Peanut and tree nut allergies garner attention because reactions to these common foods are characteristically severe, are responsible for the majority of fatalities caused by food allergy, are persistent, and appear to be increasing in prevalence. Although there is great interest in tracking the prevalence of these allergies, determining the exact number of those affected over time has remained elusive.
To estimate the general population prevalence of food allergies, researchers have sometimes had to content themselves with assessments based on self-report of “convincing” reactions, because the diagnostic standard of oral challenge is impractical, risky, and expensive. Using this approach, Sicherer et al (J Allergy Clin Immunol 2010;125:1322-6) report findings of the most recent cross-sectional telephone survey to collect self-reported information on peanut, tree nut, and, additionally, sesame allergy. They employed the same survey used in 1997 and 2002 to assess prevalence in 2008, then compared the results from all three surveys.
Significant increases in peanut/tree nut and tree nut allergy in children were reported from 2002 to 2008, though increase in peanut allergy was not significant in that period. Self-reported peanut allergy in children increased significantly from 0.4% in 1997 to 1.4% in 2008. Tree nut allergy also showed significant increased from 0.2% to 1.1% across the same period. Sesame allergy was reported from only 13 survey participants at a rate of 0.1%; however, 2008 was the first year that information on sesame allergy was collected. The authors report that no significant increase in peanut and/or tree nut allergy was reported in adults.
They suggest that possible explanations for the increased rate of self-reported peanut allergy might be increased availability of peanuts in many food products, especially in highly allergenic roasted form, as well as oral exposure that is either immunologically too early or late, and/or environmental exposure. Also, Sicherer et al. point out that the prevalence in US children is similar to the prevalence reported by recent studies in Canada, the UK, and Australia.
We asked lead author Scott Sicherer, MD, from Mount Sinai School of Medicine, to comment on the study. “To my knowledge, this is the first attempt to track these allergies on a population basis in the US using the same methods thrice over a decade,” says Sicherer. “A recent review of the food allergy literature in JAMA [Journal of the American Medical Association] pointed out that due to various methodological issues, we do not have solid data on prevalence, with estimates that food allergy affects more than 1-2% but less than 10% of the population and there are limited data on time trends. Although our study has limitations inherent to self reported allergy and participation rates of telephone surveys, it provides an interesting perspective supporting a likely increase of childhood peanut/tree nut allergies and underscores that millions are affected by these allergies.”
Readers interested in this topic might also want to see the article by Ben-Shoshan et al., also in the June issue (J Allergy Clin Immunol 2010;125: 1327-1335), which looks at prevalence of peanut, tree nut, fish, shellfish, and sesame allergies in Canada.
We want to hear from you. Please feel free to post your questions or comments below. All questions and comments will be forwarded to the authors for a response.
Tuesday, June 1, 2010
Exactly how can specific IgE levels help in the diagnosis of food allergy?
An important question for researchers and clinicians who work with food allergies is whether food-specific IgE and skin prick test results can be used reliably as ersatz measures of allergen sensitization (see also our News Beyond Our Pages blog from May 14). The reason is that the clinical standard for food allergy diagnoses is double-blind, placebo-controlled food challenge, which is expensive, costly, and requires dedicated personnel and facilities because of the risk of anaphylaxis.
In a Letter to the Editor in JACI (J Allergy Clin Immunol 2010;125:1391-2), van Nieuwaal et al. report results from a study conducted in 103 children with suspected peanut allergy. Peanut-specific IgE levels were correlated to results of diagnostic food challenge to evaluate the predictive power of specific IgE and food challenges were performed regardless of a possible history of anaphylaxis. The population was very atopic as well, with greater than 80% having atopic dermatitis. The authors report that peanut-specific IgE was correlated to positive food challenge results in approximately 55% of the children. Specificity of IgE values of 10.4 [92%], 24.8 [98%] and 25.5 kU/L [100%] were significant for predicting outcome of food challenge. The authors note that the specific IgE levels were not sensitive, though, and that values lower than these do not indicate that there would be no reaction to oral food challenge.
