Ambient Air Quality and Fatal Asthma Exacerbations among Children in North Carolina.

BACKGROUND: Little is known about the role of air quality in fatal asthma exacerbations among children. METHODS: We collected information about 80 deaths that occurred in North Carolina from 2001 through 2016, among children aged 5-17 years, with asthma identified as the primary cause of death. We linked information about each death with county-level estimates of particulate matter ≤2.5 µm (PM2.5) and ozone (O3). Using the linked data, we conducted a case-crossover analysis of associations between PM2.5 and O3 lagged by 3-5 days with the odds of fatal asthma exacerbations. RESULTS: In the highest tertile of PM2.5 lag(3-5), the odds of a fatal exacerbation of asthma were more than twice the odds in the lowest tertile (odds ratio = 2.2; 95% confidence interval = 1.1, 4.6). CONCLUSION: These findings from North Carolina provide evidence to support the hypothesis that ambient air pollution increases the risk of fatal exacerbations of asthma among children.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Caregiver Perceptions about their Decision to Pursue Tracheostomy for Children with Medical Complexity.

OBJECTIVE: To describe the perceptions of caregivers of children with medical complexity (CMC) about their decision to pursue tracheostomy for their children, in particular the satisfaction with their decision. STUDY DESIGN: In this qualitative study conducted in western North Carolina between 2013 and 2014, we interviewed 56 caregivers of 41 CMC who had received tracheostomies in the past 5 years. Three of the CMC were deceased at the time of the interview; 8 were decannulated. In-depth interviews (35 English, 6 Spanish) were conducted, audio-recorded, and transcribed verbatim. We used ATLAS.ti software to manage data and identified themes related to caregiver perceptions about tracheostomy decision. RESULTS: We found that caregivers often chose tracheostomy because extending the lives of their children and being able to care for them at home were important. Caregivers reported the many benefits of tracheostomy including improvement in respiratory symptoms, physical and developmental health, quality of life, and means to provide medical care quickly when needed. There were negative effects of tracheostomy such as mucous plugs, excessive secretions, accidental decannulation necessitating emergency tracheostomy tube change, and the increased infection risk. Providing medical care for CMC with tracheostomy at home was difficult, but improved over time. Caregivers were generally satisfied with their decision to pursue tracheostomy for their CMC. CONCLUSIONS: Decisional satisfaction with tracheostomy for CMC is high. In counseling caregivers about tracheostomy, clinicians should present both the benefits and risks. Future studies should quantify the outcomes described in this study.

Prehospital Administration of Epinephrine in Pediatric Anaphylaxis - A Statewide Perspective.

OBJECTIVE: Timely administration of epinephrine is critical in the treatment of anaphylaxis. This study sought to determine the frequency of administration of epinephrine by EMS providers caring for pediatric patients in the prehospital setting. METHODS: We examined data from the NC EMS database (PreMIS) from 2010-3 to determine frequency of epinephrine administration in pediatric patients with anaphylaxis. We studied patients <18 years of age with an EMS provider impression of "allergic reaction." Anaphylaxis was present if there was hypotension (defined as SBP < 90 or DBP < 45 for patients age 11 and older, and SBP < 70 + (2 × age) for patients ages 0-10), or impaired respirations (defined as description of labored or absent respirations, or RR < 12 or > 30). We determined the overall frequency of epinephrine administration. A multivariate logistic regression was then constructed to examine the impact of the following variables on appropriate epinephrine administration: age < 10, non-white race, rural county of case origin, duration of transportation from scene, and presence of a paramedic. RESULTS: A total of 504 patients met inclusion criteria, of which 471 demonstrated anaphylaxis as previously defined. A total of 153 patients with anaphylaxis received epinephrine (32.4%, 95% CI 28.3-36.9%). Age < 10 was associated with increased odds of not receiving epinephrine appropriately (OR 2.90, 95% CI 1.85-4.54, p < 0.001). Other variables did not have statistically significant impact on epinephrine administration. CONCLUSION: There are missed opportunities for prehospital administration of epinephrine in pediatric patients with anaphylaxis. Very young children (age < 10) had increased odds for not receiving epinephrine.

