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.

Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers-Danlos syndrome clinic: A retrospective review.

The new 2017 diagnostic criteria for hypermobile Ehlers-Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.

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.

Characterization of Patients with Ibuprofen Hypersensitivity.

BACKGROUND: Ibuprofen is the most frequently used over-the-counter nonsteroidal anti-inflammatory drug (NSAID) in North America. While it has been commonly implicated in drug-induced hypersensitivity reactions, there is limited literature specifically on ibuprofen hypersensitivity. OBJECTIVES: To characterize the demographics and clinical course of hypersensitivity reactions in a cohort of patients with ibuprofen allergy. METHODS: A retrospective chart review of patients diagnosed with ibuprofen allergy was conducted between 2008 and 2016 in an allergy clinic at a tertiary care academic institution. Demographics and clinical information were obtained, and severity of reactions was assessed by a standardized grading system. RESULTS: A total of 41 patients were included of whom 27 were female. The mean age at first reaction to ibuprofen was 33 ± 13.9 years. The medi an time from the first reaction to the time of diagnosis was 1 year (0-3). The median time from ibuprofen exposure to the onset of symptoms was 30 min (16-101). The median duration of symptoms was 180 min (60-1,440). Urticaria and angioedema were seen in 90% of patients. The reactions were either mild (46%) or moderate (51%) in severity, but 1 patient had severe anaphylaxis. Cross-reactivity to other NSAIDs or acetaminophen was seen and presented with mostly mild reactions. CONCLUSION: In our cohort of patients, ibuprofen hypersensitivity affected females more commonly than males, and presented with mainly cutaneous manifestations. Onset of symptoms was rapid (< 60 min). Reactions typically ranged in severity from mild to moderate although there was a risk of severe anaphylaxis. There was potential cross-reactivity with other NSAIDs or acetaminophen. The results of our study contribute to the understanding of the demographics and clinical course of ibuprofen hypersensitivity reactions.

Severe and near-fatal anaphylactic reactions triggered by chlorhexidine-coated catheters in patients undergoing renal allograft surgery: a case series.

PURPOSE: Although intraoperative anaphylaxis during surgery is a rare event, we describe five patients who experienced perioperative anaphylactic reactions during renal transplantation and were referred for investigation. CLINICAL FEATURES: Skin-prick and intradermal skin tests were done to investigate potential allergies to drugs given perioperatively prior to the development of anaphylaxis, including basiliximab, propofol, cefazolin, cis-atracurium, fentanyl, latex, remifentanil, and chlorhexidine. In addition, in vitro serologic testing for specific IgE was done in patients suspected to have had chlorhexidine anaphylaxis. All five patients were male, with a mean age of 48 yr (range 30-69). Skin testing for all drugs was non-reactive except for chlorhexidine, which was positive in four of five patients (one patient refused intradermal testing). In vitro test results for chlorhexidine-specific IgE were positive in all of the patients. Anesthetic records showed that intraoperative anaphylaxis had occurred immediately after insertion of a chlorhexidine-coated central venous catheter. CONCLUSIONS: Intraoperative insertion of chlorhexidine-coated central venous catheters can trigger life-threatening anaphylaxis in susceptible patients undergoing renal transplantation.

Underestimation of N2 O emissions in a comparison of the DayCent, DNDC, and EPIC models.

Process-based models are increasingly used to study agroecosystem interactions and N2 O emissions from agricultural fields. The widespread use of these models to conduct research and inform policy benefits from periodic model comparisons that assess the state of agroecosystem modeling and indicate areas for model improvement. This work provides an evaluation of simulated N2 O flux from three process-based models: DayCent, DNDC, and EPIC. The models were calibrated and validated using data collected from two research sites over five years that represent cropping systems and nitrogen fertilizer management strategies common to dairy cropping systems. We also evaluated the use of a multi-model ensemble strategy, which inconsistently outperformed individual model estimations. Regression analysis indicated a cross-model bias to underestimate high magnitude daily and cumulative N2 O flux. Model estimations of observed soil temperature and water content did not sufficiently explain model underestimations, and we found significant variation in model estimates of heterotrophic respiration, denitrification, soil NH4+ , and soil NO3- , which may indicate that additional types of observed data are required to evaluate model performance and possible biases. Our results suggest a bias in the model estimation of N2 O flux from agroecosystems that limits the extension of models beyond calibration and as instruments of policy development. This highlights a growing need for the modeling and measurement communities to collaborate in the collection and analysis of the data necessary to improve models and coordinate future development.

