Adrenal insufficiency is a contraindication for omalizumab therapy in mast cell activation disease: risk for serum sickness.

Omalizumab is an effective therapeutic humanized murine IgE antibody in many cases of primary systemic mast cell activation disease (MCAD). The present study should enable the clinician to recognize when treatment of MCAD with omalizumab is contraindicated because of the potential risk of severe serum sickness and to report our successful therapeutic strategy for such adverse event (AE). Our clinical observations, a review of the literature including the event reports in the FDA AE Reporting System, the European Medicines Agency Eudra-Vigilance databases (preferred search terms: omalizumab, Xolair®, and serum sickness) and information from the manufacturer's Novartis database were used. Omalizumab therapy may be more likely to cause serum sickness than previously thought. In patients with regular adrenal function, serum sickness can occur after 3 to 10 days which resolves after the antigen and circulating immune complexes are cleared. If the symptoms do not resolve within a week, injection of 20 to 40 mg of prednisolone on two consecutive days could be given. However, in MCAD patients whose adrenal cortical function is completely suppressed by exogenous glucocorticoid therapy, there is a high risk that serum sickness will be masked by the MCAD and evolve in a severe form with pronounced damage of organs and tissues, potentially leading to death. Therefore, before the application of the first omalizumab dose, it is important to ensure that the function of the adrenal cortex is not significantly limited so that any occurring type III allergy can be self-limiting.

Multicenter analysis of endoclot as hemostatic powder in different endoscopic settings of the upper gastrointestinal tract.

Gastrointestinal bleeding (GIB) still presents a demanding situation with high morbidity and mortality rates; thus hemostatic powders such as EndoClot (EC) have been developed to improve endoscopic armament. The aim of the present study was to determine which indications triggered the application of EC and to assess resulting hemostasis rates. Forty three patients undergoing endoscopical procedures in three hospitals; two tertiary care and one university hospital, were included. EC was applied in 48 endoscopies in 43 patients (27 male, age 65.5 years, range 28 - 92 years) following four different indications. EC was used in active GIB as rescue or first-line therapy giving a short-term and long-term hemostasis in 13/17 patients (76.5%). In the setting of non-active GIB, following conventionally achieved hemostasis or endoscopic interventions, EC was found to prevent bleeding in 19/21 patients (90.4%). EC induced hemostasis in 8/10 patients (80%) with impaired coagulation. EC failures resulted from tumor bleeding, Forrest I lesions or perforated duodenal ulcers. No major adverse events were recorded and one technical failure (2.1%) occurred. EC was applied as first line or salvage treatment in ongoing bleedings with promising results. Furthermore, EC was used after successful hemostasis or following endoscopic interventions to further reduce re-bleeding rates. We saw promising results in all indications, albeit lacking a control group.

Endoscopic full-thickness resection (EFTR) in the lower gastrointestinal tract.

BACKGROUND: Endoscopic full-thickness resection (EFTR) significantly expands the spectrum of endoscopic colorectal resection methods for lesions that show no lifting sign, submucosal lesions and mucosal carcinomas. The aim of our study was to evaluate the efficacy and safety of EFTR using a commercially available full thickness resection device (FTRD) by assessing the completeness of the full-thickness resection, the technical success, as well as complications in a cohort of patients from three referral centers in Germany. Another aim was to determine which patient subpopulations benefit most in clinical practice. METHODS: This retrospective multicenter study was conducted on consecutive patients who were admitted to three referral centers in Germany between November 2014 and December 2017. The EFTR was conducted according to the standard indications using the FTRD System (OVESCO, Tübingen, Germany). Data were obtained from prospectively maintained institutional databases. RESULTS: There were 70 patients, 42 males and 25 females with a mean age of 79.5 years (range 25-89 years) who had colonoscopy for EFTR. In three patients EFTR was not feasible because the lesions were too large. Of the remaining 67 patients, 52 had recurrent adenomas, 10 had high-grade intraepithelial neoplasia or mucosal carcinoma and five had a subepithelial lesion. Resection was technically successful in 65 patients (97.0%). Histologically complete resection (R0) was achieved in 59/65 patients (90.8%). The R0 resection rate was lower for lesions > 20 mm (86.5%) versus lesions ≤ 20 mm (92.9%). The total complication rate was 14.9%: there was one major complication (perforation of sigmoid colon), while all other complications were minor. CONCLUSIONS: EFTR yields excellent resection rates for benign recurrent adenomas with non-lifting sign, advanced histopathological findings or submucosal lesions when the procedure is performed in experienced hands and for the correct indication. Thus, surgery can be avoided in many cases. For all lesions the risk of R1 resection goes up with the size of the lesion and careful patient selection is mandatory.

