Pearls and pitfalls in food protein-induced enterocolitis syndrome (FPIES).

Background: Food protein-induced enterocolitis syndrome (FPIES) is a rare, non-immunoglobulin E (IgE) mediated gastrointestinal food hypersensitivity. It is a clinical diagnosis commonly characterized by profuse vomiting 1 to 4 hours after ingestion of the triggering food(s). Objective: The objective was to increase awareness of FPIES and review the epidemiology, clinical presentation, pathogenesis, diagnosis, and management of FPIES. The lack of availability of a definite biomarker or diagnostic tool often leads to a delay in diagnosis. Methods: A literature search of salient articles that described case reports and case series of FPIES and their management were analyzed. Results: A case of FPIES with a literature review is presented with emphasis on clinical pearls and pitfalls. FPIES is a diagnosis of exclusion and the mainstay of treatment is avoidance of the trigger food(s) for at least 12-18 months from the last exposure. Conclusion: As FPIES is a non-IgE-mediated reaction, allergy testing via skin-prick test or blood tests to measure food IgE antibodies is not routinely recommended. Many children outgrow FPIES by 3-4 years of age. Supervised oral food challenge is recommended to assess acquisition of tolerance.

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. METHODS: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). RESULTS: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. CONCLUSION: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. CLINICAL IMPLICATIONS: HCT is a definitive cure for DADA2 with > 95% survival.

The immunologic response to severe acute respiratory syndrome coronavirus 2.

Background: The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has precipitated the worst global pandemic in a century, which has caused millions of infections and deaths as well as massive economic repercussions. Objective: As with any pathogenic virus, it is crucial to understand its unique interactions with the human immune system so that pharmaceutical and prophylactic interventions can be deployed to effectively control the pandemic. Methods: A literature search by using PubMed was conducted in 2020 with variants of the terms "COVID-19," "SARS-CoV-2," and "immunological response." English language articles that presented original data about the immunologic response to coronavirus disease 2019 (COVID-19) were selected for review. This article reviewed the current understanding of the innate and adaptive immune responses to SARS-CoV-2 infection, including their relationship to current therapeutic and diagnostic strategies. Results: SARS-CoV-2 uses several unique molecular techniques to evade detection by the innate immune system early in the course of infection, and upregulation of these innate immune pathways may possibly accelerate the time to recovery and prevent severe disease. Although the majority of cases results in the patients' recovery, a significant proportion of infections result in deaths prompted by the host's inflammatory overreaction to the infection, a response that can be attenuated with corticosteroids and potentially other immune modulators. Conclusion: Current work by the scientific community to further understand how SARS-CoV-2 interacts with the human immune system will be invaluable to our response and preparedness for future coronavirus pandemics.

Etoposide phosphate for pediatric orthopedic malignancies after intravenous etoposide hypersensitivity.

BACKGROUND: Hypersensitivity reactions to etoposide have been reported and patients have been safely transitioned to etoposide phosphate for continued therapy. However, the safety and efficacy of substituting etoposide phosphate for etoposide has not been well established in pediatric orthopedic malignancies. The aim of this study is to determine whether etoposide phosphate can be substituted for etoposide in pediatric orthopedic malignancies. METHODS: A chart review of pediatric patients who developed hypersensitivity reactions to etoposide while being treated for orthopedic malignancies was performed at a large academic medical center. Three patients were identified, two with Ewing sarcoma and one with an osteosarcoma. All three patients experienced hypersensitivity reactions to their first doses of etoposide and were switched to etoposide phosphate for further therapy. RESULTS: After premedication, all three patients tolerated full doses of etoposide phosphate without a graded dose challenge or desensitization. Two of the patients were premedicated with diphenhydramine alone, while the third received diphenhydramine and dexamethasone. CONCLUSIONS: Etoposide phosphate is a potentially safe alternative for pediatric patients with orthopedic malignancies who experience etoposide hypersensitivity. However, caution is needed as there are cases of etoposide phosphate hypersensitivity.

Clinical presentation of hereditary angioedema.

