Extrinsic and Intrinsic Modulators of Anaphylaxis.

The severity of anaphylaxis is determined by many factors. The allergenic source as well as the age of the affected individual and the route of allergen exposure encompass the major contributors of the clinical outcome. Moreover, the severity can be modulated further by intrinsic and extrinsic factors. Among these, the genetic predisposition, certain comorbidities such as uncontrolled asthma, and hormonal fluctuations have been proposed as intrinsic and antihypertensive medications or physical activity as extrinsic factors. Recent advances have highlighted immunologic pathways that may exacerbate the response to allergens through receptors on mast cells, basophils, platelets, and other granulocytes. Atopy, platelet-activating factor acetylhydrolase deficiency, hereditary alpha tryptasemia, and clonal mast cell disorders are examples associated with genetic alterations that may predispose to severe anaphylaxis. Identifying risk factors that lower the threshold of reactivity or increase the severity of multisystem reactions is important in the management of this patient population.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Platelet Activating Factor (PAF): A Mediator of Inflammation.

Platelet-activating factor (PAF) is a phospholipid-derived mediator with an established role in multiple inflammatory states. PAF is synthesized and secreted by multiple cell types and is then rapidly hydrolyzed and degraded to an inactive metabolite, lyso-PAF, by the enzyme PAF acetylhydrolase. In addition to its role in platelet aggregation and activation, PAF contributes to allergic and nonallergic inflammatory diseases such as anaphylaxis, sepsis, cardiovascular disease, neurological disease, and malignancy as demonstrated in multiple animal models and, increasingly, in human disease states. Recent research has demonstrated the importance of the PAF pathway in multiple conditions including the prediction of severe pediatric anaphylaxis, effects on blood-brain barrier permeability, effects on reproduction, ocular diseases, and further understanding of its role in cardiovascular risk. Investigation of PAF as both a biomarker and a therapeutic target continues because of the need for directed management of inflammation. Collectively, studies have shown that therapies focused on the PAF pathway have the potential to provide targeted and effective treatments for multiple inflammatory conditions.

Tillage and manure effects on runoff nitrogen and phosphorus losses from frozen soils.

In cold regions, nutrient losses from dairy agroecosystems are a longstanding and recurring problem, especially when manure is applied during winter over snow-covered frozen soils. This study evaluated two tillage (fall chisel tillage [CT] and no-tillage [NT]) and three manure-type management treatments (unmanured control, liquid manure [<5% solids], and solid manure [>20% solids]). The liquid and solid manure used in this study were from the same animal species (Bos taurus) and facility. The six management treatments were field tested in south-central Wisconsin during the winters (November-April) of 2017-2018 and 2018-2019 with a complete factorial design. Seasonal runoff losses were significantly lower from fall CT compared with NT during both seasons. Manure applications (both liquid and solid) on top of snow significantly increased most of the nutrients (NH4 + , dissolved reactive phosphorus, total Kjeldahl nitrogen, and total phosphorus) in runoff compared with unmanured control. Irrespective of tillage and multiple runoff events, solid manure was present on the surface for longer periods, potentially releasing nutrients each time it interacted with runoff. In contrast, liquid manure infiltrated the snowpack and was partly lost with snowmelt and infiltrated soil depending upon soil frost and surface conditions. Overall, results indicate that wintertime manure applications over snow-covered frozen soils pose a risk of nutrient loss irrespective of tillage and manure type, but in unavoidable situations, prioritizing tillage × manure type combination can help reduce losses.

Updates to the Annual P Loss Estimator (APLE) model.

