Allergy respectively). Exposure to allergens was not found to be significantly associated with early transient wheeze. There was an association between cat allergen and per- ϭ PREDICTION, PREVENTION, AND THE “HYGIENE sistent wheeze (odds ratio: 2.22; P .11). In children of HYPOTHESIS” atopic mothers, there was a positive association between mite exposure and diagnosed asthma. In children of Allergen Exposure in Infancy and the nonatopic mothers, there was a positive association be- Development of Sensitization, Wheeze, and tween dog dander exposure and persistent wheeze. Asthma at 4 Years Overall, allergen exposure was not highly associated Brussee JE, Smit HA, van Strien RT, et al. J Allergy Clin with physician-diagnosed asthma; however, in children Immunol. 2005;115:946–952 with atopic mothers, dust mite exposure was associated with asthma diagnosis (odds ratio: 3.52; P ϭ .07). PURPOSE OF THE STUDY. To determine to what extent allergen exposure in infancy (3 months old) leads to sensitiza- CONCLUSIONS. The association between allergen exposure tion, wheeze, and physician-diagnosed asthma at 4 years and sensitization was demonstrated for dust mite and cat of age. allergens at 4 years. Cat allergen exposure and sensiti- zation were associated with persistent wheeze. Early STUDY POPULATION. This study is of a subsample of a prospec- mite and dog allergen exposure might lead to asthma tive birth cohort (n ϭ 4146 children) recruited in the and persistent wheeze in subgroups defined by maternal Netherlands. Subjects were children (n ϭ 1127) classi- atopy. fied as high risk (n ϭ 464, atopic mother) and low risk (n ϭ 663, nonatopic mother). REVIEWER COMMENTS. Similar to other longitudinal cohort studies, this study demonstrates an association between METHODS. Mothers were identified during pregnancy as allergen exposure and sensitization and provides some atopic or nonatopic using a validated screening ques- additional evidence for the link between allergen expo- tionnaire on asthma and inhalant allergies. Children sure and persistent asthma. Long-term follow-up of such were recruited on the basis of high-risk (atopic mothers) cohorts is necessary to help us better understand the and low-risk (nonatopic mothers) for close follow-up relationship between early allergen exposure and devel- including a home visit at 3 months of age and a medical opment of atopy and asthma. examination at 4 years of age. At the home visit, dust samples were collected from the child’s mattress and URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900D analyzed for house dust mite (Der p 1), cat (Fel d 1), and Josh Kennedy, BA dog (Can f 1) with samples adjusted for season of col- Stacie M. Jones, MD lection. At 4 years of age, blood samples were drawn for Little Rock, AR specific IgE levels to inhalant allergens. Data on demo- graphic factors, respiratory symptoms, and risk factors Breast-feeding Reduces the Risk for Childhood for asthma were collected by yearly questionnaires. Par- Eczema ticipants were assessed and placed into a diagnostic cat- Kull I, Bo¨hme M, Wahlgren CF, Nordvall L, Pershagen egory: never wheeze, early transient wheeze (at least 1 G, Wickman M. J Allergy Clin Immunol. 2005;116:657– episode of wheeze within 3 years of life and no wheeze 661 during fourth year), late-onset wheeze (no wheeze in first 3 years of life and at least 1 in fourth year), persis- PURPOSE OF THE STUDY. To investigate the effect of breastfeed- tent wheeze (1 episode of wheeze in the first 3 years of ing in various phenotypes of eczema. life and at least 1 episode in the fourth year), and phy- STUDY POPULATION. A birth cohort of 4089 children followed sician-diagnosed asthma. up to 4 years of age. RESULTS. Allergen sensitization was noted to dust mite, cat, METHODS. Data on breastfeeding, allergic symptoms, and or dog allergens in 14%, 7%, and 4%, respectively. potential confounders were obtained from question- Transient wheeze was noted among 24% and persistent naires when the children were 2 months and 1, 2, and 4 wheeze among 11% of participants, with 4% having years old. At 4 years, blood allergen-specific immuno- physician-diagnosed asthma at 4 years. Allergen expo- globulin E was analyzed. Children with symptoms of sure was less than detection limits for 42%, 13%, and eczema and asthma during the period of breastfeeding 68% to Der p 1, Fel d 1, and Can f 1, respectively, with were excluded in most analyses on risk assessment of no significant differences between the children of non- eczema and asthma, respectively, to avoid disease-re- atopic and atopic mothers. Of those with allergen expo- lated modification of exposure. sure, only exposure to house dust mite and cat allergen were found to increase the risk of sensitization at 4 years RESULTS. Exclusive breastfeeding for Ն4 months reduced (odds ratio: 3.22, P ϭ .01; and odds ratio: 2.60, P ϭ .06, the risk for eczema at the age of 4 years (odds ratio [OR]:

PEDIATRICS Volume 118, Supplement 1, August 2006 S3 Downloaded from www.aappublications.org/news by guest on September 28, 2021 0.78; 95% confidence interval [CI]: 0.63–0.96) irrespec- REVIEWER COMMENTS. The results of this study found a signif- tive of combination with asthma, sensitization to com- icant protective effect of prolonged breastfeeding on the mon allergens, or parental allergic disease. This de- prevalence of allergic disease, which was most pro- creased risk was most evident for children with onset of nounced for hay fever. An interesting observation in this eczema during the first 2 years persisting to 4 years (OR: study was the inverse association of breastfeeding dura- 0.59; 95% CI: 0.45–0.77). Among children with early- tion and risk of allergic disease in children without an onset eczema, irrespective of persistency, followed by allergic predisposition. The history of allergy in either late onset of asthma or early-onset asthma, irrespective parent seemed to neutralize the protective effect of pro- of persistency, followed by late-onset eczema to 4 years, longed breastfeeding. This has not been observed in a protective effect of breastfeeding was also seen (OR: studies regarding the prevention effect of breastfeeding 0.48; 95% CI: 0.30–0.76). in Westernized countries, where protection was stronger when the family risk was higher. This study suggests that CONCLUSIONS. Breastfeeding Ն4 months reduces the risk although breastfeeding seems to be protective in the for eczema and asthma to 4 years of age. development of allergies, family history and genetics REVIEWER COMMENTS. Many studies to date have shown that may provide an overriding factor, at least in this study breastfeeding confers a protective effect against early population. atopic diseases including eczema. This is yet another URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900F argument to support breastfeeding. Wanda Phipatanakul, MD, MS URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900E Boston, MA Anna Nowak-Wegrzyn, MD New York, NY

Infantile Eczema at One Month of Age Is Associated With Cord Blood Eosinophilia and The Association of Prolonged Breastfeeding Subsequent Development of Atopic Dermatitis and Allergic Disease in Poor Urban Children and Wheezing Illness Until Two Years of Age Obihara CC, Marals BJ, Gie RP, et al. Eur Respir J. Matsumoto K, Shimanouchi Y, Kawakubo K, et al. Int 2005;25:970–977 Arch Allergy Immunol. 2005;137:69–76

PURPOSE OF THE STUDY. To determine the association between PURPOSE OF THE STUDY. To determine if a correlation exists allergic disease in children and prolonged breastfeeding. between the prevalence of neonatal skin eruptions at 1 month of age and the later development of atopic der- STUDY POPULATION. A random sample (n ϭ 861) of 15% of matitis. In addition, the authors sought to determine if households from 2 poor suburbs of Cape Town, South the presence of cord blood eosinophils correlated with Africa. the development of later skin disease. METHODS. Parents completed a validated International STUDY POPULATION. One hundred five newborn infants born Study on Asthma and Allergies in Childhood question- by normal vaginal delivery in Mitoyo General Hospital naire on allergic diseases for children aged 6 to 14 years. (Kagawa, Japan) from May 1987 to March 1989. Other questions included breastfeeding duration, mater- nal smoking, and parental allergy. Results were adjusted METHODS. The cord blood eosinophil count was measured for possible confounders and possible clustering within at the time of delivery. The neonates were examined at the household. 1 (all subjects) and 24 (98 subjects) months of age by a doctor who was unaware of the cord blood eosinophil RESULTS. Of the 861 children included in the study, allergic count. The subjects’ histories of allergic symptoms or disease in general and hay fever in particular were sig- physician-diagnosed wheezing bronchitis or asthma dur- nificantly less frequent in those with prolonged (Ͼ6 ing the first 8 years of life were also determined by direct months) breastfeeding. There was a significant linear examination or interviews with the guardians (67 sub- inverse association between breastfeeding duration and jects). The age of each subject at the onset of the allergic allergic disease in children without allergic parents but symptoms was determined. Skin eruptions at 1 month of not in children with an allergic predisposition. age were classified into 4 categories: (1) infantile ec- CONCLUSIONS. These results from a developing country sug- zema; (2) seborrheic dermatitis; (3) intertrigo; or (4) gest a protective effect of prolonged breastfeeding on the diaper dermatitis. The diagnosis of atopic dermatitis was development of allergic disease, particularly hay fever, in made according to the criteria by Hanifin and Rajka children born to nonallergic parents. This protective ef- (Hanifin JM, Rajka G. Diagnostic features of atopic fect was not found in children with an allergic predispo- dermatitis. Arch Dermatol Venereol. 1980;92:44–47), and sition. each rash was defined carefully by appearance.

S4 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 RESULTS. At 1 month of age, infantile eczema, seborrheic RESULTS. The prevalence of AD did not differ by birth dermatitis, intertrigo, and diaper dermatitis were diag- weight. AD at 3.5 years was associated with raised serum nosed in a total of 29, 7, 14, and 24 neonates, respec- immunoglobulin E, wheezing, asthma, rash, or eczema tively. No associations (such as family history of allergic at 1 year. In multivariate analysis adjusting for parental disease or mode of feeding) were found for the preva- atopy and breastfeeding, AD at 3.5 years was associated lence of these eruptions. Neonates with infantile eczema with atopic disease in the parents (maternal atopy only had a significantly higher number of eosinophils in the [adjusted odds ratio (aOR): 3.83; 95% confidence inter- cord blood (P Ͻ .0001). In contrast, no such tendency val (CI): 1.2–12.2]; paternal atopy only [aOR: 3.6; 95% was found for any other skin eruption. In neonates with CI: 1.09–11.75]; both parents atopic [aOR: 6.12; 95% CI: infantile eczema at 1 month of age, the diagnosis of 2.0–18.5]). There was a higher risk of AD with longer atopic dermatitis had been made significantly earlier, duration of breastfeeding (Ͻ6 months [aOR: 6.13; 95% and the prevalence of wheezing illness was significantly CI: 1.5–25.9]; Ͼ6 months [aOR: 9.70; 95% CI: 2.5– higher compared with infants who did not have infantile 38.2]) compared with never breastfeeding. AD at 3.5 eczema. years had a negative association with cat ownership CONCLUSIONS. Infantile eczema, but not other skin erup- (aOR: 0.5; 95% CI: 0.2–0.97) but was not associated tions, precedes the development of atopic dermatitis and with owning a dog at 3.5 years, having pets at 1 year, or wheezing illness during early infancy. This may be sec- with older siblings. AD at 3.5 years was not associated ondary to the activation of eosinophils before birth. with gender, socioeconomic status, maternal smoking, parity, mold exposure, immunizations, BMI, or antibi- REVIEWER COMMENTS. Patients with infantile eczema are at otic use in the first year of life. increased risk for atopic disease. The measurement of cord blood eosinophils may aid in predicting which in- CONCLUSIONS. A personal and a parental history of atopic fants will develop infantile eczema and, in addition, may disease are risk factors for AD at 3.5 years. Duration of have diagnostic utility in predicting which patients are at breastfeeding was associated with an increased risk of risk for the development of further allergic disease. AD. No association was found with factors implicated by the hygiene hypothesis. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900G REVIEWER COMMENTS. This is one of many studies to look at Jennifer M. Maloney, MD various risk factors for atopy, here focusing on AD. Sim- Scott H. Sicherer, MD New York, NY ilar to other studies, the authors show that family history of atopy is a risk factor for AD. However, compared with other studies, the authors did not find any association with gender, socioeconomic status, environmental risks, Risk Factors for Atopic Dermatitis in New or BMI. This discrepancy is probably attributable to dif- Zealand Children at 3.5 Years of Age ferences in populations and different environmental fac- Purvis DJ, Thompson JMD, Clark PM, et al. Br J tors. The data on atopy prevention by breastfeeding Dermatol. 2005;152:742–749 remain unclear and may be affected by reverse causation (breastfeeding longer in response to observing AD); al- PURPOSE OF THE STUDY. To examine factors associated with a though this is one of several negative studies, meta- diagnosis of atopic dermatitis (AD) at 3.5 years of age, analyses of multiple studies typically show a prevention especially factors implicated by the hygiene hypothesis. effect. STUDY POPULATION. There were 871 children enrolled at birth for the Auckland Birthweight Collaborative study, URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900H 744 (85.4%) participated at 1 year, and 550 (63.2%) at Jonathan M. Spergel, MD, PhD 3.5 years. AD was diagnosed in 87 (15.8%) children at Philadelphia, PA 3.5 years.