Anticoagulant-related gastrointestinal bleeding: a real-life data analysis on bleeding profiles, frequency and etiology of patients receiving direct oral anticoagulants versus vitamin K antagonists.

Vitamin K antagonists (VKA) continue to be the standard of long-term anticoagulation. Direct oral anticoagulants(DOAC) are increasingly used. In many trials DOAC were at least as effective as VKA. In this study we evaluate the bleeding profiles, frequencies and etiologies of patients receiving DOAC versus VKA in a real-life setting. All patients presenting with suspected gastrointestinal bleeding (GIB) in the emergency department of the University Hospital Erlangen in one year were enrolled in this study. They were looked up for the intake of either DOAC (dabigatran, rivaroxaban and apixaban) or VKA. The results showed that 406 patients with suspected GIB were admitted to the emergency unit of the University Hospital Erlangen. In 228 of those patients GIB could be verified (56.2%). Fifty four of those patients (23.7%) were administered either VKA or DOAC. In 35 of those 54 patients (64.8%) GIB was classified as 'major bleeding'. In 27 patients with administration of VKA upper GIB was recorded and lower GIB was detected four times. In 16 patients with administration of DOAC upper GIB was found and lower GIB was found in 7 patients. The presented data do not show higher GIB rates for DOAC (mainly dabigatran and rivaroxaban), but do also not indicate a significantly higher safety of DOAC concerning GIB than VKA. This finding represents a clear contrast to the reduced bleeding rates of DOAC for intracerebral bleeding and other non-GIB events. According to our study, the absolute number of DOAC-associated GIB events is lower than in the VKA group.

Outcome, comorbidity, hospitalization and 30-day mortality after closure of acute perforations and postoperative anastomotic leaks by the over-the-scope clip (OTSC) in an unselected cohort of patients.

BACKGROUND: Acute gastrointestinal (GI) wall defects contain a high risk of morbidity and mortality and may be closed endoscopically by a full-thickness over-the-scope clip (OTSC). METHODS: Unselected consecutive patients presenting with acute non-surgical perforations or postoperative anastomotic leaks or perforations underwent attempted OTSC placement as primary closure method after interdisciplinary consensus in three tertiary referral centres. Their clinical data and intervention characteristics were evaluated in an intention to treat analysis during a 24-month period to assess closure rates, 30-day mortality, hospitalization and comorbidity. RESULTS: In total, 34 patients (16 females, 18 males, 69.5 years) were included with 22 non-surgical perforations and 12 postoperative anastomotic leaks or perforations. Definitive closure of the perforations and leaks was achieved in 26/34 patients (76.5 %). Successful closure of the GI wall defect resulted in a significantly shorter hospital stay (8 days, p = 0.03) and was significantly correlated with comorbidity (r = 0.56, p = 0.005). In the group with OTSC failure, hospitalization was 18 days and 6 of 8 patients (75 %) required immediate surgery. Three deaths occurred in the group with successful OTSC closure due to comorbidity, while one death in the OTSC failure group was related to a refractory perforation. Favourable indications and locations for a successful OTSC procedure were identified as PEG complications, endoscopic or postoperative leaks of stomach, colon or rectum, respectively. CONCLUSIONS: In unselected patients, OTSC was effective for closure of acute GI wall defects in more than 75 % of all patients. Clinical success and short hospitalization were best achieved in patients without comorbidity, but closure of the perforation or the anastomotic leak was found to be not the only parameter relevant for patient outcome and mortality.

Plasma histamine and tumour necrosis factor-alpha levels in Crohn's disease and ulcerative colitis at various stages of disease.

