Preparing the Allergist/Immunologist for the Next Pandemic.

The COVID-19 pandemic had a profound impact on society in general and allergists' practices in particular. The adverse effects included a loss of practice productivity and income, staffing, and in-office procedures due to concerns about the spread of infection and the need for social/physical distancing as well as isolation. Allergy training programs and research activities also suffered. Federal financial assistance, rapid adoption of telehealth with Medicare waivers, and adaptation of practice sites, training programs, and research activities allowed for some return to normal, although still with significant restrictions in staffing and in-office procedures. There were positive aspects to the pandemic in the form of telehealth initiatives, pathways for rapid development and approval of tests and treatments, opportunities for new collaborations, and expertise in vaccines. Preparation for the next pandemic needs to be considered now to avoid the mistakes and missteps that occurred with the COVID-19 pandemic. On a national level, a strategy to overcome the societal divisions, misinformation/disinformation, and distrust of science needs to be developed based on better communication, as well as advocacy for continued improvement in our public health system. Practices and training programs as well as research centers need to institutionalize changes made during the pandemic so they can quickly be reinitiated when necessary.

The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

Consensus report from the Food Allergy Research & Education (FARE) 2019 Oral Immunotherapy for Food Allergy Summit.

Food allergy is a major health problem affecting 5% to 10% of the population in developed nations, including an estimated 32 million Americans. Despite the large number of patients suffering from food allergies, up until the end of January 2020, no treatment for food allergies had been approved by the US Food and Drug Administration. The only options were avoidance of food allergen triggers and acute management of allergic reactions. A considerable body of data exists supporting oral immunotherapy (OIT) as a promising, novel treatment option, including that for the now Food and Drug Administration-approved peanut OIT product Palforzia (Aimmune Therapeutics, Brisbane, Calif). However, data for long-term quality-of-life improvement with OIT varies, depending on the measures used for analysis. Like many therapies, OIT is not without potential harms, and burdens, and the evaluation of patient-specific risk-benefit ratio of food OIT produces challenges for clinicians and patients alike, with many unanswered questions. Food Allergy Research & Education organized the Oral Immunotherapy for Food Allergy Summit on November 6, 2019, modeled after the PRACTALL sessions between the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology to address these critical issues. Health care providers, patient representatives, researchers, regulators, and food allergy advocates came together to discuss OIT and identify areas of common ground as well as gaps in existing research and areas of uncertainty and disagreement. The purpose of this article was to summarize that discussion and facilitate collaboration among clinicians and patients to help them make better-informed decisions about offering and accepting OIT, respectively, as a therapeutic option.

Successful use of cyclosporine as treatment for eosinophilic cystitis: a case report.

BACKGROUND: Eosinophilic cystitis is a rare inflammatory disorder characterized by eosinophilic infiltration of all layers of the urinary bladder wall. Due to lack of consensus and potential for side effect from various therapeutic options, treatment of the disease is often challenging. CASE PRESENTATION: A 64-year old woman with hypertensive nephropathy resulting in stage III chronic kidney disease, obstructive sleep apnea, and obstructive lung disease presented with a 4 month history of dysuria, urgency, frequency, and persistent hematuria. Based on eosinophilic infiltration on bladder wall biopsy in the absence of any evidence of infection, malignancy, or immune disorder, she was diagnosed with eosinophilic cystitis. Despite multiple medication regimens, her symptoms persisted, requiring high-dose prednisone with steroid-related side effects. After four months, she was started on cyclosporine, which led to symptomatic improvement and reduction in prednisone dosage. At that time, repeat urine cytology and cystoscopy did not reveal friable tissues or eosinophiluria. CONCLUSION: This case illustrates the utility of using cyclosporine to treat eosinophilic cystitis in adult patient with multiple comorbid conditions.

Methylotroph Infections and Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in production of phagocyte-derived reactive oxygen species, which leads to recurrent infections with a characteristic group of pathogens not previously known to include methylotrophs. Methylotrophs are versatile environmental bacteria that can use single-carbon organic compounds as their sole source of energy; they rarely cause disease in immunocompetent persons. We have identified 12 infections with methylotrophs (5 reported here, 7 previously reported) in patients with CGD. Methylotrophs identified were Granulibacter bethesdensis (9 cases), Acidomonas methanolica (2 cases), and Methylobacterium lusitanum (1 case). Two patients in Europe died; the other 10, from North and Central America, recovered after prolonged courses of antimicrobial drug therapy and, for some, surgery. Methylotrophs are emerging as disease-causing organisms in patients with CGD. For all patients, sequencing of the 16S rRNA gene was required for correct diagnosis. Geographic origin of the methylotroph strain may affect clinical management and prognosis.

Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency.