METHODS. The Auckland Birthweight Collaborative study is a case-control study of risk factors for small-for-gesta- BCG Immunization at Birth and Atopic tional-age infants. Case subjects were born at term with Diseases in a Homogeneous Population of birth weight at Յ10th percentile; controls were appro- Spanish Schoolchildren priate for gestational age, with birth weight Ͼ10th per- Garcı´a-MarcosL, Sua´rez-Varela M, Miner Canflanca I, centile. AD was defined as the presence of an itchy rash et al. Int Arch Allergy Immunol. 2005;137:303–309 in the past 12 months with Ն3 of the following by history: flexural involvement, generally dry skin, atopic PURPOSE OF THE STUDY. To investigate the effect of vaccination disease in parents or siblings, or visible flexural derma- with BCG on the development of atopic diseases in a titis by photographic protocol. homogeneous population of Spanish schoolchildren.

PEDIATRICS Volume 118, Supplement 1, August 2006 S5 Downloaded from www.aappublications.org/news by guest on September 28, 2021 STUDY POPULATION. Children aged 6 to 7 years who were living admitted to a hospital in the first 12 months with respi- in 3 cities (Bilbao, San Sebastian, and La Coruna) and 1 ratory syncytial virus (RSV)–proven bronchiolitis. province (Asturias) of the North Atlantic coast of Spain. STUDY POPULATION. Data from a large, population-based, METHODS. The International Study of Asthma and Aller- birth cohort (Avon Longitudinal Study of Parents and gies in Childhood (ISAAC) core and environmental Children) were used. questionnaires were used in 4 different centers of the METHODS. Outcomes considered were 12-month preva- Spanish North Atlantic coast. Bilbao, San Sebastian, and lence of wheeze at 2 ages (between 30–42 and 69–81 Asturias have a universal BCG immunization policy dur- months), cumulative prevalence of doctor-diagnosed ing the first days of life, whereas La Coruna discontinued asthma at 91 months, and skin-prick test–defined atopy this practice in 1989. Except for this center, immuniza- at 7 years. Multivariable logistic-regression models were tion coverage was Ͼ90%. Parents of children aged 6 and used to calculate odds ratios for outcomes adjusted for 7 years were surveyed from a random sample of schools potential confounders. of Asturias or all schools in the city district among the remainder of the centers. RESULTS. A total of 150 infants (1.1% of the cohort) were admitted to a hospital within 12 months of birth with RESULTS. The participation rate was Ͼ70%. After exclud- RSV bronchiolitis. The prevalence of wheezing was ing those children born outside Spain, there were 6762 28.1% in the RSV group and 13.1% in controls at 30 to immunized and 2828 nonimmunized. After adjusting for 42 months and 22.6% vs 9.6% at 69 to 81 months. The gender, age, smoking habits of the father and mother, cumulative prevalence of asthma was 38.4% in the RSV truck traffic near the household, presence of older and group and 20.1% in the controls at 91 months. Atopy younger siblings, and ownership of a cat or a dog during was found in 14.6% of those in the RSV group and in the first year of the child’s life, the adjusted odds ratios of 20.7% of the controls at 7 years. RSV bronchiolitis was the BCG-immunized children according to disease out- associated with subsequent wheezing between 30 to 42 come were 0.87 for asthma (95% confidence interval months (odds ratio [OR]: 2.3; 95% confidence interval [CI]: 0.76–1.00), 0.87 for hay fever (95% CI: 0.75–1.01), [CI]: 1.3–3.9) and 69 to 81 months (OR: 3.5; 95% CI: and 0.89 for atopic dermatitis (95% CI: 0.76–1.05). 1.8–6.6) and with the cumulative prevalence of asthma CONCLUSIONS. BCG immunization offers weak protection at 91 months (OR: 2.5; 95% CI: 1.4–4.3) but not with against atopic diseases in Spanish schoolchildren. atopy (OR: 0.7; 95% CI: 0.2–1.7).

REVIEWER COMMENTS. BCG vaccination has received atten- CONCLUSIONS. In a population-based birth cohort, RSV tion because of its ability to provoke a T-helper (Th)1 bronchiolitis was associated with subsequent wheezing response. Many investigators have hypothesized that and asthma but not with the development of atopy by 7 vaccination with BCG may offer protection from Th2- years of age. skewed diseases such as asthma, allergic rhinitis, and REVIEWER COMMENTS. Because infants who have severe RSV atopic dermatitis. Although this study reveals that im- infection have recurrent wheezing later in life, RSV has munization with BCG offers weak protection against been suggested to be a risk factor for asthma. Some also asthma and allergic rhinitis in a homogeneous popula- postulate that early RSV infection may predispose chil- tion, it is important to remember that these diseases are dren to atopy; however, this has been controversial. multifactorial, with genetic and environmental influ- Henderson et al show in their large prospective cohort ences also impacting pathogenesis. that severe RSV infection requiring hospitalization is URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900I associated with wheezing but not atopy. These results Jennifer M. Maloney, MD indicate that RSV infection may be a risk factor for Scott H. Sicherer, MD nonallergic asthma. New York, NY URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900J Julie Wang, MD Hospitalization for RSV Bronchiolitis Before New York, NY 12 Months of Age and Subsequent Asthma, Atopy and Wheeze: A Longitudinal Birth Cohort Study Early Respiratory Infections, Asthma, and Henderson J, Hilliard TN, Sherriff A, Stalker D, Al Allergy: 10-Year Follow-up of the Oslo Birth Shammari N, Thomas HM. Pediatr Allergy Immunol. Cohort 2005;16:386–392 Nafstad P, Brunekreef B, Skrondal A, Nystad W. PURPOSE OF THE STUDY. To compare asthma and atopy out- Pediatrics. 2005;116(2). Available at: comes of children according to whether they had been www.pediatrics.org/cgi/content/full/116/2/e255

S6 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 PURPOSE OF THE STUDY. As one dimension of the hygiene Exposure to Pets, and the Association With hypothesis, early infections may protect against the de- Hay Fever, Asthma, and Atopic Sensitization velopment of atopic disease. However, there are few in Rural Children long-term follow-up studies of the influence of early Waser M, von Mutius E, Riedler J, et al. Allergy. 2005; respiratory infections. This study investigates associa- 60:177–184 tions between early respiratory infections and diagnosed PURPOSE OF THE STUDY. To evaluate the effect of exposure to asthma, allergic rhinitis, and skin-prick sensitization in animals on the development of hay fever, asthma, and children at 10 years of age. atopy. STUDY POPULATION. A total of 2540 Norwegian children were STUDY POPULATION. Cross-sectional study of 2618 families of followed prospectively from birth to the age of 10 years Swiss, German, and Austrian decent, living in a rural in the Oslo Birth Cohort. location. Families were assigned to 1 of 2 categories: METHODS. Information on child’s health and environmen- farming and nonfarming. tal exposures, including experiences with respiratory in- METHODS. Information was collected by standardized ques- fections, was recorded at birth and at 6 and 12 months. tionnaire and interview. Mattress dust was collected and Current symptoms and “ever” doctor-diagnosed asthma measured for content of endotoxin and cat allergen. and allergic rhinitis were compared with these early life Specific immunoglobulin E levels to multiple common exposures. A subset of the cohort underwent skin-prick allergens and immunoglobulin G4 to cat were mea- testing. sured.

RESULTS. “Ever” diagnosis of asthma was positively associ- RESULTS. Complete data were available for 812 children. ated with measures of early life infection. Current Among them, 319 were farmers’ children and 493 were asthma was related to lower respiratory tract infection nonfarmers’ children. In the entire group, early (Ͻ1- (adjusted odds ratio [aOR]: 2.1; 95% confidence interval year-old) and current exposure to cats was associated [CI]: 1.3–3.0) and croup (aOR: 2.3; 95% CI: 1.3–4.2) in with a reduced risk of wheezing and grass pollen the first year. ORs for allergic rhinitis and skin-prick sensi- sensitization. Current contact with dogs was inversely tization were smaller but “mainly positive.” Birth order and associated with hay fever, asthma, and sensitization to child care attendance at 1 year of age were not significantly cat allergen and grass pollen. Early exposure to dog associated with any of the studied outcomes. did not have any significant effects. When farm-ani- mal contact was controlled for, most of these associa- CONCLUSIONS. Early respiratory infections did not protect tions were weakened but were strongest in farmers’ against the development of atopic disease during the first children. 10 years of life. Rather, infections increased the risk for asthma at age 10. CONCLUSIONS. There was an inverse relationship between dog exposure and asthma, hay fever, and allergy. How- REVIEWER COMMENTS. The hygiene hypothesis has been used ever, much of this protective effect was explained by to explain an inverse relation between early-life infec- exposure to farm animals. tion and allergic disease. Although a number of studies have described the relationship of early childhood infec- REVIEWER COMMENTS. There are several studies that report tions and atopic disease, few have done so prospectively. pet exposure to be associated with a reduced risk for This study, with its ORs near 1 with narrow CIs, shows atopic disease. In this study, the primary outcome of a positive relationship of infections to atopy. Thus, it does decreased clinical manifestations of atopy was con- not support the view of protection with increasing infec- founded by exposure to farm animals. Although the tion, bringing to light that this relationship is not as simple exposure to pets did not show an overall statistically or direct as was first described. Additional prospective stud- significant association, the results approached signifi- ies with long-term follow-up are required to further define cance, and a larger study population may have re- this relationship. In addition, these results support previous vealed significant differences. Also, the study ulti- conclusions that early childhood infection may be associ- mately found that animal exposure is most likely to ated with an increased risk for future development of provide a protective effect when the total level of asthma. There continues to be many unanswered ques- exposure is highest (ie, those children exposed to pets tions regarding the risks in susceptible hosts. and farm animals).

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900K URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900L Anne Marie Singh, MD Justin Skripak, MD Mark H. Moss, MD Robert A. Wood, MD Madison, WI Baltimore, MD

PEDIATRICS Volume 118, Supplement 1, August 2006 S7 Downloaded from www.aappublications.org/news by guest on September 28, 2021 Early Childhood Environment Related to PURPOSE OF THE STUDY. To investigate the association be- Microbial Exposure and the Occurrence of tween asthma and neighborhood-level social and phys- Atopic Disease at School Age ical indicators. A secondary goal was to identify individ- de Meer G, Janssen NA, Brunekreef B. Allergy. 2005; ual-level predictors for developing childhood asthma. 60:619–625 STUDY POPULATION. Cross-sectional study comprised of 2544 PURPOSE. There has been much interest in the effect of children, aged 5 to 18 years, from a network of 6 Mid- various microbial exposures early in life on the subse- western urban primary care clinics (Indiana University quent development of atopic disease. This study aimed Medical Group in Marion County, Indiana). A total of to examine the effects of several exposure types on 1541 black children (947 females and 594 males) and atopic sensitization. 1003 white children (568 females and 435 males) were evaluated. STUDY POPULATION. This was a cross-sectional study of 4111 Dutch schoolchildren aged 8 to 13 years. METHODS. A medical chart review was conducted to iden- tify those with physician-diagnosed asthma and record METHODS. A questionnaire evaluating day care attendance demographic data to ascertain socioeconomic indicators. before age 4, cats or dogs in the home before age 2, Other data for neighborhood factors such as median age siblings, history of doctor-treated airway disease before of housing, family income, education, single-parent age 2, and current respiratory status was used. Atopic family, and language isolation were obtained through status was tested by either skin-prick testing or antigen- specific immunoglobulin E levels to multiple common the Social Assets and Vulnerabilities Indicators Project. antigens. Medical chart data were used to compute age- and gen- der-adjusted BMI percentiles. Multiple logistic-regres- RESULTS. Complete data were available for 1555 of the sion models were used to analyze the data. participants. Atopic sensitization was less frequent in children who attended day care (adjusted odds ratio: RESULTS. On the individual level, this study found that 0.74; 95% CI: 0.56–0.99) or had a pet in the home asthma prevalence for black children was 4% higher (adjusted odds ratio: 0.78; 95% CI: 0.61–0.99). There than for white children and that males had a 9% higher was no statistically significant association between the risk than females. BMI had different effects for males presence of siblings or the occurrence of doctor-treated and females. Males who were normal weight and those airway disease and atopy. at risk of being overweight had similar risks of asthma. However, males who were overweight had a higher risk CONCLUSION. Day care attendance and having a pet in the of asthma than boys who were at risk of being over- home may provide a protective effect against atopic sen- weight. In contrast, females who were overweight and sitization. those at risk of being overweight had similar risks of REVIEWER COMMENTS. This study attempts to help clarify fac- asthma, and the rates were substantially higher com- tors that may be associated with the primary develop- pared with those for females who were normal weight. ment of atopy, which has been an area of great interest, On the neighborhood level, there was no trend in rising especially given the rising prevalence of allergic disease. asthma rate with the rise in the median age of housing. The results are consistent with many other studies indi- Children from very-low-income–level neighborhoods cating that microbial exposure early in life may have a had the same asthma rates as those children from mod- preventive effect. Additional studies, including prospec- erate- or middle-income neighborhoods. tive cohorts, are being performed to define these associ- CONCLUSIONS. The authors concluded that in a predomi- ations more clearly. With luck, one day we will be able nantly urban population of children, the highest likeli- to use this information to design effective preventive hood of having asthma is among young, black, over- strategies. weight males and the lowest rate is among older, white, normal-weight females. There was no association be- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900M tween asthma and neighborhood characteristics or me- Justin Skripak, MD dian family incomes. Robert A. Wood, MD Baltimore, MD REVIEWER COMMENTS. Although the data from this study did not support the hypothesis that lower neighborhood socioeconomic status and older age of homes were asso- ciated with childhood risk of asthma, other studies Individual and Neighborhood-Level Factors in through the National Cooperative Inner-City Asthma Predicting Asthma Study suggest that other environmental factors may be Saha C, Riner ME, Liu G. Arch Pediatr Adolesc Med. involved in urban populations, such as higher cock- 2005;159:759–763 roach, rat, and mouse allergen levels found in inner-city

