Direct Versus Indirect Query Performance of ICD-9/-10 Coding to Identify Anaphylaxis.

BACKGROUND: Anaphylaxis is an often under =diagnosed, severe allergic event for which epidemiological data are sporadic. Researchers have leveraged administrative and claims data algorithms to study large databases of anaphylactic events; however, little longitudinal data analysis is available after transition to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM). OBJECTIVE: Study longitudinal trends in anaphylaxis incidence using direct and indirect query methods. METHODS: Emergency department (ED) and inpatient data were analyzed from a large state health care administration database from 2011 to 2020. Incidence was calculated using direct queries of anaphylaxis ICD-9-CM and ICD-10-CM codes and indirect queries using a symptom-based ICD-9-CM algorithm and forward mapped ICD-10-CM version to identify undiagnosed anaphylaxis episodes and to assess algorithm performance at the population level. RESULTS: An average of 2.4 million inpatient and 7.5 million ED observations/y were analyzed. Using the direct query method, annual ED anaphylaxis cases increased steadily from 1,454 (2011) to 4,029 (2019) then declined to 3,341 in 2020 during the coronavirus disease 2019 (COVID-19) pandemic. In contrast, inpatient cases remained relatively steady, with a slight decline after 2015 during the ICD version transition, until a significant drop occurred in 2020. Using the indirect queries, anaphylaxis cases increased markedly after the ICD transition year, especially involving drug-related anaphylaxis. CONCLUSIONS: Nontypical drug associations with anaphylaxis episodes using the ICD-10-CM version of the algorithm suggest poor performance with drug-related codes. Further, the increased granularity of ICD-10-CM identified potential limitations of a previously validated symptom-based ICD-9-CM algorithm used to detect undiagnosed cases.

Life-Threatening Allergies: Using a Patient-Engaged Approach.

BACKGROUND: Adolescents at risk for anaphylaxis are a growing concern. Novel training methods are needed to better prepare individuals to manage anaphylaxis in the community. INTRODUCTION: Didactic training as the sole method of anaphylaxis education has been shown to be ineffective. We developed a smartphone-based interactive teaching tool with decision support and epinephrine auto-injector (EAI) training to provide education accessible beyond the clinic. METHODS: This study consisted of two parts: (1) Use of food allergy scenarios to assess the decision support's ability to improve allergic reaction management knowledge. (2) An assessment of our EAI training module on participant's ability to correctly demonstrate the use of an EAI by comparing it to label instructions. RESULTS: Twenty-two adolescents were recruited. The median (range) baseline number of correct answers on the scenarios before the intervention was 9 (3-11). All subjects improved with decision support, increasing to 11 (9-12) (p < .001). The median (range) demonstration score was 6 (5-6) for the video training module group and 4.5 (3-6) for the label group (p < 0.001). DISCUSSION: Results suggest that the use of this novel m-health application can improve anaphylaxis symptom recognition and increase the likelihood of choosing the appropriate treatment. In addition, performing EAI steps in conjunction with the video training resulted in more accurate medication delivery with fewer missed steps compared to the use of written instructions alone. CONCLUSION: The results suggest that mobile health decision support technology for anaphylaxis emergency preparedness may support traditional methods of training by providing improved access to anaphylaxis training in the community setting.

X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis.

PURPOSE: X-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene. METHODS: Whole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry. RESULTS: A 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells. CONCLUSIONS: The clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.

Subcutaneous Immunoglobulin Replacement Therapy with Hizentra® is Safe and Effective in Children Less Than 5 Years of Age.

BACKGROUND: Hizentra® (IGSC 20%) is a 20% liquid IgG product approved for subcutaneous administration in adults and children 2 years of age and older who have primary immunodeficiency disease (PIDD). There is limited information about the use of IGSC 20 % in very young children including those less than 5 years of age. METHODS: A retrospective chart review involved 88 PIDD infants and children less than 5 years of age who received Hizentra®. RESULTS: The mean age at the start of Hizentra® was 34 months (range 2 to 59 months). IGSC 20 % was administered weekly to 86 infants (two additional infants received twice weekly and three times weekly infusions, respectively) and included an average of 63 infusions (range 6-182) for an observation period up to 45.5 months. Infusion by manual delivery occurred in 15 patients. The mean dose was 674 mg/kg/4 weeks. The mean IgG level was 942 mg/dL while on IGSC 20 %, compared to a mean trough IgG level of 794 mg/dL (p < 0.0001) during intravenous or subcutaneous IgG administration prior to IGSC 20 %. Average infusion time was 47 (range 5-120) minutes, and the median number of infusion sites was 2 (range 1-4). Local reactions were mostly mild and observed in 36/88 (41%) children. No serious adverse events were reported. A significant increase in weight percentile (7 % ± 19.2, p = 0.0012) among subjects was observed during IGSC 20% administration. The rate of serious bacterial infections was 0.067 per patient-year while receiving IGSC 20%, similar to previously reported efficacy studies. CONCLUSIONS: Hizentra® is effective in preventing infections, and is well tolerated in children less than age 5 years.

Subcutaneous immunoglobulin replacement therapy with Hizentra® is safe and effective in two infants.

Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age. We report two infants less than 2 years in which administration of Hizentra® was safe and effective.

Dopamine-induced plasticity, phospholipase D (PLD) activity and cocaine-cue behavior depend on PLD-linked metabotropic glutamate receptors in amygdala.