BACKGROUND AND OBJECTIVES: Immunoglobulin replacement is a standard therapy for patients with primary immunodeficiencies. Subcutaneous administration of immunoglobulin offers more constant IgG levels than intravenous administration and simplifies administration for some patients. Use of L-proline as an excipient contributes to the stability of highly concentrated IgG preparations. The aims of the present study were to evaluate the pharmacokinetics of IgPro20 (Hizentra®), a new 20% subcutaneous IgG solution, and compare the area under the serum concentration-time curve (AUC) with that of a similar intravenous 10% IgG solution (IgPro10; Privigen®). At the request of the US FDA, an algorithm for determining IgG trough level ratios (TLRs) was developed in order to provide physicians with a practical tool for monitoring doses during steady-state IgPro20 therapy. METHODS: This was a prospective, open-label, multicentre, single-arm, phase III clinical trial conducted in the US. The study was performed in a primary-care setting. Eligible patients were males or females aged 6-75 years with a primary immunodeficiency (common variable immunodeficiency or X-linked agammaglobulinaemia) who had received regular treatment with IgPro10 for at least 3 months prior to entering this study and had achieved serum trough concentration (C(trough)) values ≥5 g/L. IgPro20 was administered subcutaneously once weekly at initial doses equivalent to 130% of patients' previous doses, based on the results obtained in a Vivaglobin® study and due to an FDA request. After run-in, each patient's dose was adjusted to achieve an AUC comparable to that achieved with IgPro10 administered intravenously. RESULTS: Eighteen patients completed the study. Mean IgPro20 : IgPro10 dose ratio (dose adjustment coefficient) was 1.53 (range 1.26-1.87). The resulting mean AUCs were 105.6 g · day/L for IgPro20 versus 103.2 g · day/L for IgPro10 (geometric mean ratio 1.002; lower one-sided 95% confidence limit [CL] 0.951). Thus, the primary endpoint of the study was met, as this result exceeded the pre-specified criterion of the lower one-sided 95% CL of ≥0.8 for non-inferiority. At these AUCs, which were considered equivalent, the mean IgPro20 : IgPro10 TLR, determined by the developed algorithm, was 1.29 (range 1.18-1.73). Titres of specific antibodies tested were well above respective product specifications, suggesting that protection against infection would be effective. CONCLUSION: Steady-state AUCs with subcutaneous IgPro20 and intravenous IgPro10 were equivalent. Mean dose adjustment coefficient and mean TLR can be used for initial dose conversion without risk of under-protection but vary too widely to be considered measures of equivalence. Trial registration number (clinicaltrials.gov): NCT00419341.

Sublingual immunotherapy in patients with allergic rhinoconjunctivitis caused by ragweed pollen.

BACKGROUND: Specific allergen immunotherapy is most often delivered subcutaneously, but sublingual immunotherapy may confer greater benefit in terms of tolerability and safety, accessibility, and improved antigen delivery. OBJECTIVE: This randomized, double-blind, placebo-controlled trial was conducted to identify a safe and effective maintenance dose range of sublingual standardized glycerinated short ragweed pollen extract in adults with ragweed-induced rhinoconjunctivitis. METHODS: In May 2006, a total of 115 patients with ragweed-induced rhinoconjunctivitis were randomly allocated to placebo (n = 40), medium-dose extract (4.8 microg Amb a 1/d; n = 39), or high-dose extract (48 microg Amb a 1/d; n = 36). In a 1-day (rush) dose-escalation regimen, ragweed pollen extract was administered sublingually in incremental doses until maximum tolerable or scheduled dose was reached and then maintained during the ragweed pollen season. Patient diaries were used to monitor nasal and ocular symptoms and medication. The primary endpoint was symptom score. RESULTS: Both active treatment groups achieved a 15% reduction in total rhinoconjunctivitis symptom scores compared with placebo during the entire ragweed pollen season, but the difference was not statistically significant (P > .10) However, in an analysis of covariance correcting for preseasonal symptoms, both mean daily symptom scores (0.19 +/- 1.16 vs 1.00 +/- 2.30) and medication scores (0.0003 +/- 1.64 vs 0.63 +/- 1.06) for the entire pollen season were significantly reduced in the high-dose versus placebo groups, respectively (P

Combined airways: impact of upper airway on lower airway.

PURPOSE OF REVIEW: This article reviews recent literature on the important relationship between the nose, paranasal sinuses and lungs. Recent advances in the understanding of the pathophysiological mechanisms underlying the association between upper and lower airways are discussed. RECENT FINDINGS: Epidemiological, clinical, and immunopathological data demonstrate an important link between upper and lower airways beyond the well recognized association of allergic rhinitis and asthma. Other upper airway diseases including occupational rhinitis, chronic rhinosinusitis, nasal polyposis with or without aspirin sensitivity, and obstructive sleep apnea have all been linked to asthma and/or asthma severity, as well as other lower airway diseases. Although the underlying mechanisms to explain these associations are unclear, recent work suggests the presence of systemic inflammation triggered by both the adaptive and innate immune system as a major driving force in combined airway diseases. SUMMARY: Epidemiological data, clinical observations, and immunopathological studies demonstrate an important link between upper and lower airways. An understanding of how the upper airway impacts on lower airway disease has important diagnostic, therapeutic and prognostic implications.

Clinical manifestations of food allergy: differentiating true allergy from food intolerance.