S8 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 homes and sensitization to these allergens as a risk factor trol group. There were no significant differences in noc- for developing asthma in urban neighborhoods. Asthma turnal symptoms, exercise-related symptoms, medica- is the most common chronic childhood disease; thus, the tion use, emergency visits for wheeze, nasal symptoms, findings from this study, that increased BMI is associated or skin rash. with increased risk of asthma, is additionally concerning REVIEWER COMMENTS. Asthma and allergic diseases likely re- because the rate of childhood obesity is increasing sult from a combination of environmental and genetic among our nation’s children. factors. This study showed that the prevalence of asthma URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900N was decreased after an intervention program imple- Sally Joo Bailey, MD mented early in life. Thus, recommending environmen- New York, NY tal controls as a safe method to decrease the risk of developing asthma in high-risk patients is reasonable. It is unclear from this study whether a specific environ- mental control or a combination of interventions is more The Canadian Childhood Asthma Primary effective. It is interesting that no difference was noted in Prevention Study: Outcomes at 7 Years of Age the prevalence of allergic rhinitis or atopic dermatitis Chan-Yeung M, Ferguson A, Watson W, et al. J Allergy between the groups, which, theoretically, could also be Clin Immunol. 2005;116:49–55 affected by environmental controls. PURPOSE OF THE STUDY. To evaluate the effects of a multifac- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900O eted intervention program involving high-risk infants on the development of asthma at 7 years of age. Rajiv Arora, MD Cecilia P. Mikita, MD STUDY POPULATION. Of the original 545 high-risk infants in Washington, DC the Canadian Childhood Asthma Primary Prevention Study, 380 were evaluated at 7 years of age. Infants at high risk for asthma development were defined as those The PREVASC Study: The Clinical Effect of a with at least 1 first-degree relative with asthma or 2 Multifaceted Educational Intervention to first-degree relatives with other immunoglobulin E–me- Prevent Childhood Asthma diated allergic diseases. Schonberger HJ, Dompeling E, Knottnerus JA, et al. METHODS. The initial 545 high-risk infants were randomly Eur Respir J. 2005;25:660–670 assigned before birth to a multifaceted intervention PURPOSE OF THE STUDY. To evaluate the clinical effectiveness group (n ϭ 279) or the control group (n ϭ 266). The of a multifaceted education intervention to prevent multifaceted intervention program, which was imple- childhood asthma. mented before birth and during the first year of life, included house dust mite–control measures, pet-avoid- STUDY POPULATION. General practitioners recruited 476 ance measures, avoidance of environmental tobacco high-risk children during the prenatal period. smoke, breastfeeding, and/or using partially hydrolyzed METHODS. These high-risk children were randomly as- whey formula. This study describes the follow-up assess- signed to either a control group, receiving usual care, or ment of 380 subjects at 7 years of age who completed a an intervention group, in which families received in- questionnaire and were evaluated by a pediatric allergist struction from nurses on how to reduce exposure of for asthma. Allergy skin testing and methacholine chal- newborns to dust mite, pet, and food allergens and pas- lenge were also performed. sive smoking. RESULTS. A significantly lower number of subjects had pe- RESULTS. A total of 443 infants were followed up for 2 diatric allergist–diagnosed asthma in the intervention years. At 2 years of age, those in the intervention group group (14.9%) than in the control group (23.0%; ad- (n ϭ 222) had less asthma-like symptoms, including justed relative risk [RR]: 0.44). The prevalence of wheezing, shortness of breath, and nighttime cough, asthma, defined as wheeze plus bronchial hyperreactiv- compared with those in the control group (n ϭ 221). No ity (methacholine challenge), was also significantly significant differences in total and specific immunoglob- lower in the intervention group when compared with ulin E were found between the groups. During the first the control group (12.9% vs 25%, respectively; adjusted 2 years of life, the incidence of asthma-like symptoms RR: 0.39). There was no significant difference in the was similar in both groups; however, subanalysis re- diagnosis of allergic rhinitis or atopic dermatitis, allergen vealed a significant reduction in the females but not in skin-test reactivity, or bronchial hyperreactivity alone the males in the intervention group. between the 2 groups. Symptoms of wheeze and wheeze apart from colds in the last 12 months were significantly CONCLUSIONS. The intervention used in this study was not lower in the intervention group compared with the con- effective in reducing asthma-like symptoms in high-risk

PEDIATRICS Volume 118, Supplement 1, August 2006 S9 Downloaded from www.aappublications.org/news by guest on September 28, 2021 children during the first 2 years of life, although it was asthma) and had better lung function. Those with cur- modestly effective at 2 years. Follow-up is necessary to rent asthma at age 18 were more atopic at age 18, with confirm whether the intervention can actually prevent higher skin-test reactivity for house dust mite and cat. the development of asthma. They had higher bronchial hyperreactivity by methacho- line at all age points between 9 and 18 than their coun- REVIEWER COMMENTS. This is a well-designed study in a pri- terparts in remission. Of the 68 subjects in remission at mary care environment to investigate the clinical effec- age 18, 44 remained in remission and 24 relapsed by age tiveness of a multifaceted approach to prevent the de- 26. Multiple logistic-regression analysis identified dust velopment of asthma in high-risk children. It seemed mite sensitization at age 13 (odds ratio [OR]: 2.63; 95% that the intervention was moderately able to reduce confidence interval [CI]: 1.23–5.61) and decreased exposure to dust mite, pet, and food allergens, but no forced expiratory volume in 1 second/forced vital capac- significant effect was observed on parentally observed ity ratio at age 18 (OR: 0.9 per 1% higher ratio; 95% CI: symptoms or allergen-specific immunoglobulin E in the 0.81–0.99). Those with better lung function had lower first 2 years of life. Perhaps a more focused intervention likelihood of asthma relapse by 16 years of age. Variables or longer follow-up period would have proven more such as methacholine reactivity and tobacco smoking useful. The effectiveness of a variety of multifaceted were not significant predictors. randomized intervention trials on asthma prevention has yet to be determined. Although a host of epidemio- CONCLUSIONS. Approximately one third of young adults logic studies have helped identify risk factors, we will all with a history of asthma in childhood in remission at 18 be interested in determining whether any practical in- years of age will relapse by 26 years of age. Most will terventions may be promising in preventing asthma de- have mild disease at relapse. There were weak associa- velopment. tions with atopy and lower lung function at a young age as predictors of asthma relapse. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900P Wanda Phipatanakul, MD, MS REVIEWER COMMENTS. Families often ask if their child will Boston, MA “outgrow” asthma. This study was consistent with other studies in finding that approximately one third of those in remission may have relapse, but the factors found by Asthma in Remission: Can Relapse in Early other groups as potential predictors such as atopy, lower Adulthood Be Predicted at 18 Years of Age? lung function, and tobacco smoking were not as strong. Taylor DR, Cowan JO, Greene JM, Willan AR, Sears URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900Q MR. Chest. 2005;127:845–850 Mary Beth Bollinger, DO PURPOSE OF THE STUDY. To determine the frequency of asthma Baltimore, MD relapse in young adults in remission at 18 years over an 8-year follow-up period and to determine possible prog- Adult Asthma Severity in Individuals With a nostic indicators of relapse. History of Childhood Asthma STUDY POPULATION. A subset of 68 subjects in asthma remis- Limb SL, Brown KC, Wood RA, et al. J Allergy Clin sion at 18 years of age from of a cohort of 1037 subjects Immunol. 2005;115:61–66 born in New Zealand from 1972 to 1973 followed from PURPOSE OF THE STUDY. Childhood asthma has a range of out- birth through the Dunedin Multidisciplinary Health and comes in adulthood. This study sought to identify clinical Development Study. features and exposures associated with persistence and METHODS. The cohort was enrolled at 3 years old and severity of childhood asthma in adulthood. followed every 2 years until age 15 and again at ages 18, STUDY POPULATION. Subjects had been previously enrolled in 21, and 26. Subjects were given respiratory question- the Childhood Asthma Study, a double-blind, random- naires and lung-function assessment by spirometry. ized, placebo-controlled trial designed to study the role Methacholine testing for bronchial hyperreactivity was of immunotherapy as an adjunct treatment. The 121 performed at 9, 11, 13, 15, and 21 years of age in some. original study members, aged 5 to 12 years at the time of Atopy was assessed by skin tests at ages 13 and 21 years. randomization, had moderate-to-severe asthma and had Remission of asthma at 18 years was defined as no been followed for at least 1 year before enrollment. current symptoms with previous reported symptoms at Evaluations performed during the original study in- Ն2 previous assessments. cluded daily medication-symptom diaries, home allergen RESULTS. At 18 years of age, there were 108 subjects with analysis, allergy skin testing, and methacholine chal- current asthma and 68 subjects with previous asthma in lenges. The cohort had varied socioeconomic status, gen- remission. Those in remission at age 18 had a later age of ders, and ethnicities. For this study an attempt was made onset of asthma (6.4 Ϯ 4.5 vs 4.7 Ϯ 4 years for current to enroll all original participants.