Individualized therapy for persistent asthma in young children.

BACKGROUND: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications. METHODS: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response. RESULTS: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/µL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments. CONCLUSIONS: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.

Candidate gene analysis of the surfactant protein D gene in pediatric diffuse lung disease.

Mutations in surfactant-associated genes cause childhood diffuse lung disease. Mice lacking surfactant protein D develop lung disease with age. However, we identified no novel surfactant protein D gene (SFTPD) coding or splice region variants in 73 unrelated children with diffuse lung disease from a cohort enriched for genetic surfactant dysfunction.

The role of religion and spirituality in caregiver decision-making about tracheostomy for children with medical complexity.

Children with medical complexity (CMC) receive life-sustaining treatments such as tracheostomy. The objective of this paper is to explore the roles of religion and spirituality (R&S) of caregivers of children with medical complexity (CMC) in their decision to pursue tracheostomy for their children. We conducted 41 in-depth interviews of caregivers of CMC who had received tracheostomies in the prior 5 years. Four themes emerged: (1) Caregivers believed R&S to be powerful for their children's healing, and helped them cope with their children's illnesses; (2) Spirituality was an important factor for caregivers in the decision to pursue tracheostomy for their children; (3) Many caregivers did not discuss their spirituality with clinicians for a variety of reasons; (4) Clergy and hospital chaplains played a major supportive role overall; however, they did not play a significant role in the decision-making process. Our study shows the importance of R&S, and the roles of clergy and chaplains in pediatric tracheostomy decision-making.

Surfactant dysfunction.

Mutations in genes encoding proteins needed for normal surfactant function and metabolism cause acute lung disease in newborns and chronic lung disease in older children and adults. While rare these disorders are associated with considerable pulmonary morbidity and mortality. The identification of genes responsible for surfactant dysfunction provides clues for candidate genes contributing to more common respiratory conditions, including neonatal respiratory distress syndrome and lung diseases associated with aging or environmental insults. While clinical, imaging and histopathology features of these disorders overlap, certain features are distinctive for surfactant dysfunction. Natural histories differ depending upon the genes involved and a specific diagnosis is important to provide accurate information concerning prognosis and mode of inheritance. Diagnosis of surfactant dysfunction can be made by biopsy, but identification of the specific gene involved requires molecular genetic testing, which is non-invasive. Currently there are no effective medical treatments for surfactant dysfunction. Development of therapies is a priority for research, which may benefit patients with other lung diseases.

Fatal familial lung disease caused by ABCA3 deficiency without identified ABCA3 mutations.

OBJECTIVE: To test the hypothesis that some functionally significant variants in the gene encoding member A3 of the ATP Binding Cassette family (ABCA3) are not detected using exon-based sequencing approaches. STUDY DESIGN: The first of 2 female siblings who died from neonatal respiratory failure was examined for mutations with sequence analysis of all ABCA3 exons and known regulatory elements within the 5' untranslated region. Lung tissue from both siblings was immunostained for ABCA3 and examined with electron microscopy. Segregation of ABCA3 alleles was determined with analysis of polymorphisms in the parents and all children. RESULTS: No mutations were identified with ABCA3 sequence analysis in the first affected infant. Affected siblings were concordant for their ABCA3 alleles, but discordant from those of their unaffected siblings. ABCA3 protein was not detectable with immunostaining in lung tissue samples from both affected infants. Electron microscopy demonstrated small, dense lamellar bodies, characteristically seen with ABCA3 mutations. CONCLUSIONS: The segregation of ABCA3 alleles, absence of ABCA3 immunostaining, lung pathology, and ultrastructural findings support genetic ABCA3 deficiency as the cause of lung disease in these 2 infants, despite the lack of an identified genetic variant.

Lung function and late pulmonary complications among survivors of hematopoietic stem cell transplantation during childhood.