The Annual P Loss Estimator (APLE) is a spreadsheet-based model developed for predicting annual field-scale P loss in surface runoff and changes in soil test P. This empirically based model was designed for use by those without significant modeling experience. However, a significant limitation with the model is that it does not calculate runoff. Moreover, APLE is deterministic and thus predicts a single value for a given set of inputs, thereby ignoring any uncertainties associated with model inputs. Here, we describe modifications to APLE that allow users to estimate runoff using the Curve Number method. Using Monte Carlo simulations, the updated version of APLE also provides users the ability to account for model input uncertainties in estimating model prediction errors. We provide examples of using the revised version of APLE (ver. 3.0) for calculating P loss from two fields in Mississippi over a 4-yr period and calculating the change in Mehlich-3 P concentrations over a 9-yr period at three locations in Maryland following cessation of P application. Both examples demonstrate that incorporating estimates of uncertainties in both measured data and model predictions provides modelers with a more realistic understanding of the model's performance.

Envisioning the manureshed: Toward comprehensive integration of modern crop and animal production.

The specialization and intensification of agriculture have produced incredible gains in productivity, quality, and availability of agricultural commodities but have resulted in the separation of crop and animal production. A by-product of this separation has been the accumulation of manure regions where animal production is concentrated. Enter the "manureshed," an organizing framework for integrating animal and crop production where budgeting of manure nutrients is used to strategically guide their recycling and reuse in agricultural production systems where manure resources are of highest value. To move beyond regional nutrient balance analyses into the transformational realm required to mitigate "wicked" manure problems, manureshed management requires recognition of the challenges to systematically reorganizing resource flows. In better integrating crop and livestock systems, manureshed management must account for the unique nature of managing manure nutrients within individual livestock industries, anticipate trade-offs in substituting manure for commercial fertilizer, promote technologies to refine manure, and engage extensive social networks across scales that range from the farmgate to nation and beyond.

Manuresheds offer a system-level strategy for recovering manure's fertilizer value. Manuresheds address nutrient imbalances and environmental and socioeconomic outcomes. Manuresheds scale from single operations to a "mega-manureshed" transecting the southeastern United States. Manureshed management supports the strategic alignment of technologies, markets, and networks.

Platelet-activating factor acetylhydrolase is a biomarker of severe anaphylaxis in children.

BACKGROUND: There is limited ability to predict the severity of allergic reactions in children. Data derived predominantly from adults have implicated the platelet-activating factor pathway as a potential contributor to severe anaphylaxis. In this study, we sought to prospectively assess involvement of key components of the platelet-activating factor pathway in pediatric patients with anaphylaxis. METHODS: Forty-six pediatric patients (<18 years) presenting with acute anaphylaxis were assessed. Anaphylaxis severity was graded and serum anaphylaxis markers were measured acutely and in 36 children who returned for follow-up >4 weeks after their acute presentation. These markers were compared with pediatric laboratory reference sera. RESULTS: Severe anaphylaxis was experienced by 12/46 (26%) and mild-moderate anaphylaxis in 34/46 (74%) children. Platelet-activating factor acetylhydrolase (PAF-AH) activity was inversely associated with severe anaphylaxis: 9/12 children with severe anaphylaxis had reduced PAF-AH activity as compared with 14/34 with mild-moderate anaphylaxis (p < .05). Furthermore, 3/3 children who required intensive care had markedly reduced mean PAF-AH (nmol/ml/min) (13.73, 95%CI: 7.42-20.03) versus 20/23 who required ward/emergency department care (17.81, 95%CI: 16.80-18.83; p < .05). In children with anaphylaxis, PAF-AH during acute anaphylaxis was unchanged relative to the child's basal levels (mean, 17.26, 95%CI: 16.10-18.42 vs 17.50, 95%CI: 16.21-18.78, p = .63) and was lower than healthy pediatric controls (mean 19.21; 95%CI:18.21-20.21; p < .05). CONCLUSION: Decreased serum PAF-AH activity is a biomarker of severe anaphylaxis. Levels of this enzyme do not change from basal levels during acute anaphylaxis. Our results show that PAF-AH is a biomarker of anaphylaxis severity in children. This key regulatory enzyme may modulate susceptibility to severe anaphylaxis.

Sensitivity and uncertainty analysis for predicted soil test phosphorus using the Annual Phosphorus Loss Estimator model.

