CD100 boosts the inflammatory response in the challenge phase of allergic contact dermatitis in mice.

BACKGROUND: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal-resident memory CD8+ T (TRM ) cells play a key role. The mechanisms involved in the activation of CD8+ TRM cells during allergic flare-up responses are not understood. METHODS: The expression of CD100 and its ligand Plexin B2 on CD8+ TRM cells and keratinocytes before and after allergen exposure was determined by flow cytometry and RT-qPCR. The role of CD100 in the inflammatory response during the challenge phase of ACD was determined in a model of ACD in CD100 knockout and wild-type mice. RESULTS: We show that CD8+ TRM cells express CD100 during homeostatic conditions and up-regulate it following re-exposure of allergen-experienced skin to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB). Furthermore, Plexin B2 is up-regulated on keratinocytes following exposure to some contact allergens. We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1ß and decreased recruitment of neutrophils to the epidermis. CONCLUSION: Our study demonstrates that CD100 is expressed on CD8+ TRM cells and is required for full activation of CD8+ TRM cells and the flare-up response of ACD.

The junctional adhesion molecule-like protein (JAML) is important for the inflammatory response during contact hypersensitivity.

BACKGROUND: The junctional adhesion molecule-like protein (JAML) plays important roles in wound healing and activation of epidermal γδ T cells in mice. Whether JAML plays a role in contact hypersensitivity (CHS), the animal model of allergic contact dermatitis (ACD), is not known. METHODS: To examine the role of JAML in CHS, we used various mouse models of CHS in JAML knockout (KO) and wild-type (WT) mice. Furthermore, the expression of the JAML ligand coxsackievirus and adenovirus receptor (CXADR) on keratinocytes was accessed in vitro and in vivo. RESULTS: JAML KO mice had a diminished inflammatory response during both the sensitization and elicitation phase of CHS and had reduced numbers of CD8+ and CD4+ T cells in the epidermis. Furthermore, interferon γ (IFNγ), interleukin 1ß (IL-1ß) and CXCL10 production were significantly reduced in JAML KO mice during the elicitation phase. We found that CD8+ T cells express JAML and that JAML is essential for rapid flare-up responses to contact allergens. Finally, we show that keratinocytes up-regulate the JAML ligand CXADR following exposure to contact allergens. CONCLUSION: Our study is the first to show a central role of JAML in CHS and reveals a potential new target for the treatment of ACD in humans.

CD4+ T cells inhibit the generation of CD8+ epidermal-resident memory T cells directed against clinically relevant contact allergens.

BACKGROUND: CD8+ epidermal-resident memory T (TRM ) cells play central roles in local flare-up responses to experimental contact allergens by inducing massive influx of neutrophils to the epidermis upon allergen challenge. Whether similar immunopathogenic mechanisms are involved in the responses to clinically relevant contact allergens is unknown. METHODS: The immune response to cinnamal, ρ-phenylenediamine (PPD) and methylisothiazolinone (MI) was studied in a well-established mouse model for allergic contact dermatitis that includes formation of TRM cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols. RESULTS: We show that the formation of CD4+ and CD8+ epidermal TRM cells and the inflammatory response are highly allergen-dependent. However, the magnitude of the flare-up responses correlated with the number of epidermal CD8+ TRM cells, CXCL1/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4+ T cells strongly enhanced the number of epidermal CD8+ TRM cells, the flare-up response and the epidermal infiltration of neutrophils for all allergens. CONCLUSION: As the first, this study demonstrates that clinically relevant contact allergens have the ability to generate pathogenic, epidermal CD8+ TRM cells that recruit neutrophils following re-exposure to the allergen, but that this normally is counteracted by the simultaneous induction of anti-inflammatory CD4+ T cells.

Making US poison centers a part of the solution to the COVID-19 pandemic.