Hematopoietic stem cell transplantation (HSCT) is used to treat an expanding array of malignant and non-malignant disorders. Pulmonary complications represent a significant source of morbidity and mortality in HSCT recipients. Young children, whose lungs are still developing and growing, may be especially susceptible to the insults of irradiation, drug toxicities, and recurrent infections associated with immunosuppression. Late pulmonary complications, those occurring more than three months after transplantation, are often noninfectious and present with nonspecific symptomatology. Pulmonary function testing (PFT) is a mainstay of monitoring pulmonary health in HSCT recipients. The pulmonologist should be familiar with common patterns seen on PFT in recipients of HSCT during childhood. In this review, we describe the findings in studies which have examined lung function over time in patients who underwent HSCT during childhood. We discuss patterns of PFT abnormalities, associated noninfectious syndromes and their clinical implications, as well as directions for future research.

Cardiac and kidney hormones cure up to 86% of human small-cell lung cancers in mice.

BACKGROUND: Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, and the kidney hormone urodilatin have anticancer effects in vitro. MATERIALS AND METHODS: These cardiac hormones and urodilatin were infused subcutaneously for 28 days with weekly fresh hormones since they lose biological effects at body temperature for more than a week at 0.3 nm kg(-1) body weight in athymic mice bearing human small-cell lung carcinomas. RESULTS: Long acting natriuretic peptide, vessel dilator, kaliuretic peptide, atrial natriuretic peptide and urodilatin eliminated 86%, 71%, 57%, 43% (P < 0.001 for the cardiac hormones) and 25% (P < 0.05; urodilatin) of the human small-cell lung carcinomas. The treated small-cell lung carcinomas that were not cured grew rapidly, similar to the untreated controls, whose volume was 7 fold larger in 1 week, 18-fold increased in 2 weeks, 39-fold increased in 3 weeks, 63-fold increased in 1 month and 97-fold increased in volume in 6 weeks. One vessel dilator treated small-cell lung carcinoma animal developed a large tumour (8428 mm3 volume) on treatment and this tumour was eliminated with utilizing atrial natriuretic peptide and then long acting natriuretic peptide sequentially. CONCLUSIONS: Four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas in athymic mice. Urodilatin can also eliminate small-cell lung carcinomas but at a lower cure rate of 25%. Unresponsive lesions can be eliminated by utilizing different hormones synthesized by the atrial natriuretic peptide gene in a sequential manner.

Comorbidities of asthma in U.S. children.

BACKGROUND: Few epidemiologic population-based data are available to describe the wide range of health conditions that affect children with asthma. We conducted this study to identify common comorbidities of asthma during childhood and compare the prevalences of selected comorbidities among children with and without asthma. METHODS: We analyzed weighted data from the 2012 National Health Interview Survey child sample, a sample of 10,954 U.S. children aged 3-17 years. Information about each child's health, including history of asthma and other health conditions, was provided by an adult proxy respondent. We conducted binomial regression to compare the prevalences of 41 selected health conditions among children with and without current asthma. RESULTS: An estimated 10.4% of children aged 3-17 years (n = 1202) were identified as having current asthma. Nearly all conditions considered were more common among children with than without asthma. Compared to children without asthma, children with asthma had higher prevalences of hay fever or respiratory allergies (prevalence difference [PD]: 30.5%; 95% CI: 26.6, 34.4), eczema or skin allergies (PD: 14.1%; 95% CI: 10.7, 17.5), sinusitis (PD: 11.3%; 95% CI: 8.4, 14.1), food or digestive allergies (PD: 10.4%; 95% CI: 7.7, 13.1), and difficulty with emotions, concentration, behavior, or getting along (PD: 7.9%; 95% CI: 4.7, 11.1). CONCLUSIONS: These results highlight the burden of comorbidities among children with asthma. Improved understanding of the impact of comorbidities among children with asthma may help develop best practices for the assessment, treatment, and control of coexisting health conditions.

Congestive heart failure: increased cardiac and extracardiac atrial natriuretic peptide gene expression.