Temperature and Manure Placement in a Snowpack Affect Nutrient Release from Dairy Manure during Snowmelt.

Agricultural nutrient management is an issue due to N and P losses from fields and water quality degradation. Better information is needed on the risk of nutrient loss in runoff from dairy manure applied in winter. We investigated the effect of temperature on nutrient release from liquid and semisolid manure to water, and of manure quantity and placement within a snowpack on nutrient release to melting snow. Temperature did not affect manure P and NH-N release during water extraction. Manure P release, but not NH-N release, was significantly influenced by the water/manure solids extraction ratio. During snowmelt, manure P release was not significantly affected by manure placement in the snowpack, and the rate of P release decreased as application rate increased. Water extraction data can reliably estimate P release from manure during snowmelt; however, snowmelt water interaction with manure of greater solids content and subsequent P release appears incomplete compared with liquid manures. Manure NH-N released during snowmelt was statistically the same regardless of application rate. For the semisolid manure, NH-N released during snowmelt increased with the depth of snow covering it, most likely due to reduced NH volatilization. For the liquid manure, there was no effect of manure placement within the snowpack on NH-N released during snowmelt. Water extraction data can also reliably estimate manure NH-N release during snowmelt as long as NH volatilization is accounted for with liquid manures for all placements in a snowpack and semisolid manures applied on top of snow.

Estimating Legacy Soil Phosphorus Impacts on Phosphorus Loss in the Chesapeake Bay Watershed.

Agricultural nutrient management is an issue due to P loss from fields and water quality degradation. This is especially true in watersheds where a history of P application in excess of crop needs has resulted in elevated soil P (legacy P). As practices and policy are implemented in such watersheds to reduce P loss, information is needed on time required to draw down soil P and how much P loss can be reduced by drawdown. We used the Annual P Loss Estimator (APLE) model to simulate soil P drawdown in Maryland, and to estimate P loss at a statewide scale associated with different combinations of soil P and P transport. Simulated APLE soil P drawdown compared well with measured rates from three field sites, showing that APLE can reliably simulate P dynamics for Maryland soils. Statewide APLE simulations of average annual P loss from cropland (0.84 kg ha) also compared well with estimates from the Chesapeake Bay Model (0.87 kg ha). The APLE results suggest that it is realistic to expect that a concerted effort to reduce high P soils throughout the state can reduce P loss to the Chesapeake Bay by 40%. However, P loss reduction would be achieved gradually over several decades, since soil P drawdown is very slow. Combining soil P drawdown with aggressive conservation efforts to reduce P transport in erosion could achieve a 62% reduction in state-level P loss. This 62% reduction could be considered a maximum amount possible that is still compatible with modern agriculture.

Quantifying the Impact of Seasonal and Short-term Manure Application Decisions on Phosphorus Loss in Surface Runoff.

Agricultural phosphorus (P) management is a research and policy issue due to P loss from fields and water quality degradation. Better information is needed on the risk of P loss from dairy manure applied in winter or when runoff is imminent. We used the SurPhos computer model and 108 site-years of weather and runoff data to assess the impact of these two practices on dissolved P loss. Model results showed that winter manure application can increase P loss by 2.5 to 3.6 times compared with non-winter applications, with the amount increasing as the average runoff from a field increases. Increased P loss is true for manure applied any time from late November through early March, with a maximum P loss from application in late January and early February. Shifting manure application to fields with less runoff can reduce P loss by 3.4 to 7.5 times. Delaying manure application when runoff is imminent can reduce P loss any time of the year, and sometimes quite significantly, but the number of times that application delays will reduce P loss is limited to only 3 to 9% of possible spreading days, and average P loss may be reduced by only 15% for winter-applied manure and 6% for non-winter-applied manure. Overall, long-term strategies of shifting manure applications to low runoff seasons and fields can potentially reduce dissolved P loss in runoff much more compared with near-term, tactical application decisions of avoiding manure application when runoff is imminent.

Use of Annual Phosphorus Loss Estimator (APLE) Model to Evaluate a Phosphorus Index.

