This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the joint Council of Allergy, Asthma & Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing “Environmental assessment and remediation: a practice parameter.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single person, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).
Allergy; cockroach; sensitization; disease; morbidity
Atopic dermatitis and psoriasis are common inflammatory diseases, canonically described as involving distinct T-helper polarization and granulocytic infiltration. Acute atopic dermatitis lesions are associated with TH2 and eosinophilic inflammation, while psoriasis lesions are associated with TH1/17 and neutrophilic inflammation. Despite intensive investigation, these pathways remain incompletely understood in vivo in human subjects.
Using atopic dermatitis and psoriasis lesional skin as exemplar TH2 and TH1/17 diseased tissue, we sought to clarify common and unique molecular and pathophysiologic features in inflamed skin with different types of inflammatory polarization.
We conducted gene expression microarray analyses to identify distinct and commonly dysregulated expression in atopic dermatitis (by Hanifin & Rajka criteria) and psoriasis lesions. We defined gene sets comprising genes encoding cytokines, chemokines, and growth factors that were uniquely or jointly dysregulated in atopic dermatitis and psoriasis, and calculated aggregate gene set expression scores for lesional skin of these dermatoses and healthy control skin.
The atopic dermatitis gene set score correlated with systemic and local measures of allergic inflammation including serum IgE, blood eosinophil count, and tissue eosinophils. Unexpectedly, genes encoding neutrophil chemoattractants among the common gene set were highly expressed in atopic dermatitis lesional skin. H&E and immunohistochemical analyses showed the numbers of neutrophils in atopic dermatitis lesional skin were comparable to those in psoriasis lesional skin, and both were correlated with the extent of expression of neutrophil chemoattractant genes.
These data are evidence that neutrophilic inflammation is a feature of lesional atopic dermatitis pathology, comorbid with allergic inflammation.
Atopic dermatitis; psoriasis; TH2; TH17; gene expression microarray; neutrophil; eosinophil
There are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American individuals are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care, or whether there is a predisposing genetic component.
To assess the relationship between genetic ancestry and severe exacerbations among African American individuals with asthma.
Participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These individuals were 12–56 years of age; received care from a single, large health system; and had a physician diagnosis of asthma. Genetic ancestry was estimated using a set of validated ancestry informative markers. Severe exacerbations (i.e., asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims.
We assessed genetic ancestry in 392 African American individuals with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among males but not among females. The association among males persisted after adjusting for potential confounders (relative risk of 4.30 for every 20% increase in African ancestry; P-value 0.029).
African ancestry was a significantly and positively associated with severe exacerbations among African American males. These findings suggest that a portion of the risk of asthma exacerbations in this high risk group is attributable to a genetic risk factor which partitions with ancestry.
asthma; continental population groups; African continental ancestry group; genetic association study; health status disparities; minority health
RAG2; Omenn syndrome; hyper-IgM syndrome
Tissue factor (TF), a primary initiator of blood coagulation, also plays a pivotal role in angiogenesis. TF expression in the airways is associated with asthma, a disease characterized in part by subepithelial angiogenesis.
To determine potential sources of TF and the mechanisms of its availability in the lung microenvironment.
Normal Human Bronchial Epithelial (NHBE) cells grown in air-liquid interface (ALI) culture were subjected to a compressive stress of 30 cmH2O; this is comparable to that generated in the airway epithelium during bronchoconstriction in asthma. Conditioned media and cells were harvested to measure TF mRNA and TF protein. We also tested bronchoalveolar lavage fluid (BALF) and airway biopsies from asthmatics and healthy controls for TF.
TF mRNA was upregulated 2.2-fold after 3 hours of stress compared to unstressed cells. Intracellular and secreted TF proteins were enhanced 1.6-fold and over 50-fold, respectively, compared to that of control cells after onset of compression. The amount TF in BALF from patients with asthma was found at mean concentrations that were 5 times greater than that of healthy controls. Immunohistochemical staining of endobronchial biopsies identified epithelial localization of TF with increased expression in asthma.
Exosomes isolated from the conditioned media of NHBECs and BALF of asthmatic subjects by ultracentrifugation contained TF.
Our in vitro and in vivo studies show that mechanically-stressed bronchial epithelial cells are a source of secreted TF and that exosomes are potentially a key carrier of the TF signal.