S10 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 METHODS. Eighty-five of the original subjects participated while also exploring geographic variations in indoor al- in the adult evaluation, underwent spirometry and in- lergen levels. halant allergy skin testing, and completed question- STUDY POPULATION. Subjects were children aged 5 to 11 naires regarding their interim medical history, asthma years (n ϭ 937) from 7 inner-city and metropolitan areas symptoms, and medications. Asthma severity was clas- across the United States participating in the Inner City sified by using a modified version of the 1997 National Asthma Study. Asthma Education and Prevention Program algorithm. Postbronchodilator spirometry was used for severity cat- METHODS. In a fully crossed factorial design, participants egorization. Subjects were categorized in the most severe were randomly assigned to receive an allergen interven- category for which they qualified. tion, bimonthly feedback of the child’s health status to their primary care physicians, both interventions, or no RESULTS. Thirteen (15.3%) of these young adults, aged 17 intervention (control group, n ϭ 234). At baseline, a to 30 years, were in remission. Another 19 (22%) had only mild intermittent asthma. There were 12 (14%) clinical interview with the child’s primary caregiver (in- with mild persistent asthma, 25 (29%) with moderate cluding demographics, asthma morbidity, home charac- persistent asthma, and 16 (19%) with severe persistent teristics, and exposure to tobacco smoke) was conducted disease. Subjects in remission, compared with subjects with skin-prick tests to aeroallergens. Morbidity was with mild intermittent or persistent asthma, had lower measured at 2-month intervals during a 24-month pe- serum immunoglobulin E in childhood (412 vs 1136 vs riod. Home visits including a visual inspection and dust- 968 ng/mL, respectively) and fewer positive allergy skin sample collection (dust mite, cockroach, cat and dog tests (7 vs 9 vs 10, respectively, from a panel of 18 dander) were conducted at baseline and every 6 months. allergens). Subjects in remission also had milder child- RESULTS. Of 1059 children tested, 94% had at least 1 pos- hood asthma, indicated by lower average daily medica- itive skin test. Allergen sensitivities varied widely across tion usage scores and lower percentage of days on in- the study sites, with cockroach (69%), dust mites (62%), haled corticosteroids (13.7% vs 24.7% vs 40.9%). There and molds (50%) being the most predominant. Cock- was no association found between current asthma se- roach sensitivity was highest in The Bronx, New York, verity and childhood immunotherapy. New York City, New York, and Dallas, Texas (81%, 79%, CONCLUSIONS. The prognosis of childhood allergic asthma and 79%, respectively), whereas dust mite sensitivities in adulthood is largely determined early in life. The were highest in Dallas and Seattle, Washington (84% degree of atopy seems to be a critical determinant of and 78%, respectively). At least 30% of the subjects asthma persistence. were allergic to cats at all sites. Cockroach levels were highest (Ͼ50% of homes) in Chicago, Illinois, New York REVIEWER COMMENTS. The authors point out that numerous City, The Bronx, and Dallas and were lower in Seattle studies of the natural history of asthma have suggested and Tucson, Arizona (8% and 11% of homes, respec- associations between childhood atopy and disease sever- tively). Dust mite levels were highest in Seattle and ity with risk of asthma persistence and severity in later Dallas. Cockroach levels were higher in high-rise and childhood and adulthood. It remains to be seen whether low-rise apartments, whereas dust mite levels were there is any sort of intervention at a very early phase in higher in detached homes. No correlation was seen be- the disease that will more favorably alter the course of tween animal dander and housing type. asthma. Thus far, there are no compelling candidates. CONCLUSIONS. There were significant differences between URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900R geographic study sites and the type of indoor allergen Timothy Andrews, MD exposure and skin-test sensitivity in this study group. James R. Banks, MD Cockroach predominated in the Northeast, whereas dust Arnold, MD mite predominated in the South and Northwest. Al- though most children in the study were allergic to dust mite and/or cockroaches, only the children who were ALLERGENS AND ENVIRONMENTAL EXPOSURES sensitive and exposed to cockroach had increased Inner City Asthma Study: Relationships asthma morbidity. Among Sensitivity, Allergen Exposure, and REVIEWER COMMENTS. This study demonstrates the associa- Asthma Morbidity tion of allergen sensitivities and exposures (particularly Gruchalla RS, Pongracic J, Plaut M, et al. J Allergy Clin cockroach allergens) to increased asthma morbidity in Immunol. 2005;115:478–485 children with moderate-to-severe asthma living in in- PURPOSE OF THE STUDY. To describe the relationship between ner-city areas. Physicians can use this knowledge to allergen sensitivities, allergen exposures, and asthma identify significant risk factors in asthmatic patients, im- morbidity in children with moderate-to-severe asthma plement appropriate prevention measures (ie, environ-

PEDIATRICS Volume 118, Supplement 1, August 2006 S11 Downloaded from www.aappublications.org/news by guest on September 28, 2021 mental intervention), and more aggressive medical man- tion of tolerance remains unclear, and it is also not agement to decrease the level of asthma morbidity. known whether this immune response represents dura- ble allergic tolerance. Future studies investigating these URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900S issues are needed to move toward potential primary Michael Le Bras, DO prevention therapy for allergic disease. Stacie M. Jones, MD Little Rock, AR URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900T Hemant Sharma, MD Elizabeth Matsui, MD Initial High-Dose Nasal Allergen Exposure Baltimore, MD Prevents Allergic Sensitization to a Neoantigen Riedl MA, Landaw EM, Saxon A, Diaz-Sanchez D. FOOD ALLERGY J Immunol. 2005;174:7440–7445 The Natural History of Tree Nut Allergy PURPOSE OF THE STUDY. Epidemiologic studies have suggested Fleischer DM, Conover-Walker MK, Matsui EC, Wood that high-dose allergen exposure may protect against RA. J Allergy Clin Immunol. 2005;116:1087–1093 primary allergic sensitization—the formation of immu- noglobulin E (IgE) after initial antigen exposure. This PURPOSE OF THE STUDY. To estimate the proportion of children study uses a human nasal allergic sensitization model to who outgrow tree nut (TN) allergy and examine predic- evaluate the effect of the dose of the antigen on the rate tors of outgrowing it. of primary sensitization to a neoantigen, keyhole limpet STUDY POPULATION. All children with TN allergy followed at hemocyanin (KLH). the authors’ pediatric allergy clinic.

STUDY POPULATION. Fifty-one healthy nonsmoking atopic METHODS. Patients with TN allergy, defined as a history of subjects aged 18 to 55 years. Atopic status was defined reaction on ingestion and evidence of TN-specific immu- by a positive skin-prick test to at least one aeroallergen; noglobulin E (TN-IgE) or positive TN-specific IgE level the subjects therefore had a propensity to mount an but no history of ingestion, were evaluated. If all current allergic (IgE) response to respiratory antigen exposure. Ͻ TN-IgE levels were 10 kU of antibody (kUA)/L, double- METHODS. Subjects underwent a 33-day sensitization pro- blind, placebo-controlled food challenges were offered. tocol including initial exposure to 0.1-, 10-, 1000-, or Patients who had undergone open oral TN challenges as 100 000-␮g doses of intranasal KLH as well as later part of routine clinical care were also included. exposure to adjuvant intranasal diesel exhaust particles. RESULTS. Two hundred seventy-eight patients with TN al- At the conclusion of protocol, antigen-specific IgE, IgG, lergy were identified. One hundred one (36%) had a and IgG4 were measured in nasal lavage samples. history of acute reactions, 12 (12%) of whom had reac- RESULTS. The rates of allergic sensitization, defined as de- tions to multiple TNs and 73 (63%) of whom had a tectable KLH-specific IgE, for the 0.1-, 10-, 1000-, or history of moderate-to-severe reactions. Nine of 20 pa- 100 000-␮g dose groups were 0, 100, 57, and 11%, tients who had previously reacted to a TN passed chal- respectively. Furthermore, the mean KLH-specific IgE lenges, so that 9 (8.9%; 95% confidence interval: 4%– levels decreased with increasing doses of initial antigen 16%) of 101 patients with a history of previous TN exposure. Antigen-specific IgG and IgG4 were produced reactions outgrew TN allergy. Of 19 patients who had by all subjects, with the highest levels observed in the never ingested TNs but had detectable TN-specific IgE high-dose group. levels, 14 passed challenges. One hundred sixty-one did not meet the challenge criteria, and 78 met the criteria CONCLUSIONS. Initial high levels of respiratory antigen ex- but declined challenges. Looking at specific TN-IgE val- posure may prevent primary allergic sensitization Յ ues, 58% with TN-IgE levels of 5kUA/L and 63% with through induction of an antigen-specific non-IgE hu- Յ TN-IgE levels of 2kUA/L passed challenges. moral immune response. CONCLUSIONS. Approximately 9% of patients outgrow TN REVIEWER COMMENTS. In children at high risk of allergic sen- allergy, including some who had previous severe reac- sitization, a means of preventing primary sensitization tions. Although ideal cutoffs for challenge cannot be and inducing durable allergic tolerance would be of great firmly recommended on the basis of these data, patients value. This study found that initial high-dose exposure aged 4 years or older with all TN-IgE levels of Յ5kU /L to a neoantigen, KLH, results in a humoral immune A should be considered for physician-supervised oral food response with high levels of antigen-specific IgG, includ- challenges. ing IgG4, and low levels of KLH-specific IgE. Whether these findings apply to other respiratory antigens re- REVIEWER COMMENTS. This is the first study to comprehen- mains unclear. The mechanism underlying this induc- sively address the natural history of TN allergy. Although

S12 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 the 9% chance of outgrowing TN allergy may seem low, sistent bleeding and histologic evidence of AC at 6 weeks it may be an underestimate of the actual resolution rate, were changed to an amino acid–based formula. because a large number of eligible patients declined di- RESULTS. Of 22 subjects, 14 (63.6%) had histologic evi- agnostic food challenges. The results of this study should dence of AC. Five had normal biopsies and 3 had non- encourage regular follow-up of children with TN allergy specific colitis. Seven of the 14 with AC were formula and consideration, when clinically indicated, for physi- fed. Six of the 7 had resolution of bleeding, on average, cian-supervised oral food challenges to determine the in 1.8 weeks (range: 1–5 weeks). One of the 7 was possibility of resolution. Because these oral food chal- changed to an amino acid formula at 3 weeks and had lenges can trigger anaphylaxis, they are generally under- resolution of bleeding at 5 weeks. The remainder of the taken under the supervision of an allergist and with 14 were breastfed. Six were followed to completion of immediate access to medications and equipment to treat the study. One had a delayed diagnoses because of de- a significant allergic reaction. velopment of worsening rectal bleeding and an abnor- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900U mal biopsy at week 3 despite a normal biopsy at the Anna Nowak-Wegrzyn, MD onset of the study. The infant failed to improve with New York, NY hydrolyzed formula but had resolution of bleeding by week 8 after initiation of an amino acid formula. Of the remaining 5, 2 had normal histology at week 3 with Prevalence and Outcome of Allergic Colitis in maternal elimination of cow’s milk. Two had improve- Healthy Infants With Rectal Bleeding: A ment by week 3, and 1 had no change. The average time Prospective Cohort Study for resolution in the breastfed group was 5.6 weeks Xanthakos SA, Schwimmer JB, Melin-Aldana H, (range: 2–8 weeks). For the 5 infants without histologic Rothenberg ME, Witte DP, Cohen MB. J Pediatr evidence of colitis, the average time for resolution of Gastroenterol Nutr. 2005;41:16–22 bleeding was 3.25 weeks. In those with nonspecific co- litis, 2 had resolution by week 6, and the third was PURPOSE OF THE STUDY. To determine the prevalence of aller- ultimately diagnosed with inflammatory bowel disease. gic colitis (AC) in a cohort of healthy infants with rectal bleeding. A secondary purpose was to determine if CONCLUSIONS. A significant proportion of infants with rectal bleeding would resolve in untreated infants with rectal bleeding may not have AC and may undergo unneces- bleeding without biopsy-proven AC. sary, expensive formula or maternal diet changes that may discourage breastfeeding. STUDY POPULATION. There were 22 infants Յ6 months of age with rectal bleeding recruited from the referral area of REVIEWER COMMENTS. This small study provides important in- Cincinnati Children’s Hospital Medical Center (Cincin- sights about the prevalence and natural course of proc- nati, OH). All subjects had a negative history of bleeding tocolitis. A much larger prospective placebo-controlled disorders, negative stool cultures, positive hemoccult, study that compares treatment versus no treatment and a negative history and physical examination for would be very helpful. signs of infection, Hirschsprung disease, and inflamma- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900V tory bowel disease. Casey Geaney, MD METHODS. AC was defined histologically as colonic mucosa Colorado Springs, CO with Ն6 eosinophils per high-power field and/or eosin- ophils in the colonic crypts or muscularis mucosae. For- Food Allergen Sensitization in Inner-City mula or maternal diet was changed only for infants with Children With Asthma histologic findings of AC. Formula-fed infants were Wang J, Visness CM, Sampson HA. J Allergy Clin switched to an extensively hydrolyzed formula and were Immunol. 2005;115:1076–1080 rebiopsied at 3 weeks. If the biopsy was normal, they were continued on the formula and managed clinically. PURPOSE OF THE STUDY. To determine the prevalence of food Those with continued histologic evidence of colitis were allergen sensitization and its association with asthma changed to an amino acid–based formula and rebiopsied symptoms and health care utilization in an inner-city at 6 weeks. Breastfed infants continued breastfeeding asthma population. while mothers followed a milk-protein–free diet. Those STUDY POPULATION. Random serum samples were obtained with resolution of bleeding and normal biopsies at 3 from children (n ϭ 544) aged 4 to 9 years (median: 6 weeks continued with breastfeeding and a restricted ma- years) with asthma living in inner-city areas enrolled in ternal diet. Those with persistent histologic evidence of the National Cooperative Inner City-Asthma Study. colitis were rebiopsied at 6 weeks with no further dietary change. Those with persistent bleeding were changed to METHODS. Information regarding demographics, health hydrolysate and rebiopsied at 6 weeks. Those with per- history, medication use, health care utilization, and