Mast cells secrete numerous mediators and this study investigated plasma levels of histamine, and tumor necrosis factor alpha (TNF-α) in chronic inflammatory bowel disease (IBD). Plasma levels of histamine were determined in 68 patients with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 13 controls. TNF-α levels were assessed in 29 CD patients, 11 UC patients, and in 11 controls. Plasma histamine levels in the control group were 0.25 ng (0.14 - 0.33) and showed no difference to CD (0.19 ng, 0.09 - 0.35) or UC (0.23 ng, 0.11 - 0.60). Significantly lower histamine levels were only found in CD patients on 5-aminosalicylic acid treatment (P ≤ 0.04). Plasma TNF-α levels in the control group were significantly lower 0.44 ml/m(2) (0 - 1.15) than in CD patients (4.62 ml/m(2), 1.82 - 9.22, P = 0.005) or UC (3.14 ml/m(2); 0.08 - 11.34, P = 0.01). In CD disease activity, fistula, and extraintestinal manifestations (EM) were associated with significantly higher plasma TNF-α values, but not the type of treatment. We concluded that in contrast to TNF-α, histamine levels were normal in CD and UC. There is no correlation with histamine and thus the proportion of TNF-α secreted from mast cells in the plasma in patients with IBD is less important.

[Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options]. / Systemische Mastzellaktivierungserkrankung: Ein praxisorientierter Leitfaden zu Diagnostik und Therapie.

In the present paper clinical phenotypes, pathogenetic relationships, and diagnostic algorithms as well as therapeutic concepts of/for systemic mast cell activation disease are reviewed. The reader should be able to recognize and diagnose a systemic mast cell activation disease, as well as to counsel a personalized drug therapy. In the case of chronic multisystem polymorbidity systemic mast cell activation disease should be considered as a differential diagnosis at an early stage. In most cases, specific, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy can be initiated.

Mast cell tryptase levels in gut mucosa in patients with gastrointestinal symptoms caused by food allergy.

BACKGROUND AND AIMS: Mast cells, which are important effector cells in food allergy, require a special histologic treatment for quantification in endoscopic gastrointestinal samples. The objective of this study was to investigate whether mast cell tryptase (T), a typical mast cell-associated marker, may help to detect patients with food allergy. METHODS: Mast cell T was investigated from 289 colorectal samples of 73 controls, 302 samples from 43 patients with food allergy and gastrointestinal symptoms, and 72 samples from 12 patients with partial or complete remission of allergic symptoms. Endoscopically taken samples were immediately put into liquid nitrogen, mechanically homogenized by a micro-dismembrator with three homogenization steps and tissue T content (ng T/mg wet weight) was measured by fluoroenzyme immunoassay. RESULTS: Tissue T levels from the lower gastrointestinal tract were significantly elevated (p < 0.0001) in patients with manifest gastrointestinal allergy (median: 55.7, range: 9.3-525.0) compared with controls (median: 33.5, range: 8.0-154.6). A subgroup of 12 patients with remission of allergy showed markedly decreased symptom scores and mucosal T levels after more than 1 year of antiallergic therapy (pretreatment median: 54.1, range: 37.0-525.0 and posttreatment median: 28.4, range: 19.8-69.1; p = 0.01). CONCLUSIONS: High T levels in the gut of food-allergic patients support the role of stimulated mast cells or an increased mast cell number.

[Histamine intolerance syndrome (HIS): plethora of physiological, pathophysiological and toxic mechanisms and their differentiation]. / Histaminintoleranz-Syndrom (HIS): Vielfalt der Mechanismen von physiologischer, pathophysiologischer und toxischer Wirkung und deren Unterscheidung.

BACKGROUND: Non-immunological types of foodstuffs intolerance are reported by about 15-20% people of the population. The intolerance of histamine and to some extent of other biogenic amines (such as cadaverine, putrescine, tyramine etc.) plays an important role in the differential diagnosis of the foodstuff intolerances and has to be strictly separated from immunologically mediated foodstuffs reactions (foodstuffs allergies, 2-5% of the population). METHODS: Clinical data from the Erlangen interdisciplinary data register of allergic and chronic inflammatory gastro-intestinal diseases were analysed respecting the existence of a histamine intolerance, then classified and summarised; in addition a selective literature research was undertaken in May 2011. RESULTS: In non-immunological cases of foodstuffs intolerance, the patient's intolerance of histamine plays quite a significant role, clinically it has been exactly proven only in a small subgroup of patients by standardised blinded provocation reactions. The histamine intolerance syndrome (HIS) often presents in a non-specific manner and has to be separated from other pseudo-allergic reactions, idiopathic intolerance reactions, organic differential diagnosis (for example, chronic infections, allergies, mastocytosis etc.) as well as medicamentous adverse effects and psychosomatic reactions. CONCLUSION: The clinical picture of histamine intolerance should be definitely assured, after the exclusion of other differential diagnosis, by standardised histamine provocation. The avoidance of histamine and biogenic amines, the use of antihistaminics and the instauration of a proportionate nutrient matter are the most important therapeutic options next to a detailed education of the patient.