Cocaine-cue associations induce synaptic plasticity with long lasting molecular and cellular changes in the amygdala, a site crucial for cue-associated memory mechanisms. The underlying neuroadaptations can include marked alterations in signaling via dopamine (DA) receptors (DRs) and metabotropic glutamate (Glu) receptors (mGluRs). Previously, we reported that DR antagonists blocked forms of synaptic plasticity in amygdala slices of Sprague-Dawley rats withdrawn from repeated cocaine administration. In the present study, we investigated synaptic plasticity induced by exogenous DA and its dependence on mGluR signaling and a potential role for phospholipase D (PLD) as a downstream element linked to mGluR and DR signaling. Utilizing a modified conditioned place preference (CPP) paradigm as a functional behavioral measure, we studied the neurophysiological effects after two-weeks to the last cocaine conditioning. We recorded, electrophysiologically, a DR-induced synaptic potentiation in the basolateral to lateral capsula central amygdala (BLA-lcCeA) synaptic pathway that was blocked by antagonists of group I mGluRs, particularly, the PLD-linked mGluR. In addition, we observed 2-2.5 fold increase in PLD expression and 3.7-fold increase in basal PLD enzyme activity. The enhanced PLD activity could be further stimulated (9.3 fold) by a DA D1-like (D1/5R) receptor agonist, and decreased to control levels by mGluR1 and PLD-linked mGluR antagonists. Diminished CPP was observed by infusion of a PLD-linked mGluR antagonist, PCCG-13, in the amygdala 15 minutes prior to testing, two weeks after the last cocaine injection. These results imply a functional interaction between D1/5Rs, group I mGluRs via PLD in the amygdala synaptic plasticity associated with cocaine-cues.

Cocaine withdrawal reduces group I mGluR-mediated long-term potentiation via decreased GABAergic transmission in the amygdala.

Cocaine relapse can occur when cocaine-associated environmental cues induce craving. Conditioned place preference (CPP) is a behavioral paradigm modeling the association between cocaine exposure and environmental cues. The amygdala is involved in cocaine cue associations with the basolateral amygdala (BLA) and central amygdala (CeA) acting differentially in cue-induced relapse. Activation of metabotropic glutamate receptors induces synaptic plasticity, the mechanism of which is thought to underlie learning, memory and drug-cue associations. The goal of this study was to examine the neural alterations in responses to group I metabotropic glutamate receptor (mGluR) agonists in the BLA to lateral capsula of CeA (BLA-CeLc) pathway in slices from rats exposed to cocaine-CPP conditioning and withdrawn for 14 days. mGluR1, but not mGluR5, agonist-induced long-term potentiation (mGluR1-LTP) in the BLA-CeLc pathway was reduced in rats withdrawal from cocaine for 2 and 14 days, and exhibited an altered concentration response to picrotoxin. Cocaine withdrawal also reduced γ-aminobutyric acid (GABA)ergic synaptic inhibition in CeLc neurons. Blocking cannabinoid receptor 1 (CB(1) ) reduced mGluR1-LTP in the saline-treated but not cocaine-withdrawn group. Response to CB(1) but not CB(2) agonist was altered after cocaine. Additionally, increasing endocannabinoid (eCB) levels abolished mGluR1-LTP in the saline but not cocaine-withdrawn group. However, CB(1) and CB(2) protein levels were increased in the amygdala of cocaine-withdrawn rats while mGluR1 and mGluR5 remained unchanged. These data suggested that the mechanisms underlying the diminished mGluR1-LTP in cocaine-withdrawn rats involve an altered GABAergic synaptic inhibition mediated by modulation of downstream eCB signaling. These changes may ultimately result in potentiated responses to environmental cues that would bias behavior toward drug-seeking.

Dopamine receptor mechanisms mediate corticotropin-releasing factor-induced long-term potentiation in the rat amygdala following cocaine withdrawal.

Corticotropin-releasing factor (CRF) in the amygdala is involved in stress responses. Moreover, dopaminergic neurotransmission in the brain reward system including the amygdala plays a significant role in the pathology of cocaine addiction. The present study analysed CRF-induced synaptic plasticity, its pharmacological sensitivity and interactions with the dopamine (DA) system in the basolateral to lateral capsula central amygdala (lcCeA) pathway after a 2-week withdrawal from repeated cocaine administration. A physiologically relevant CRF concentration (25 nm) induced long-term potentiation (LTP) that was enhanced after cocaine withdrawal. In saline-treated rats, CRF-induced LTP was mediated through N-methyl-d-aspartate (NMDA) receptors, L-type voltage-gated calcium channels (L-VGCCs) and CRF(1) receptors. However, in cocaine-withdrawn animals, activation of CRF(1) and CRF(2) receptors was found to enhance LTP. This enhanced CRF-induced LTP after cocaine withdrawal was mediated through endogenous activation of both D1- and D2-like receptors. Furthermore, expression of the D1 receptor (D1R) but not the D2R, D3R, D4R or D5R was significantly increased after cocaine withdrawal. CRF(1) but not CRF(2) protein expression was increased, suggesting that elevated levels of these proteins contributed to the enhancement of CRF-induced LTP during cocaine withdrawal. CRF interactions with the DA system in the amygdala may represent a fundamental neurochemical and cellular mechanism linking stress to cocaine-induced neuronal plasticity.