OBJECTIVES: Our six goals are: 1) describe the relationship between the National Strategy for the COVID-19 Response and Pandemic Preparedness and the 55 US poison centers (PCs); 2) detail FDA emergency Use Authorization (EUA) COVID-19 vaccine-related regulatory procedures and associated acronyms; 3) list availability of specific vaccine clinical information to support PC staff COVID-19 vaccination and adverse event (AE) data collection; 4) describe required health care practitioner COVID-19 vaccine AE reporting to the Vaccine AE Reporting System (VAERS) and PC reporting options; 5) document public and health care professionals' use of PCs for COVID-19 vaccine information; and 6) propose strategy to maximize PCs contribution to the pandemic solution. METHODS: We reviewed 13-Feb-2020 through 15-Apr-2021 National Poison Data System (NPDS) COVID-19 records for changes over time. We examined NPDS cases and VAERS COVID-19 vaccine reports 1-Nov-2020 through 2-Apr-2021 for vaccine manufacturer, patient characteristics, state, and clinical effects. RESULTS: PCs reported 1,052,174 COVID-19 contacts; maximum (peak) contacts/day (12,163) on 16-Mar-2020. As of 5-Apr-2021 the US reported >167 million administrations of COVID-19 vaccines (Pfizer-BioNTech, Moderna or Janssen). US PCs reported 162,052 COVID-19 vaccine contacts. Most (61.1%) were medical information calls, 34.9% were drug information, and 2.58% were exposures. Over the same period VAERS reported 49,078 COVID-19 vaccine cases reporting 226,205 symptoms - headache most frequent, ranging from 20% to 40% across the 3 vaccines. CONCLUSIONS AND RECOMMENDATIONS: Although differences exist between the intent and content of the 2 data sets, NPDS volume is compelling. The PC nationwide 800 number facilitates data collection and suggests comingling the 2 data streams has merit. PC professionals received tens of thousands of calls and can: 1) support fact-based vaccine information; 2) contribute vaccine AE follow-up information: 3) advocate for best-case coding and reporting, especially for vaccine adverse experiences.

CD8+ tissue-resident memory T cells recruit neutrophils that are essential for flare-ups in contact dermatitis.

BACKGROUND: Allergic contact dermatitis (ACD) is classically described as a delayed-type hypersensitivity reaction. However, patients often experience flare-ups characterized by itching erythema, edema, and often vesicles occurring within hours after re-exposure of previously sensitized skin to the specific contact allergen. Recent studies have indicated that skin-resident memory T (TRM ) cells play a central role in ACD. However, the pathogenic role of TRM cells in allergen-induced flare-ups is not known. METHODS: By the use of various mouse models and cell depletion protocols, we investigated the role of epidermal TRM cells in flare-up reactions to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene. The inflammatory response was measured by changes in ear thickness, and the cellular composition in epidermis was determined by flow cytometry and confocal microscopy. Finally, adaptive transfer and inhibitors were used to determine the role of TRM cells, neutrophils, and CXCL1/CXCL2 in the response. RESULTS: We show that CD8+ TRM cells initiate massive infiltration of neutrophils in the epidermis within 12 h after re-exposure to the contact allergen. Depletion of neutrophils before re-exposure to the allergen abrogated the flare-up reactions. Furthermore, we demonstrate that CD8+ TRM cells mediate neutrophil recruitment by inducing CXCL1 and CXCL2 production in the skin, and that blockage of the C-X-C chemokine receptor type 1 and 2 inhibits flare-up reactions and neutrophil infiltration. CONCLUSION: As the first, we show that epidermal CD8+ TRM cells cause ACD flare-ups by rapid recruitment of neutrophils to the epidermis.