Analysis of immediate ex vivo release of nitric oxide from human colonic mucosa in gastrointestinally mediated allergy, inflammatory bowel disease and controls.

Nitric oxide (NO) is a local mediator in inflammation and allergy. The aim of this study was to investigate whether live incubated colorectal mucosal tissue shows a direct NO response ex vivo to nonspecific and specific immunological stimuli and whether there are disease-specific differences between allergic and chronic inflammatory bowel disease (IBD). We took biopsies (n=188) from 17 patients with confirmed gastrointestinally mediated food allergy, six patients with inflammatory bowel disease, and six control patients. To detect NO we employed an NO probe (WPI GmbH, Berlin, Germany) that upon stimulation with nonspecific toxins (ethanol, acetic acid, lipopolysaccharides), histamine (10(-8)-10(-4)M), and immune-specific stimuli (anti-IgE, anti-IgG, known food allergens) directly determined NO production during mucosal oxygenation. Non-immune stimulation of the colorectal mucosa with calcium ionophore (A23187), acetic acid, and ethanol induced a significant NO release in all groups and all biopsies. Whereas, immune-specific stimulation with allergens or anti-human IgE or -IgG antibodies did not produce significant release of NO in controls or IBD. Incubation with anti-human IgE antibodies or allergens produced a ninefold increase in histamine release in gastrointestinally mediated allergy (p<0.001), but anti-human IgE antibodies induced NO release in only 18% of the allergy patients. Histamine release in response to allergens or anti-human IgE antibodies did not correlate with NO release (r(2)=0.11, p=0.28). These data show that nonspecific calcium-dependent and toxic mechanisms induce NO release in response to a nonspecific inflammatory signal. In contrast, mechanisms underlying immune-specific stimuli do not induce NO production immediately.

[Foreign bodies in the upper gastrointestinal tract]. / Fremdkörper im oberen Gastrointestinaltrakt.

Foreign bodies in the upper GI tract are an important medical problem and cause about 5% of emergency endoscopies. Endoscopic removal is the method of the choice and is successful in 99% of cases. Nevertheless, endoscopic removal is not necessary in every case because most foreign bodies can pass through the digestive tract and be evacuated in the natural way. An immediate emergency endoscopy is indicated for foreign bodies in the esophagus with signs of obstruction, which is present in more than 75% of cases, because the risk of complications increases with retention time. The endoscopist has myriad possibilities for finding the best and safest way to extract the foreign body.

Colonoscopy-associated perforation: a 7-year survey of in-hospital frequency, treatment and outcome in a German university hospital.

AIM: Perforation occurs rarely after colonoscopy, but is associated with high morbidity and mortality. In this study, we assessed the perforation rate in our hospital, its clinical diagnosis and the long-term outcome. METHOD: During the study period, 7535 examinations were performed, of which 4830 were diagnostic and 2705 therapeutic. The latter included polypectomy, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), dilatation and argon plasma coagulation (APC). RESULTS: Overall, 25 (0.33%) perforations occurred with two (0.026%) procedure-related deaths. Seven (0.14%) perforations occurred during a diagnostic procedure and 18 (0.67%) occurred during a therapeutic procedure. Dilation, submusous resection (SMR) and APC accounted for more perforations than polypectomy or diagnostic colonoscopy. Pre-existing gastrointestinal disease was present in 24 (96%) perforations. Three (12%) patients were treated conservatively and 22 (88%) underwent surgery. The site of perforation was closed by suture in four (18%) patients and resected with colonic anastomosis in five (23%) patients. Two patients underwent endoscopic clipping. A stoma was created after resection in 13 (59%) patients. CONCLUSION: Death from perforation after colonoscopy is rare, occurring in 1/3500 examinations. The risk is increased in therapeutic colonoscopy and in the presence of previous gastrointestinal disease. Dilatation, SMR and APC appeared to confer a higher risk of perforation than polypectomy or diagnostic colonoscopy.

Small-bowel capsule endoscopy in patients with gastrointestinal food allergy.