Food allergy is an abnormal immunologic reaction to food proteins. In this article, we differentiate food allergy from food intolerance and other conditions that may mimic food allergy. We describe clinical presentations of food allergy, outline a practical approach for evaluating patients with suspected food allergy, and discuss recommendations for management.

Sinonasal outcomes after endoscopic sinus surgery in asthmatic patients with nasal polyps: a difference between aspirin-tolerant and aspirin-induced asthma?

OBJECTIVES/HYPOTHESIS: Aspirin-sensitivity, asthma, and nasal polyposis (NP) comprise the clinical entity of Samter's triad. The aim of this study is to report the sinonasal outcomes of endoscopic sinus surgery (ESS) in treating NP in asthmatic patients, comparing aspirin-induced asthmatic (AIA) patients with aspirin-tolerant asthmatics (ATA). STUDY DESIGN: Retrospective chart review. METHODS: The records of 66 patients with NP and asthma were retrospectively reviewed. Forty-one AIA patients were compared with 25 ATA patients. For each patient, a Lund-Mackay computed tomography (CT) score of the preoperative scans and the available postoperative CT scans in a period of 18 months were calculated and used as primary endpoint. Sinonasal improvement assessed by patients and reported with a symptoms scale was used as the secondary endpoint for the comparison immediately before surgery and 6 months and 12 months following ESS. RESULTS: Preoperative CT scores in AIA patients compared with ATA patients were significantly higher 19 (standard deviation, 4.82) vs. 14 (standard deviation, 6.8), respectively (P = .006). This difference was sustained for the available postoperative CT scans (P < .0001). During the period of 18 months follow-up, 63.4% of AIA patients vs. 96% of ATA patients had CT improvement with a statistically significant difference between the two groups (P = .003). At 6 months following ESS, 63.4% of AIA patients vs. 56% of ATA patients had symptomatic improvement. At 12 months, 68.3% of AIA patients vs. 60% of ATA patients had symptomatic improvement, with no significant difference between the two groups. CONCLUSION: AIA patients had more extensive sinonasal disease than ATA patients. Both groups showed statistically significant improvement in sinonasal outcomes after ESS. The difference between the two groups was statistically significant for patients' CT improvement with worse CT scores being seen in AIA patients.

Asthma outcomes after endoscopic sinus surgery in aspirin-tolerant versus aspirin-induced asthmatic patients.

BACKGROUND: Certain diseases affect both upper and lower airways. Aspirin-induced asthma (AIA) is a clinical entity characterized by asthma, nasal polyposis, and aspirin intolerance. To understand the response of the lower airway to surgical treatment of the sinuses, we examined asthma outcomes in AIA compared with a second group of aspirin-tolerant asthmatic (ATA) patients to establish if there were any differences between the two groups after endoscopic sinus surgery (ESS). METHODS: A retrospective record review was performed of 91 asthmatic subjects with chronic rhinosinusitis. Forty-one subjects had AIA and 50 subjects had ATA. Subjective and objective asthma outcome parameters were used to compare between the two groups at three time points: immediately before ESS and 6 and 12 months after ESS. RESULTS: Preoperatively, AIA patients had significantly higher asthma severity (p<0.0001) and lower forced expiratory volume in 1 second values (p=0.04). At 12 months after ESS, a statistically significant difference between the two groups with better results in AIA patients was seen in asthma severity improvement (p=0.010) and in the decrease of ICS doses (p<0.0001), without significant differences between the two groups in other asthma outcome parameters. CONCLUSION: AIA patients usually present with more severe asthma. The asthmatic complaints of AIA and ATA patients continue to improve significantly over 6 and 12 month after ESS. Although ESS helped both groups of patients, AIA had statistically significant better results compared with ATA patients in asthma severity scores and decreased need for ICS.

Dermatologic food allergy.

Cutaneous reactions to foods represent one of the most common presentations of food allergy in children. IgE-mediated (urticaria, angioedema, flushing, pruritus), cell-mediated (contact dermatitis, dermatitis herpetiformis), mixed IgE- and cell-mediated (atopic dermatitis), and nonimmune-mediated (irritant contact dermatitis, Frey's syndrome) reactions to foods have all been reported. It is important for the pediatrician to recognize the variety of skin reactions potentially related to food allergy and to consider timely referral to an allergy specialist for further evaluation and definitive diagnosis.

Desensitization for the management of clopidogrel hypersensitivity: initial clinical experience.

Platelet activation and aggregation play an important role in the pathogenesis of arterial thrombosis in coronary, cerebral and peripheral vascular beds. The antiplatelet agent clopidogrel has become a mainstay of treatment for patients with acute coronary syndromes and stroke, and to reduce ischemic complications after percutaneous coronary and peripheral interventions. There are, however, increasing numbers of reports of hypersensitivity reactions to clopidogrel. We present here a protocol for clopidogrel desensitization in isolated cutaneous reactions. Eight patients have completed the protocol successfully. Three subsequently underwent coronary intervention, and all are currently tolerating a daily clopidogrel dose a median of 7.5 months after desensitization. Desensitization may allow for the safe use of clopidogrel in patients with a history of prior cutaneous hypersensitivity reactions.