AAP 2006: New Research in Asthma, Eczema, and Urticaria

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researchOn Saturday, October 7, 2006, the AAP Section on Allergy and Immunology sponsored a session reviewing recent publications in the fields of asthma, eczema, and urticaria.

Asthma Diagnosis and Management

The first speaker was Dr. Paul Williams, Northwest Asthma and Allergy Center in Seattle, Washington, who was Chairman of the Section on Allergy and Immunology at AAP. He highlighted recent articles on the prevention of and care for patients with asthma. He reviewed studies covering the epidemiology of asthma, identification of severity and proper severity classification, and variation in symptom severity.[1]

A study by Morgan and coauthors[2] provided insight into the natural history of asthma development. This study represented the long-term follow-up of an Arizona cohort of children who first experienced wheezing before age 3 years. That group was divided into those with "transient wheezing" that did not persist and those with persistent wheezing. These children were compared to children who never wheezed, or to a fourth group that developed wheezing later in childhood (after age 3 but before age 6).

The cohort had entered adolescence by the time of this study, and the patients had major assessments at approximately ages 11 and 13 years. In addition, pulmonary function testing was completed at 16 years. Two groups -- those with late-onset wheezing and those with persistent wheezing -- had relative risk (RR) of wheezing at age 16 that was > 3 times that of the children who had never wheezed. Pulmonary function measures at age 16 were lower in the children with early wheezing -- whether transient or persistent, but not in those who had later-onset wheezing. In one encouraging finding, the study did not demonstrate declining lung function over time, even in the persistent wheezers.

The National Asthma Education and Prevention Program guidelines for diagnosing and treating asthma are symptom-based for children younger than 5 years of age, focusing on day- or nighttime symptom frequencies to classify children as persistent asthmatics.[3] There has been an ongoing concern that these criteria, though objective and a considerable improvement over past classifications, did not identify children with significant symptoms.

Galant and coauthors[4] collected data from 2002-2005, as part of a mobile asthma van outreach, to determine whether the guidelines (based on symptoms) could accurately identify the children who had experienced asthma morbidity in the previous year. Data were collected from more than 20 preschool and public school sites in California during the study period, and the subjects were either known asthmatics or children suspected to have asthma (by parents or school staff) and therefore referred to the outreach program. The students were all from low-income populations and mostly Hispanic.

The investigators completed extensive histories, physical examinations, and completed skin-prick testing for common allergens along with spirometry in children aged 4 years and older. Investigators assigned asthma severity classifications based on symptom frequency, as set forth in the guidelines, and then compared those symptom-based classifications to the histories of the patients to determine whether the symptom-based classification would identify children with significant morbidities such as hospitalizations and emergency department (ED) visits.

This study involved 826 children who were "controller-naive." Asthma severity classifications at enrollment were 34% mild intermittent (MI), 10.2% mild persistent (MIP), 31.5% moderate persistent (MOP), and 24% severe persistent (SP). For children aged 2 years or younger, there was a clear bimodal spread with 41.6% having MI disease but 31.5% having SP disease. Older children were more likely to have a more balanced distribution among the classifications, but the percent SP was never below 22% regardless of age. All measures of morbidity outcome correlated with asthma severity classification when patients were not subgrouped by age. For example, there was almost a stair-step relationship between severity classification and percentage of children who had 2 or more ED visits, with 12.3% of MI, 21.4% of MIP, 20.4% of MOP, and 31.3% of SP children having at least 2 ED visits. There was not such an additive association with hospitalization, with only 8.5% of MI patients being hospitalized vs 16.2%-17.9 % of MIP, MOP, or SP patients. Among children aged 2 years or younger, the percentages experiencing excessive healthcare use generally increased with increasing asthma severity classification, but the relationship did not reach statistical significance. The authors concluded that the asthma severity classifications are valid for children > 5 years old but may fail to appropriately classify younger children.

The speaker also reviewed 2 studies by Fuhlbrigge and colleagues[5,6] that drove home the point that providers should assess symptom severity more aggressively in asthmatics. In the first study,[5] the authors surveyed 871 children, 4-18 years old, and their parents to determine short- and long-term symptom frequency and the impact of these symptoms on child activity. The authors assessed perceived asthma control, healthcare use, physical limitations, as well as knowledge of their disease and management plans used. The authors found that use of daytime symptom frequencies underestimated the functional impact of asthma symptoms, meaning that children who would have been classified as MI by daytime symptoms still experienced notable functional impairment (20% of patients with MI asthma had global functional impairment). When additional measures of symptom frequency were included, such as nocturnal symptoms and questions of functional limitation, the authors noted improved classification match with measures of impairment (meaning that asking more questions helps to properly classify patients). The speaker was distressed to note that these findings, collected in 2004, were very similar to findings by the same investigator group in 1998, suggesting that there has not been great improvement in patients' identification and treatment of their own symptoms despite the public educational attempts regarding asthma.