PEDIATRICS Volume 118, Supplement 1, August 2006 S13 Downloaded from www.aappublications.org/news by guest on September 28, 2021 asthma symptoms was recorded on the basis of 3-month viders should consider screening for food sensitization in recall at baseline and at 3-month intervals for a period of patients with severe or poorly controlled asthma. 12 months. No information regarding food allergy diag- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900W noses or reactions was obtained. Skin-prick testing to 13 environmental allergens was performed at enrollment in Kelly D. Burks, MD Stacie M. Jones, MD the National Cooperative Inner City-Asthma Study. The Little Rock, AR random serum samples were evaluated for specific im- munoglobulin E (IgE) (UniCap System) to egg, milk, soy, peanut, wheat, and fish. On the basis of IgE levels, subjects were stratified into 4 groups: group 1, food- Risk of Celiac Disease Autoimmunity and specific IgE levels that had Ͼ95% positive predictive Timing of Gluten Introduction in the Diet of value for food allergy; group 2, probable food allergy Infants at Increased Risk of Disease (IgE Ն 0.7 kU/L); group 3, any sensitization (IgE Ն 0.35 Norris JM, Barriga K, Hoffenberg EJ, et al. JAMA. kU/L); and group 4, no evidence of food allergy (IgE Ͻ 2005;293:2343–2351 0.35 kU/L). PURPOSE OF THE STUDY. Patients with HLA-DR3 or DR4 alleles RESULTS. There was a significant correlation between sen- are at increased risk for the development of celiac dis- sitization to foods and sensitization to aeroallergens, ease. However, not all genetically susceptible individuals with sensitization to the highest number of aeroallergens develop celiac disease. The objective of this study was to correlating with sensitization to soy, wheat, and peanut. investigate whether there was an association between Forty-five percent of study patients were sensitized to at the timing of exposure to gluten and subsequent devel- least one food (groups 1–3): 4% of the participants were opment of celiac disease autoimmunity (CDA) in chil- categorized to group 1, 26% to group 2, and 14% to dren with a genetic predisposition for celiac disease. group 3. Fifty-five percent were not sensitized to any of STUDY POPULATION. Children (n ϭ 1560) were identified in the 6 foods (group 4). Food allergy to egg and peanut the Denver, Colorado, metropolitan area with an in- were associated with the highest specific IgE levels. Pa- creased risk for celiac disease (or type 1 diabetes), de- tients who were sensitized to at least one food had fined as having either a first-degree relative with type 1 higher rates of hospitalization and steroid medication diabetes or positive cord blood screening for HLA-DR3 or use. The food-sensitized groups required more medica- DR4 alleles. This study was conducted over 10 years with tions in general, but this difference was not significant. a mean follow-up of 4.8 years. Most group 1 children (96%) demonstrated sensitization to Ͼ1 food, with 25% of the patients sensitized to all 6 METHODS. This was a prospective, observational study. In- foods tested. Most group 2 patients (75%) and 19% of fant diet data were collected during telephone or face- group 3 patients were sensitized to multiple foods. There to-face interviews at 3, 6, 9, 12, and 15 months of age. was a significant increase in hospitalizations for asthma No dietary advice was given to the families. Children had in children sensitized to Ͼ1 food. When specific foods blood drawn at 9, 15, and 24 months and annually were examined, a correlation between higher asthma thereafter for the measurement of the celiac disease morbidity and sensitization to fish or soy was noted. autoantigen, and tissue transglutaminase (tTG). After 1 or 2 positive tTG autoantibody results, small-bowel bi- CONCLUSIONS. Food sensitization correlated with increased opsy was offered to the families, although not all had this asthma severity in the study population. The prevalence procedure performed. The primary outcome of the study of food allergy was not determined because of the nature was the time to development of CDA defined as the of the study (anonymous serum samples and lack of presence of tTG autoantibodies on 2 consecutive results blinded food challenges); however, on the basis of the or a positive small-bowel biopsy after a single tTG-posi- study results, the authors predicted that inner-city chil- tive test. dren with asthma were more likely than the general RESULTS. Fifty-one children developed CDA. Children ex- population to have food allergy. The association of in- posed to foods containing wheat, barley, or rye in the creased asthma morbidity with at least 1 food sensitiza- first 3 months of life had a 5 times increased odds ratio tion, and findings that patients with sensitization to mul- (P ϭ .02) of CDA as compared with children first ex- tiple foods had significantly more asthma morbidity than posed to gluten at 4 to 6 months of age. Twenty-five of those with single-food sensitization, suggest that food the CDA-positive children had biopsy-proven celiac dis- sensitization is a marker for increased asthma severity. ease. In these children, exposure to gluten in the first 3 REVIEWER COMMENTS. This study suggests that the prevalence months of life had a 23 times increased risk (P ϭ .001) of of food sensitization, and possibly food allergy, is in- CDA. In the biopsy-proven cohort, children not exposed creased in patients with asthma and may be a useful to gluten until Ͼ7 months of age also had a significantly marker for increased asthma severity. Health care pro- increased risk of CDA (odds ratio: 4; P ϭ .04). There was

S14 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 no association between the development of CDA and the significant linear increase of the crude incidence from timing of introduction of oats or rice. No protective effect 1993–2000. During the period of 1993–2000 there was a of breastfeeding was found with the development of significant increase in the diagnosis of CD with partial CDA. Although all children in the cohort were exposed villous atrophy of the small-bowel mucosa and a relative to gluten by 12 months of age, the first positive tTG decrease in the diagnosis with subtotal villous atrophy. autoantibody test did not occur until 2 years of age, with Fewer children are presenting with abdominal disten- a mean age of positive conversion of 4.7 years. tion, chronic diarrhea, and failure to thrive, and more children are presenting with weight Ͻ10th percentile, CONCLUSIONS. In children at increased risk of developing abdominal pain, and lassitude. celiac disease, timing of gluten exposure in the diet is associated with the appearance of CDA. Exposure to CONCLUSIONS. The increase in newly diagnosed cases of CD gluten in the first 3 months of life is thought to be seems to represent greater awareness of the disease and associated with increased risk because of immature or the availability of serologic tests. The increase in the incomplete intestinal barrier function. The authors spec- number of children with CD diagnosed with small-bowel ulate that late gluten exposure may have been associated biopsy specimens showing partial villous atrophy sug- with CDA because of greater amounts introduced in the gests increased recognition of milder cases older infants. REVIEWER COMMENTS. In the United States, CD now seems to REVIEWER COMMENTS. It is important to understand that this affect ϳ0.5 to 1.0% of the population (10 times higher study population was specific children with genetic and than previous estimates). In the past, diagnosis of CD has family history characteristics at increased risk for the taken an average of 10 years. Serologic screening (eg, development of celiac disease and may not be general- tissue transglutaminase immunoglobulin A antibodies) izable to the entire population. Mean follow-up of this should be considered for children with symptoms of population was just under 5 years, and long-term fol- diarrhea, abdominal cramping, pain, and distention as low-up of these patients is needed to determine if earlier well as short stature and delayed puberty; individuals exposure to gluten simply leads to earlier appearance of with Down syndrome or type 1 diabetes mellitus; and CDA and that many (if not all) exposed at-risk children first-degree relatives of patients with biopsy-proven CD. would eventually develop CDA. This study also does not Positive serologic tests should be followed up by small- address the relationship between CDA and celiac disease. bowel biopsy. Increased awareness of CD allows earlier URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900X diagnosis and institution of a gluten-free diet.

Alan B. Goldsobel, MD URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900Y San Jose, CA John E. Duplantier, MD Indianapolis, IN

A National Prospective Study on Childhood Celiac Disease in the Netherlands 1993–2000: An Increasing Recognition and a Changing ATOPIC DERMATITIS Clinical Picture Long-term Treatment of Atopic Dermatitis Steens RF, Csizmadia CG, George EK, Ninaber MK, With Pimecrolimus Cream 1% in Infants Does Hira Sing RA, Mearin ML. J Pediatr. 2005;147:239–243 Not Interfere With the Development of Protective Antibodies After Vaccination PURPOSE OF THE STUDY. To investigate whether the incidence Papp KA, Breuer K, Meurer M, et al. J Am Acad of diagnosed celiac disease (CD) is increasing in the Dermatol. 2005;52:247–253 Netherlands and whether the clinical presentation is changing. PURPOSE OF THE STUDY. To examine if pimecrolimus 1% cream in the treatment of atopic dermatitis would have STUDY POPULATION. Children between the ages of 0 and 14 any effect on vaccinations. years with newly diagnosed cases of CD from 1993– 2000. STUDY POPULATION. A total of 91 children with mild-to-se- vere atopic dermatitis (AD), aged 3 to 23 months at METHODS. Diagnosis of CD was based on biopsy of the enrollment. small intestine. The following data were collected: age, gender, weight, height, and aspects of the presenting METHODS. Children were enrolled in a 1-year double-blind clinical picture. study (76 children received pimecrolimus, and 15 chil- dren received placebo). All 91 children were enrolled in RESULTS. The overall crude incidence rate for CD from a 1-year open-label extension study of pimecrolimus 1% 1993–2000 was 0.81 per 1000 live births. There was a cream. Patients were treated with either pimecrolimus

PEDIATRICS Volume 118, Supplement 1, August 2006 S15 Downloaded from www.aappublications.org/news by guest on September 28, 2021 1% cream or placebo for initial symptoms, and more 37.5% of the patients in the study were treated for Ͼ3 potent topical corticosteroids were used for flares not years. prevented by pimecrolimus 1% cream. Patients were RESULTS. Improvements in efficacy parameters were ob- vaccinated at normal scheduled times (4 doses of tetanus served within 1 week of treatment and continued for the and diphtheria and 1 or 2 doses of measles and rubella). duration of the study. Common adverse events included Response was evaluated at months 18 and 24 of the skin burning, pruritus, skin infection, skin erythema, 2-year period. flu-like symptoms, and headache. The incidence of ad- RESULTS. The seropositivity rates of 93.6% for tetanus, verse events, including cutaneous infections, did not 88.6% for diphtheria, 88.5% for measles, and 84.4% for increase with time on treatment. rubella were comparable with those reported in the lit- CONCLUSION. Tacrolimus ointment therapy is a rapidly ef- erature. Seropositivity was not significantly affected by fective and safe treatment for the management of AD in the use of pimecrolimus at the time of vaccinations (Ϯ28 pediatric and adult patients for up to 4 years. days). These seropositivity rates were within the ranges of 87% to 100% for tetanus, 83.3% to 99.3 for diphthe- REVIEWER COMMENTS. This study shows no long-term adverse ria, 60.5% to 97.1% for measles, and 55.6% to 88.1% effects of this topical calcineurin inhibitor in the treat- for rubella, similar to those reported in age-matched ment of AD. Most patients had Ͼ21⁄2 years of treatment pediatric populations. without increase in the number or incidence of infec- tions. If these drugs were systemically immunosuppres- CONCLUSION. Topical pimecrolimus in the treatment of sive, the number of cutaneous or systemic infections atopic dermatitis had no effect on the response to rou- would have been expected to increase. tine childhood vaccination. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900AA REVIEWER COMMENTS. Topical pimecrolimus, similar to top- ical tacrolimus (J Am Acad Dermatol. 2005;53[2 suppl Jonathan M. Spergel, MD, PhD Philadelphia, PA 2]:S206–S213), had no effect on routine childhood vac- cination. These topical calcineurin inhibitors did not af- fect basic B-cell function as measured by postvaccination titers. Efficacy and Tolerability of Pimecrolimus and Tacrolimus in the Treatment of Atopic URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900Z Dermatitis: Meta-analysis of Randomised Jonathan M. Spergel, MD, PhD Controlled Trials Philadelphia, PA Ashcroft DM, Dimmock P, Garside R, Stein K, Williams HC. BMJ. 2005;330:516–524 Efficacy and Safety of Tacrolimus Ointment PURPOSE OF THE STUDY. To determine the efficacy and tolera- Treatment for up to 4 Years in Patients With bility of topical pimecrolimus and tacrolimus compared Atopic Dermatitis with other treatments for atopic dermatitis. Hanifin JM, Paller AS, Eichenfeld L, et al. J Am Acad Dermatol. 2005;53:S186–S194 METHODS. Randomized, controlled trials of topical pime- crolimus or tacrolimus reporting efficacy outcomes or PURPOSE OF THE STUDY. This study was designed to evaluate tolerability from the Cochrane Library, Medline, and the long-term safety and efficacy of 0.1% tacrolimus Embase were identified. Eligible trials were evaluated for ointment in adult and pediatric patients with atopic der- efficacy, identified as investigators’ global assessment of matitis (AD). response; patients’ global assessment of response; pro- STUDY POPULATION. A total of 408 adult and 391 pediatric portions of patients with flares of atopic dermatitis; and patients with moderate-to-severe AD who had partici- improvements in quality of life. Trials were also evalu- pated in a previous clinical trial of tacrolimus ointments. ated for tolerability, identified as overall rates of with- The pediatric patients were from 2 to 15 years of age drawal, withdrawal resulting from adverse events, and (185 patients aged 2–6 years, and 206 patients aged proportions of patients with burning of the skin and skin 7–15 years), and 93.5% of the patients had severe AD. infections.