Asthma; tissue factor; exosomes; bronchoconstriction; mechanotransduction; bronchial epithelium
Viral upper respiratory infections have been implicated as a major cause of asthma exacerbations among school age children. Regular hand washing is the most effective method to prevent the spread of viral respiratory infections but, effective hand washing practices are difficult to establish in schools.
This randomized controlled trial evaluated whether a standardized regimen of hand washing plus alcohol-based hand sanitizer could reduce asthma exacerbations more than schools’ usual hand hygiene practices.
This was a two year, community-based, randomized controlled crossover trial. Schools were randomized to usual care then intervention (Sequence 1) or intervention then usual care (Sequence 2). Intervention schools were provided with alcohol-based hand sanitizer, hand soap, and hand hygiene education. The primary outcome was the proportion of students experiencing an asthma exacerbation each month. Generalized estimating equations were used to model the difference in the marginal rate of exacerbations between sequences while controlling for individual demographic factors and the correlation within each student and between students within each school.
527 students with asthma were enrolled among 31 schools. The hand hygiene intervention did not reduce the number of asthma exacerbations as compared to the schools’ usual hand hygiene practices (p=0.132). There was a strong temporal trend as both sequences experienced fewer exacerbations during Year 2 as compared to Year 1 (p<0.001).
While the intervention was not found to be effective, the results were confounded by the H1N1 influenza pandemic that resulted in substantially increased hand hygiene behaviors and resources in usual care schools. Therefore, these results should be viewed cautiously.
asthma; schools; children; hand hygiene; hand sanitizer
Asthma is heritable, influenced by the environment, and is modified by in utero exposures and aging; all of these features are also common to epigenetic regulation. Furthermore, the transcription factors that are involved in the development of mature T cells that are critical to the Th2 immune phenotype in asthma are regulated by epigenetic mechanisms. Epigenetic marks - DNA methylation, modifications of histone tails, and non-coding RNAs – work in concert with other components of cellular regulatory machinery to control spatial and temporal level of expressed genes. Technology to measure epigenetic marks on genomic scale and comprehensive approaches to data analysis have recently emerged and continue to improve. Alterations in epigenetic marks have been associated with exposures relevant to asthma, particularly air pollution and tobacco smoke, as well as asthma phenotypes in a few population-based studies. On the other hand, animal studies have begun to decipher the role of epigenetic regulation of gene expression associated with the development of allergic airway disease. Epigenetic mechanisms represent a promising line of inquiry that may, in part, explain the inheritance and immunobiology of asthma.
asthma; atopy; epigenetics; gene expression; DNA methylation; histone marks; noncoding RNAs
Genome-wide association studies of asthma have implicated many genetic risk factors, with
well-replicated associations at approximately 10 loci that account for only a small proportion of
the genetic risk.
We aimed to identify additional asthma risk loci by performing an extensive replication
study of the results from the EVE Consortium meta-analysis.
We selected 3186 SNPs for replication based on the p-values from the EVE Consortium
meta-analysis. These SNPs were genotyped in ethnically diverse replication samples from nine
different studies, totaling to 7202 cases, 6426 controls, and 507 case-parent trios. Association
analyses were conducted within each participating study and the resulting test statistics were
combined in a meta-analysis.
Two novel associations were replicated in European Americans: rs1061477 in the
KLK3 gene on chromosome 19 (combined OR = 1.18; 95% CI 1.10 – 1.25)
and rs9570077 (combined OR =1.20 95% CI 1.12–1.29) on chromosome 13q21. We could not
replicate any additional associations in the African American or Latino individuals.
This extended replication study identified two additional asthma risk loci in populations
of European descent. The absence of additional loci for African Americans and Latino individuals
highlights the difficulty in replicating associations in admixed populations.
Asthma; genetic risk factors; meta-analysis; KLK3
Eosinophils; Esophagitis; Symptoms; Therapy
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphoproliferation, accumulation of double-negative T cells, hypergammaglobulinemia G and A, and autoimmune cytopenia.
Although mostly associated with FAS mutations, different genetic defects leading to impaired apoptosis have been described in patients with ALPS, including the FAS ligand gene (FASLG) in rare cases. Here we report on the first case of complete FAS ligand deficiency caused by a homozygous null mutant.