The authors conclude that using these IgE levels as cutoffs would obviate diagnostic oral food challenges in at least some of the children. Oral food challenge would still be needed to determine the sensitivity and severity of the peanut allergy.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
In a Letter to the Editor in JACI (J Allergy Clin Immunol 2010;125:1391-2), van Nieuwaal et al. report results from a study conducted in 103 children with suspected peanut allergy. Peanut-specific IgE levels were correlated to results of diagnostic food challenge to evaluate the predictive power of specific IgE and food challenges were performed regardless of a possible history of anaphylaxis. The population was very atopic as well, with greater than 80% having atopic dermatitis. The authors report that peanut-specific IgE was correlated to positive food challenge results in approximately 55% of the children. Specificity of IgE values of 10.4 [92%], 24.8 [98%] and 25.5 kU/L [100%] were significant for predicting outcome of food challenge. The authors note that the specific IgE levels were not sensitive, though, and that values lower than these do not indicate that there would be no reaction to oral food challenge.
The authors conclude that using these IgE levels as cutoffs would obviate diagnostic oral food challenges in at least some of the children. Oral food challenge would still be needed to determine the sensitivity and severity of the peanut allergy.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Monday, May 3, 2010
Food allergy: An immunological picture of atopy development
What, exactly, does the phenotypic evolution of food allergy look like? Which factors, such as environment or genotype, exert the most influence? Is food allergen avoidance the key or is it irrelevant? The NIH/NIAID-supported Consortium of Food Allergy Research (CoFAR) has established an infant cohort with likely milk and/or egg allergy with the intent to describe and characterize the natural history of food allergies in children in hopes of being able to answer these questions.
In this month's issue of the JACI, Sicherer et al. present early results from the 1st of several studies being conducted by CoFAR. [Access this article for free at: http://www.jacionline.org/article/S0091-6749(10)00430-6/fulltext.] Their question: Among infants presenting with a clinical reaction to milk and/or egg, and a positive prick skin test (PST) to either, or children with moderate to severe atopic dermatitis and a positive skin test to milk or egg, what factors will be associated with developing a peanut allergy and resolution or persistence of milk/egg allergy? The authors note that known clinical allergy to peanuts was an exclusion; nevertheless, almost 70% of the infants had evidence of sensitization to peanut, with 27% having greatly elevated peanut-IgE (> 5 kUA/L). They compare sensitivity of PST and serum IgE and report significant association of wheal size and IgE concentrations across milk, egg, and peanut. They do note that there was unexpected discordance between peanut PST and peanut-specific serum IgE, where some infants have one positive and the other negative. In these cases, the serum IgE is more sensitive than the PST in detecting sensitization, which is in contradiction to the conventional wisdom that PST in infants is more sensitive.
In vitro analyses demonstrate that CD25 and IL4 expression are up-regulated in milk and peanut sensitized infants; this is not the case for egg sensitivity, where there was only a slight increase in CD25 expression and no related increase in IL4. The authors further address Th2 bias by looking at GATA3/Tbet ratios. Surprisingly, they found no increased GATA3/Tbet ratios, though GATA3 was detectable. Since Sicherer et al. speculate that Th2 activation is the background to food allergy, what is providing the increased IL4? The authors suggest that basophils may have been the source of IL4 in the sensitized infants.
Wrapping up, Sicherer et al. address the astonishingly high prevalence of peanut sensitization in their cohort and suggest that this indicates a need for caution in introducing peanut to infants with the enrollment characteristics and that clinical testing for food allergy may be warranted.
We asked first author Scott Sicherer, MD, for his take on the study's findings:
JACI: In your opinion, what is the most likely point of exposure leading to peanut sensitization in the infants?
Dr. Sicherer: We will be evaluating potential determinants that could include maternal ingestion, household exposure and other factors, but these are under analysis.
JACI: The findings associated with CD25 and IL4 gene expression under egg stimulation were not remarkable and you attributed this to possible effects of using whole egg extracts. What mechanism might account for the diminished IL4 expression associated with whole extracts?
Dr. Sicherer: We were surprised that egg behaved differently in the in vitro studies and are currently considering the possibility that if we had used a stimulant that was enriched with a major egg allergen, for example ovomucoid, we may have seen a response that was more similar to the milk (caseins) or peanut response.
