 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks
Key Findings:
At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo)
Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment
In the discussion, the authors state that “we recommend monitoring symptoms and signs of adrenal insufficiency when administrating topical-acting corticosteroids over prolonged time periods, in particular in children and when using higher dosages.”
My take (from discussion): “EoE requires a proper long-term anti-inflammatory therapy because, without active treatment, the vast majority of patients experience a relapse within the first 100 days after cessation of the medication.”
This is a really lousy clinical practice guideline but a pretty good review of small intestinal bacterial overgrowth (SIBO). The reason why it is lousy: it provides virtually no recommendations on how to define/diagnose SIBO, does not recommend specific testing and equivocates on specific treatments.
Here are a few of the “best practice advice” as examples:
#1 The definition of SIBO as a clinical entity lacks precision and consistency; it is a term generally applied to a clinical disorder where symptoms, clinical signs, and/or laboratory abnormalities are attributed to changes in the numbers of bacteria or in the composition of the bacterial population in the small intestine
#5 A major impediment to our ability to accurately define SIBO is our limited understanding of normal small intestinal microbial populations
#6 Controversy remains concerning the role of SIBO in the pathogenesis of common functional symptoms, such as those regarded as components of irritable bowel syndrome
#9 There is a limited database to guide the clinician in developing antibiotic strategies for SIBO
While not providing ‘best practical advice,’ the article does provide details regarding limitations in testing, underlying pathogenesis, and potential treatment regimens for adults.
A recent correspondence letter (CJ Black, AC Ford. AJG 2020; doi: 10.14309/ajg.0000000000000932. Full text: Efficacy of Ondansetron for Irritable Bowel Syndrome With Diarrhea) shows that ondansetron could be an effective option for irritable bowel syndrome with diarrhea. Thanks to Ben Gold for this reference.
“We found histologic evidence of UC activity (Geboes score ≥ 2B.1) in biopsies from 182 patients (65%) and endoscopic evidence of UC activity in 149 patients (53%) (substantial agreement, κ = 0.60).”
“Histologic features of UC activity were associated with increased rates of systemic corticosteroid use, colectomy, and hospitalization in the entire cohort (P < .05 for all) and associated with increased rates of systemic corticosteroid use in an analysis limited to patients in endoscopic remission (P < .001).”
At ileo-colonoscopy, 63% of patients had endoscopic healing and 55% had histologic evidence of healing. The level of agreement between endoscopic and histologic activity was fair (62%, K = 0.2250, P = .0064)
On multivariate analysis, only histologic healing was associated with decreased risk of clinical relapse (hazard ratio [HR], 2.05; 95% CI, 1.07–3.94; P = .031), medication escalation (HR, 2.17; 95% CI, 1.2–3.96; P = .011), and corticosteroid use (HR, 2.44; 95% CI, 1.17–5.09; P = .018).
Kaplan-Meier analysis of effect of endoscopic and histologic activity on (A) clinical relapse-free survival versus histologic healing, (B) clinical relapse-free survival versus endoscopic healing
D Kevans et al. Inflamm Bowel Dis 2020; 26: 1722-1729. Histological Markers of Clinical Relapse in Endoscopically Quiescent Ulcerative Colitis Key finding: In endoscopically quiescent UC (n=76), active histological inflammation …[is] adjunctive histological marker associated with increased likelihood of disease relapse. The associated editorial (1730-32 by Asher Kornbluth) quotes Voltaire: “A wise Italian says that the best is the enemy of the good.” He notes that there is “a very real risk of abandoning an effective drug while chasing the goal of some yet to be universally defined histologic remission.” Currently organizational guidelines (ACG, AGA, ECCO, IOIBD) do NOT suggest the use of histologic normalization as an endpoint at this point.
My take: These studies show that histologic healing in ileal Crohn’s disease and in ulcerative colitis are associated with better outcomes that endoscopic appearance. However, there are a lot questions because many patients, possibly a majority, will not achieve histologic healing despite aggressive treatment. Related technical issues include how many biopsies are needed to assess histology and having a validated histologic assessment.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
Background: AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells.
Methods: In this phase 2 trial, the authors randomly assigned adults (n=65) who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo
Key findings:
The mean percentage change in gastrointestinal eosinophil count was −86% in the combined AK002 group, as compared with 9% in the placebo group
Treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo
The authors note that AK002 “also resulted in alleviation of dysphagia in patients with a history of concomitant eosinophilic esophagitis.”
Limitations: Small study and 10% developed antibodies to drug
My take: Larger phase 3 studies with AK002 are underway (NCT04322604 & NCT04322708). AK002 looks promising for eosinophilic gastrointestinal diseases.
Change in total symptom score over 14 weeks. “Shown is the least-squares mean percentage change from baseline in total symptom score over time.” The total symptom score ranges from 0 to 80, with higher scores indicating greater symptom severity. Each of eight symptoms are given a score of 0 to 10: abdominal pain, nausea, vomiting, early satiety, loss of appetite, abdominal cramping, bloating and diarrhea.
Listed below are the 10 ‘Best Practice Advice’ recommendations. I think the acknowledgement that “hemostatic powder should be preferentially used as a rescue therapy and not for primary hemostasis, except in cases of malignant bleeding or massive bleeding with inability to perform thermal therapy or hemoclip placement” (#7) is very useful.
“Best Practice Advice:”
Endoscopic therapy should achieve hemostasis in the majority of patients with NVUGIB.
This may include clips, thermal (heater probes, bipolar/multipolar catheters, hemostatic forceps), diluted epinephrine injection, and hemostatic spray
Initial management of the patient with NVUGIB should focus on resuscitation, triage, and preparation for upper endoscopy. After stabilization, patients with NVUGIB should undergo endoscopy with endoscopic treatment of sites with active bleeding or high-risk stigmata for rebleeding.
Endoscopists should be familiar with the indications, efficacy, and limitations of currently available tools and techniques for endoscopic hemostasis, and be comfortable applying conventional thermal therapy and placing hemoclips.
Monopolar hemostatic forceps with low-voltage coagulation can be an effective alternative to other mechanical and thermal treatments for NVUGIB, particularly for ulcers in difficult locations or those with a rigid and fibrotic base.
Hemostasis using an over-the-scope clip should be considered in select patients with NVUGIB, in whom conventional electrosurgical coagulation and hemostatic clips are unsuccessful or predicted to be ineffective.
Hemostatic powders are a noncontact endoscopic option that may be considered in cases of massive bleeding with poor visualization, for salvage therapy, and for diffuse bleeding from malignancy.
Hemostatic powder should be preferentially used as a rescue therapy and not for primary hemostasis, except in cases of malignant bleeding or massive bleeding with inability to perform thermal therapy or hemoclip placement.
Endoscopists should understand the risk of bleeding from therapeutic endoscopic interventions (eg, endoluminal resection and endoscopic sphincterotomy) and be familiar with the endoscopic tools and techniques to treat intraprocedural bleeding and minimize the risk of delayed bleeding.
In patients with endoscopically refractory NVUGIB, the etiology of bleeding (peptic ulcer disease, unknown source, post surgical); patient factors (hemodynamic instability, coagulopathy, multi-organ failure, surgical history); risk of rebleeding; and potential adverse events should be taken into consideration when deciding on a case-by-case basis between transcatheter arterial embolization and surgery.
Prophylactic transcatheter arterial embolization of high-risk ulcers after successful endoscopic therapy is not encouraged.
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