METHODS. Tacrolimus ointment 0.1% was applied twice RESULTS. A total of 4186 of 6897 participants in 25 ran- daily either intermittently or continuously to the af- domized, controlled trials received pimecrolimus or ta- fected areas. Efficacy and safety assessments included crolimus. Both drugs were significantly more effective percent body surface area affected, Eczema Area and than a vehicle control. Tacrolimus 0.1% was as effective Severity Index score, individual signs of AD, and the as potent topical steroids at 3 weeks and more effective incidence of adverse events. Patients were treated for a than combined treatment with hydrocortisone butyrate range of 1 to 1186 days (median: 982 days). A total of 0.1% plus hydrocortisone acetate 1% at 12 weeks (num-

S16 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 ber needed to treat [NNT]: 6). Tacrolimus 0.1% was also bacillus fermentum) or placebo twice daily for 8 weeks. Pa- more effective than hydrocortisone acetate 1% (NNT: 4). tients were stratified and block-randomized by SCORAD In comparison, tacrolimus 0.03% was more effective index, topical corticosteroid potency, and age. Partici- than hydrocortisone acetate 1% (NNT: 5) but less effec- pants were evaluated at baseline and weeks 2, 4, and 8 tive than hydrocortisone butyrate 0.1% (NNT: Ϫ8). Di- of the intervention period, with a final postintervention rect comparisons of tacrolimus 0.03% and tacrolimus evaluation at week 16. The primary outcome measure 0.1% consistently favored the higher strength formula- was change in AD extent and severity as assessed by the tion. Pimecrolimus was far less effective than beta- modified SCORAD index. Secondary outcome measures methasone valerate 0.1% (NNT: Ϫ3 at 3 weeks). included (1) change in family quality of life, (2) change in topical corticosteroid use, and (3) parental impression CONCLUSIONS. Both topical pimecrolimus and topical ta- crolimus are more effective than placebo treatments for of the intervention. atopic dermatitis, but in the absence of studies that show RESULTS. The SCORAD index of the children in the inter- long-term safety gains, any advantage over topical cor- vention group was significantly reduced over time com- ticosteroids is unclear. Topical tacrolimus is similar to pared with those in the placebo group, and the effect potent topical corticosteroids and may have a place for continued 2 months after the intervention was com- long-term use in patients with resistant atopic dermatitis pleted. Statistically significant improvement over base- on sites at which adverse effects from topical corticoste- line was seen in 92% of the intervention participants roids might develop quickly. In the absence of key com- compared with 63% of children in the placebo group. parisons with mild corticosteroids, the clinical need for Secondary outcome measures were not significantly dif- topical pimecrolimus is unclear. The usefulness of either ferent between groups. There were significantly fewer treatment in patients whose conditions have failed to reported lower respiratory tract infections in the inter- respond adequately to topical corticosteroids is also un- vention group and no clinically significant adverse clear. events recorded in either group.

REVIEWER COMMENTS. With the recent worry of “black-box” CONCLUSIONS. Probiotics are beneficial in decreasing sever- warnings on these medications, it is useful to see a ity and extent of moderate-to-severe AD among children meta-analysis of controlled trials on pimecrolimus and Ͻ2 years old. tacrolimus as an alternative to steroids in the treatment of atopic dermatitis. The results of this study suggest that REVIEWER COMMENTS. This is the first study to examination the usefulness of either treatment in patients whose the effects of probiotics among young children with conditions have failed to respond to topical corticoste- moderate-to-severe AD (mean SCORAD index: 41); pre- roids is unclear but that they may provide an alternative vious studies examined children with milder disease to steroids in certain clinical scenarios. One should keep (mean SCORAD index: 16). Similar to previous reports, in mind the risk/benefit ratio of all immunosuppressive the current study found significant improvements in medications in the treatment of atopic dermatitis. objective signs of disease in terms of severity and extent.

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900BB However, there were no significant differences in paren- tal subjective observations or topical steroid use. The Wanda Phipatanakul, MD, MS chronic nature of AD makes it difficult to assess subtle Boston, MA changes in quality of life or parental perceptions of dis- ease in such a short period of time. It is possible that improvements in subjective findings and medication use Effects of Probiotics on Atopic Dermatitis: A would have been more evident if the study period was Randomised Controlled Trial longer. There was a considerable placebo effect, and Weston S, Halbert A, Richmond P, Prescott SL. Arch although statistically insignificant, more than half of the Dis Child. 2005;90:892–897 participants receiving placebo showed improvement at PURPOSE OF THE STUDY. To examine the effects of probiotics the end of the study period. This effect was likely, in on moderate-to-severe atopic dermatitis (AD) in young part, because of improved adherence with medications children. as a result of being in the study. Future long-term studies should be conducted in this population to further assess STUDY POPULATION. Fifty-six children (aged 6–18 months) with moderate-to-severe AD (a modified scoring AD long-term efficacy, changes in quality of life, medication [SCORAD] index of Ն25). Patients were excluded if they use, and effects on development of other atopic diseases had previous exposure to probiotics, were currently tak- such as allergic rhinitis and asthma. ing antibiotics, or had other major medical problems. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900CC METHODS. Study participants were randomly assigned to Tamara T. Perry, MD receive probiotics (1 ϫ 109 colony forming units Lacto- Little Rock, AR

PEDIATRICS Volume 118, Supplement 1, August 2006 S17 Downloaded from www.aappublications.org/news by guest on September 28, 2021 ANAPHYLAXIS rine should be recommended to all food-allergic pa- tients, children seem to be at lower risk for having severe Allergic Reactions in the Community: A reactions requiring treatment with multiple doses of epi- Questionnaire Survey of Members of the nephrine. Anaphylaxis Campaign Uguz A, Lack G, Pumphrey R, et al. Clin Exp Allergy. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900DD 2005;35:746–750 Anna Nowak-Wegrzyn, MD New York, NY PURPOSE OF THE STUDY. To investigate the circumstances and clinical characteristics of food allergies in adults and children in the community. Parental Use of EpiPen for Children With Food Allergies STUDY POPULATION. Six thousand of the United Kingdom Kim JS, Sinacore JM, Pongracic JA. J Allergy Clin Anaphylaxis Campaign members, both children and Immunol. 2005;116:164–168 adults. The Anaphylaxis Campaign is the major British patient resource group for people who have suffered PURPOSE OF THE STUDY. Food allergy affects up to 6% of chil- severe allergic reactions. dren, and adverse reactions can be fatal. Appropriate emergency treatment consists of early administration of METHODS. The Anaphylaxis Campaign members were injectable epinephrine. Previous studies have revealed asked via a newsletter to report any food reactions dur- deficiencies in parental knowledge surrounding indica- ing the 6-month period. tions for self-injection, deficiencies in the method of RESULTS. One hundred nine respondents reported 126 re- EpiPen administration, and underuse in children expe- actions during the study period; 75 were children (Ͻ16 riencing anaphylaxis. This study explores whether un- years old; median: 6 years old at the time of reaction). deruse of EpiPen may be attributed to parental discom- More boys than girls were reported to have had reac- fort with administration, as measured by a lack of tions, but more women reported reactions than men parental empowerment and knowledge of proper ad- (P Ͻ .05). Specific foods were identified in 112 (89%) of ministration. the reports; peanut and tree nuts were responsible for STUDY POPULATION. Parents of children with physician-diag- most reactions in both children and adults. Children nosed food allergy who had been prescribed an EpiPen. with asthma reported more severe reactions than those without asthma (P ϭ .008), although frequency or se- METHODS. A self-administered survey was mailed to par- verity of recent asthma symptoms was not associated ents of children with food allergy, recruited through a with severity of allergic reaction reported. One fifth of food-allergy support group and a pediatric allergist’s the children reported a reaction in school or day care. practice. The questionnaire collected demographic infor- mation, medical history, history of previous “life-threat- Self-injectable epinephrine was used in 35% of the se- ening allergic reaction(s),” past experience with EpiPen vere reactions and 13% of the nonsevere reactions (P ϭ use, and knowledge of EpiPen indications. Knowledge .01). One quarter of the adults (3 of 12) who received a was assessed with a series of multiple-choice and true/ dose of epinephrine also received a second dose, false queries. Perceived parental comfort with EpiPen ad- whereas only 10% of the children (one of 10) required ministration was measured with a 10-cm analog scale, a second dose of epinephrine. anchored with “uncomfortable” versus “very comfortable” CONCLUSIONS. The allergens implicated in this report reflect at either end. Empowerment was measured with a 16-item previous data from similar patient groups in North instrument, including statements directly from or modified America. Asthmatic children suffer more severe reac- from the previously validated Family Empowerment Scale. tions than nonasthmatic children. Even when it is pre- RESULTS. Of 360 mailed surveys, 165 eligible surveys were scribed and available, self-injectable adrenaline seems included in the study (46%). The majority of respon- underused in severe reactions. The incidence of severe dents were married white mothers with college or ad- but nonfatal allergic reactions in the United Kingdom vanced degrees. The children of respondents ranged in may have been underestimated in the past. age from 1 to 19 years. Previous anaphylaxis was re- REVIEWER COMMENTS. Limited data are available regarding ported in 70 responses (42%). Fourteen parents (8%) details of treatment of food allergic reactions in the had administered the EpiPen to their child. Factors cor- community, but published experience consistently dem- relating with parental comfort with EpiPen administra- onstrates underuse of epinephrine for treatment of food tion included previous administration of EpiPen, EpiPen anaphylaxis. This underscores the need to continually training, and high empowerment scores. Neither a his- educate food-allergic patients on the indications for epi- tory of previous anaphylaxis nor parental knowledge nephrine administration. In addition, although the correlated with an increased level of reported comfort availability of the second dose of self-injectable epineph- with EpiPen administration.

S18 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 CONCLUSIONS. Increased empowerment scores directly cor- Before the seminar, 24% of child care centers would ad- related with increased parental comfort with EpiPen use. minister intramuscular epinephrine for a severe allergic Although increased knowledge scores did not prove to reaction. After the seminar, 77% of centers stated they be a significant contributor to parental comfort, training would administer intramuscular epinephrine (P Ͻ .001). on EpiPen use is an important component in improving In addition, center staff significantly improved their knowl- parental comfort. The authors question the impact of edge of symptoms of allergic reactions and the correct other psychological factors, such as fear, that may con- methods of intramuscular epinephrine administration. tribute to underuse of the EpiPen. CONCLUSIONS. There is a knowledge deficit in anaphylaxis REVIEWER COMMENTS. Previous studies of parental EpiPen ad- education at child care centers for children 1 to 6 years ministration have reported incorrect use of autoinjectors old. Intervention with individual education seminars despite training at the time of prescription. This study can significantly increase the ability of child care center suggests that factors beyond parental knowledge are crit- staff to recognize, evaluate, and treat anaphylaxis. ical for proper administration of this potentially life- REVIEWER COMMENTS. Although it is encouraging that the saving medication. The importance of hands-on training staffs at child care centers seem to be able to learn how to increase caregiver comfort is underscored by this to recognize and treat allergic reactions and anaphylaxis, study. Demonstration units and training videos are it is at the same time discouraging that such a small available free of charge through the manufacturers for percentage would have done so correctly before the EpiPen and the Twinject, another epinephrine self-in- seminar. Most child care centers receive their education jection unit not discussed in this study. from discussions with parents. However, studies have URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900EE shown that only 50% of parents could identify all the Karla L. Davis, MD critical steps for proper usage of epinephrine. Therefore, Cecilia P. Mikita, MD I agree with the authors that it is critical that health care Washington, DC professionals become more involved in the education of parents and the staffs of child care centers. In addition, detailed treatment plans should be written to help guide Recognition, Evaluation, and Treatment of centers in the proper care of allergic reactions. Anaphylaxis in the Child Care Setting URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900FF Bansal PJ, Marsh R, Patel B, Tobin MC. Ann Allergy Asthma Immunol. 2005;94:55–59 Helen Skolnick, MD Princeton, NJ PURPOSE OF THE STUDY. Although many young children with a history of allergic reactions or anaphylaxis spend con- siderable time in child care centers, little is known about Differences in Race, Ethnicity, and the centers’ knowledge of, experience with, and capacity Socioeconomic Status in Schoolchildren to treat anaphylaxis. The purpose of this study was to Dispensed Injectable Epinephrine in 3 evaluate the ability of child care centers to recognize, Massachusetts School Districts evaluate, and treat anaphylaxis episodes. Hannaway PJ, Connelly ME, Cobbett RM, Dobrow PJ. Ann Allergy Asthma Immunol. 2005;95:143–148 STUDY POPULATION. Children aged 1 to 6 who attended child care center in the suburbs of Chicago, Illinois. PURPOSE OF THE STUDY. To analyze the demographic charac- teristics of schoolchildren dispensed injectable epineph- METHODS. Eighty-five independent child care centers in rine in 3 school districts with widely diverse socioeco- suburbs of Chicago were selected randomly. They were nomic, racial, and ethnic populations. contacted by telephone and asked to join the study by completing an initial questionnaire about allergic reactions STUDY POPULATION. Students (prekindergarten to grade 12) and anaphylaxis. The center directors and teachers were from 3 school districts in Massachusetts (n ϭ 21 875) then offered an allergy seminar on anaphylaxis avoidance, were evaluated. Two of the school districts were afflu- recognition, evaluation, and treatment. After the seminar, ent, suburban towns outside of Boston (5855 students). center directors were given a posttest that included some of The third district (16 020 students) was also a Boston the questions from the original questionnaire. suburb but with a very low per-capita income, with 23% of the school-age population living below the poverty RESULTS. Of the 85 centers, 44 agreed to participate. Forty- line. The 2 suburban districts were 92% and 95% white, two centers completed the surveys before the seminar respectively, and the third district was 60% nonwhite. and 39 after the seminar. On average, each center had up to 7 children with an identifiable food allergy. The METHODS. All school districts in Massachusetts are required most commonly reported source of education concern- to report the number of students using daily or as- ing allergies was information provided by the parents. needed prescription medications to the Department of