2021 Annual Report of the National Poison Data System© (NPDS) from America's Poison Centers: 39th Annual Report.

ABSTRACTINTRODUCTION: This is the 39th Annual Report of America's Poison Centers' National Poison Data System (NPDS). As of 1 January, 2021, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 4.87 [4.38, 8.62] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system. METHODS: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. RESULTS: In 2021, 2,851,166 closed encounters were logged by NPDS: 2,080,917 human exposures, 62,189 animal exposures, 703,086 information requests, 4,920 human confirmed nonexposures, and 54 animal confirmed nonexposures. Total encounters showed a 14.0% decrease from 2020, and human exposure cases decreased by 2.22%, while health care facility (HCF) human exposure cases increased by 7.20%. All information requests decreased by 37.0%, medication identification (Drug ID) requests decreased by 20.8%, and medical information requests showed a 61.1% decrease, although these remain about 13-fold higher than before the COVID-19 pandemic. Drug Information requests showed a 146% increase, reflecting COVID-19 vaccine calls to PCs. Human exposures with less serious outcomes have decreased 1.80% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.56% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (11.2%), household cleaning substances (7.49%), cosmetics/personal care products (5.88%), antidepressants (5.61%), and sedatives/hypnotics/antipsychotics (4.73%). As a class, antidepressant exposures increased most rapidly, by 1,663 cases/year (5.30%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (10.8%), household cleaning substances (10.7%), analgesics (8.16%), dietary supplements/herbals/homeopathic (7.00%), and foreign bodies/toys/miscellaneous (6.51%). Drug identification requests comprised 3.64% of all information contacts. NPDS documented 4,497 human exposures resulting in death; 3,809 (84.7%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and the need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

2020 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 38th Annual Report.

INTRODUCTION: This is the 38th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January, 2020, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 6.15 [4.60, 8.62] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system. METHODS: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. RESULTS: In 2020, 3,316,738 closed encounters were logged by NPDS: 2,128,198 human exposures, 66,745 animal exposures, 1,116,568 information requests, and 5,160 human confirmed nonexposures. Total encounters showed a 28.9% increase from 2019, while health care facility (HCF) human exposure cases decreased by 10.6%. While all information requests increased by 218.0%, medication identification (Drug ID) requests decreased by 31.5%, and human exposure cases decreased by 0.928%. Medical Information requests showed a 32.6-fold increase, reflecting COVID-19 pandemic calls to PCs. Human exposures with less serious outcomes have decreased 1.90% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.59% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.3%), household cleaning substances (8.37%), cosmetics/personal care products (6.53%), antidepressants (5.30%), and sedatives/hypnotics/antipsychotics (4.92%). As a class, antidepressant exposures increased most rapidly, by 1,793 cases/year (5.84%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (11.8%), household cleaning substances (11.3%), analgesics (7.57%), foreign bodies/toys/miscellaneous (6.71%), and dietary supplements/herbals/homeopathic (6.44%). Drug identification requests comprised 2.89% of all information contacts. NPDS documented 4,488 human exposures resulting in death; 3,869 (86.2%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Pathogenic CD8+ Epidermis-Resident Memory T Cells Displace Dendritic Epidermal T Cells in Allergic Dermatitis.

The skin is our interface with the outside world, and consequently it is exposed to a wide range of microbes and allergens. Recent studies have indicated that allergen-specific skin-resident memory T (TRM) cells play a role in allergic contact dermatitis (ACD). However, the composition and dynamics of the epidermal T-cell subsets during ACD are not known. Here we show that exposure of the skin to the experimental contact allergen DNFB results in a displacement of the normally occurring dendritic epidermal T cells (DETC) concomitant with an accumulation of epidermal CD8+CD69+CD103+ TRM cells in mice. By studying knockout mice, we provide evidence that CD8+ T cells are required for the displacement of the DETC and that DETC are not required for recruitment of CD8+ TRM cells to the epidermis following allergen exposure. We demonstrate that the magnitude of the allergic reaction correlates with the number of CD8+ epidermal TRM cells, which again correlates with allergen dose and number of allergen exposures. Finally, in an attempt to elucidate why CD8+ epidermal TRM cells persist in the epidermis, we show that CD8+ epidermal TRM cells have a higher proliferative capability and are bioenergetically more stable, displaying a higher spare respiratory capacity than DETC.

Evaluation of toxicity after acute accidental methotrexate ingestions in children under 6 years old: a 16-year multi-center review.