JACI: Is it conceivable that basophils might be the source of IL4?
Dr. Sicherer: Our preparations were enriched for CD25. Basophils constitutively express CD25, are enriched with mononuclear cells during density gradient isolation and produce high levels of IL-4 in sensitized subjects. Recently, basophils have been implicated in allergy model systems for playing an important role in priming and enhancing memory Th2 responses. Murine basophils have been shown to express IL-4 in the absence of detectable GATA-3 or c-maf, expression, suggesting that IL-4 may be regulated distinctly in these cells. Thus, new paradigms are emerging that basophils play a key role in directing Th2 responses and our data may provide additional support for this observation. Preliminary studies utilizing flow cytometry revealed that basophils (CD3- CD123+ CD203+ HLA-DR dim and IL4+) are present in the CD25 preparation.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
In this month's issue of the JACI, Sicherer et al. present early results from the 1st of several studies being conducted by CoFAR. [Access this article for free at: http://www.jacionline.org/article/S0091-6749(10)00430-6/fulltext.] Their question: Among infants presenting with a clinical reaction to milk and/or egg, and a positive prick skin test (PST) to either, or children with moderate to severe atopic dermatitis and a positive skin test to milk or egg, what factors will be associated with developing a peanut allergy and resolution or persistence of milk/egg allergy? The authors note that known clinical allergy to peanuts was an exclusion; nevertheless, almost 70% of the infants had evidence of sensitization to peanut, with 27% having greatly elevated peanut-IgE (> 5 kUA/L). They compare sensitivity of PST and serum IgE and report significant association of wheal size and IgE concentrations across milk, egg, and peanut. They do note that there was unexpected discordance between peanut PST and peanut-specific serum IgE, where some infants have one positive and the other negative. In these cases, the serum IgE is more sensitive than the PST in detecting sensitization, which is in contradiction to the conventional wisdom that PST in infants is more sensitive.
In vitro analyses demonstrate that CD25 and IL4 expression are up-regulated in milk and peanut sensitized infants; this is not the case for egg sensitivity, where there was only a slight increase in CD25 expression and no related increase in IL4. The authors further address Th2 bias by looking at GATA3/Tbet ratios. Surprisingly, they found no increased GATA3/Tbet ratios, though GATA3 was detectable. Since Sicherer et al. speculate that Th2 activation is the background to food allergy, what is providing the increased IL4? The authors suggest that basophils may have been the source of IL4 in the sensitized infants.
Wrapping up, Sicherer et al. address the astonishingly high prevalence of peanut sensitization in their cohort and suggest that this indicates a need for caution in introducing peanut to infants with the enrollment characteristics and that clinical testing for food allergy may be warranted.
We asked first author Scott Sicherer, MD, for his take on the study's findings:
JACI: In your opinion, what is the most likely point of exposure leading to peanut sensitization in the infants?
Dr. Sicherer: We will be evaluating potential determinants that could include maternal ingestion, household exposure and other factors, but these are under analysis.
JACI: The findings associated with CD25 and IL4 gene expression under egg stimulation were not remarkable and you attributed this to possible effects of using whole egg extracts. What mechanism might account for the diminished IL4 expression associated with whole extracts?
Dr. Sicherer: We were surprised that egg behaved differently in the in vitro studies and are currently considering the possibility that if we had used a stimulant that was enriched with a major egg allergen, for example ovomucoid, we may have seen a response that was more similar to the milk (caseins) or peanut response.
JACI: Is it conceivable that basophils might be the source of IL4?
Dr. Sicherer: Our preparations were enriched for CD25. Basophils constitutively express CD25, are enriched with mononuclear cells during density gradient isolation and produce high levels of IL-4 in sensitized subjects. Recently, basophils have been implicated in allergy model systems for playing an important role in priming and enhancing memory Th2 responses. Murine basophils have been shown to express IL-4 in the absence of detectable GATA-3 or c-maf, expression, suggesting that IL-4 may be regulated distinctly in these cells. Thus, new paradigms are emerging that basophils play a key role in directing Th2 responses and our data may provide additional support for this observation. Preliminary studies utilizing flow cytometry revealed that basophils (CD3- CD123+ CD203+ HLA-DR dim and IL4+) are present in the CD25 preparation.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Vitamin D and corticosteroid use in children
Evidence is accumulating rapidly for the association between vitamin D insufficiency, lung function, and corticosteroid use and sensitivity. Pivotal studies have been published examining a number of parameters, including effect of latitude, skin pigmentation, and body mass index.