Hereditary angioedema (HAE) is a rare, autosomal dominant disease caused by a deficiency in the C1-inhibitor protein. It is characterized by recurrent episodes of nonpruritic, nonpitting, subcutaneous or submucosal edema that typically involves the extremities or the gastrointestinal tract. However, the genitourinary tract, face, oropharynx, and/or larynx may be affected as well. Symptoms often begin in childhood, worsen at puberty, and persist throughout life, with unpredictable severity. Patients who are untreated may have frequent attacks, with intervals that can range from every few days to rare episodes. Minor trauma and stress are frequent precipitants of swelling episodes, but many attacks occur without clear triggers. HAE attacks may be preceded by a prodrome and/or be accompanied by erythema marginatum. The swelling typically worsens over the first 24 hours, before gradually subsiding over the subsequent 48 to 72 hours. Although oropharyngeal swelling is less frequent, more than half of patients have had at least one episode of laryngeal angioedema during their lifetime. Attacks may start in one location and spread to another before resolving. HAE attacks that involve the abdomen or oropharynx have been associated with significant morbidity and mortality. Abdominal attacks can cause severe abdominal pain, nausea, and vomiting. Bowel sounds are often diminished or silent, and guarding and rebound tenderness may be present on physical examination. These findings may lead to unnecessary abdominal imaging and procedures. Fluid shifts into the interstitial space or peritoneal cavity can cause clinically significant hypotension. Laryngeal edema poses the greatest risk for patients with HAE. Although prompt diagnosis and treatment improves outcomes, the variable presentation of HAE can make it difficult to diagnose.

A 79-year-old man with persistent eosinophilia and elevated immunoglobulin E.

The differential diagnoses for eosinophilia include allergic, infectious, autoimmune, and neoplastic diseases. We presented the case of a 79-year-old man with eosinophilia and elevated immunoglobulin E that persisted despite adequate treatment for possible environmental exposures. Further specialized testing based on his initial workup led to his diagnosis. This case highlights the importance of sequential and targeted testing to evaluate for rare causes of eosinophilia.

Idiopathic CD4 lymphocytopenia.

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a rare disorder of unknown etiology. Diagnostic criteria include a persistent CD4 T-cell lymphopenia with no underlying primary or secondary immune deficiencies and a CD4 T-cell count of 300 cells/mL or 20% total lymphocyte on multiple occasions. OBJECTIVE: To increase awareness of ICL and to provide a review of the clinical characteristics, diagnosis, and management of this disease process. Presently, many of these patients receive prophylactic treatment similar to other T-cell deficient conditions, most notably patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome; however, the same indications may not necessarily apply to this patient population because the T cells are not affected by a virus as in HIV. METHODS: A literature search of salient articles that describe case reports and case series of ICL and their management were analyzed. RESULTS: A case of ICL with a literature review is presented with emphasis on clinical pearls and pitfalls. The patients with ICL are usually identified with a CD4 count of 200 cells/mL when complications develop. Opportunistic infections are the most common initial manifestations. Current therapies used to increase CD4 levels include interleukin 2, interferon gamma, interleukin 7, and allogeneic hematopoietic stem cell transplantation, with variable results. CONCLUSION: ICL is a diagnosis of exclusion when there is no identifiable underlying cause for a low CD4 count. Although the nature of the T-cell problem is not the same in ICL and HIV, in the absence of specific guidelines, patients receive the same prophylactic treatment as patients with HIV.

A 73-year-old woman with persistent diarrhea and onychomycosis.

We present a case of a 73-year-old woman who presented with chronic watery diarrhea, weight loss, and frequent sinus and nail fungal infections. Her previous workup with a gastroenterologist failed to reveal any causative agent for her symptoms. She considered herself healthy until a thymic tumor was discovered and removed years ago. Subsequently, she developed multiple sinus infections refractory to treatment. Relevant immunology laboratory tests were conducted, which led to the diagnosis. This case illustrated the need for a detailed history and thorough immunologic assessment, and the requirement to maintain a broad differential diagnosis.

Case Report: Insulin hypersensitivity in youth with type 1 diabetes.

