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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.

Eosinophilic Esophagitis (EoE) is an inflammatory disease caused by inhaled or ingested food allergies, and characterized by the infiltration of eosinophils in the esophagus. The gold standard for diagnosing EoE is to conduct endoscopy and obtain multiple biopsy specimens from different portions of the esophagus; an exam is considered positive if more than 15 eosinophils per high power field (HPF) in any of the biopsies. This method of diagnosis is problematic because endoscopic biopsy is expensive and poorly tolerated and the esophageal eosinophil burden needs to be monitored frequently during the course of the disease. Spectrally encoded confocal microscopy (SECM) is a high-speed confocal microscopy technology that can visualize individual eosinophils in large microscopic images of the human esophagus, equivalent to more than 30,000 HPF. Previously, we have demonstrated that tethered capsule SECM can be conducted in unsedated subjects with diagnosed EoE. However, speckle noise and the relatively low resolution in images obtained with the first capsule prototypes made it challenging to distinguish eosinophils from other cells. In this work, we present a next-generation tethered SECM capsule, which has been modified to significantly improve image quality. First, we substituted the single mode fiber with a dual-clad fiber to reduce speckle noise. A gradient-index multimode fiber was fusion spliced at the tip of the dual-clad fiber to increase the effective numerical aperture of the fiber from 0.09 to 0.15, expanding the beam more rapidly to increase the illumination aperture at the objective. These modifications enabled the new SECM capsule to achieve a lateral resolution of 1.8 µm and an axial resolution of 16.1 µm, which substantially improves the capacity of this probe to visualize cellular features in human tissue. The total size of the SECM capsule remained 6.75 mm in diameter and 31 mm in length. We are now in the process of testing this new SECM capsule in humans. Early results using this new SECM capsule suggest that this technology has the potential to be an effective tool for the diagnosis of EoE.

Eosinophilic Esophagitis (EoE) is caused by food allergies, and defined by histological presence of eosinophil cells in the esophagus. The current gold standard for EoE diagnosis is endoscopy with pinch biopsy to detect more than 15 eosinophils/ High power field (HPF). Biopsy examinations are expensive, time consuming and are difficult to tolerate for patients. Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technology capable of imaging individual eosinophils as highly scattering cells (diameter between 8 µm to 15 µm) in the epithelium. Our lab has developed a tethered SECM capsule that can be swallowed by unsedated patients. The capsule acquires large area confocal images, equivalent to more than 30,000 HPFs, as it traverses through the esophagus. In this paper, we present the outcome of a clinical study using the tethered SECM capsule for diagnosing EoE. To date, 32 subjects have been enrolled in this study. 88% of the subjects swallowed the capsules without difficulty and of those who swallowed the capsule, 95% preferred the tethered capsule imaging procedure to sedated endoscopic biopsy. Each imaging session took about 12 ± 2.4 minutes during which 8 images each spanning of 24 ± 5 cm2 of the esophagus were acquired. SECM images acquired from EoE patients showed abundant eosinophils as highly scattering cells in squamous epithelium. Results from this study suggest that the SECM capsule has the potential to become a less-invasive, cost-effective tool for diagnosing EoE and monitoring the response of this disease to therapy.

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.

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)

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.

Drug desensitization is the process of safely administering a needed medication to a drug-allergic individual. The procedure involves the cautious administration of incremental doses of the drug over a period of hours to days and it is used primarily in the management of IgE-mediated drug hypersensitivity reactions. Desensitization has also safely been used for drug hypersensitivity reactions that result in mast cell degranulation that are not IgE-mediated. Desensitization is antigen-specific or drug-specific and is sustained only as long as the drug is continuously administered. The recommendation for drug desensitization should be made along with an Allergy and Immunology specialist.

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.