In this study we conducted a sensitivity and uncertainty analysis using the Annual P Loss Estimator (APLE) model focusing on model predictions of soil test phosphorus (STP). We calculated and evaluated the sensitivity coefficients of predicted STP and changes in STP using 1- and 10-yr simulations with and without P application. We also compared two methods for estimating prediction uncertainties: first-order variance approximation (FOVA) and Monte Carlo simulation (MCS). Finally, we compared uncertainties in APLE-predicted STP with uncertainties in measured STP collected from multiple sites in Maryland under different manuring and cropping treatments. Results from our sensitivity analysis showed that predicted STP and changes in STP for 1-yr simulations without P inputs were most sensitive to initial STP, whereas model STP predictions were most sensitive to manure and fertilizer application rates when sensitivity analyses included P inputs. For the 10-yr simulations without P application inputs, the range in sensitivity coefficients for crop uptake and precipitation were much greater than for the 1-yr simulations. Prediction uncertainties from FOVA were comparable to those from MCS for model input uncertainties up to 50%. Using FOVA to calculate APLE STP prediction uncertainties using the Maryland data set, the mean measured STP for nearly all site years fell within the 95% confidence intervals of the STP prediction uncertainties. Our results provide users of APLE insight into what model inputs require the most careful measurement when using the model to predict changes in STP under conditions of P drawdown (i.e., no P application) or P buildup.

Reproducibility of Symptom Sequences Across Episodes of Recurrent Anaphylaxis.

BACKGROUND: Anaphylactic reactions may present with varying levels of severity, ranging from mild multisystem involvement to severe, and sometimes fatal, anaphylaxis. The severity of anaphylaxis is variable from one reaction to the next within the same individuals. OBJECTIVE: To compare the temporal sequence of symptoms within individuals and between individuals across multiple anaphylactic reactions. METHODS: Patients were evaluated for recurrent anaphylaxis in a tertiary care allergy clinic between 2012 and 2018. At each visit, patients were asked to record the temporal sequence in which symptoms of anaphylaxis appeared. These data were recorded at each visit and retrieved through retrospective chart review. Patients with a history of ≥2 anaphylactic reactions were included; those with anaphylaxis due to multiple allergens were excluded. The Fleiss Kappa method was used to assess reproducibility of the order of appearance of specific symptoms during anaphylaxis within individual patients and between individuals with similar triggers. RESULTS: The mean patient age was 35.6 years (standard deviation = 13.9; range: 1-68 years); 113 of 149 (76%) patients were female. The mean Fleiss Kappa reproducibility score within individuals was 0.94, 5th percentile was 0.53, and 95th percentile was 1.0. The mean Kappa score between individuals was -0.03 (range, -0.14 to 0.05). Among the 16 of 149 patients who recorded reactions of varying severity grades, the mean within-patient Kappa score was 0.96. CONCLUSION: Individual patients experience reproducibly stereotypic anaphylactic reactions over time, which are unique to a given patient, irrespective of the cause of anaphylaxis, including foods, medications, mast cell disorders, and idiopathic anaphylaxis. In contrast, symptom sequences during anaphylaxis are not reproducible between individuals.

Characterizing telemedicine use in clinical immunology and allergy in Canada before the COVID-19 pandemic.

RATIONALE: There exists a geographic barrier to access CIA care for patients who live in rural communities; telemedicine may bridge this gap in care. Herein we characterized the use of telemedicine in CIA at a population-based level and single centre. METHODS: Before the COVID-19 pandemic, telemedicine care was provided via the Ontario Telemedicine Network (OTN) in Ontario, Canada. Descriptive data were collected from the OTN administrative database and from electronic medical records at a single academic centre during 2014 to 2019. The potential distance travelled and time saved by telemedicine visits were calculated using postal codes. RESULTS: A total of 1298 telemedicine visits was conducted over OTN, with an average of 216 visits per year. Only 11% of the allergists/immunologists used telemedicine to provide care before the COVID-19 pandemic. In the single centre that provided the majority of the telemedicine care, 66% patients were female and the overall mean age was 46. The most common diagnosis was immunodeficiency (40%), followed by asthma (13%) and urticaria (11%). Most patients required at least one follow-up via telemedicine. The average potential two-way distance travelled per visit was 718 km and the average potential time travelled in total was 6.6 h. CONCLUSION: Telemedicine was not widely used by allergists/immunologists in Ontario, Canada before the COVID-19 pandemic. It could offer a unique opportunity to connect patients who live in remote communities and allergists/immunologists who practice in urban centres in Canada. Independent of the current pandemic, our study further highlights the need for more physicians to adopt and continue telemedicine use as well as for healthcare agencies to support its use as a strategic priority once the pandemic is over.