In this month's JACI, Searing et al. provide the first report on prevalence of vitamin D insufficiency or deficiency in children with asthma living in latitudes higher than 20° N. [This article can be accessed for free at http://www.jacionline.org/article/S0091-6749(10)00505-1/fulltext.] Several significant correlations are reported: age, BMI, and positive skin tests are inversely correlated to vitamin D levels, while FEV1% and FEV1/FVC ratio are significantly correlated to vitamin D level.
The authors demonstrate significant association between inhaled corticosteroids, oral steroid use, and total steroid dose with low levels of vitamin D. They suggest that insufficient vitamin D might increase asthma severity, requiring greater treatment intervention or possibly that down-regulation of glucocorticoid pathways due to insufficient vitamin D dictates the need for increased steroid doses.
In vitro analyses of vitamin D activity in PBMCs demonstrated that vitamin D augments induction of MKP-1 and IL10 by steroids. Additionally, effects were observed that support vitamin D supplementation to increase steroid sensitivity, thereby permitting lower doses to obtain an optimal response.
We asked Dr. Daniel Searing, first author on the paper, about the implications of this research:
JACI: Is there baseline evidence of decreased vitamin D levels secondary to corticosteroid exposure in pediatric asthma patients?
Dr. Searing: Our study demonstrated correlations between vitamin D levels and steroid exposure in pediatric asthmatic patients from northern latitudes. To our knowledge, this is the first study looking at vitamin D levels in this patient population. Our study was not designed to examine causation of the low vitamin D levels. We are conducting a study currently looking to examine vitamin D levels in patients with asthma while also controlling for other known confounders (age, BMI, etc) to examine how strong the correlation of corticosteroid use and vitamin D levels is.
JACI: Is it possible that vitamin D insufficiency/deficiency is iatrogenic in children with asthma?
Dr. Searing: It is possible that low vitamin D levels are iatrogenic. However, the vitamin D levels in our patients with asthma seem to mirror levels in the general pediatric population. Whether escalating amounts of corticosteroid therapy in worsening asthma directly lower vitamin D levels versus other potential causes, such as vitamin D having effects on glucocorticoid pathways that leads to higher doses to achieve treatment effect is unknown at the present time. Future studies will help clarify this issue.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
In this month's JACI, Searing et al. provide the first report on prevalence of vitamin D insufficiency or deficiency in children with asthma living in latitudes higher than 20° N. [This article can be accessed for free at http://www.jacionline.org/article/S0091-6749(10)00505-1/fulltext.] Several significant correlations are reported: age, BMI, and positive skin tests are inversely correlated to vitamin D levels, while FEV1% and FEV1/FVC ratio are significantly correlated to vitamin D level.
The authors demonstrate significant association between inhaled corticosteroids, oral steroid use, and total steroid dose with low levels of vitamin D. They suggest that insufficient vitamin D might increase asthma severity, requiring greater treatment intervention or possibly that down-regulation of glucocorticoid pathways due to insufficient vitamin D dictates the need for increased steroid doses.
In vitro analyses of vitamin D activity in PBMCs demonstrated that vitamin D augments induction of MKP-1 and IL10 by steroids. Additionally, effects were observed that support vitamin D supplementation to increase steroid sensitivity, thereby permitting lower doses to obtain an optimal response.
We asked Dr. Daniel Searing, first author on the paper, about the implications of this research:
JACI: Is there baseline evidence of decreased vitamin D levels secondary to corticosteroid exposure in pediatric asthma patients?
Dr. Searing: Our study demonstrated correlations between vitamin D levels and steroid exposure in pediatric asthmatic patients from northern latitudes. To our knowledge, this is the first study looking at vitamin D levels in this patient population. Our study was not designed to examine causation of the low vitamin D levels. We are conducting a study currently looking to examine vitamin D levels in patients with asthma while also controlling for other known confounders (age, BMI, etc) to examine how strong the correlation of corticosteroid use and vitamin D levels is.