Double-negative T-cell counts and plasma IL-10 and FAS ligand concentrations were determined as ALPS markers. The FASLG gene was sequenced, and its expression was analyzed by means of Western blotting. FAS ligand function was assessed based on reactivation-induced cell death.
We describe a patient born to consanguineous parents who presented with a severe form of ALPS caused by FASLG deficiency. Although the clinical presentation was compatible with a homozygous FAS mutation, FAS-induced apoptosis was normal, and plasma FAS ligand levels were not detectable. This patient carries a homozygous, germline, single-base-pair deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation, confirming its recessive trait.
FAS ligand deficiency should be screened in patients presenting with ALPS features but lacking the usual markers, including plasma soluble FAS ligand and an in vitro apoptotic defect. An activation-induced cell death test could help in discrimination.
Autoimmune lymphoproliferative syndrome; Fas ligand; diagnosis
Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.
Childhood asthma; natural history
A recent study of peanut allergic subjects treated with omalizumab generated some results that were concordant with a study of cat allergics being treated with omalizumab. However, there were differences that provided additional insights into the nature of the cellular responses in allergic patients.
Determine the cause for failure to suppress the allergen-induced basophil response during treatment with omalizumab.
Peanut allergic patients were treated with omalizumab. Clinical, serological and cellular indices relevant to the response of the patient and their peripheral blood basophils (specific-to-total IgE ratio, cell surface FceRI expression, histamine release responses to anti-IgE Ab or peanut allergen) were obtained at 3 times.
Following treatment, approximately 60% of the subjects’ basophil responses to peanut allergen did not significantly decrease. In 40% of cases, the in vitro basophil response to peanut allergen increased 2–7 fold. The increases were associated with two primary factors, a high (>10%) specific-to-total IgE ratio and an increase in the intrinsic response of the basophil to IgE-mediated stimulation. The extent to which the basophil response to peanut allergen increased was inversely correlated with the improvement in the individual’s ability to tolerate ingestion of peanut.
The basophil response during treatment with omalizumab is a consequence of two competing factors, suppression of allergen-specific IgE on the cell surface vs. increased intrinsic sensitivity to IgE-mediated stimulation. In peanut allergy, the basophil response appears to mitigate against the ability of omalizumab to improve the patients’ tolerance of oral allergen.
basophil; anti-IgE; peanut; syk; IgE receptor
The evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized and a minimal important difference (MID) is not established.
We assessed the reliability, validity, and responsiveness to change of the ASUI in a population of adult asthma patients. We also sought to determine the MID for the ASUI.
Adult asthma patients (n = 1648) from two previously completed multicenter randomized trials were included. Demographic information, spirometry, ASUI scores, and other asthma questionnaire scores were obtained at baseline and during follow-up visits. Participants also kept a daily asthma diary.
Internal consistency reliability of the ASUI was 0.74 (Cronbach’s alpha). Test-retest reliability was 0.76 (intra-class correlation). Construct validity was demonstrated by significant correlations between ASUI scores and Asthma Control Questionnaire (ACQ) scores (Spearman correlation r = −0.79, 95% CI [−0.85, −0.75], P<0.001) and Mini Asthma Quality of Life Questionnaire (Mini AQLQ) scores (r = 0.59, 95% CI [0.51, 0.61], P<0.001). Responsiveness to change was demonstrated, with significant differences between mean changes in ASUI score across groups of participants differing by 10% in the percent predicted FEV1 (P<0.001), and by 0.5 points in ACQ score (P < 0.001). Anchor-based methods and statistical methods support an MID for the ASUI of 0.09 points.
The ASUI is reliable, valid, and responsive to changes in asthma control over time. The MID of the ASUI (range of scores 0–1) is 0.09.
Asthma Symptom Utility Index; reliability; validity; responsiveness; minimal important difference
Infection with human papilloma virus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and DOCK8 are typically associated with extensive HPV infections, whereas several other primary immune defects have severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them.
Immunodeficiency; human papilloma virus; HPV; warts; squamous; carcinoma; dysplastic
Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in TH2 priming and polarization.
We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection.
Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12.
OX40L was expressed mainly on CD11c+MHC class II (MHCII)+CD11b+ DCs but not CD103+ DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection.