The Phosphorus (P) Index was developed to provide a relative ranking of agricultural fields according to their potential for P loss to surface water. Recent efforts have focused on updating and evaluating P Indices against measured or modeled P loss data to ensure agreement in magnitude and direction. Following a recently published method, we modified the Maryland P Site Index (MD-PSI) from a multiplicative to a component index structure and evaluated the MD-PSI outputs against P loss data estimated by the Annual P Loss Estimator (APLE) model, a validated, field-scale, annual P loss model. We created a theoretical dataset of fields to represent Maryland conditions and scenarios and created an empirical dataset of soil samples and management characteristics from across the state. Through the evaluation process, we modified a number of variables within the MD-PSI and calculated weighting coefficients for each P loss component. We have demonstrated that our methods can be used to modify a P Index and increase correlation between P Index output and modeled P loss data. The methods presented here can be easily applied in other states where there is motivation to update an existing P Index.

Revised Method and Outcomes for Estimating Soil Phosphorus Losses from Agricultural Land in the Chesapeake Bay Watershed Model.

Current restoration efforts for the Chesapeake Bay watershed mandate a timeline for reducing the load of nutrients and sediment into receiving waters. The Chesapeake Bay watershed model (WSM) has been used for two decades to simulate hydrology and nutrient and sediment transport; however, spatial limitations of the WSM preclude edge-of-field scale representation of phosphorus (P) losses. Rather, the WSM relies on literature-derived, county-scale rates of P loss (targets) for simulated land uses. An independent field-scale modeling tool, Annual Phosphorus Loss Estimator (APLE), was used as an alternative to the current WSM approach. Identical assumptions of county-level acreage, soil properties, nutrient management practices, and transport factors from the WSM were used as inputs to APLE. Incorporation of APLE P-loss estimates resulted in greater estimated total P loss and a revised spatial pattern of P loss compared with the WSM's original targets. Subsequently, APLE's revised estimates for P loss were substituted into the WSM and resulted in improved WSM calibration performance at up to 79% of tributary monitoring stations. The incorporation of APLE into the WSM will improve its ability to assess P loss and the impact of field management on Chesapeake Bay water quality.

Improved Simulation of Edaphic and Manure Phosphorus Loss in SWAT.

Watershed models such as the Soil Water Assessment Tool (SWAT) and the Agricultural Policy Environmental EXtender (APEX) are widely used to assess the fate and transport of agricultural nutrient management practices on soluble and particulate phosphorus (P) loss in runoff. Soil P-cycling routines used in SWAT2012 revision 586, however, do not simulate the short-term effects of applying a concentrated source of soluble P, such as manure, to the soil surface where it is most vulnerable to runoff. We added a new set of soil P routines to SWAT2012 revision 586 to simulate surface-applied manure at field and subwatershed scales within Mahantango Creek watershed in south-central Pennsylvania. We corroborated the new P routines and standard P routines in two versions of SWAT (conventional SWAT, and a topographically driven variation called TopoSWAT) for a total of four modeling "treatments". All modeling treatments included 5 yr of measured data under field-specific, historical management information. Short-term "wash off" processes resulting from precipitation immediately following surface application of manures were captured with the new P routine whereas the standard routines resulted in losses regardless of manure application. The new routines improved sensitivity to key factors in nutrient management (i.e., timing, rate, method, and form of P application). Only the new P routines indicated decreases in soluble P losses for dairy manure applications at 1, 5, and 10 d before a storm event. The new P routines also resulted in more variable P losses when applying manure versus commercial fertilizer and represented increases in total P losses, as compared with standard P routines, with rate increases in dairy manure application (56,000 to 84,000 L ha). The new P routines exhibited greater than 50% variation among proportions of organic, particulate, and soluble P corresponding to spreading method. In contrast, proportions of P forms under the standard P routines varied less than 20%. Results suggest similar revisions to other agroecosystem watershed models would be appropriate.

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis.