PEDIATRICS Volume 118, Supplement 1, August 2006 S19 Downloaded from www.aappublications.org/news by guest on September 28, 2021 Public Health. Data were taken from reports filed by METHODS. In vivo (skin tests and challenges) and in vitro school nurses monthly for all students from the 2003– tests (for specific immunoglobulin E) were performed 2004 school year for these 3 school districts. with a standard concentration of penicillins and cepha- losporins. RESULTS. A total of 181 schoolchildren (0.83%) in the 3 districts were dispensed injectable epinephrine during RESULTS. When 1170 children with a clinical history of the school year studied. Diagnoses listed for the prescrip- allergy to penicillins and/or cephalosporins were tested tion of epinephrine included peanut/tree nut allergy in vivo for immediate hypersensitivity to ␤-lactams, (65%), stinging-insect allergy (19%), seafood allergy 58.3% of cases overall were found to be skin- or chal- (6%), and egg or dairy allergy (3%). A miscellaneous lenge-test–positive. Among them, 94.4% of patients group (7%) included diagnoses for latex, chocolate, pol- were positive to penicillins and 35.3% to cephalosporins. len, fruit, cold air, and ibuprofen allergy. Males were The frequency of positive reactions in the in vivo testing more likely to be dispensed epinephrine than females was in the range of 36.4% to 88.1% for penicillins and (odds ratio [OR]: 1.44; P Ͻ .02). White students were from 0.3% to 29.2% for cephalosporins. However, nearly 5 times more likely to have been dispensed epi- 31.5% of the penicillin-allergic children cross-reacted to nephrine for peanut and tree nut allergy (OR: 4.5; P Ͻ some cephalosporin. If a child was allergic to a cephalo- .001) and almost 9 times more likely for stinging-insect sporin, the frequency of positive reactions to penicillin allergy (OR: 8.7; P Ͻ .001). Seventy-five percent of stu- was 84.2%. The cross-reactivity between cephalosporins dents dispensed epinephrine for peanut or tree nut allergy and penicillins varied between 0.3% and 23.9%. The were enrolled in prekindergarten through grade 5. cross-reactivity among different generations of cephalo- sporins varied between 0% and 68.8%, being the high- CONCLUSIONS. Significant racial and socioeconomic differ- est for first- and second-generation cephalosporins and ences for prescribing self-injectable epinephrine was 0% for third-generation cephalosporins. seen in 3 school districts in Massachusetts. CONCLUSIONS. The frequency of immediate allergic reac- REVIEWER COMMENTS. This study describes the racial and so- tions to cephalosporins is considerably lower compared cioeconomic demographics of children prescribed inject- with penicillins, and the degree of cross-reactivity be- able epinephrine but does not address the reasons for the tween cephalosporins and penicillins depends on the disparity between affluent and nonaffluent or white and generation of cephalosporins, being higher with earlier- nonwhite populations. This study suggests that minority, generation cephalosporins. The cross-reactivity among socioeconomically disadvantaged students are being ei- cephalosporins is lower compared with cross-reactivity ther underdiagnosed or undertreated for potential ana- between penicillins and cephalosporins. phylactic reactions that require epinephrine. Other stud- ies have not shown racial differences in the incidence of REVIEWER COMMENTS. Penicillins and cephalosporins are food allergies, suggesting that other factors are involved common antibiotics inducing immunoglobulin E–medi- in the lower rate of epinephrine dispensed to disadvan- ated reactions in children. This large pediatric prospec- taged minority students. tive study revealed that more than half of the children with a history of drug reaction to penicillin and/or ceph- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900GG alosporins were skin- or challenge-test–positive, unlike Alan B. Goldsobel, MD adults in whom the majority of those with a history of San Jose, CA penicillin allergy are found to be skin test–negative. Almost one third of penicillin-allergic children are sensitized to DRUG ALLERGY cephalosporins. However, this sensitization was only to first- and second-generation cephalosporins; there was no Immediate Allergic Reactions to cross-reactivity seen with third-generation cephalosporins. Cephalosporins and Penicillins and Their Interestingly, there was less cross-reactivity among the dif- Cross-Reactivity in Children ferent cephalosporins. The results of this study can help Atanaskovic-Markovic M, Velickovic TC, Gavrovic- guide antibiotic choices for penicillin-allergic children. Jankulovic M, Vuckovic O, Nestorovic B. Pediatr Allergy Immunol. 2005;16:341–347 URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900HH Julie Wang, MD PURPOSE OF THE STUDY. To evaluate the frequency of anaphy- New York, NY lactic reactions to cephalosporins and penicillins and their cross-reactivity in a pediatric population.

STUDY POPULATION. A prospective survey was conducted in a Hypersensitivity Reactions to Paracetamol in group of 1170 children with suspected immediate aller- Children: A Study of 25 Cases gic reactions to cephalosporins and/or penicillins, which Boussetta K, Ponvert C, Karila C, Bourgeois ML, Blic J, were examined during a period of 8 years. Scheinmann P. Allergy. 2005;60:1174–1177

S20 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 PURPOSE OF THE STUDY. Reports of paracetamol (acetamino- in children with a history suggestive of adverse reactions phen) allergic and nonallergic hypersensitivity reactions to paracetamol. are rare. However, urticaria, angioedema, dyspnea, and URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900II allergic and nonallergic anaphylactic reactions have Karla L. Davis, MD been reported in both children and adults in association Cecilia P. Mikita, MD with paracetamol administration. Most reactions to Washington, DC paracetamol occur in patients with a nonallergic hyper- sensitivity to nonsteroidal antiinflammatory drugs (NSAIDs). Alternatively, reactions may result from an A Review of Evidence Supporting the allergic hypersensitivity to paracetamol, with tolerance American Academy of Pediatrics of NSAIDs. This study reports an investigation of 25 Recommendation for Prescribing Cephalosporin children with suspected paracetamol hypersensitivity. Antibiotics for Penicillin-Allergic Patients Pichichero ME. Pediatrics. 2005;115:1048–1057 STUDY POPULATION. Twenty-five children, aged 8 months to 15 years, with a history of adverse reactions associated PURPOSE OF THE STUDY. The American Academy of Pediatrics, with paracetamol administration. In 12 of the 25 chil- in their evidence-based guidelines for treatment of otitis dren studied, paracetamol adverse reactions were asso- media and sinusitis, endorse the use of cephalosporin ciated with concurrent administration of other medica- antibiotics for patients with reported allergies to peni- cillin. Many physicians, however, remain reluctant to tions or biological agents. prescribe such agents. This article reviews evidence in METHODS. Diagnosis of paracetamol hypersensitivity was support of the American Academy of Pediatrics recom- based on either clinical history or the results of an oral mendations for administration of cephalosporins to pen- challenge test. Reported reactions included urticaria, an- icillin-allergic children. gioedema, conjunctivitis, dyspnea, and a maculopapular STUDY POPULATION AND METHODS. The author reviewed data rash. Oral challenge tests with paracetamol were per- from published studies related to penicillin and cepha- formed in the hospital setting. Paracetamol dosing was losporin allergies in children and adults and in animal initiated at 1 mg and gradually increased until the ap- models. propriate cumulative dose for age and weight was achieved. An oral challenge with acetylsalicylic acid was RESULTS. Included in this review is an examination of the performed in 1 child with a history highly suggestive of types and incidence of reactions to penicillins and ceph- paracetamol hypersensitivity. alosporins, the frequency of cross-reactivity between these 2 groups of agents, and a thorough discussion of RESULTS. Paracetamol hypersensitivity was diagnosed in 1 the clinical guidelines related to penicillin and cephalo- patient (4%) on the basis of clinical history. The child sporin allergy. Experimental and clinical studies that reported accelerated reactions on 2 occasions, including suggest that side chain–specific antibodies predominate facial angioedema, conjunctivitis, and dyspnea with in the immune response to cephalosporins, thereby ex- wheezing, after isolated intake of paracetamol. Oral plaining the lack of cross-sensitivity between most ceph- challenge to acetylsalicylic acid in this patient induced alosporins and penicillins. Specific recommendations for urticaria and angioedema. Oral challenges to paraceta- the treatment of patients on the basis of their responses mol in the 24 other children studied were tolerated. to previously prescribed agents are summarized.

CONCLUSIONS. Results of this study of 25 children with sus- CONCLUSIONS. The author concludes that there is a low but pected paracetamol hypersensitivity concur with those measurable (0.5%) attributable risk associated with ad- of previous reports: paracetamol hypersensitivity is rare ministration of a first-generation or selected second- and is associated with hypersensitivity reactions to anti- generation cephalosporin to a patient with penicillin inflammatory medications. allergy. This increased risk is not present for third- or fourth-generation cephalosporins or for second-genera- REVIEWER COMMENTS. Adverse reactions temporally associ- tion molecules with non–cross-reactive side chains. ated with paracetamol may result from reactions to other medications or the underlying conditions for REVIEWER COMMENTS. This is a very careful, comprehensive, which these medications have been prescribed. Diagnos- and clinically useful review article. I recommend this tic evaluation of suspected paracetamol hypersensitivity article to physicians who would like to understand the is complicated further by the lack of validated, available evidence base and immunologic concepts underlying the skin or in vitro testing. Adverse reactions to paracetamol use of cephalosporins in penicillin-allergic individuals. can be both allergic and nonallergic in nature. The re- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900JJ sults of this study underscore the need for careful eval- James E. Gern, MD uation for both paracetamol and NSAID hypersensitivity Madison, WI

PEDIATRICS Volume 118, Supplement 1, August 2006 S21 Downloaded from www.aappublications.org/news by guest on September 28, 2021 The Upper Airway gens, are needed to further define the future role of SLIT in the United States.