In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and TH2 polarization, accounting for the enhanced response on reinfection.
Respiratory syncytial virus; OX40 ligand; thymic stromal lymphopoietin
Formal economic evaluation using a model-based approach is playing an increasingly important role in healthcare decision making.
To develop a model using an objective measure of lung function, prebronchodilator forced expiratory volume in 1 second as a percent of predicted (FEV1% predicted), as the primary independent factor to predict the frequency of adverse events related to exacerbation of asthma on a population level.
We developed a Markov simulation model of childhood asthma using data from the Childhood Asthma Management Program (CAMP). The primary outcomes were the result of asthma exacerbations defined as: hospitalizations, emergency department (ED) visits, and the need for oral corticosteroid therapy. Predicted monthly frequencies for each acute event were based on negative binomial regression equations estimated from the placebo arm of CAMP with covariates of age, prebronchodilator FEV1% predicted, time in study, prior hospitalizations, and prior nocturnal awakenings.
Simulated versus observed mean number of acute events were similar within the placebo and treatment groups. While the trial demonstrated treatment effects of 48% reduction in hospitalizations, 46% reduction in ED visits, and 44% reduction in the need for oral corticosteroid therapy at 48 months; the model simulated similar reductions of 49% in hospitalizations, 41% in ED visits, and 46% in the need for oral corticosteroid therapy.
Our findings suggest that longitudinal intervention effects may be modeled through FEV1% predicted to estimate hospitalizations, ED visits, and need for oral corticosteroid therapy in childhood asthma for planning and evaluation purposes.
asthma; pediatric patients; lung function; FEV percent predicted; hospitalizations; emergency department visits; model
Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 may disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococci, especially Staphylococcus aureus. Here, we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococci.
Primary immunodeficiency diseases; signal transducer and activator of transcription; STAT1; STAT3; IL-17; Candida; Staphylococcus
Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype.
We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD.
A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD.
The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Mattft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD.
In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.
Allergy; association; atopic dermatitis; atopy; eczema; filaggrin; flaky tail; Matt; mattrin; mouse; mutation; Tmem79; AD, Atopic dermatitis; DM, Double mutant; FLG, Filaggrin; HDM, House dust mite; hpf, High-power field; MAPEG, Membrane-associated proteins in eicosanoid and glutathione metabolism; OR, Odds ratio; SNP, Single nucleotide polymorphism; TEWL, Transepidermal water loss; WT, Wild-type
We performed this study to evaluate how age and device affect the systemic exposure of inhaled fluticasone propionate (FP) in children. The findings indicate an anti-static valved holding chamber significantly increases systemic exposure of FP.
valved holding chamber; lung bioavailability; fluticasone propionate; asthma
IgE-mediated allergic reactions to cashews and other nuts can trigger life-threatening anaphylaxis. Proactive therapies to decrease reaction severity do not exist.
We aimed to determine the efficacy of pepsin-digested cashew proteins used as immunotherapy in a murine model of cashew allergy.
Mice were sensitized to cashew and then underwent challenges with digested or native cashew allergens to assess the allergenicity of the protein preparations. Using native or pepsinized cashew proteins, mice underwent oral or intraperitoneal sensitization protocols to determine the immunogenic properties of the protein preparations. Finally, cashew-sensitized mice underwent an immunotherapy protocol with native or pepsinized cashew proteins and subsequent provocation challenges.
Pepsinized cashew proteins elicited weaker allergic reactions than native cashew proteins but importantly retained the ability to stimulate cellular proliferation and cytokine production. Mice sensitized with pepsinized proteins reacted on challenge with native allergens, demonstrating that pepsinized allergens retain immunogenicity in vivo. Immunotherapy with pepsinized cashew allergens significantly decreased allergic symptoms and body temperature decrease relative to placebo after challenge with native and pepsinized proteins.
Immunologic changes were comparable after immunotherapy with native or pepsinized allergens: TH2-type cytokine secretion from splenocytes was decreased, whereas specific IgG1 and IgG2a levels were increased.
Pepsinized cashew proteins are effective in treating cashew allergy in mice and appear to work through the same mechanisms as native protein immunotherapy.
Food allergy; tree nut allergy; cashew; immunotherapy; pepsin; murine model