OBJECTIVES: The present investigation was designed to determine if atrial natriuretic peptide (ANP) gene expression increases in extracardiac as well as within the heart in congestive heart failure. METHODS: Congestive heart failure (CHF) was induced by producing cardiac hypertrophy secondary to an aortocaval fistula in Sprague-Dawley rats. To characterize this model, control and CHF rats had cardiac catheterizations and transthoracic echocardiography. ANP messenger RNA was measured by RNAase protection analysis in atria, ventricles, liver, colon, and stomach of CHF and sham rats and quantitated by 2-D scanning. The product of ANP gene expression was determined in each of these tissues with high performance-gel permeation chromatography. To help determine if increased degradation of atrial natriuretic peptides occur in congestive heart failure, the circulating concentrations and the excretion of the atrial natriuretic peptides into urine were measured by specific radioimmunoassays. RESULTS: ANP steady-state mRNA increased 4.2 +/- 0.05 and 4.3 +/- 0.06-fold, respectively, in the antrum of the stomach and within the heart ventricle of CHF rats compared with age-matched sham rats. ANP gene expression was present but not increased in atria, liver, and gastrointestinal tract of the CHF rats. High-performance gel permeation chromatography revealed that the product of this ANP gene expression within the stomach and heart ventricle in CHF animals was the ANP prohormone. There was not any decrease in the metabolism of these peptides by the kidney in CHF. CONCLUSIONS: ANP steady-state mRNA increases in extracardiac (i.e., stomach antrum) tissue as well as in the ventricle of the heart in CHF. The product of the ANP gene expression, i.e., the ANP prohormone is the same in the extracardiac tissues as within the heart. Whether the increased extracardiac ANP steady-state mRNA and its resultant increased atrial natriuretic peptides helps prevent bowel wall edema in CHF needs to be elucidated.

Atrial natriuretic hormone, vessel dilator, long-acting natriuretic hormone, and kaliuretic hormone decrease the circulating concentrations of total and tree T4 and free T3 with reciprocal increase in TSH.

The present investigation was designed to determine whether atrial natriuretic peptides (ANPs) consisting of amino acids 1-30 [i.e. long-acting natriuretic hormone (LANH)], 31-67 (vessel dilator), 79-98 (kaliuretic hormone), and 99-126 (atrial natriuretic hormone [ANH]) of the 126-amino acid ANH prohormone decrease the circulating concentrations of total and free T4 and/or free T3 in healthy humans (n = 30). Vessel dilator, kaliuretic hormone, LANH, and ANH decreased the circulating concentrations of total T4 by 61%, 58%, 47%, and 55% and of free T4 by 60%, 67%, 79%, and 79%, whereas free T3 decreased 72%, 67%, 71%, and 67% (P < 0.05 for each), respectively, when infused at 100 ng/kg BW x min for 60 min. Vessel dilator, kaliuretic hormone, LANH, and ANH simultaneously increased circulating TSH concentrations 4- to 12.5-fold (P < 0.004). The decreases in T4 and T3 with reciprocal increases in TSH lasted 2-3 h after cessation of the respective ANP infusions. The reciprocal increase in TSH with the decreases in T4 and T3 suggests that their modulation of T4 and T3 concentrations occurs in the thyroid rather than in the pituitary or hypothalamus, because TSH would be decreased in the circulation if their inhibitory effects were in either the hypothalamus or pituitary.

Evaluation of NH2-terminus gastrins in gastrinoma syndrome.

Forty-six patients with the gastrinoma syndrome were divided into 2 categories: 1) benign sporadic gastrinoma (n = 30), and 2) gastrinoma with metastases to liver (n = 16). Thirteen of the 46 patients had multiple endocrine neoplasia type I syndrome. Serum gastrin levels in patients fasted overnight were determined by RIA using antisera directed toward the NH2- and COOH-terminals of heptadecapeptide gastrin (G17) and the NH2-terminus of the triacontatetrapeptide (G34). These results were compared with findings in 50 normal subjects. In the normal subjects, the mean COOH-terminal gastrin-17 level was higher [65 +/- 8 (+/- SEM) pg/ml] than the NH2-terminal gastrin-17 level (11 +/- 0.2 pg/ml) and lower than the NH2-terminal gastrin-34 level (134 +/- 20 pg/ml). The levels of NH2-terminal gastrin-17 were higher in patients with metastatic disease than in those with benign gastrinoma, whereas the COOH-terminal gastrin-17 and the NH2-terminal gastrin-34 levels were similarly high in both groups. The mean ratio of NH2-terminal gastrin-17 to COOH-terminal gastrin-17 was less than 1 in normal subjects (0.22 +/- 0.02) and benign gastrinoma patients (0.2 +/- 0.04), and it was 2.2 +/- 0.41 in the patients with metastatic gastrinoma. An NH2 to COOH gastrin-17 ratio greater than 1 was found in 13 of 16 patients with metastatic gastrinoma, but in none of the patients with benign gastrinoma or normal subjects. Similar results were found in multiple endocrine neoplasia type I patients with benign and metastatic disease. A high NH2 to COOH gastrin-17 ratio is suggestive of metastatic gastrinoma. In 4 patients with metastatic gastrinoma, the NH2 to COOH gastrin-17 ratio fell in parallel with the response to chemotherapy.