In the second study by Fuhlbrigge,[6] the authors assessed how use of spirometry, when added to the symptom questions, would change the asthma classification of a group of 417 children aged 5-12 years. These patients had mild to moderate-persistent asthma at enrollment. The investigators measured FEV1 (without bronchodilators) 3 times yearly and correlated those findings with patient-reported symptom scores and asthma-related healthcare use in the 4 months following each FEV1 measurement. The FEV1 measurements were grouped according to percent of expected, and the authors were able to demonstrate a clear relationship between FEV1 measurements and later asthma-related episodes. For example, children with FEV1 measurements that were 60%-79% of expected had RR for asthma exacerbation that was 4.8 times that of the 100% of expected FEV1 group. Similarly, children with FEV1 measurements that were 60%-80% of expected had RR for asthma exacerbation that was 1.8 times (almost double) that of the 100% of expected FEV1 group. The authors concluded that while symptom-related classifications can be helpful, FEV1 measurements should be added to the asthma severity classification in order to better predict patient symptoms and to better assess level of control.

Reviewer Comment on Asthma Symptom Identification

The Galant study[4] definitely contained mixed findings -- the classifications worked generally for older children, but not for younger ones. Younger children are more likely to be taken to the ED for fever and other reasons that might coexist with wheezing, and that alone may have reduced the correlation between asthma severity classification and ED visits. In addition, the fact that 31.5% of the children aged 2 years or younger were classified as SP (much higher than the 22.1%-23.5% of the older groups) raises the possibility that young children are "overclassified" by symptom-based ratings (based on cough frequency symptoms, usually), a situation that would again reduce correlation between severity scores and measures of morbidity. Nevertheless, the take-home message is that the symptom-based guidelines are good rules of thumb for children older than 5 years. Younger children are more difficult to classify, and one should consider leaning toward controller use if emergent healthcare use is excessive in younger children with asthma.

In a similar manner, the studies by Fuhlbrigge and colleagues[5,6] demonstrate that providers and patients still have a long way to go in properly assessing asthma severity. The take-home messages are: ask more questions (nocturnal symptoms, functional limitations) and take more measurements such as spirometry.

What's New With Atopic Dermatitis and Urticaria

Dr. Anne-Marie Irani[7] of Virginia Commonwealth University reviewed recent evidence concerning atopic dermatitis and urticaria. Although she reviewed multiple topics, I have focused my review of her presentation on a consensus statement, a meta-analysis of maternal dietary interventions to try to prevent atopic dermatitis in offspring, and 2 reports relating to safety concerns for patients with atopic dermatitis.

Dr. Irani began with a quick mention of the 2006 consensus report on the diagnosis and treatment of atopic dermatitis.[8] This consensus statement was put together by the European Academy of Allergy and Clinical Immunology in cooperation with the American Academy of Allergy, Asthma, and Immunology. This report is meant to serve as a clinical practice guideline for practitioners in North America and Europe. The report is notable for breaking down the treatment approach to atopic dermatitis into 4 steps.

Step 1: Patients with dry skin require only basic care. This basic treatment includes skin moisturization to help reestablish the protective barrier functions of the skin and avoidance of triggers (inhaled, food, or topical irritants).

Step 2: Patients with mild to moderate atopic dermatitis will require the step 1 treatments along with low- to mid-potency topical corticosteroids. Topical calcineurin inhibitors can also be used in patients older than 2 years. In addition, one should be vigilant in looking out for complicating factors such as topical bacterial infection.

Step 3: Patients with moderate to severe atopic dermatitis should receive mid- to high-potency topical corticosteroids. Topical calcineurin inhibitors can also be used in patients older than 2 years.

Step 4: Patients with recalcitrant or severe atopic dermatitis may require systemic therapy such as systemic antibiotics for bacterial colonization, short courses of systemic steroids, and even immune suppression with drugs such as cyclosporin A or azathioprine.

Treatment options with less clear indications of benefit include antihistamines (at least with regard to skin appearance), phototherapy in children, and immunotherapy. Education of patients regarding their care is imperative.

