A Case Report of Allergic Hypersensitivity to Color Additives in Slurpee® Beverages.

Introduction: Many commercially available foods and beverages contain color additives to which patients may develop allergic hypersensitivity. Several color additives currently approved for commercial sale in the United States have raised health concerns to a varying degree as testing and evidence of carcinogenicity, genotoxicity, and hypersensitivity has thus far been inadequate. Common uses for color additives include baked goods (eg, cakes, pastries, candy), flavored dairy products such as yogurt, sports-themed drinks (eg, Gatorade® Fruit Punch), and red-dyed Slurpee® beverages. Methods: We present the case of a patient who experienced color additive-related allergic hypersensitivity reactions after consumption of Slurpee® beverages, which may place her at risk when consuming other commercially available beverages and food products containing color additives. Percutaneous skin testing and an oral challenge were administered using three different red color additives (two color additives for skin testing and one color additive for the oral challenge). Results: The specific color additive precipitating her symptoms was not conclusively identified. Review of the literature acknowledges the idea that further research into color additive-related allergy should be conducted as there are many commercially available color additives that can elicit hypersensitivity reactions after consumption. Conclusion: Current research shows that of the red color additives available, Citrus Red, Red No. 3, and Red No. 40 are recognized to elicit such reactions. In order to lessen the burden of color additive-related hypersensitivity in the general population, public education, increased research, and subsequent regulations should be implemented.

Healthcare Economics of a Coronavirus Disease 2019 Pop-Up Vaccination Center.

Introduction: Creation of pop-up vaccination sites at trusted community locations has been encouraged to address vaccine hesitancy and provide equitable access to COVID-19 vaccination in minority communities. This study sought to study the healthcare economics of a community-based COVID-19 pop-up vaccination center in terms of the following: costs associated with operating the vaccination center, analysis of billing data from patients who received the Moderna COVID-19 vaccine, and costs of hospitalization for COVID-19 which may be avoided with widespread vaccination. Methods: The pop-up vaccination center was located in Port Jefferson Station, NY, USA. Costs associated with operation of the COVID-19 pop-up vaccination center were quantified, itemized, and tabulated. Current Procedural Technology codes were used to identify patients who received the Moderna COVID-19 vaccine. Billing data were quantified for the cohort as well as per each patient to receive the vaccine. Costs associated with provision of urgent care, emergency, and hospital services to patients with COVID-19 were obtained. Results: The total cost to operate the vaccination center was $25,880. The vaccination center administered the initial dose of the Moderna COVID-19 vaccine to N=251 patients between March and May, 2021. The standard hospital costs for patients admitted to the medical ICU due to COVID-19 ranged from $8,913 to $190,714, per patient. Conclusion: Since the Moderna COVID-19 vaccine series is effective in preventing hospitalization for 93% of patients, this community-based vaccination center's administration of the vaccine series to 240 patients meant aversion of hospitalization due to COVID-19 related morbidity for 223 patients. Therefore, the true impact of this vaccination center, measured in averted hospital costs, ranges from $1,987,599 to $42,529,222.

Rux largely restores lungs in Iraq PM-exposed mice, Up-regulating regulatory T-cells (Tregs).

Background Military personnel post-deployment to Iraq and Afghanistan have noted new-onset respiratory illness. This study's primary objective was to further develop an animal model of Iraq Afghanistan War Lung Injury (IAW-LI) and to test a novel class of anti-injury drug called RuX. Methods Particulate Matter (PM) samples were obtained in Iraq then characterized by spectromicroscopy. C57BL/6 mice underwent orotracheal instillation with PM, followed by drinkable treatment with RuX. Lung histology, inspiratory capacity (FlexiVent), thymic/splenic regulatory T cell (Treg) number, and whole-lung genomics were analyzed. Results Tracheal instillation of Iraq PM led to lung septate thickening and lymphocytic inflammation. PM-exposed mice had suppression of thymic/splenic regulatory T-cells (Tregs). Drinking RuX after PM exposure attenuated the histologic lung injury response, improved lung inspiratory capacity, and increased Tregs. Pooled whole lung genomics suggest differences among gene expression of IL-15 among control, PM, and PM + RuX groups. Conclusions RuX, a ruthenium and alpha-lipoic acid complex, attenuates lung injury by improving histology and inspiratory capacity via upregulation of Tregs in Iraq PM-exposed C57BL/6. Plausible genomic effects may involve IL-15 whole lung gene expression.

Gross Hematuria and Lower Urinary Tract Symptoms Associated With Military Burn Pits Exposures in US Veterans Deployed to Iraq and Afghanistan.