Characterization of the in vivo and in vitro inhibition of gastrin secretion from gastrinoma by a somatostatin analogue (SMS 201-995).

Earlier experiments characterized the effect of SMS 201-995 on gastrin secretion from gastrinoma in vivo. The results showed that the somatostatin analogue inhibits basal as well as secretin- and calcium-stimulated gastrin secretion. The current study examined the effect of SMS 201-995 on gastrin secretion from gastrinoma in vitro. Gastrinoma cells were prepared in cell culture or acute cell dispersion to study basal gastrin release. In cell culture, SMS 201-995 at 10(-9) M, 10(-8) M, and 10(-7) M significantly stimulated gastrin secretion (basal medium gastrin, 157 +/- 7.9 pg/ml; with SMS 201-995 10(-9) M, 786 +/- 62 pg/ml; with SMS 201-995 10(-8) M, 569 +/- 72 pg/ml; and with SMS 201-995 10(-7) M, 258 +/- 26 pg/ml). In contrast, in acute cell dispersion, the somatostatin analogue inhibited gastrin secretion (basal medium gastrin, 12.8 +/- 1.3 ng/ml; with SMS 201-995 10(-9) M, 9.0 +/- 0.1 ng/ml; with SMS 201-995 10(-8) M, 8.4 +/- 1.5 ng/ml; and with SMS 201-995 10(-7) M, 7.9 +/- 0.2 ng/ml). Gastrinoma cells were prepared in cell culture to study the effect of SMS 201-995 on gastrin secretion stimulated by secretin and by post-receptor increases in adenosine cyclic nucleotide. The somatostatin analogue inhibited gastrin secretion stimulated by secretin (10(-6) M) (797 +/- 48 pg/ml for secretin alone, compared with 396 +/- 9.4 pg/ml for secretin plus SMS 201-995). SMS 201-995 did not inhibit gastrin secretion stimulated by dibutyryl cyclic AMP (10(-7) M) (617 +/- 62 pg/ml for dibutyryl cyclic AMP alone, compared with 778 +/- 55 pg/ml for the two together). In vitro, SMS 201-995 inhibits basal gastrin secretion from gastrinoma prepared in acute cell dispersion, but not gastrinoma in cell culture, probably due to differences in basal secretory rates. The effect in vitro is less than that in vivo. SMS 201-995 does not inhibit postreceptor increases in adenosine nucleotide. This indirectly supports the hypothesis that SMS 201-995 acts in gastrinoma cells to inhibit gastrin secretion by inhibition of adenylate cyclase activity.

hNT neurons express an immunosuppressive protein that blocks T-lymphocyte proliferation and interleukin-2 production.

Ntera2/D1 cells had an A1 B8 Bw6 Cw7 DR3 DR52 major histocompatibility complex (MHC) genotype. Its neuronal derivative, hNT neurons, expressed A1 B8 Bw6 MHC class I molecules, but did not activate, and its hNT supernatant suppressed allogeneic mixed lymphocyte cultures (MLC) >98% (p<0.01), phytohemagglutinin (PHA)-activated T-cell proliferation >87% (p<0.01), even 48 h after stimulation, suppressed phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced T-cell proliferation >99% (p<0.001), and reduced interleukin-2 (IL-2) production (p<0.01), while maintaining T cells in a quiescent G(0)/G(1) state without lowering their viability. This immunosuppressive activity was attributed to a 40-100-kDa anionic hNT protein with an isoelectric point of 4.8.