Anaphylaxis is an acute, severe, life-threatening multisystem allergic reaction resulting from the sudden systemic release of biochemical mediators and chemotactic substances. Release of both preformed granule-associated mediators and newly generated lipid-derived mediators contributes to the amplification and prolongation of anaphylaxis. Platelet-activating factor (PAF) is a potent phospholipid-derived mediator the central role of which has been well established in experimental models of both immune-mediated and non-immune mediated anaphylaxis. It is produced and secreted by several types of cells, including mast cells, monocytes, tissue macrophages, platelets, eosinophils, endothelial cells, and neutrophils. PAF is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in increased vascular permeability, circulatory collapse, decreased cardiac output, and various other biological effects. PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF acetylhydrolase, the activity of which has shown to correlate inversely with PAF levels and predispose to severe anaphylaxis. In addition to its role in anaphylaxis, PAF has also been implicated as a mediator in both allergic and nonallergic inflammatory diseases, including allergic rhinitis, sepsis, atherosclerotic disease, and malignancy, in which PAF signaling has an established role. The therapeutic role of PAF antagonism has been investigated for several diseases, with variable results thus far. Further investigation of its role in pathology and therapeutic modulation is highly anticipated because of the pressing need for more selective and targeted therapy for the management of severe anaphylaxis.

Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis.

BACKGROUND: Platelet-activating factor (PAF) is an important mediator and correlates with anaphylaxis severity. How well PAF correlates with severity relative to histamine or tryptase is not known. OBJECTIVE: To analyze the levels of PAF, histamine, and tryptase as a function of severity in patients with acute allergic reactions. METHODS: PAF, histamine, and tryptase levels were measured in blood samples collected from 23 healthy volunteers and from 41 patients during acute allergic reactions. Reactions were stratified by severity from grade 1 (least severe) to grade 3 (most severe). RESULTS: Among the 3 reaction grades, there were significant differences by ANOVA for PAF (P < .0001). The proportion of elevated PAF values increased across severity groups (P = .0009). Increased PAF levels were observed in 20%, 66.7%, and 100% of the patients with grades 1, 2, and 3 allergic reactions, respectively. While the proportion of elevated histamine values increased from 40% to 57% to 70% across grades 1, 2, and 3, respectively, these were not significantly different (P = .40). For tryptase, the proportion of elevated values increased monotonically from 0 in grade 1 to 4.8% in grade 2 to 60% in grade 3 (P = .0002). CONCLUSIONS: The PAF level was significantly elevated in proportion to the severity of acute allergic reactions. Whereas the PAF level was elevated in all patients with severe anaphylaxis, this was not true for either histamine or tryptase. Neither histamine nor tryptase showed as good correlations with severity scores as did PAF. These data are consistent with a pivotal role for PAF as a mediator of anaphylaxis.

Heterogeneity in presentation and treatment of catamenial anaphylaxis.

BACKGROUND: Few reports have documented the uncommon association of the female menstrual cycle with anaphylaxis, an entity known as cyclic or catamenial anaphylaxis. OBJECTIVE: To examine cases of perimenstrual anaphylaxis, focusing on differences in presentation and response to treatment, in the hopes of enriching the description of this rare entity. METHODS: A cohort of 8 women with catamenial anaphylaxis were identified and retrospectively compared with regard to age at onset, organ involvement, diagnostic studies, and response to therapy. RESULTS: The median age at onset was 34 years (range, 14-40 years), and the median number of perimenstrual anaphylactic episodes at presentation was 10 per patient (range, 4-24 per patient). Most had cutaneous and gastrointestinal symptoms. The results of extensive investigations for anaphylactic triggers were negative, and masquerading conditions, such as carcinoid syndrome, pheochromocytoma, and systemic mastocytosis, were ruled out in all patients. Skin test results for progesterone were negative in all but 1 of 4 patients tested. None had elevated total serum IgE levels. Response to suppressive treatments regimens varied considerably, but none treated with high-dose systemic steroids had improvement. Similarly, ketotifen, celecoxib, rofecoxib, and oral contraceptives failed to control the anaphylactic reactions. Although antihistamines failed in 7 patients, 1 had improvement. Others responded to leuprolide, medroxyprogesterone, or salpingo-oophorectomy. CONCLUSION: Whether the mechanism causing cyclical anaphylaxis may involve hypersensitivity to progesterone or prostaglandins, the variable response to suppressive medications in these cases suggests that catamenial anaphylaxis is a heterogeneous disorder in which a number of mechanisms and mediators may play a role. It is an emergent and probably underrecognized entity in the medical literature.