CONTEXT: There is little data on the frequency of adverse events following acute methotrexate ingestions in pediatric patients. Likewise, recommendations for observation length, site and management strategies in this population are not well established. Therefore, most recommendations are modeled after management of chronic overdose in patients with underlying medical conditions. OBJECTIVE: The primary objective of this study is to determine the frequency of acute toxicity after acute methotrexate accidental unsupervised ingestions in patients less than six years. In addition, we describe the frequency of late toxicity and characterize the management site and approaches. MATERIALS AND METHODS: This is a retrospective cohort study of pediatric accidental unsupervised methotrexate ingestions reported to six poison centers in the United States over a 16 year period. Demographic information, exposure details, signs, symptoms, treatments, length and location of observation and outcomes were collected. RESULTS: 103 patients met inclusion criteria. Methotrexate dose was reported in 86 patients (84%) and ranged from 1.3 mg-75 mg. The majority of cases (97%) ingested a dose ≤20 mg. The significant majority of cases experienced no clinical effects (99 of 103 cases; 96%). Three children experienced minor outcome (3%). There were no patients with a major outcome or death. CONCLUSIONS: The incidence of toxicity from pediatric single, acute ingestions of methotrexate is rare and when it occurs is generally limited to no or only minimally concerning effects. Because concentrations from single ingestions were consistent with low subtoxic exposures, we believe that home monitoring without hospital referral and without methotrexate specific therapy is reasonable in those with acute ingestions up to 20 mg.

Effect of using pediatric emergency department virtual observation on inpatient admissions and lengths of stay.

OBJECTIVE: To determine whether using emergency department (ED) virtual observation for select pediatric conditions decreases admission rates for these conditions, and to examine effects on length of stay. METHODS: The option of ED virtual observation care for 9 common pediatric conditions was introduced in 2009; associated order sets were developed. Retrospective secondary analyses of administrative data from our tertiary care pediatric ED and children's hospital were performed for the year before (year 0) and after (year 1) this disposition option was introduced. The proportion of visits admitted to the inpatient unit and length of stay (LOS) were determined for all visits considered eligible for ED virtual observation care on the basis of diagnosis codes for both study years. RESULTS: There were 1614 observation-eligible visits in year 0 and 1510 in year 1. In year 1, 18% (n = 266) of observation-eligible visits received ED virtual observation care. Admission rates for observation-eligible visits were similar after this model of care was introduced (25% year 0, 29% year 1, P = .02). Median LOS for ED virtual observation visits was 8.8 hours (interquartile range 6.5-12.4). ED LOS was shorter for ED discharges (5.6 hours year 0, 5.1 hours year 1, P < .001) and unchanged for admissions (6.0 hours year 0, 5.8 hours, year 1, P = .41) after introducing ED virtual observation. CONCLUSIONS: Admission rates for observation-eligible visits were not lower in the year after ED virtual observation care was introduced. LOS decreased for ED discharges and was unchanged for admissions. Reevaluation of the effects of pediatric ED virtual observation on admission rates and LOS after longer periods of use is indicated.

Underlying Rationale and Approach to Treat Hypertension in Adolescents by Physicians of Different Specialty.

OBJECTIVE: To describe the underlying clinical decision-making rationale among general pediatricians, family physicians, pediatric cardiologists and pediatric nephrologists in their approach to an adolescent with hypertension. METHODS: We conducted semi-structured phone interviews with a convenience sample of physicians from the above-mentioned 4 specialties. Each participant was asked to "think aloud" regarding their approach to a hypothetical patient - 12 year old boy with persistent hypertension for 6 months. Standardized open-ended questions about potential factors that could affect physicians' diagnosis and treatment strategies (e.g., patient age) were used. Interviews were audio-recorded; transcribed verbatim; transcripts were independently coded by 2 investigators; emergent themes identified and inter-coder agreement achieved. Thematic analysis was performed based on grounded theory. RESULTS: Nineteen participants included 5 general pediatricians, 5 pediatric cardiologists, 5 pediatric nephrologists and 4 family physicians. Five themes emerged: 1) Accuracy of blood pressure measurement and hypertension diagnosis, 2) Shift in the epidemiology of pediatric hypertension from secondary to primary hypertension, 3) Patient characteristics considered in the decision to initiate workup, 4) Obesity-centered choice of diagnostic tests and lifestyle modifications, and 5) Variable threshold for initiating antihypertensive pharmacotherapy vs. referral to hypertension specialists. CONCLUSIONS: There is variation across primary care and specialty physicians who provide care for children and adolescents with hypertension. Key areas of variability include the willingness to initiate antihypertensive medications, the use of diagnostic tests (e.g., ambulatory blood pressure monitoring), and the perceived need for specialty referral. Further study is needed to assess whether different treatment paradigms result in differential patient outcomes.

