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.

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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.

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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.”

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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.”

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Genome-wide association studies

What are we to make of genome-wide association studies (GWAS)? In an editorial highlighting 3 articles in this month’s issue (Wu et al.; Li et al.; and Mathias et al.), Donata Vercelli, MD, explores this question. Dr. Vercelli points out the advantage that GWAS offer over linkage and candidate gene studies; namely, that GWAS can look for susceptibility SNPs across a whole genome without a priori assumptions. That’s also the difficulty, because GWAS are now uncovering SNP associations from surprising gene families, and biological validation will be required for these results. Additionally, currently available GWAS technologies may contribute to variability of results because they do not account for rare SNPs and admixed populations. Finally, Dr. Vercelli talks about the bugbear of epigenetic influence, which is difficult to account for in GWAS.

As for the articles themselves:

Mathias et al. look at genome-wide associations in asthmatic and non-asthmatic African American and African Caribbean populations. They identify only 3 SNPs in 3 genes with significant association from combined analysis of the results of GWAS of each population. The role of the genes they single out–ADRA1B, PRNP, and DPP10–in asthma susceptibility is not yet understood. The authors also report that their results did not generalize to 2 white populations. They also stress the difficulties inherent to studying non-Caucasian populations by using genotyping platforms designed to assess variants common in Caucasians.

Li et al. investigate SNP associations in severe and difficult-to-treat, white, asthmatic populations using 14, highly replicated, candidate genes. Li and co-authors show that SNPs in two regions, RAD50-IL13 and HLA-DR/DQ, have consistent association with asthma, with SNPs in the RAD50 region having the strongest association. While the former regions have functional impact on Th2 cytokine expression and antigen-presentation respectively, RAD50 is involved in DNA repair and its effect on asthma susceptibility isn’t known. Li et al. propose that a RAD50 region characterized in mice as affecting Th cytokine expression may have a functional role in humans. The authors suggest that variants in the RAD50locus should be considered new asthma candidates.

Wu et al. report results of a GWA study that focused on previously published asthma candidate genes in the hope that this approach would improve signal detection. Out of 118 asthma candidate genes, 4 with multiple SNPs had significant associations in the pediatric asthma/Mexican population studied: TGFB1, IL1RL1, IL18R1, and DPP10.

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Omalizumab pre-treatment and immunotherapy

Following up on significant results from a study that demonstrated benefit of pre-treatment with omalizumab prior to initiation of specific allergen immunotherapy (SIT) in subjects with ragweed allergic rhinitis, Massanari et al. report their results from a similarly designed study in subjects with persistent allergic asthma undergoing SIT.

Study subjects with at least moderate persistent allergic asthma that was inadequately controlled by inhaled corticosteroid (ICS) therapy were enrolled to receive 13 weeks pre-treatment with omalizumab or placebo before initiation of 4 weeks cluster regimen SIT followed by 7 weeks of maintenance therapy.

Compared to placebo, the omalizumab group had fewer systemic allergic reactions (SARs) during SIT (placebo: 26.2%; omalizumab: 13.5%), improved asthma symptoms and rescue medication use during pre-treatment, and were more likely to achieve target maintenance dose. Discontinuations due to SARs, were higher in the placebo group (9.6%) than in the omalizumab group (5.0%)

Grade 3 respiratory SARs were most common. Among 30 documented SARs, 24 of the subjects were on placebo and 6 were on omalizumab. Additionally, 87% of the omalizumab group achieved targeted maintenance dose in contrast to 72% of the placebo group.

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.

Air cleaners and filters - A rostrum

We focus this week on a Rostrum contribution, "Air filters and air cleaners: Rostrum by the American Academy of Allergy, Asthma & Immunology Indoor Allergen Committee," by Sublett et al. (J Allergy Clin Immunol 2009;125:32-38). The authors tackle the topic of air cleaners and air filtration by providing technical information on efficiency testing, and specifications of available technology as well as summarizing a literature review on the effects of air cleaning on asthma and allergy. Two air cleaning modalities are covered: portable room air cleaners and whole-house systems installed in HVAC units. The published studies reviewed by the authors typically presented findings from a single method air cleaner across short durations up to 6 months. The authors note that most results demonstrated minimal or no benefit. Overall, HEPA-filtered, portable air cleaners, and HVAC filtration systems that used high-efficiency filters and frequent routine maintenance had limited benefits. Sublett and coauthors suggest that air cleaning should be viewed as mitigation of disease progression rather than treatment for asthma and allergies. The authors go on to conclude that short-duration, single-method studies are not enough to demonstrate mitigation and that long-duration studies involving multiple air-cleaning methods are needed.

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.