OBJECTIVE: The aim of the study is to describe rates of hematuria and other lower urinary tract symptoms, including self-reported cancer rates, among veterans postburn pits emissions exposure during deployment to Iraq and Afghanistan. METHODS: US post-9/11 veterans with burn pits emissions exposure confirmed via DD214 forms in the Burn Pits360.org Registry were sent a modified survey. Data were deidentified and anonymously coded. RESULTS: Twenty-nine percent of the 155 respondents exposed to burn pits self-reported seeing blood in their urine. The average index score of our modified American Urological Association Symptom Index Survey was 12.25 (SD, 7.48). High rates of urinary frequency (84%) and urgency (76%) were self-reported. Bladder, kidney, or lung cancers were self-reported in 3.87%. CONCLUSIONS: US veterans exposed to burn pits are self-reporting hematuria and other lower urinary tract symptoms.

Attenuation of Human Growth Hormone-Induced Rash With Graded Dose Challenge.

Adult growth hormone (GH) deficiency is rare and requires replacement with extrinsic/synthetic injection. GH hypersensitivity has been reported; specifically, atopic patients may develop rashes from somatotropin therapy. Allergic and non-allergic skin reactions to recombinant human GH are uncommon and infrequently reported. We describe a graded-dose challenge with intravenous Norditropin® in a 65-year-old atopic adult woman who developed a severe whole-body rash with Norditropin FlexPro® administration on several occasions but was negative on skin-prick testing to Norditropin® percutaneously and intradermally, but the patch testing was positive for gold and nickel. The patient was registered as a direct admission to the emergency room at a university hospital for a rapid antigen coronavirus disease 2019 (COVID-19) testing after having received two COVID-19 vaccinations and re-testing four months after vaccination. She was then directly admitted to a non-COVID-19 intensive care unit with direct bedside supervision by a registered nurse and a physician board certified in internal medicine, allergy/immunology, and pulmonary diseases. The patient brought a Norditropin® pen which our pharmacy team attached to a compatible syringe for dilutions. A graded dose challenge at a final dosage of 0.1 mL was performed and the patient was monitored for allergic and other adverse drug reactions, which did not occur. At the time of writing this case report, the patient has been maintained on Norditropin FlexPro® 0.1 mL and has not experienced any adverse reactions, including recurrent skin eruptions. The case presented is the first to describe a patient who successfully tolerated a graded dose challenge of an adult patient to GH replacement therapy (as Norditropin®) under supervision in an intensive care unit, whereas prior to reporting of this case, a graded dose challenge to GH replacement therapy had only been successfully performed in a child using another formulation of somatotropin (Humatrope®). Hence, this case lends support that graded dose challenge with somatotropin analogs may be considered for patients with isolated GH deficiency such as in the case presented here.

Vasoactive Intestinal Peptide Knockout (VIP KO) mouse model of sulfite-sensitive asthma: up-regulation of novel lung carbonyl reductase.

BACKGROUND: We earlier reported spontaneous features of asthma in Vasoactive Intestinal Peptide knockout mice (VIP KO): 1) peribronchiolar airway inflammation, with accumulation of lymphocytes and eosinophils, 2) pro-inflammatory cytokine production of IL-5, IL-6, with IFN-γ, and 3) airway hyper-responsiveness to inhaled methacholine. In human asthma, a phenotype with sulfite sensitivity leads to airway inflammation and hyper-responsiveness to inhaled sulfites, and is associated with upregulation of anti-oxidant protein lung carbonyl reductase. For the present experiments, we examined the role of VIP in modulating anti-oxidant genes and their proteins, including lung carbonyl reductase. RESULTS: Four male VIP KO mice and four wild-type age- and gender matched mice had lungs examined for whole genome microarray and a proteomics approach using mass spectrometry. The proteomics analysis revealed that a novel variant of anti-oxidant protein lung carbonyl reductase (car3) was uniquely and markedly elevated in the VIP KO mice. RT-PCR indicated that carbonic anhydrase 3, which is an anti-oxidant protein, was elevated in the VIP KO mice. CONCLUSIONS: These data support the concept that VIP influences the endogenous oxidant/antioxidant balance. One potential implication is that VIP and its analogues may be used to treat inflammatory diseases, including asthma.

VIP and endothelin receptor antagonist: an effective combination against experimental pulmonary arterial hypertension.

