Workup for eosinophilia.

With automated differentials being a common part of routine blood counts, the finding of eosinophilia is a relatively frequent occurrence. The first step in elucidating the cause is to determine the absolute eosinophil count (AEC), which is calculated from multiplying the percentage of eosinophils by the total white blood cell count. Eosinophilia is defined as an AEC of >500 eosinophils/µL, whereas hypereosinophilia is defined as an AEC of ≥1500 eosinophils/µL, a separation that is useful as an initial approach to the evaluation of such patients. Peripheral blood eosinophilia is most commonly secondary to allergies but can also be caused by certain infections, medication reactions, autoimmune diseases, or other conditions. However, hypereosinophilia is rarely, if ever, explained by allergy alone and should always prompt a further workup. A meticulous approach to exploring key aspects of the medical history is recommended for assessing increased AECs because it helps to narrow the list of possible etiologies, and treatment varies, depending on the underlying diagnosis. Special attention should be paid to the onset of eosinophilia and any coincident events, such as travel or the start of new medications. Another critical part of the history is a thorough attempt to identify any possible eosinophil-associated end-organ damage, although a biopsy of suspected involved areas is often necessary for confirmation. Because the causes of an elevated AEC are broad, determining the trigger or underlying disorder becomes an important intellectual riddle that can usually be solved with careful attention to history, physical examination, and appropriate laboratory work.

Urticaria and angioedema.

Urticaria, also known as hives, may affect up to 20% of the population at some time. Urticaria is described as pruritic erythematous, raised, circumscribed lesions with central pallor that blanch with pressure. Urticaria is closely associated with angioedema in 40% of individuals; approximately 10% of patients experience angioedema without urticaria. Urticarial lesions often are generalized, with multiple lesions in no specific distribution; angioedema tends to be localized and commonly affects the face (periorbital and perioral regions) or tongue. Urticaria is subdivided into acute and chronic urticaria based on the duration of symptoms. Acute urticaria lasts < 6 weeks, and an identifiable cause, such as food products, medications (aspirin, nonsteroidal anti-inflammatory drugs, antibiotics), or insect stings, may be discovered. Urticaria that lasts for >6 weeks is designated as chronic urticaria, and an etiology is seldom identified and thus considered spontaneous. Chronic urticaria may have an autoimmune basis. There is a well-documented association between autoimmune hypothyroidism (Hashimoto disease) and urticaria and angioedema, with a higher incidence of antithyroid (antithyroglobulin and antiperoxidase) antibodies in these patients, who are usually euthyroid. Furthermore, results of studies revealed a circulating immunoglobulin G (IgG) antibody directed against the high affinity IgE receptor alpha subunit IgE receptor (FcεRI) or IgE in 40-60% of patients with chronic urticaria. A stepwise approach to the treatment of urticarial is recommended with second-generation H1 antihistamines being the first line of therapy.

Idiopathic anaphylaxis.

Idiopathic anaphylaxis (IA) is defined as anaphylaxis without any identifiable precipitating agent or event. The clinical manifestations of IA are the same as allergen-associated (immunologic) anaphylaxis and include urticaria, angioedema, hypotension, tachycardia, wheezing, stridor, pruritus, nausea, vomiting, flushing, diarrhea, dysphagia, light-headedness, and loss of consciousness. Patients usually tend to have the same manifestations on repeated episodes. IA is a prednisone-responsive disease that is ultimately a diagnosis of exclusion. Approximately 40% of patients are atopic. Serum tryptase (or urine histamine or its metabolite) will be elevated acutely, but, if elevated in the absence of anaphylaxis, should suggest alternative diagnoses, including indolent systemic mastocytosis. A focused history, examination, and follow-up will dictate whether a patient's symptoms may be attributable to disorders that mimic anaphylaxis, such as indolent systemic mastocytosis, carcinoid syndrome, pheochromocytoma, hereditary angioedema or acquired C1 esterase inhibitor deficiency, or panic attacks. The presence of urticaria may help limit the differential diagnosis because urticaria does not usually accompany any of the above-mentioned disorders, except for indolent systemic mastocytosis. IA is classified according to the symptoms as well as the frequency of attacks. Patients who experience six or more episodes in a year, or two or more episodes in 2 months are classified as having IA-frequent (IA-F). Patients who experience fewer episodes are classified as having IA-infrequent (IA-I). This distinction is important because patients with IA-F will initially require prednisone as disease-modifying therapy, whereas most patients who with IA-I will not require prednisone. Patients with IA must carry and know when and how to self-administer epinephrine.

Dermal ß-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation.