JACI: Is it possible that vitamin D insufficiency/deficiency is iatrogenic in children with asthma?
Dr. Searing: It is possible that low vitamin D levels are iatrogenic. However, the vitamin D levels in our patients with asthma seem to mirror levels in the general pediatric population. Whether escalating amounts of corticosteroid therapy in worsening asthma directly lower vitamin D levels versus other potential causes, such as vitamin D having effects on glucocorticoid pathways that leads to higher doses to achieve treatment effect is unknown at the present time. Future studies will help clarify this issue.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Friday, April 2, 2010
Administration of influenza vaccines to egg-allergic patients
In this month’s issue, John Kelso, MD, wrangles with the very important clinical issue of vaccinating patients with egg allergy against influenza. Starting with a review of the Vaccine Adverse Event Reporting System (VAERS) from 1990 to 2005, he finds only 4 reports of deaths that occurred after vaccination and were attributed to anaphylaxis. Approximately 747 million vaccinations were given during the time period. On the down side, about 540,000 deaths from seasonal influenza were reported for the same 15 years. Kelso poses the conundrum: most of those deaths could have been prevented by vaccination, and, in particular, many of them may have been egg-allergic patients.
Two recent JACI publications are addressed in the editorial. The first, a Clinical Pearls article by Rank and Li, recommends vaccination protocols for asthma patients. Specifically, the vaccination protocol for asthma patients with confirmed or suspected egg allergy was conservative and included skin prick testing and intradermal testing of both ovalbumin and influenza vaccine, followed by 2-dose or graded multiple dose vaccine administration. Rank and Li imply the possibility of no vaccination, though this is considered the least desirable approach.
The second article, by Waibel and Gomez, challenges this highly conservative approach, noting previous research establishing that a 2-dose protocol is safe in egg-allergic patients when the vaccine contains ≤ 1.2μg/ml of egg. Manufacturers of vaccines approved by FDA in 2009-2010 state a maximum ovalbumin content of ≤ 1μg/dose, with only one exception reporting greater than that. Since there is more than one vaccine dose, the authors tested lots of H1N1 and/or seasonal flu vaccines from 6 manufacturers to determine the μg/ml ovalbumin content. In all cases, the actual ovalbumin content was lower than the manufacturers stated content, leading Waibel and Gomez to suggest a single dose administration of vaccines with ≤ 1.2μg/ml ovalbumin to egg-allergic patients.
In the editorial, Kelso argues that pre-testing of egg-allergic patients was a good idea when the maximum ovalbumin content was not provided by manufacturers, but in light of safety research and voluntary reporting by manufacturers, these recommendations may be too conservative.
Kelso points out that egg allergic patients react to egg ingestion, but typically not flu vaccination. He suggests there is sufficient clinical and epidemiological evidence to support single dose vaccinations for egg allergic patients, unless the ovalbumin content is not known or if the egg allergy is severe.
We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Two recent JACI publications are addressed in the editorial. The first, a Clinical Pearls article by Rank and Li, recommends vaccination protocols for asthma patients. Specifically, the vaccination protocol for asthma patients with confirmed or suspected egg allergy was conservative and included skin prick testing and intradermal testing of both ovalbumin and influenza vaccine, followed by 2-dose or graded multiple dose vaccine administration. Rank and Li imply the possibility of no vaccination, though this is considered the least desirable approach.
The second article, by Waibel and Gomez, challenges this highly conservative approach, noting previous research establishing that a 2-dose protocol is safe in egg-allergic patients when the vaccine contains ≤ 1.2μg/ml of egg. Manufacturers of vaccines approved by FDA in 2009-2010 state a maximum ovalbumin content of ≤ 1μg/dose, with only one exception reporting greater than that. Since there is more than one vaccine dose, the authors tested lots of H1N1 and/or seasonal flu vaccines from 6 manufacturers to determine the μg/ml ovalbumin content. In all cases, the actual ovalbumin content was lower than the manufacturers stated content, leading Waibel and Gomez to suggest a single dose administration of vaccines with ≤ 1.2μg/ml ovalbumin to egg-allergic patients.