BACKGROUND: Pulmonary Arterial Hypertension (PAH) remains a therapeutic challenge, and the search continues for more effective drugs and drug combinations. We recently reported that deletion of the vasoactive intestinal peptide (VIP) gene caused the spontaneous expression of a PH phenotype that was fully corrected by VIP. The objectives of this investigation were to answer the questions: 1) Can VIP protect against PH in other experimental models? and 2) Does combining VIP with an endothelin (ET) receptor antagonist bosentan enhance its efficacy? METHODS: Within 3 weeks of a single injection of monocrotaline (MCT, s.c.) in Sprague Dawley rats, PAH developed, manifested by pulmonary vascular remodeling, lung inflammation, RV hypertrophy, and death within the next 2 weeks. MCT-injected animals were either untreated, treated with bosentan (p.o.) alone, with VIP (i.p.) alone, or with both together. We selected this particular combination upon finding that VIP down-regulates endothelin receptor expression which is further suppressed by bosentan. Therapeutic outcomes were compared as to hemodynamics, pulmonary vascular pathology, and survival. RESULTS: Treatment with VIP, every other day for 3 weeks, begun on the same day as MCT, almost totally prevented PAH pathology, and eliminated mortality for 45 days. Begun 3 weeks after MCT, however, VIP only partially reversed PAH pathology, though more effectively than bosentan. Combined therapy with both drugs fully reversed the pathology, while preventing mortality for at least 45 days. CONCLUSIONS: 1) VIP completely prevented and significantly reversed MCT-induced PAH; 2) VIP was more effective than bosentan, probably because it targets a wider range of pro-remodeling pathways; and 3) combination therapy with VIP plus bosentan was more effective than either drug alone, probably because both drugs synergistically suppressed ET-ET receptor pathway.

VIP Regulates the Development & Proliferation of Treg in vivo in spleen.

BACKGROUND: Mounting evidence supports a key role for VIP as an anti-inflammatory agent and promoter of immune tolerance. It suppresses TNF-α and other inflammatory cytokines and chemokines, upregulates anti-inflammatory IL-10, and promotes immune tolerant cells called T regulatory (Treg) cells. VIP KO mice have recently been demonstrated to have spontaneous airway and pulmonary perivascular inflammatory responses, as part of asthma-like and pulmonary hypertension phenotypes, respectively. Both inflammatory responses are correctable with VIP. Focusing on this model, we have now investigated the influence of VIP not only on inflammatory cells but also on Treg cells. METHODS: Using flow cytometric analysis, we examined the relative preponderance of CD25+CD4+ cells and anti-inflammatory Treg cells, in extracts of thymus and spleen from VIP KO mice (5 VIP KO; 5 VIP KO+ VIP; 10 wild-type). This method allowed antibody-based flow cytometric identification of Treg cells using surface markers CD25 and CD4, along with the: 1) intracellular activation marker FoxP3; and 2) Helios, which distinguishes cells of thymic versus splenic derivation. CONCLUSIONS: Deletion of the VIP gene results in: 1) CD25+CD4- cell accumulation in the thymus, which is corrected by VIP treatment; 2) more Treg in thymus lacking Foxp3 expression, suggesting VIP is necessary for immune tolerance; and, 3) a tendency towards deficiency of Treg cells in the spleen, which is normalized by VIP treatment. Treg lacking Helios are induced by VIP intrasplenically rather than by migration from the thymus. These results confirm the dual role of VIP as an anti-inflammatory and immune tolerance-promoting agent.

Plausible Role of Asthma Biological Modifiers in the Treatment of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a T-helper type-2 (Th2/T2) cell-mediated disease characterized by 15 or more eosinophils per high-powered esophageal biopsy microscopy field (eos/hpf), excluding other causes. EoE is often clinically characterized by symptoms such as dysphagia, nausea, food impaction, and chest pain that do not respond to antacids. Two-thirds of patients are unresponsive to proton pump inhibitors (PPIs). Steroids may be effective but pose long-term health risks and can lose efficacy in patients with serum eosinophilia greater than 1,500 cells/µL. Because EoE is not IgE-mediated, allergy skin testing for food may benefit a subset of patients. These therapies have shortcomings, which necessitate further investigation. Herein, we report a patient successfully treated with benralizumab (anti-IL-5Rα), demonstrating a potential solution to the lack of effective treatments for EoE.

Angioedema in a child with a liver transplant, intussusception, and normal c4 levels.