Dermal fibroblasts are required for structural integrity of the skin and for hair follicle development. Uniform Wnt signaling activity is present in dermal fibroblast precursors preceding hair follicle initiation, but the functional requirement of dermal Wnt signaling at early stages of skin differentiation and patterning remains largely uncharacterized. We show in mice that epidermal Wnt ligands are required for uniform dermal Wnt signaling/ß-catenin activity and regulate fibroblast cell proliferation and initiation of hair follicle placodes. In the absence of dermal Wnt signaling/ß-catenin activity, patterned upregulation of epidermal ß-catenin activity and Edar expression are absent. Conversely, forced activation of ß-catenin signaling leads to the formation of thickened dermis, enlarged epidermal placodes and dermal condensates that result in prematurely differentiated enlarged hair follicles. These data reveal functional roles for dermal Wnt signaling/ß-catenin in fibroblast proliferation and in the epidermal hair follicle initiation program.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

Allergy/Immunology Trainee Experiences During the COVID-19 Pandemic: AAAAI Work Group Report of the Fellows-in-Training Committee.

As a result of the coronavirus disease 2019 (COVID-19) global pandemic, medical trainees have faced unique challenges and uncertainties. To capture the experiences of allergy and immunology fellows throughout the United States and Canada during this time, a 17-item electronic questionnaire was distributed to 380 fellow-in-training (FIT) members of the American Academy of Allergy, Asthma, and Immunology enrolled in US and Canadian allergy/immunology fellowship programs. Voluntary and anonymous responses were collected from April 15 to May 15, 2020. In addition to summary statistics, categorical data were compared using χ2 tests (Fisher's exact). Responses were obtained from FITs across all years of training and primary specialties (Internal Medicine, Pediatrics, and Medicine-Pediatrics) with a response rate of 32.6% (124 of 380). Reassignment to COVID-19 clinical responsibilities was reported by 12% (15 of 124) of FITs, with the largest proportion in the US northeast region. A majority of FITs used telehealth (95%) and virtual learning (82%) during the pandemic. Overall, 21% (25 of 120) of FITs expressed concern about potentially lacking clinical experience for independently practicing allergy and immunology. However, FITs using telehealth reported lower concern compared with those who did not (18.4% [21 of 114] vs 66.7% [4 of 6]; P = .01). The survey shows that allergy and immunology trainee experiences have varied considerably since the COVID-19 outbreak. Notably, the adoption of telehealth and virtual learning was commonly reported, and optimization of these virtual experiences will be helpful. Even outside of pandemics, training on the use of telemedicine may be a sound strategy in preparation for future health care delivery and unexpected events.

Clinical presentation, pathophysiology, diagnosis, and treatment of acquired and hereditary angioedema: Exploring state-of-the-art therapies in RI.

Hereditary and acquired angioedema are potentially life-threatening diseases characterized by spontaneous episodes of subcutaneous and submucosal swelling of face, lips, oral cavity, larynx, and GI tract. Hereditary angioedema (HAE) usually presents within the first and second decades of life, whereas acquired angioedema presents in adults after 40 years of age. These clinical symptoms together with reduced C1 inhibitor levels and/or activity can usually confirm the diagnosis. In recent years, multiple novel therapies for treating hereditary angioedema have emerged including C1 inhibitor concentrates, ecallantide/kallikrein inhibitor, and icatibant/bradykinin receptor antagonist. This article reviews the clinical presentation, diagnosis, treatment, and prophylaxis of HAE. Lastly, this article takes into consideration that, in reality, acute care treatment can often be limited by each hospital's formulary, included is a review of HAE treatments available at the nine major hospitals in Rhode Island. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login].

Improving the detection of fungi in eosinophilic mucin: seeing what we could not see before.

OBJECTIVE: To investigate the improvement in histologic detection of fungi with Gomori methenamine silver (GMS) stain by trypsin predigestion in the mucus of patients with chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective, single group, descriptive analysis. SETTING: Multi-institutional. SUBJECTS AND METHODS: Thirty-four sinus specimens from 12 surgical patients with CRS were stained with hematoxylin and eosin, GMS stain, GMS with trypsin digestion, immunofluorescence stains for chitinase, and anti-Alternaria. All patients received skin testing, total IgE serology, and radioallergosorbent tests (RAST) for 23 fungal-specific IgE antibodies. RESULTS: The conventional GMS stain detected fungi in only 9 of 34 (27%) specimens. Predigesting the specimen with trypsin dramatically improved the visualization of fungi (31/34, 91%). The chitinase immunofluorescence visualized fungi in 32 of 34 (94%), and anti-Alternaria visualized 33 of 34 specimens (97%). Only 8 of 12 (75%) patients had detectable allergies. CONCLUSIONS: This report describes a simple modification of the conventional GMS stain that can significantly improve the visualization of fungi on histology and explains the lack of detection in previous studies. These novel, more sensitive histologic methods reveal the presence of fungi within the eosinophilic mucin in allergic and also nonallergic CRS patients, further questioning a crucial role of an IgE-mediated pathophysiology.