Dr. Irani highlighted a Cochrane Collaboration review by Kramer and Kakuma[9] published in 2006 evaluating the existing data on whether atopic dermatitis could be prevented by maternal dietary interventions/modifications during pregnancy. The review included data from 4 trials involving a total of more than 330 subjects.

Overall, the 4 trials revealed that maternal dietary restriction either during pregnancy or during lactation (after birth) did not reduce the risk of developing atopic dermatitis in offspring by age 18 months (RR 1.01, 95% CI 0.57-1.79). However, it is evident from the review that the trials were not considered to be of very high quality: several did not employ intention-to-treat analyses, only one had adequate concealment allocation (meaning that the practitioners were masked to the fact that the infant was exposed to a restricted diet), and others did not detail randomization procedures well. Besides the fact that there was no improvement in the primary outcome, the mothers experienced reduced weight gain during pregnancy.

The authors of the review concluded that there is insufficient evidence to recommend dietary restriction to pregnant mothers who are at higher risk of having offspring with atopic diseases. Dr. Irani cautioned that this review should not be taken as the final word on maternal dietary restriction because of the still relatively low number of subjects in the 4 trials and the methodologic limitations noted above.

Children with atopic dermatitis are subject to developing eczema herpeticum, an extensive eruption, when they contract varicella. Since the current varicella vaccine contains a live-attenuated virus, and some children will develop vaccine-associated varicella, there has been a concern that children with atopic dermatitis who receive the vaccine will be at risk for developing vaccine-associated eczema herpeticum.

A study by Kreth and co-investigators[10] evaluated the safety and efficacy of the vaccine in 160 children with atopic dermatitis. The children were 1-9 years old and were randomized to receive the vaccine in either the first or second year of the study. Receipt of varicella vaccine was not associated with worsening atopic dermatitis scores, and none of the vaccine recipients experienced a complication. The seroconversion rate was 88.9% at 12 months, suggesting an excellent immune response by the subjects. None of the children developed a vesicular rash. The authors concluded that live-attenuated varicella vaccine was safe and effective in children with atopic dermatitis. The speaker raised the concern that the number of patients -- 160 -- may not have been large enough to fully evaluate whether varicella vaccine is safe in atopic dermatitis patients. Complications are expected to be rare, and the inclusion of fewer than 200 patients may not have been sufficient to detect them.

Dr. Irani also reviewed a consensus report on topical calcineurin inhibitors.[11] This report was compiled by the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology. The group specifically commented on the safety and efficacy of these drugs. The conclusion of the task force was that the risks and benefits of these drugs were similar to those of other agents, including topical steroids. So, although the report supported the ongoing use of these agents, it suggested that they not be used as first-line agents. In addition, they should be used only in children older than 2 years. Dr. Irani also mentioned the findings of Paul and coauthors,[12] who published a review evaluating the safety and efficacy of 1% pimecrolimus in infants. Six clinical trials were included in the review, totaling over 1000 children. In a small number of children who had blood pimecrolimus levels assessed, the levels were very low over a follow-up period of up to 12 months. In the larger cohort, followed for 2 years, there were no demonstrable signs of systemic infection, different rates of topical skin infection, and no limitation of immune response to vaccination among the subjects exposed to pimecrolimus. The authors and the speaker concluded that this study was the best yet in terms of demonstrating the safety of this agent.

Dr. Irani concluded by reviewing a study by Hernandez and Cohen[13] that made recommendations to practitioners about how to deal with insect bite hypersensitivity (papular urticaria). Papular urticaria due to insect bites can be a common and frustrating finding in pediatric care. Clues to the diagnosis are sparing of covered areas and clustering or linear distributions of lesions in the affected areas. The authors noted that during a 4-week period, patients with diverse cases of popular urticaria caused by insects comprised 5% of their visits. The lesions can be quite large -- even up to 1 cm. They can also become lichenified, developing a more chronic appearance that leads away from the diagnosis. In dark-skinned individuals, these lesions are often darkly pigmented. Research has demonstrated that eosinophilic infiltration is a component of these lesions, but there can also be mononuclear cells present, suggesting both an immediate and a delayed hypersensitivity contribution to these lesions. The authors believe that it is the delayed hypersensitivity aspects of these reactions that account for the chronic presentations that stymie diagnosticians. The authors suggest the mnemonic "SCRATCH" for diagnosis and treatment of papular urticaria:

S - Symmetrical eruptions
C - Crops or clusters of lesions
R - "Rover" (a pet), although having a pet -- or not having a pet -- does not necessarily mean that lesions will develop. (The fact that the eruptions can be delayed make it difficult to identify any single pet exposure.)
A - Age usually limited to 2-10 years old (It is rare for sensitization to occur before 2 years.)
T - Target lesions can be the predominant form, and time is required for presentations and resolution
C - "Confused" parent - not able to identify exposure
H - Household with single patient affected (This reiterates the fact that sensitization is required for such a reaction to occur - not all family members will react to the same exposure [bites].)