Disaster preparedness education and a Midwest Regional Poison Center.

OBJECTIVE: To assess knowledge and comfort related to disaster preparedness and response gained and retained from a disaster medicine workshop given to Certified Specialists in Poison Information (CSPI). DESIGN: A pilot study with a pre-post intervention design. SETTING: A Midwest Regional Poison Center. PARTICIPANTS: All CSPIs employed at the participating Poison Center (N = 27) were recruited. Participation ranged from 44 percent (n = 12) for the 4-month postworkshop knowledge quiz to 78 percent (n = 21) for the preworkshop survey. INTERVENTION: A disaster medicine workshop was given to the CSPIs. Quizzes and surveys were done preworkshop and then repeated at 1 week, 4 months, and 14 months postworkshop. MAIN OUTCOME MEASURES: CSPI knowledge and comfort pertaining to disaster-related calls. RESULTS: CSPIs' comfort levels with calls regarding major chemical or nuclear/radiation disasters significantly increased and stayed elevated during all follow-up periods [Kruskal-Wallis chi2 (3) = 13.1, p = 0.01]. The average preworkshop quiz score was 58.2 percent. A statistically significant increase in mean quiz score was demonstrated amongst preworkshop and postworkshop scores at all tested time intervals (F = 18.8, p < 0.001). CONCLUSIONS: CSPIs' knowledge regarding disaster management significantly increased after a disaster medicine workshop, and this knowledge was significantly retained for the 14-month duration of this study. Currently, there are no uniform guidelines for Poison Centers regarding disaster response training. Studies targeted at the development of educational competencies for CSPIs and disaster response would help to standardize this much needed education.

Amanita bisporigera ingestion: mistaken identity, dose-related toxicity, and improvement despite severe hepatotoxicity.

Ingestion of wild mushrooms has led to unintentional poisonings caused by mistaken identity. We report 3 cases of exposure to Amanita bisporigera, demonstrating dose-related toxicity. The use of nasobiliary drainage as a novel approach to interrupting the enterohepatic circulation of amatoxins is illustrated. Pathophysiology and treatment of Amanita poisoning are reviewed.

Skin breakdown and blisters from senna-containing laxatives in young children.

BACKGROUND: At the direction of the Food and Drug Administration, phenolphthalein was removed from all over-the-counter laxatives in 1999. Phenolphthalein was then replaced in most laxative products with the natural product senna from Cassia acutifolia Delile, which contains various anthraquinones. No data are available on the safety of senna use in children <6 years of age. OBJECTIVE: To describe the clinical outcomes of exposure to unintentional ingestion of senna-containing laxatives in young children. METHODS: All ingestion exposures of senna-containing laxatives in children <5 years of age from 6 poison centers over a 9-month period were evaluated. Inclusion criteria required 24-hour follow-up and the presence of diarrhea to confirm ingestion. Parents were told routinely that severe diaper rash was possible and to protect the perianal area with frequent cleansing and a barrier ointment if the child was wearing diapers. RESULTS: During the study period, 111 cases were reported: 19 children experienced no diarrhea, 4 were lost to follow-up, and 88 exposures were evaluated. Fifty-two children (59%) were