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Histopathologic analysis of biopsy specimens obtained via white light endoscopy (WLE) is the gold standard for the diagnosis of several mucosal diseases in the upper gastrointestinal (GI) tract. However, this standard of care entails a series of critical shortcomings such as missing depth information, high costs, time inefficiency, low-resolution imaging in vivo, high sampling variability, missing intrinsic tissue-specific contrast, and anesthesia related risk. In the quest for a diagnostic technology to replace the current standard of care, in vivo optical endomicroscopy has emerged as a promising alternative. This paper tells the story of a cluster of optical microscopy-based modalities invented, further developed, or first-validated in the laboratory of Dr. Guillermo J. Tearney (Tearney Lab) at the Wellman Center for Photomedicine of Massachusetts General Hospital over the past two decades, that combined lead to a novel method for diagnosis of eosinophilic esophagitis (EoE). Rather than being a comprehensive literature review, this paper aims to describe the translational journey towards a disease specific diagnostic and research tool for this increasingly recognized yet poorly understood immune-mediated disorder of the esophagus.

Background Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots. Objective We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019). Methods TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated. Results NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment. Conclusions Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naive T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naive T-cell phenotyping as part of follow-up flow cytometry.

A 9-day-old girl was admitted to this hospital because of vomiting, decreased oral intake, and decreased activity. On examination, she appeared to be dehydrated; laboratory evaluation revealed metabolic acidosis and azotemia. A diagnosis was made.

Although almond specific IgE-mediated food allergies have traditionally been equated with other tree nut allergies, outcomes of oral food challenges to almond and the utility of clinical testing to predict IgE-mediated almond hypersensitivity are not well known.To describe almond oral challenge outcomes and assess the predictive value of clinical testing.A total of 603 almond challenges performed for 590 patients, aged 1 to 66 years, were analyzed from Massachusetts General Hospital allergy practices. Reactions were graded using the Niggemann and Beyer allergic reaction grading system and the Sampson 2006 National Institute of Allergy and Infectious Diseases anaphylaxis definition.Almond challenges included 545 passes (92%), 15 (3%) indeterminates, and 30 (5%) failures, in contrast with 31% challenge failures for other foods. Most reactions were mild; 21 (4%) had grade 2/3 allergic symptoms, and 3 (0.5%) had anaphylaxis. Median almond specific IgE level was 0.89 kU/L (range,0.35 to100 kU/L), median skin prick test wheal diameter was 4.0 mm (range, 0-28 mm), and 475 subjects (81%) were sensitized to almond. Failure was associated with higher almond specific IgE level (P.001), larger almond skin prick test wheal diameter (P = .001), higher peanut IgE level (P = .003), and a history of almond reaction (P.029). Almond specific IgE level, almond skin prick test wheal diameter, and age at challenge combined demonstrated good predictive value for grade 2/3 allergic reactions by receiver-operating characteristic analysis (area under the curve, 0.83).The proportion of failed almond challenges (5%) was low in contrast with other allergens, suggesting that some almond challenges may be safely conducted with higher patient-to-staff ratios or potentially introduced at home. Although reactions are usually uncommon and mild, anaphylaxis is possible with high almond sensitization.

The causes of angioedema are not well described, especially in the inpatient setting. The purpose of this study was to examine the causes of moderate to severe angioedema in patients requiring inpatient treatment. We performed a retrospective review in patients requiring inpatient consultation by the Division of Allergy and Immunology at our institution between 1995 and 2004. We focused on potential interactions among medications that elicited life-threatening angioedema requiring intubation. The allergy/immunology service was consulted on 69 patients with moderate to severe angioedema. Medications were the most common cause of angioedema (n = 64, 93%). In most cases (n = 46, 67%), the angioedema was attributed to two or more medications. Patients previously stable on ACE inhibitors (ACEI), aspirin (ASA), or non-steroidal anti-inflammatory drugs (NSAIDs) appeared more likely to develop angioedema soon after the addition of another drug (i.e., ACEI, ASA/NSAIDs, direct mast cell degranulators, and antibiotics). ACEI, ASA/NSAID, and direct mast cell degranulators were contributing causes in 36 patients (56%), 45 patients (70%), and 23 patients (36%), respectively. Twenty patients required intubation, 14 (70%) patients were on ACEI, 12 (60%) patients were on ASA/NSAID, and 7 (35%) patients were on direct mast cell degranulators. ACEI, ASA/NSAID, or direct mast cell degranulators were a cause in 95% (n = 19) of patients requiring intubation. The combination of ACEI and ASA/NSAID was the most frequent cause of angioedema among all patients (n = 17, 25%) and those requiring intubation (n = 8, 40%). Moderate to severe angioedema often is a result of interactions between two or more medications involved in different pathways causing angioedema. In particular, combinations of ACEI, ASA/NSAID, or direct mast cell degranulators may lead to life-threatening angioedema requiring intubation.

