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.
Monday, March 8, 2010
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.”
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.
Grading systemic reactions to immunotherapy
The potential for anaphylaxis in subcutaneous specific immunotherapy (SCIT) is obvious. Current practice standards for evaluating, grading, and treating systemic reactions are vague, and in some cases, too rigid to encompass the highly variable symptom presentation. On top of this, the judicious application of epinephrine in anaphylaxis evolution has not been evaluated in a systematic way.
Cox et al., representing the AAAAI/ACAAI Joint Task Force for Grading Systemic Reactions to Immunotherapy, in collaboration with the WAO, present a draft recommendation for SCIT systemic reaction (SR) grading system in this month’s issue. It is based on the Internet Immunotherapy Safety Survey, started in 2008, from which the task force hoped to learn the incidence rate of systemic reactions, especially fatal or near-fatal reactions, and how and when epinephrine was given. The goal: to develop a global, functional SR grading system that could be used to standardize intervention, especially epinephrine use, to minimize the risk of fatal or near-fatal reactions.
The Task Force proposes a grading system based on the organ system involved and severity. Organ systems are defined as: cutaneous, conjunctival, upper respiratory, lower respiratory, gastrointestinal, cardiovascular and other. A reaction from a single organ system such as cutaneous, conjunctival, upper respiratory, but not asthma, gastrointestinal or cardiovascular is classified as a Grade 1 Symptoms from more than one organ system or asthma, gastrointestinal, cardiovascular are classified as Grades 2 or 3. Grade 4 includes the conventional clinical indicators of a severe reaction, such as loss of consciousness, hypotension, and respiratory failure, while Grade 5 is death. Clinician judgment assesses the grade. The proposed system also includes time of onset, first symptom, and time when epinephrine was given, if at all.
The authors suggest additionally that this grading system allows flexibility to accommodate the clinical management details. The task force contends that a common grading approach that can be used by clinicians and researchers will make it easier to compare SRs and interventions between different SCITs from surveillance and clinical trial data.
Dr. Cox notes, “The WAO grading system for SR has been endorsed by the following WAO Regional and National Member Societies: AAAAI, Latin American Society of Allergy and Immunology (SLAAI), Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI), and the ACAAI.
The rostrum includes an Excel spreadsheet for documenting SR grade and treatment that can downloaded and used by clinicians and researchers to collect on SR frequency, severity and response to treatment.”
We asked Dr. Cox to comment on how the treatment thresholds mentioned in the paper are more discriminating than those used in the past, given that the authors note that using response to treatment to assess severity is misleading as both mild and severe reactions may or may not resolve after IM epinephrine. Dr. Cox responded as follows:
“The grading table [uses] response to treatment or drop in PEF as an example of… a Grade 2 or 3 reaction to provide the clinicians with some general guidelines. That is why it is prefaced as an e.g. and it is not a specific requirement/criteria for... that particular grade. We also stipulate that 'The grade is determined by the physician’s clinical judgment,' so it is up to the physician to decide whether the asthma reaction is Grade 2 or 3 and they may or may not decide to include response to treatment in determining the Grade…. These were added during the review process at the request of some reviewers who wanted more specific guidelines.”
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.
Cox et al., representing the AAAAI/ACAAI Joint Task Force for Grading Systemic Reactions to Immunotherapy, in collaboration with the WAO, present a draft recommendation for SCIT systemic reaction (SR) grading system in this month’s issue. It is based on the Internet Immunotherapy Safety Survey, started in 2008, from which the task force hoped to learn the incidence rate of systemic reactions, especially fatal or near-fatal reactions, and how and when epinephrine was given. The goal: to develop a global, functional SR grading system that could be used to standardize intervention, especially epinephrine use, to minimize the risk of fatal or near-fatal reactions.
The Task Force proposes a grading system based on the organ system involved and severity. Organ systems are defined as: cutaneous, conjunctival, upper respiratory, lower respiratory, gastrointestinal, cardiovascular and other. A reaction from a single organ system such as cutaneous, conjunctival, upper respiratory, but not asthma, gastrointestinal or cardiovascular is classified as a Grade 1 Symptoms from more than one organ system or asthma, gastrointestinal, cardiovascular are classified as Grades 2 or 3. Grade 4 includes the conventional clinical indicators of a severe reaction, such as loss of consciousness, hypotension, and respiratory failure, while Grade 5 is death. Clinician judgment assesses the grade. The proposed system also includes time of onset, first symptom, and time when epinephrine was given, if at all.
The authors suggest additionally that this grading system allows flexibility to accommodate the clinical management details. The task force contends that a common grading approach that can be used by clinicians and researchers will make it easier to compare SRs and interventions between different SCITs from surveillance and clinical trial data.
Dr. Cox notes, “The WAO grading system for SR has been endorsed by the following WAO Regional and National Member Societies: AAAAI, Latin American Society of Allergy and Immunology (SLAAI), Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI), and the ACAAI.
The rostrum includes an Excel spreadsheet for documenting SR grade and treatment that can downloaded and used by clinicians and researchers to collect on SR frequency, severity and response to treatment.”
We asked Dr. Cox to comment on how the treatment thresholds mentioned in the paper are more discriminating than those used in the past, given that the authors note that using response to treatment to assess severity is misleading as both mild and severe reactions may or may not resolve after IM epinephrine. Dr. Cox responded as follows:
“The grading table [uses] response to treatment or drop in PEF as an example of… a Grade 2 or 3 reaction to provide the clinicians with some general guidelines. That is why it is prefaced as an e.g. and it is not a specific requirement/criteria for... that particular grade. We also stipulate that 'The grade is determined by the physician’s clinical judgment,' so it is up to the physician to decide whether the asthma reaction is Grade 2 or 3 and they may or may not decide to include response to treatment in determining the Grade…. These were added during the review process at the request of some reviewers who wanted more specific guidelines.”
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.
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