Effect of omalizumab for autoimmune progesterone dermatitis refractory to bilateral oophorectomy: a case report.

BACKGROUND: Autoimmune progesterone dermatitis (APD) is a rare skin condition caused by sensitivity to high levels of progesterone secreted during the luteal phase of the menstrual cycle. This may be due to various pathophysiological mechanisms including a Type I and Type IV hypersensitivity reaction. Here we present the case of a patient with APD whose episodic flares were controlled by the addition of omalizumab, after a bilateral oophorectomy failed to resolve her symptoms. CASE PRESENTATION: A 34-year-old female presented to our Endocrine clinic with marked Cushingoid features secondary to high-dose oral prednisone prescribed for APD diagnosed 6 years earlier. She first developed a pruritic maculopapular rash on her arms and legs just after the birth of her second child in 2009. The rash was also associated with headaches and diffuse angioedema. Symptoms occurred for 1-2 weeks, in a cyclical fashion, during the luteal phase of each menstrual cycle and subsided within a few days after menses. The severity of symptoms increased as time went on, and flare-ups began to also include dyspnea, nausea, vomiting and abdominal pain. Her symptoms improved with administration of oral prednisone, but she continued to experience breakthrough symptoms. After multiple failed treatment modalities, she elected bilateral oophorectomy in 2018. However, her symptoms of APD persisted and she still required high-dose oral prednisone. Her condition was further complicated by vasomotor menopausal symptoms and progressive iatrogenic Cushing's syndrome. She eventually was started on Omalizumab, which suppressed further recurrences of APD symptoms and allowed her to wean off prednisone. Vasomotor menopausal symptoms responded well to the addition of conjugated estrogens with bazedoxifene. However, her symptoms of diffuse bony pain and arthralgias which started whilst on prednisone have persisted in spite of discontinuing prednisone. CONCLUSIONS: To our knowledge, this is only the third case of APD which was successfully treated with Omalizumab and the first case where a bilateral oophorectomy failed to resolve symptoms of APD in the literature. This case also demonstrates the complications of vasomotor menopausal symptoms secondary to a bilateral oophorectomy, as well as the adverse effects of long-term glucocorticoid therapy.

Anaphylaxis to Oatmeal and Psocid Crisps.

Occasionally, a seemingly straightforward history of food-induced anaphylaxis may prove to be misleading.  Both patients and their physicians have a tendency to attribute the cause of an allergic reaction to the most conspicuous ingredient that had been ingested while overlooking less likely causes.  Here, we describe a patient whose history pointed to oatmeal allergy, but skin prick tests to oats and serologic testing for oat-specific IgE were negative. Ultimately, we found that the oatmeal had been contaminated with an allergenic insect, Psocid of the order Psocoptera.

Hydrochlorothiazide-induced systemic capillary leak.

Hypersensitivity reactions to drugs may cause very rapid physiologic derangements that can be fatal in the absence of adequate compensatory mechanisms or definitive treatment. For the most part, adverse drug reactions that progress over the course of minutes are mediated either by mast cell or complement activation. If a patient survives the acute event, appropriate long-term management requires the identification and future avoidance of the inciting drug. Here, we describe a patient who experienced two life-threatening multisystem reactions with cardiopulmonary compromise minutes after taking hydrochlorothiazide (HCTZ). The reactions were associated with systemic vascular leak resulting in hypotension and non-cardiogenic pulmonary edema.