In the editorial, Kelso argues that pre-testing of egg-allergic patients was a good idea when the maximum ovalbumin content was not provided by manufacturers, but in light of safety research and voluntary reporting by manufacturers, these recommendations may be too conservative.
Kelso points out that egg allergic patients react to egg ingestion, but typically not flu vaccination. He suggests there is sufficient clinical and epidemiological evidence to support single dose vaccinations for egg allergic patients, unless the ovalbumin content is not known or if the egg allergy is severe.
We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Monday, March 8, 2010
Stress and asthma
In this issue of JACI, Haczku and Panettieri review the evidence for the involvement of stress in asthma and find that it suggests that psychosocial stressors are important in asthma morbidity.
Chronic psychosocial stress has been correlated with asthma severity and exacerbations, as well as overall immunocompromise that leads to or worsens disease. The authors developed a mouse model of social stress in order to mimic socially disruptive stressors experienced by humans. They showed that mice exposed to allergen and persistent social stress had increased airway reactivity and lowered Th2 cell sensitivity to glucocorticoids. In their mouse model, Haczku and Panettieri noted that the social stress did not result in immunosuppression, but instead, activated innate and Th2 immune responses that resulted in sustained increases in circulating corticosterone. They suggest that this may lead to corticosteroid insensitivity and perpetuate airway inflammation.
Altered function, reduced expression and impaired translocation of the glucocorticoid receptor (GR) are among the possible mechanisms for steroid insensitivity proposed by Haczku and Panettieri. They suggest that GR may be down-regulated by agonistic ligands, or NF-κB transrepression of gene transcription. Their own studies reported increased expression of NF-κB concomitant with decreased GR nuclear translocation, DNA binding and GR expression.
Bias toward inflammatory cytokine stimulation by innate immune cells is another mechanism the authors discuss. Mice exposed to stress alone produced macrophage and dendritic cell secretion of IL-13 associated IgG1 and TARC as well as TNF-α and IL-6.
Finally, the authors talk about the role of structural cell responses to glucocorticoids, citing recent findings of reduced surfactant protein D (SP-D) in patients with chronic lung disease. Corticosteroids greatly increase the amounts of SP-D, which is known to have immunosuppressive effects, and they suggest that corticosteroid insensitivity of epithelial cells in chronic lung pathology is responsible for the impairment of this protective mechanism.
Haczku and Panettieri propose new approaches to circumvent corticosteroid non-response. They have shown that corticosteroid insensitive airway smooth muscle and whole lung tissue are still responsive to I κB and MAP kinase inhibitors, reducing cytokine secretion. This may be a possible pathway for therapeutic intervention in asthma patients who are steroid-insensitive.
We asked Dr. Haczku some questions about the implications of this review:
JACI: Since the evidence is pointing to a multiple-scale physiologic response, would this problem lend itself to a systems analysis approach to coordinate effective therapy?
Dr. Haczku: Susceptibility to the detrimental effects of chronic stress exposure on the neuro-endocrine, immune and hematopoietic systems as well as on various target organs maybe genetically regulated, organ- and cell type specific. A systems analysis approach therefore to disease assessment and effective therapy would be very beneficial.
JACI: Do you think kinase inhibitors would be primary or add-on therapy for patients with corticosteroid-resistant lung disease?
Dr. Haczku: Kinase inhibitors once developed would form a useful second line (add-on) therapy for patients with corticosteroid resistant chronic inflammatory diseases.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Chronic psychosocial stress has been correlated with asthma severity and exacerbations, as well as overall immunocompromise that leads to or worsens disease. The authors developed a mouse model of social stress in order to mimic socially disruptive stressors experienced by humans. They showed that mice exposed to allergen and persistent social stress had increased airway reactivity and lowered Th2 cell sensitivity to glucocorticoids. In their mouse model, Haczku and Panettieri noted that the social stress did not result in immunosuppression, but instead, activated innate and Th2 immune responses that resulted in sustained increases in circulating corticosterone. They suggest that this may lead to corticosteroid insensitivity and perpetuate airway inflammation.