The authors concluded by emphasizing the 3 "P"s of treatment: prevention, pruritis control, and patience. Prevention includes patient-specific measures such as clothing choice and insect repellent use but may also include eradication of infestations, especially with the rise in bedbug infestations in the United States.[14] Pruritis control can be difficult, but treatment with systemic antihistamines and topical corticosteroids should be attempted. Finally, disbelieving parents (and perhaps frustrated referring clinicians) will need patience given the chronic nature of these lesions!

Reviewer Comment on Atopic Dermatitis Reports

The manuscripts reviewed in this session were indeed diverse, but several very important resources were identified. To begin, the consensus report on the diagnosis and treatment of atopic dermatitis provides some very clear step-wise guidelines to follow when treating that condition.[8] The investigational study into the safety and immunogenicity of varicella vaccine in children with atopic dermatitis provides very useful clinical information.[10] Certainly, children with atopic dermatitis are at high risk of severe eczema herpeticum should they remain nonimmunized, so immunizing them seems to offer a safer alternative. Finally, more data seems to be needed to make definitive conclusions about maternal dietary manipulation to prevent atopic dermatitis in offspring, and perhaps even to determine whether topical calcineurin inhibitors are safe.[9,11] Topical calcineurin inhibitors can still be used, but we can clearly expect to see more experimental evidence addressing the concerns of those preparations in the years to come.

References

  1. Williams PV. Rhinitis, sinusitis, and asthma. Program and abstracts of the American Academy of Pediatrics 2006 National Conference and Exhibition ;October 7-10, 2006; Atlanta, Georgia. Session H142.
  2. Morgan WJ, Stern DA, Sherrill DL, et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med. 2005;172:1253-1258. Abstract
  3. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics--2002. J Allergy Clin Immunol. 2002;110(5 Suppl):S141-S219.
  4. Galant SP, Morphew T, Amaro S, Liao O. Current asthma guidelines may not identify young children who have experienced significant morbidity. Pediatrics. 2006;117:1038-1045. Abstract
  5. Fuhlbrigge AL, Guilbert T, Spahn J, Peden D, Davis K. The influence of variation in type and pattern of symptoms on assessment in pediatric asthma. Pediatrics. 2006;118:619-625. Abstract
  6. Fuhlbrigge AL, Weiss ST, Kuntz KM, Paltiel AD. Forced expiratory volume in 1 second percentage improves the classification of severity among children with asthma. Pediatrics. 2006;118:e347-e355. Abstract
  7. Irani A. Atopic dermatitis, urticaria, and angioedema. Program and abstracts of the American Academy of Pediatrics 2006 National Conference and Exhibition ;October 7-10, 2006; Atlanta, Georgia. Session H142.
  8. Akdis CA, Akdis M, Bieber T, et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol. 2006;118:152-169. Abstract
  9. Kramer MS, Kakuma R. Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD000133. DOI: 10.1002/14651858.CD000133.pub2.
  10. Kreth HW, Hoeger PH. Safety, reactogenicity, and immunogenicity of live attenuated varicella vaccine in children between 1 and 9 years of age with atopic dermatitis. Eur J Pediatr. 2006; 165:677-683. Abstract
  11. Fonacier L, Spergel J, Charlesworth EN, et al. Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2005;115:1249-1253. Abstract
  12. Paul C, Cork M, Rossi AB, Papp KA, Barbier N, de Prost Y. Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years. Pediatrics. 2006;117:e118-e128. Abstract
  13. Hernandez RG, Cohen BA. Insect bite-induced hypersensitivity and the SCRATCH principles: a new approach to papular urticaria. Pediatrics. 2006;118:e189-e196. Abstract
  14. Hwang SW, Svoboda TJ, De Jong IJ, Kabasele KJ, Gogosis E. Bed bug infestations in an urban environment. Emerg Infect Dis. 2005;11:533-538. Abstract
source - Medscape