Background Eosinophilic esophagitis (EoE) is a chronic, immunemediated disease of eosinophil-predominant inflammation and esophageal dysfunction. The Pediatric Quality of Life Inventory 3.0 EoE Module is a validated instrument to measure quality of life (QL) in children ages 2-18 with EoE, but no clinical research studies have been published using this survey. The objectives of this study were to compare QL reported by patients with EoE to that reported by their parents, and to determine which factors predicted QL in this cohort.

Background One half to one third of the patients with eosinophilic esophagitis (EoE) do not achieve histological remission on initial treatment. We wondered whether these treatment failure patients are a distinct clinical subset. Objective To analyze EoE treatment outcomes in a predominantly pediatric population. Methods We reviewed 100 serial EoE cases at Massachusetts General Hospital starting from 2007. We defined histological remission as peak esophageal eosinophil count of less than 10/hpf. Results Ninety-seven patients with EoE underwent initial treatments: 54 of 81 (67%) responded to dietary therapy, and 9 of 16 (56%) responded to topical glucocorticoids. Of the 34 who failed initial treatment, 24 underwent various second treatment regimens and 54% (13 of 24) responded. Eight of the remaining 11 who failed second treatment underwent additional treatments and 2 ultimately responded. The overall response rate by intent-to-treat analysis increased from 65% (63 of 97) with initial treatment to 78% (76 of 97) with rescue treatment, and further to 80% (78 of 97) with multiple treatments. On a per-protocol basis, the overall response rate was 93% (78 of 84); however, patients who failed the first 2 rounds of therapy had only a 20% response rate. Patients who responded to initial treatment were found to have more symptoms and endoscopic abnormalities. Comparison of patients who failed both initial and rescue therapy with those who responded to rescue therapy did not identify any differentiating clinical features. Conclusions More than half of the patients who failed initial EoE treatment could still achieve histological remission with individualized rescue treatments. No clinical features could predict response to rescue treatment.

BACKGROUND & AIMS: Integrins play diverse roles in cellular actions and signalling in the immune system. In the context of mucosal immune responses, the integrin alpha 4 beta 7 has received particular attention because of its intimate involvement in lymphocyte recruitment to normal gastrointestinal mucosa and associated lymphoid tissue. The aim of this study was to determine the functional relevance of alpha 4 beta 7 in the pathogenesis of colonic inflammatory disease using the colitic cotton-top tamarin, an animal model of human ulcerative colitis. METHODS: Chronically colitic cotton-top tamarins were given either a cross-reactive monoclonal antibody to human alpha 4 beta 7 or an irrelevant control monoclonal antibody. The animals were then evaluated clinically and mucosal biopsy specimens assessed by histological and quantitative morphometric analysis. RESULTS: A blocking monoclonal antibody to alpha 4 beta 7 integrin ameliorated inflammatory activity and rapidly improved stool consistency when administered to chronically colitic animals. Furthermore, using morphometric analysis of biopsy specimens, antibody therapy reduced the mucosal density of alpha 4 beta 7+ lymphocytes and alpha 4 beta 7 neutrophils and macrophages. CONCLUSIONS: These results suggest that the alpha 4 beta 7 integrin represents a novel, potentially organ- specific therapeutic target for the treatment of inflammatory bowel disease. (Gastroenterology 1996 Nov;111(5):1373-80)

The behavioral effects of selective D1 and D2, nonselective, and indirectly acting dopamine agonists were compared in squirrel monkeys using continuous observation procedures. D1 agonists including SKF 81297, SKF 82958, and R(+)-6-Br-APB produced dose-dependent increases in the frequencies of stationary postures and head movements and had little or no effect on either huddling or scratching. In contrast, SKF 75670 and R-SKF 38393, which are considered to be D1 partial agonists, had effects comparable to those of the D1 antagonist SCH 39166. That is, the D1 partial agonists increased the duration of huddling without greatly altering the frequencies of stationary postures, head movements, or scratching. Unlike the D1 agonists, the D2 agonists (+)-PHNO, quinpirole, and bromocriptine increased the frequency of scratching, but did not consistently alter other observable behaviors. The indirect dopamine agonists cocaine, GBR 12909, and d-amphetamine and the nonselective D1/D2 agonist CY 208-243, but not (-)apomorphine, had effects comparable to those of D1 agonists such as SKF 81297. That is, each of these drugs increased the frequencies of stationary postures and head movements with little or no effect on scratching or huddling. Additionally, effects of the D1 agonist SKF 82958 and the indirect dopamine agonist cocaine were surmountably antagonized by the D1 antagonist SCH 39166. The present results show that: 1) behavioral effects of D1 and D2 agonists in monkeys are qualitatively different; 2) D1 agonists presumed to differ in intrinsic activity have dissimilar effects; and 3) effects of indirect dopamine agonists are comparable to those of D1 agonists with presumably high intrinsic activity.