Swelling is a common chief complaint among patients. Swelling and hives are not typical of hereditary angioedema. Organ transplantation drugs are associated with angiodema and may complicate diagnosis. Our objective was to manage a complex case of angioedema in a setting of rashes and liver transplantation. We present an illustrative case of angioedema, rashes, and intussusception in a setting of a liver transplant and tacrolimus use with a family history of autoimmune disease. Treatment with the kallikrein inhibitor, kalbitor, eliminated angioedema and intussusception, though not permanently. Serial C1 esterase [corrected] inhibitor levels were only suppressed during severe attacks of angioedema. C1q autoantibody was elevated. Although 95% of cases of hereditary angioedema (HAE) have low [corrected] C4 levels, those with C1q immune complexes have autoantibodies leading to low-grade inflammation and eventual consumption of C1 esterase inhibitor levels with C4 unaffected. Rashes associated with angioedema are not urticarial. Physicians should learn to recognize the signs of attacks of HAE.

New-onset asthma among soldiers serving in Iraq and Afghanistan.

Since June 4, 2004, asthma diagnosed and symptomatic after the age of 12 years has been an exclusion criterion for military enlistment unless exempted via medical waiver. The Department of Defense determined that 13% of U.S. Army Medic visits in Iraq are for new-onset acute respiratory illness; case reports of veterans with asthma that began in Iraq and Afghanistan War zones have surfaced. This prompted our study to determine whether new asthma is diagnosed more frequently among Iraq/Afghanistan War troops versus stateside-based troops. Retrospective review of asthma diagnoses among computerized charts for military personnel discharged from active duty and examined between March 1, 2004 and May 1, 2007, at the Veterans Affairs Medical Center (VAMC), Northport, NY, classified soldiers by (1) deployment status-whether they were stationed in Iraq/Afghanistan for a 1-year tour of duty or stationed in the United States, and (2) VA diagnosis of asthma per International Classification of Disease codes. Associations between deployment and asthma statuses were evaluated/stratified by gender/age group. Eligibility criteria entailed (1) residence in Long Island, (2) aged 18-45 years, and (3) both U.S. military service and discharge dates between March 1, 2004 and May 1, 2007. Out of 6233 patients who served between 2004 and 2007 and were followed at the Northport VAMC, 290 new-onset/prevalent asthma cases were identified. Deployment to Iraq was associated with a significantly higher risk of asthma compared with stateside soldiers (6.6% versus 4.3%; with a crude odds ratio, 1.58; 95% CI, 1.18, 2.11). These associations persist when stratified by gender and age group. Deployment to Iraq and Afghanistan is associated with new-onset asthma. Etiologic studies, surveillance, incidence, epidemiology, and assessing response to therapy are recommended.

Allergy and Lung Injury Among Rescue Workers Exposed to the World Trade Center Disaster Assessed 17 Years After Exposure to Ground Zero.

OBJECTIVE: Investigate the following in rescue and cleanup workers exposed to the World Trade Center (WTC) disaster 17 years post-fallout: (1) allergic hypersensitivity; (2) spirometry; (3) impulse oscillometry; and (4) the reversibility of airway hyperresponsiveness and distal airways narrowing pre- and post-bronchodilator. METHODS: In subjects (n = 54) referred to our clinic from the WTC Health Program for management of allergy-immunology services, environmental allergy testing, impulse oscillometry (IOS), and spirometry results were retrospectively reviewed to determine the long-term impact of exposure to the WTC fallout. RESULTS: Rescue and cleanup workers exposed to the WTC fallout had a high incidence of allergic hypersensitivity and had evidence of permanent small airways dysfunction characterized by distal airways narrowing and airway hyperresponsiveness. CONCLUSION: Following exposure to the WTC disaster, the patients in our cohort developed allergic hypersensitivity and severe lung injury with only partial reversibility.

Post 9/11: high asthma rates among children in Chinatown, New York.

We reported increased rates of childhood asthma and worsening of preexisting asthma in Chinatown near the World Trade Center (WTC) after September 11, 2001. This conclusion was corroborated by the WTC Health Registry in 2003, which showed asthma prevalence in children <5 years old was higher than national estimates. In 2002, ethnic Chinese in New York City (NYC), based on 2000 U.S. Census addresses, were reported to have the lowest levels of asthma compared with other ethnic NYC neighborhoods. This study was designed to determine if Chinatown asthma rates are still higher than other ethnic neighborhoods and if rates decreased since 2003. We surveyed 353 parents of children at a Chinatown elementary school, conducted spirometry on 202 students, measured air pollution (PM2.5), and sampled dust from the floor of the school during 2008 for concentrations of dust-mite antigens, cat, rat, mouse, and cockroach. Asthma rates of 14.4% were reported in children who refused spirometry if they lived <1 mi from the WTC. The rate was 4.9% if they lived farther away. Twenty-nine percent of all students (4-12 years old) who had spirometry showed a forced expiratory volume at 1 second (FEV(1)) of <80% predicted normal. Among children who were alive in 2001, 17.4% had an FEV(1) of < or = 75% predicted. The concentration of PM2.5 reached a high level of 40 microg/m(3). Indoor aeroallergen concentrations were negligible. Chinatown asthma rates are still higher than among other groups (29% versus the NYC reference rate of 13%). High air pollution levels may account for increased asthma incidence. It is possible that exposure to toxins on September 11, 2001 accentuated the effect of subsequent exposure to air pollution.

Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene.

BACKGROUND: Vasoactive intestinal peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, has been reported absent in pulmonary arteries from patients with idiopathic pulmonary arterial hypertension (PAH). We have tested the hypothesis that targeted deletion of the VIP gene may lead to PAH with pulmonary vascular remodeling. METHODS AND RESULTS: We examined VIP knockout (VIP-/-) mice for evidence of PAH, right ventricular (RV) hypertrophy, and pulmonary vascular remodeling. Relative to wild-type control mice, VIP-/- mice showed moderate RV hypertension, RV hypertrophy confirmed by increased ratio of RV to left ventricle plus septum weight, and enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumen. Lung sections also showed perivascular inflammatory cell infiltrates. No systemic hypertension and no arterial hypoxemia existed to explain the PAH. The condition was associated with increased mortality. Both the vascular remodeling and RV remodeling were attenuated after a 4-week treatment with VIP. CONCLUSIONS: Deletion of the VIP gene leads to spontaneous expression of moderately severe PAH in mice during air breathing. Although not an exact model of idiopathic PAH, the VIP-/- mouse should be useful for studying molecular mechanisms of PAH and evaluating potential therapeutic agents. VIP replacement therapy holds promise for the treatment of PAH, and mutations of the VIP gene may be a factor in the pathogenesis of idiopathic PAH.

A plane screw fixation is a nidus for Paecilomyces sinusitis in a patient with aspirin exacerbated respiratory disease.

Titanium plane screw fixation of the frontal sinus is an approach used by otolaryngologists to obliterate this space in an attempt to reduce sinus infections. In this case, however, the titanium used became a nidus of infection which cultured the fungus Paecilomyces. The patient also had a hypersensitivity reaction to mold with positive skin tests and IgE, as well as eosinophilic esophagitis. Treatment entailed anti-fungals, anti-IgE, and fungal immunotherapy to multiple fungal antigens prevalent to the geographic region. The patient also had aspirin exacerbated respiratory disease which responded to aspirin desensitization. Her symptoms resolved after 3 months.

The Role of Iraqi Dust in Inducing Lung Injury in United States Soldiers-An Interdisciplinary Study.

United States soldiers are returning from the Greater Middle East with respiratory illnesses ranging from new onset asthma to constrictive bronchiolitis. The etiology of the diseases is unknown. A study was conducted to determine the possible role of local mineral dust in the development of abnormal respiratory illnesses in soldiers during and after deployment in Iraq. A dust sample obtained in proximity to a burn pit in Camp Victory, Iraq, (CVD) was characterized both chemically and mineralogically. For comparison, a dust sample from Fort Irwin, California, (FID) was also collected. The ability of the dust samples to generate reactive oxygen species (ROS) was quantified, as well as their ability to generate an inflammatory stress response (ISR) in human lung epithelial cells. Both samples are comprised of common silicate and carbonate minerals and contain heavy metals with concentration ranges expected for mineral dust. The ISR generated by each sample was within the range of inert material with the minimal stress generated associated with the carbonate phases. The findings based on this one sample suggest that the origin of the disease is not driven by the particles ability to generate ROS. However it is likely that particle overload, and associated complications, or endotoxin contribute extensively to pathogenesis.

NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.

Clozapine-associated cardiac dysfunction during a gastroenteritis outbreak.

We report that two young adult patients who were initiated with clozapine for severe psychosis during a hospital-wide gastroenteritis outbreak went into severe shock. Neither patient had troponin elevation. Each required left ventricular assist device support for myocarditis. Endomyocardial biopsy revealed lymphocytic myocarditis in one patient and eosinophilic myocarditis in the other. The former patient expired. Polymerase chain reaction testing was negative for Coxsackie virus. These two patients illustrate that myocarditis can occur at usual incipient doses and that there may be an epidemiologic risk associated with gastroenteritis. Although the white blood cell (WBC) count is expected to decrease with clozapine, these patients had persistently elevated WBC counts. In conclusion, physicians should exercise caution when prescribing clozapine, especially for those with diarrhea.