BACKGROUND: Food allergy may present with a plethora of gastrointestinal and extraintestinal symptoms such as abdominal pain, diarrhea, cardiocirculatory symptoms, cutaneous reactions, or rhinitis. Macropathological lesions like lymphofollicular hyperplasia and erosive or ulcerative lesions have seldom been described in gastroscopy and colonoscopy previously. METHODS: Fifteen patients presenting with unspecific abdominal symptoms in which food allergy was detected in due course were included. During the examination process, those patients showed various indications for small-bowel capsule endoscopy, such as weight loss and anemia. RESULTS: Fourteen (93.3%) of the 15 small-bowel capsule endoscopies could be assessed, showing nonerosive lesions such as erythema, swelling, and lymphoid hyperplasia in 8 patients (57.1%) and erosive lesions such as aphthoid lesions, erosions, and petechiae in 4 patients (28.6%) with food allergy. CONCLUSION: In 15 patients with confirmed food allergy and after exclusion of other diseases, 12 (85.7%) showed various unspecific nonerosive or erosive mucosal lesions within the small bowel, resulting, however, partially in grave consequences such as anemia. Lymphoid hyperplasia was the most prominent finding in 7 patients (50%), albeit infectious disease had been excluded. Anemia improved within 1 year after adequate antiallergic treatment.

The measurement of leukotrienes in urine as diagnostic option in systemic mastocytosis.

Clinical symptoms of patients with mastocytosis may include skin reactions, but also gastrointestinal symptoms with hyperacidity and dysmotility (e.g. ulcer, diarrhea, pain). They are mostly caused by mediators derived from activated mast cells. In order to investigate the impact of leukotrienes on the clinical symptoms excretion of leukotriene B4 (LTB4) and leukotrienes C4-D4-E4 (cysteinyl-leukotrienes) into urine was studied in 9 patients with indolent systemic mastocytosis divided into a group with high and low intensity of symptoms and in 11 healthy volunteers. Leukotriene excretion was determined by ELISA and correlated with methylhistamine excretion. Patients with systemic mastocytosis with high and low intense symptoms showed significantly higher urinary excretion of cysteinyl-leukotrienes than controls. There was a positive correlation of cysteinyl-leukotriene excretion and urinary methylhistamine excretion. LTB4 excretion was also significantly increased in patients with systemic mastocytosis compared to healthy volunteers. No correlation of urinary LTB4 excretion with urinary methylhistamine was observed. The present study demonstrates that urinary excretion of LTB4 and cysteinyl-leukotrienes LTC4-D4-E4 is clearly enhanced in indolent systemic mastocytosis Hence, determination of leukotriene excretion into urine can be used as a tool in the diagnostic and in the therapeutic monitoring of systemic mastocytosis.

Modern enteroscopic interventions and characterization of nonmalignant postsurgical biliary anastomosis by double-balloon endoscopy.

BACKGROUND: Endoscopic access to strictured biliodigestive anastomoses often is difficult and may require percutaneous transhepatic biliary drainage or reoperation. METHODS: Push- or push-and-pull enteroscopy was used to diagnose disease and treat 24 postsurgical patients with suspected strictured biliodigestive anastomosis. Endoscopic retrograde cholangiography and biliary interventional procedures were used. Endoscopic accessibility, diagnosis of disease, therapeutic success, and complication rates were investigated at a single tertiary university gastroenterology center. RESULTS: Push enteroscopy reached biliary enteroanastomoses in 5 of the 24 patients (20.8%), whereas push-and-pull enteroscopy found choledocho- or hepaticojejunostomies in 17 of the remaining 19 postsurgical patients (89.4%). In all, successful enteroscopic intervention was achieved for 21 of the 24 patients (87.5%), whereas only 3 patients had to undergo percutaneous cholangiodrainage (12.5%). Cicatricially changed biliodigestive anastomoses were found in 14 of 21 patients (66.6%) including a mucosal type stricture in 7 patients (50%), an intramural type stricture in 5 patients (35.7%), and a ductal type stricture in 2 patients (14.2%). The remaining seven patients (33.3%) were normal. Enteroscopic interventions at strictured biliodigestive anastomosis included ostium incision for 8 (57.1%) and endoprosthesis insertion for 13 (92.8%) of the 14 patients, with prompt resolution of cholestasis and cholangitis. The major complications for the 24 patients involving 68 double-balloon enteroscopy (DBE) examinations comprised 2 perforations (8.3% per patient), 1 mild peritonitis (4.1%), and 1 cholangitis (4.1%), whereas minor complications were experienced by up to 20.8% of the patients. CONCLUSIONS: Modern interventional enteroscopy yields a high rate of successful interventions for strictured biliodigestive anastomosis, requires ostium incision for mucosal and intramural types of strictures, and helps to reduce percutaneous approaches.