Altered function, reduced expression and impaired translocation of the glucocorticoid receptor (GR) are among the possible mechanisms for steroid insensitivity proposed by Haczku and Panettieri. They suggest that GR may be down-regulated by agonistic ligands, or NF-κB transrepression of gene transcription. Their own studies reported increased expression of NF-κB concomitant with decreased GR nuclear translocation, DNA binding and GR expression.
Bias toward inflammatory cytokine stimulation by innate immune cells is another mechanism the authors discuss. Mice exposed to stress alone produced macrophage and dendritic cell secretion of IL-13 associated IgG1 and TARC as well as TNF-α and IL-6.
Finally, the authors talk about the role of structural cell responses to glucocorticoids, citing recent findings of reduced surfactant protein D (SP-D) in patients with chronic lung disease. Corticosteroids greatly increase the amounts of SP-D, which is known to have immunosuppressive effects, and they suggest that corticosteroid insensitivity of epithelial cells in chronic lung pathology is responsible for the impairment of this protective mechanism.
Haczku and Panettieri propose new approaches to circumvent corticosteroid non-response. They have shown that corticosteroid insensitive airway smooth muscle and whole lung tissue are still responsive to I κB and MAP kinase inhibitors, reducing cytokine secretion. This may be a possible pathway for therapeutic intervention in asthma patients who are steroid-insensitive.
We asked Dr. Haczku some questions about the implications of this review:
JACI: Since the evidence is pointing to a multiple-scale physiologic response, would this problem lend itself to a systems analysis approach to coordinate effective therapy?
Dr. Haczku: Susceptibility to the detrimental effects of chronic stress exposure on the neuro-endocrine, immune and hematopoietic systems as well as on various target organs maybe genetically regulated, organ- and cell type specific. A systems analysis approach therefore to disease assessment and effective therapy would be very beneficial.
JACI: Do you think kinase inhibitors would be primary or add-on therapy for patients with corticosteroid-resistant lung disease?
Dr. Haczku: Kinase inhibitors once developed would form a useful second line (add-on) therapy for patients with corticosteroid resistant chronic inflammatory diseases.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Fungal exposure and inner-city children
In another effort to pin down factors that increase asthma morbidity in inner-city children, Pongracic et al. report results from their study of effects of indoor and outdoor fungal exposure in children with asthma and fungal sensitivity. The authors use a subset of children from the Inner City Asthma Study (ICAS) with positive skin tests to at least one of four fungi: Alternaria, Cladosporium, Penicillium, and Aspergillus (mixed species). Indoor and outdoor fungal sampling was performed every six months for 2 years. Questionnaires were administered by phone every 2 months collecting data about number of symptom days, nighttime awakening due to asthma, number of days the child’s activities were limited by asthma, missed school days, and ED and unscheduled doctor visits.
Compared to other subjects in the ICAS who had negative skin tests to fungi, the fungi-sensitive children had significant increases of number of symptomatic days and unscheduled clinic or ED visits on days when total combined fungal exposure was increased. Increased indoor fungal exposure was associated significantly with unscheduled visits, with Pencillium exposure having the most profound effect.
Pongracic and colleagues also report effects of specific fungal exposure in children that had negative skin tests to one or more of the 4 fungal extracts tested, but with at least one positive skin test to a fungal allergen. Increased outdoor exposure to Alternaria and Penicillium in children not sensitized to either was found to increase the number of symptomatic days, while increased indoor exposure to Penicillium was associated with increased medical visits, which is similar to the finding in children sensitive to Pencillium.
The authors discuss several limitations associated with their research. Sampling technique did not include collection of indoor floor dust samples, and was of short duration during low-activity periods in the home. The fungal sampling design did not include sampling in the homes of unsensitized children. Outdoor sample collection was short duration and episodic, which might not reflect fungal counts over a long period of time. Additionally, the finding of increased impairment among children not sensitized to one or more of the fungi used in the skin testing confounds the outcomes on numerous levels.
