Paul E. Hesterberg

Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.

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.

Risk stratification for desensitization of patients with carboplatin hypersensitivity: Clinical presentation and management

BACKGROUND Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for desensitization is uncertain. OBJECTIVES 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. METHODS Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 desensitizations to carboplatin. RESULTS 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. CONCLUSIONS 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.

Observational studies of dopamine D1 and D2 agonists in squirrel monkeys

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, andR(+)-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 andR-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, andd-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.

Ten-year study of causes of moderate to severe angioedema seen by an inpatient allergy/immunology consult service

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.

Longitudinal Perspective on Managing Refractory Eosinophilic Esophagitis

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.

Drug Desensitizations in the Management of Allergy and Anaphylaxis to Chemotherapeutic Agents and Monoclonal Antibodies

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.

Clinical Translation of Tethered Confocal Microscopy Capsule for Unsedated Diagnosis of Eosinophilic Esophagitis

Esophagogastroduodenoscopy (EGD) is a widely used procedure, posing significant financial burden on both healthcare systems and patients. Moreover, EGD is time consuming, sometimes difficult to tolerate, and suffers from an imperfect diagnostic yield as the limited number of collected biopsies does not represent the whole organ. In this paper, we report on technological and clinical feasibility of a swallowable tethered endomicroscopy capsule, which is administered without sedation, to image large regions of esophageal and gastric mucosa at the cellular level. To demonstrate imaging capabilities, we conducted a human pilot study (n = 17) on Eosinophilic Esophagitis (EoE) patients and healthy volunteers from which representative cases are presented and discussed. Results indicate that, compared to endoscopic biopsy, unsedated tethered capsule endomicroscopy obtains orders of magnitude more cellular information while successfully resolving characteristic tissue microscopic features such as stratified squamous epithelium, lamina propria papillae, intraepithelial eosinophils, and gastric cardia and body/fundic mucosa epithelia. Based on the major import of whole organ, cellular-level microscopy to obviate sampling error and the clear cost and convenience advantages of unsedated procedure, we believe that this tool has the potential to become a simpler and more effective device for diagnosing and monitoring the therapeutic response of EoE and other esophageal diseases.

Case 23-2017

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.

Tethered SECM endoscopic capsule for the diagnosis of eosinophilic esophagitis (Conference Presentation)

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.

Clinical experience using the tethered capsule-based spectrally encoded confocal microendoscopy for diagnosis of eosinophilic esophagitis(Conference Presentation)

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.