Objective: Immediate type I, type III, and delayed type IV hypersensitivity reactions to insulin are rare, but potentially serious complications of exogenous insulin administration required for the treatment of type 1 diabetes (T1D). Methods: We present four cases of insulin hypersensitivity reactions occurring in youth with T1D and a literature review of this topic. Results: Insulin hypersensitivity reactions included types I, III, and IV with presentations ranging from localized urticaria, erythematous nodules, and eczematous plaques to anaphylaxis with respiratory distress. Reactions occurred in youth with newly diagnosed T1D and in those with long-standing T1D who were using both injection and insulin pump therapy. Multidisciplinary care involving pediatric endocrinology and allergy/immunology utilizing trials of many adjunct therapies yielded minimal improvement. Despite the use of various treatments, including antihistamines, topical therapies, immunosuppressant medications, desensitization trials, and intravenous immune globulin, cutaneous reactions, elevated hemoglobin A1c levels, and negative effects on quality of life remain persistent challenges. One patient became one of the youngest pancreas transplant recipients in the world at age 12 years due to uncontrollable symptoms and intolerable adverse effects of attempted therapies. Conclusion: Although rare, insulin hypersensitivity reactions negatively affect glycemic control and quality of life. These cases demonstrate the varying severity and presentation of insulin hypersensitivity reactions along with the limited success of various treatment approaches. Given the life-sustaining nature of insulin therapy, further studies are needed to better understand the underlying pathophysiology of insulin hypersensitivity and to develop targeted treatment approaches.

The Future of Telehealth in Allergy and Immunology Training.

With emerging interest in the use of telemedicine, allergy-immunology should be at the forefront of adoption and implementation of these services. Patients report a greater desire for telemedicine services as well as satisfaction with video-based visits with their providers. Interim virtual visits can accommodate overscheduled clinics, reduce burdens of travel to distant sites, improve access to subspecialty care, and increase adherence during monitoring of chronic allergic conditions. The outpatient nature of allergy-immunology coupled with the ease of conducting many aspects of a routine visit via telemedicine makes the incorporation of telehealth training into fellowship programs highly desirable. The short-term closure of hospital-affiliated clinics, in particular, for vulnerable or immunodeficient patients, in the setting of a global pandemic demonstrates the timeliness of this topic. A framework for implementing telemedicine into the allergy-immunology curriculum, training faculty on appropriate supervision, providing elective clinical experience in the form of continuity clinics, and simulating telemedicine delivery is discussed. Proposed telemedicine competencies desired for the independent practice of telemedicine are suggested.

Experience with Intravenous Plasma-Derived C1-Inhibitor in Pregnant Women with Hereditary Angioedema: A Systematic Literature Review.

Consensus guidelines recommend plasma-derived C1 inhibitor (C1-INH) as first-line treatment in pregnant women with hereditary angioedema (HAE). We conducted a systematic review of the literature that describes experience with plasma-derived C1-INH during pregnancy. A literature search of PubMed was conducted in November 2018 using variants of "hereditary angioedema" and "pregnancy." English language articles that presented original data about the use of plasma-derived C1-INH during pregnancy were selected for data extraction. The search returned 253 unique records, of which 40 described the use of C1-INH during pregnancy (91 patients, 136 pregnancies). When the number of doses was reported, a total of 1562 doses were administered ranging from 500 to 3000 IU. Infusions were administered during all 3 trimesters and were most commonly administered during the third trimester. Overall, 1,490,500 IU of plasma-derived C1-INH were administered during pregnancy. Of the 128 fetuses for which outcomes were reported, 3 (2%) resulted in spontaneous abortion, 1 (1%) was stillborn, and 1 (1%) was a vanishing twin. Use of plasma-derived C1-INH in women with HAE during pregnancy has been widely reported in the scientific literature and has a favorable safety profile, supporting treatment guideline recommendations.

Long-term efficacy and safety of subcutaneous C1-inhibitor in women with hereditary angioedema: subgroup analysis from an open-label extension of a phase 3 trial.

BACKGROUND: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial. METHODS: In this multicenter, randomized, parallel-arm trial, eligible subjects (age ≥ 6 years with ≥ 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age ≥ 15 to ≤ 45 years), including subjects who became pregnant during the evaluation period. RESULTS: Overall, 91% (69/76) of female subjects were classified as responders (≥ 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities. CONCLUSIONS: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies.Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353.