Dr. Pongracic shared the following comments with us:
“It is our hope that these findings, which have shed light on the role of outdoor and indoor fungi in asthma morbidity among inner-city children, will lead us and others to several avenues of clinical and translational investigation. Future directions include (1) environmental interventions directed against fungi and their ability to reduce asthma exacerbations and to improve asthma control; (2) mechanistic studies of the health effects of fungi on non-sensitized individuals; (3) development of novel methodologies to assess ongoing fungal allergen exposure; (4) exploration of viral-fungal allergen and pollutant-fungal allergen interactions as they pertain to asthma exacerbations in urban populations; and (5) performing similar studies of other populations, including suburban and rural children, to ascertain whether these relationships exist beyond the inner city.
There are a variety of opportunities to extend these findings to clinical practice. Certainly, assessment of the inner-city child with asthma should include investigation for sensitization to multiple fungal allergens, through skin testing or in vitro testing. Our findings should also prompt health care providers to not only consider cockroach, mouse and dust mite allergens in their assessment of the home environment but also fungal allergens. Given the extensive use of cellphones among inner-city families and the widespread availability of digital camera functionality on these phones, individuals could be instructed to photograph household conditions that promote/reveal mold growth to help identify specific sources of problems and inform potential interventions. Broader education should be instituted regarding understanding risk factors for household mold contamination, how to identify it when it occurs and how to intervene. Public service announcements for notification of periods of high concentrations of outdoor airborne fungi could be an efficient and effective means to inform people of potential increased exposures and to recommend keeping windows closed to reduce indoor entry of fungal allergens.”
We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Compared to other subjects in the ICAS who had negative skin tests to fungi, the fungi-sensitive children had significant increases of number of symptomatic days and unscheduled clinic or ED visits on days when total combined fungal exposure was increased. Increased indoor fungal exposure was associated significantly with unscheduled visits, with Pencillium exposure having the most profound effect.
Pongracic and colleagues also report effects of specific fungal exposure in children that had negative skin tests to one or more of the 4 fungal extracts tested, but with at least one positive skin test to a fungal allergen. Increased outdoor exposure to Alternaria and Penicillium in children not sensitized to either was found to increase the number of symptomatic days, while increased indoor exposure to Penicillium was associated with increased medical visits, which is similar to the finding in children sensitive to Pencillium.
The authors discuss several limitations associated with their research. Sampling technique did not include collection of indoor floor dust samples, and was of short duration during low-activity periods in the home. The fungal sampling design did not include sampling in the homes of unsensitized children. Outdoor sample collection was short duration and episodic, which might not reflect fungal counts over a long period of time. Additionally, the finding of increased impairment among children not sensitized to one or more of the fungi used in the skin testing confounds the outcomes on numerous levels.
Dr. Pongracic shared the following comments with us:
“It is our hope that these findings, which have shed light on the role of outdoor and indoor fungi in asthma morbidity among inner-city children, will lead us and others to several avenues of clinical and translational investigation. Future directions include (1) environmental interventions directed against fungi and their ability to reduce asthma exacerbations and to improve asthma control; (2) mechanistic studies of the health effects of fungi on non-sensitized individuals; (3) development of novel methodologies to assess ongoing fungal allergen exposure; (4) exploration of viral-fungal allergen and pollutant-fungal allergen interactions as they pertain to asthma exacerbations in urban populations; and (5) performing similar studies of other populations, including suburban and rural children, to ascertain whether these relationships exist beyond the inner city.
There are a variety of opportunities to extend these findings to clinical practice. Certainly, assessment of the inner-city child with asthma should include investigation for sensitization to multiple fungal allergens, through skin testing or in vitro testing. Our findings should also prompt health care providers to not only consider cockroach, mouse and dust mite allergens in their assessment of the home environment but also fungal allergens. Given the extensive use of cellphones among inner-city families and the widespread availability of digital camera functionality on these phones, individuals could be instructed to photograph household conditions that promote/reveal mold growth to help identify specific sources of problems and inform potential interventions. Broader education should be instituted regarding understanding risk factors for household mold contamination, how to identify it when it occurs and how to intervene. Public service announcements for notification of periods of high concentrations of outdoor airborne fungi could be an efficient and effective means to inform people of potential increased exposures and to recommend keeping windows closed to reduce indoor entry of fungal allergens.”
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