Management of patients with carboplatin-induced hypersensitivity reactions (HSR) has been complicated by high false-negative rates of carboplatin skin test (ST) results. These patients might be at risk for future carboplatin-induced HSRs. In this article we identify a strategy to improve risk stratification of patients with a history of carboplatin-induced HSRs by using a protocol that includes repeat skin testing and drug desensitization.We sought to identify a management strategy for patients with a history of carboplatin-induced HSRs with negative carboplatin ST results.From 2008-2010, patients with carboplatin-induced HSR underwent risk stratification per a protocol using 3 repeat STs with intervening drug desensitizations.Of the 44 patients with carboplatin-induced HSRs, 39 completed the protocol. Patients were classified as having positive ST results (n = 16), having negative ST results (n = 11), or ST converters when the ST result converted to positive after an initial negative result (n = 12). ST converters are more likely to have HSRs during subsequent desensitizations than patients with negative ST results (56.1% vs 4.5%, P .001). ST converters had a significantly longer time interval between their initial HSR and initial ST evaluation compared with either patients with true-negative ST results (22.1 vs 6.0 months, P = .03) or patients with positive ST results (22.1 vs 1.8 months, P = .001).Our experience suggests that repeat STs are necessary for risk stratification in patients with a remote clinical history of HSR and an initial negative ST result because there is a significant rate of conversion to a positive ST result. ST converters have an increased risk of HSRs during subsequent carboplatin treatment.

Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for desensitization is uncertain.To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin desensitization.Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 desensitizations to carboplatin.Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR (3 months), 20 of 24 (83%) tested positive, whereas 5 of 14 (36%) with remote HSR (9 months) tested positive (P.01). Nineteen carboplatin ST+ and 11 ST- patients underwent desensitization to carboplatin. Seven ST+ patients (37%) had mild HSR during desensitization but completed the desensitization with additional treatment or protocol modification. ST- patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST- with repeated testing. Six of 8 ST- patients (75%) with remote HSR reacted during desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST+ before the second desensitization. Carboplatin desensitization was successfully completed in 105 of 106 (99%) treatment courses.The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent desensitization. Initial ST- patients with a remote history of HSR are at high risk for conversion to ST+ and can develop more severe HSR.

INTRODUCTION: Repeated esophagogastroduodenoscopies (EGDs) are required to identify food trigger(s) in patients with eosinophilic esophagitis (EoE) treated with dietary therapy. However, there is limited data on the safety of repeated endoscopic procedures in these patients. OBJECTIVE: To evaluate the safety of serial EGDs in EoE patients undergoing dietary treatment. METHODS: A literature review and an analysis of our internal database were conducted to determine the safety of EGDs in identifying food trigger(s) in EoE. Using Pubmed database, a systematic search was performed for published articles since 1977 with a combination of keywords "eosinophilic esophagitis", "diagnostic endoscopy", "endoscopy", "esophagogastroduodenoscopies", "safety", "complications", and "clinical outcome". Reports studying dietary treatment for EoE were included for the analysis if the presence or absence of EGD complications was reported. Furthermore, we retrospectively reviewed the medical and endoscopy records of all the EoE patients who underwent dietary therapy at Massachusetts General Hospital Food Allergy Center (MGH FAC) from 2010-2013. Diagnosis of EoE was defined as 1 or more biopsies showing >15 eosinophils/hpf after at least 6 weeks of high dose proton pump inhibitor. RESULTS: Our literature search identified 408 references, of which 5 were included in the final analysis. Four are retrospective studies while one is prospective. Only one article explicitly reported the average number EGD per patient (5.6, n = 39, JPGN 2011;53: 145-149). At MGH FAC, 81 EoE patients underwent an average of 7.1 EGDs/patient to identify food trigger(s). From our dataset and the selected articles, there were a total of 542 EoE patients (71.0% male, mean age of 11.9 ± 10.7) who underwent diagnostic EGDs for dietary treatment. Three studies described clinical outcomes of serial food reintroduction to identify food trigger(s) and the overall success rate for identification of a trigger food was 96%. There were no EGD-associated complications in all five published studies and in our institution. DISCUSSION: Serial EGDs are safe and effective in identifying food trigger(s) in EoE.