A Prospective, Randomized, Double-blind, URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900KK Placebo-Controlled Multi-centre Study on the Justin Skripak, MD Efficacy and Safety of Sublingual Robert A. Wood, MD Immunotherapy (SLIT) in Children With Baltimore, MD Seasonal Allergic Rhinoconjunctivitis to Grass Pollen Rolinck-Werninghaus C, Wolf H, Liebke C, et al. Allergy. 2004;59:1285–1293 The Safety of Sublingual-Swallow Immunotherapy: An Analysis of Published PURPOSE OF THE STUDY. Subcutaneous immunotherapy Studies (SCIT) for seasonal allergic rhinitis is a well-established, Gidaro GB, Marcucci F, Sensi L, Incorvaia C, Frati F, effective, and potentially curative therapy. This study Ciprandi G. Clin Exp Allergy. 2005;35:565–571 evaluated an alternate route for immunotherapy: the oral mucosa and gastrointestinal tract. PURPOSE OF THE STUDY. To perform a meta-analysis of all pub- lished controlled studies concerning sublingual-swallow STUDY POPULATION. Ninety-seven children, aged 3 to 14 immunotherapy (SLIT) to determine rates of adverse years, with seasonal allergic rhinitis and proven sensi- events (AEs). tivity to grass pollen were studied. STUDY POPULATION. Subjects were from 25 published studies METHODS. Sensitivity to grass pollen was confirmed by (primarily European) aged 5 to 60 years (6 studies only positive skin-prick test, grass pollen–specific immuno- enrolled children, 9 only adults, and the remainder a globulin E, and conjunctival provocation test. Patients mix of both). were enrolled in a prospective, double-blind trial com- METHODS. A systematic Medline review from 1986 to May paring sublingual immunotherapy (SLIT) to placebo. 2004 was performed. Twenty-five published double- The treatment duration was 32 months. The primary blind, placebo-controlled studies using SLIT that in- outcome measure was the change in a multiple-symp- cluded efficacy and safety data were analyzed. Twelve tom/medication score (which measured eye, nasal, and studies used a high allergen dose (defined as 50–500 lung symptoms and rescue-medication use) after treat- times the standard subcutaneous dose), and 13 used a ment. Data collected included patient-reported symptom low allergen dose (defined as 1–50 times the subcutane- scores and medication use, total and antigen-specific ous dose). AEs were defined as local or systemic: local immunoglobulin E, skin-prick test, conjunctival provo- included oral itching and/or swelling and gastrointesti- cation test, nasal provocation test, spirometry, exhaled nal complaints, and systemic reactions included skin nitric-oxide concentration, atopic dermatitis score, and reactions and ocular, nasal, and chest symptoms. The eosinophilic cationic protein in nasal lavage fluid. rates of AEs were compared between the groups. The allergens used in the studies included mites, grasses, RESULTS. The multiple-symptom/medication score was sig- trees, and ragweed (single-allergen treatments). nificantly reduced by SLIT to 77.3% of the placebo group (P ϭ .049). This overall score was affected mainly by a RESULTS. Combining the studies, there were a total of 445 large reduction in rescue-medication usage among those subjects (405 placebo) in the high-allergen-dose group in the treatment group (67% of placebo; P ϭ .0025). and 302 subjects (285 placebo) in the low-allergen-dose There was no significant difference in any individual- group. Children accounted for 103 total active-dose sub- symptom score. jects. A total of 904 AEs were reported in the 198 553 active-allergen doses given, with 694 local reactions and CONCLUSION. SLIT had a positive effect on rescue-medica- 210 systemic reactions, with a rate of 0.15 to 0.2 reac- tion usage but no significant effect on symptoms alone. tions per patient. There were no reports of anaphylaxis. REVIEWER COMMENTS. SLIT represents an alternative therapy Overall, subjects in the low-allergen-dose group had with multiple potential advantages to SCIT, including significantly more local reactions than those in the high- the elimination of injections and improved safety profile. dose group. However, there was no significant difference Several studies in adults and children have found im- in the number of patients with AEs between the high- provement in symptom scores as well as reductions in and low-allergen-dose groups when compared as a ratio of the number of SLIT doses received. medication use to the point where this is now being used in clinical practice in place of SCIT in many European CONCLUSIONS. This analysis found that local reactions were countries. Additional studies, including investigation of common with SLIT but were mild and self-resolved. optimal dosing and the potential to use multiple aller- Systemic reactions occurred rarely and were not dose

S22 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 dependent. The authors conclude that SLIT is safe for use CONCLUSIONS. The results suggest that heat-killed LP33 can in adults and children. effectively improve the overall quality of life for patients with allergic rhinitis and that it may be efficacious as an REVIEWER COMMENTS. SLIT has been widely used in Europe in alternative treatment. recent years, has been found to be efficacious by other studies, and has a good safety profile (supported by the REVIEWER COMMENTS. The hygiene hypothesis suggests that meta-analysis). Another article in this same journal (Clin lack of early exposure to microorganisms is a factor in Exp Allergy. 2005;35:560–564) found SLIT to be safe in the recent rise in allergic disorders. Studies have shown children younger than 5 years. SLIT is being studied in the certain gut flora, including Lactobacillus, may have the United States as well and may be an option in the immunomodulatory effects that may be beneficial in near future for treatment of allergic rhinitis. regulating allergic responses. Concerns over safety of administering live bacteria as a therapeutic agent led URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900LL Peng and Hsu to investigate the effectiveness of heat- Mary Beth Bollinger, DO killed lactobacillus in the treatment of allergic rhinitis. Baltimore, MD The authors demonstrate that the heat-killed version is effective in improving the quality of life of patients suf- fering from allergic rhinitis.

The Efficacy and Safety of Heat-Killed URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900MM Lactobacillus paracasei for Treatment of Julie Wang, MD Perennial Allergic Rhinitis Induced by House- New York, NY Dust Mite Peng G-C, Hsu C-H. Pediatr Allergy Immunol. 2005;16: 433–438 Surgical Management of Chronic Sinusitis in PURPOSE OF THE STUDY. Live Lactobacillus paracasei 33 (LP33) Children may effectively improve the quality of life for patients Ramadan HH. Laryngoscope. 2004;114:2103–2109 with perennial allergic rhinitis. It has been demonstrated that heat-killed lactic acid bacteria suppress specific im- PURPOSE OF THE STUDY. To compare the outcomes of children munoglobulin E synthesis and stimulate interleukin-12 treated for refractory chronic sinusitis with adenoidec- production in animals. The aim of this study, therefore, tomy, endoscopic sinus surgery (ESS), or adenoidectomy was to evaluate the efficacy of heat-killed LP33 in the with ESS. treatment of allergic rhinitis induced by house-dust mite STUDY POPULATION. Children, 2 to 13 years old, with sinusitis in human subjects. that persisted after 6 months of medical treatment (eg, STUDY POPULATION. A total of 90 patients older than 5 years antibiotics, nasal steroids, decongestants, reflux medica- with perennial allergic rhinitis characterized by intermit- tions). These children had surgery (adenoidectomy, ESS, tent or continuous nasal symptoms for Ͼ1 year were or both) over the 10-year study period. enrolled in a randomized, double-blind, placebo-con- METHODS. This was a nonrandomized study in which chil- trolled trial and assigned to 3 treatment groups. dren were followed prospectively every 3 months after METHODS. Patients in groups A and B received 2 capsules the surgical approaches. Each child was evaluated pre- per day of live or heat-killed lactic acid bacteria (5 ϫ 109 operatively for allergy, immunodeficiency, and cystic colony-forming units per capsule), respectively, over a fibrosis and had a sinus computed tomography (CT) scan period of 30 days, whereas those in group C received to assess disease severity. Parents filled out a question- placebo capsules. A modified questionnaire on pediatric naire to assess improvement every 6 months for 1 year. rhinoconjunctivitis-related quality of life was adminis- Improvement based on questionnaire reports and need tered to all subjects or their parents during each clinical for more surgery were the principal outcome measures. visit. RESULTS. A total of 222 children had surgery for sinusitis RESULTS. The overall quality-of-life score decreased for during the study period (11% of children referred for groups A and B compared with the placebo group in evaluation of sinusitis), and 183 had adequate follow- terms of both frequency (9.47 Ϯ 2.89, 6.30 Ϯ 2.19, and up. The 3 surgical groups were similar with regard to Ϫ3.47 Ϯ 1.53, respectively; P Ͻ .0001) and level of gender, asthma, allergy, smoke exposure, and day care bother (5.91 Ϯ 3.21, 6.04 Ϯ 2.44, and Ϫ2.80 Ϯ 1.64, attendance. The children who had adenoidectomy alone respectively; P ϭ .004) after the 30-day treatment. The were younger and had less severe sinus disease on CT efficacy of the heat-killed LP33 was not inferior to the scan than those in the other groups. Children who had live variant. No obvious adverse effects were reported for adenoidectomy/ESS showed the greatest rate of im- either active-treatment group during the study period. provement (87%) and lowest need for more surgery

PEDIATRICS Volume 118, Supplement 1, August 2006 S23 Downloaded from www.aappublications.org/news by guest on September 28, 2021 (7%). Seventy-five percent of children after ESS alone REVIEWER COMMENTS. Children with chronic sinusitis usually were improved, and 13% of the children in this group do not need surgery. For those whose conditions fail needed revision surgery. The adenoidectomy group had medical treatment, the choice of initial surgery (ade- improvement in 52% of its subjects, and more surgery noidectomy, ESS, or both) remains problematic. This was needed for 25%. Younger children (aged Յ6) had comparison of postsurgical results has several limita- lower rates of improvement and needed revision surgery tions. The patients were not randomly assigned to the more than older children, with no difference in results groups, which was most evident in the adenoidectomy between surgical groups. Children older than 6 years group; the children in this group were younger and had had the greatest improvement rate with adenoidectomy/ less severe disease than those in the other 2 groups. It is ESS (96%). Children with asthma had lower rates of not surprising that the children in the adenoidectomy surgical success than those without (62% vs 80%); there group would have a higher rate of additional surgery, was no difference in surgical success in children with because the threshold to perform ESS in a child after and without allergies. For patients with asthma, ade- adenoidectomy alone failed is certainly lower than that noidectomy/ESS was superior. When CT scans showed of performing additional surgery on one in whom ESS mild disease, no differences were seen in the 3 surgical failed. The postoperative survey was not validated, and groups. With more severe disease on CT scan, adenoid- objective measures of improvement (school days missed, ectomy/ESS improved more patients (87%) than did number of antibiotic courses, etc) were not included. A ESS (72%) or adenoidectomy (46%) alone. comparable group treated without surgery was not stud- ied. Despite these shortcomings, this study provides clin- CONCLUSIONS. Surgery is recommended for children with ical indicators to assign appropriate surgery for the child chronic sinusitis refractory to medical therapy, and im- with refractory sinusitis. provement is seen in most children. Adenoidectomy alone is recommended for children who are 6 years old URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900NN or younger with mild sinus disease on CT scan. Adenoid- Stacey Ishman, MD ectomy/ESS should be considered for older children, David Tunkel, MD those with severe sinusitis, and those with asthma. Baltimore, MD

S24 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 Asthma was significantly greater (P ϭ .02) induction of apoptosis with pretreatment. Likewise, viral titers in the superna- tant of infected asthmatic subjects’ BECs were inhibited ␤ PATHOPHYSIOLOGY by postinfection treatment with IFN- but were most inhibited by pretreatment with IFN-␤. Responses were Asthmatic Bronchial Epithelial Cells Have a similar between ICS-treated and ICS-naive asthmatic Deficient Innate Immune Response to subjects. Infection With Rhinovirus CONCLUSIONS. Examination of early innate immune re- Wark PAB, Johnston SL, Bucchieri F, et al. J Exp Med. sponses revealed profound impairment of virus-induced 2005;201:937–947 IFN-␤ messenger RNA expression and IFN-␤ production PURPOSE OF THE STUDY. To determine if bronchial epithelial from BECs of subjects with asthma. A novel use for type cells (BECs) from asthma patients have abnormal innate 1 interferons in the treatment or prevention of virus- responses to rhinovirus infection. induced asthma exacerbations is proposed.

STUDY POPULATION. BECs from 14 subjects with moderate REVIEWER COMMENTS. How a rhinovirus infection induces an persistent asthma treated with inhaled corticosteroids asthma exacerbation remains largely speculative. Differ- (ICSs), 10 subjects with mild intermittent asthma who ences between the innate immune response to rhinovi- were never treated with ICSs, and 10 healthy controls. rus infection of asthmatic and healthy subjects are dem- onstrated by using this novel approach. Very interesting METHODS. BECs were cultured from bronchial brushings is the lack of difference seen in ICS-naive and ICS- obtained by bronchoscopy. BECs were studied prerhino- treated asthmatic subjects, which may explain why con- virus-16 infection, postinfection, and post–inactivated troversy remains regarding the role of ICSs in prevention rhinovirus-16 exposure. Cytokines and chemokines of viral-induced asthma exacerbations. These data sug- were measured. Viable cell numbers, numbers of apo- gest that impairment in IFN-␤ production may be im- ptotic cells, and cell lysate caspase activity were used to portant in the induction of immune responses resulting measure apoptotic activity. Apoptotic activity inhibition in an asthma exacerbation. The authors’ proposal that using the caspase-3 inhibitor, ZMD-fmk, was used to type 1 interferon use may treat or prevent viral-induced verify the presence of apoptosis. Rhinovirus-infection asthma exacerbations is intriguing. induction of interferon-␤ (IFN-␤) was measured. Influ- ence of IFN-␤ on apoptosis induction was evaluated by URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900OO prerhinovirus and postrhinovirus infection treatment of Mark H. Moss, MD ␤ ␤ BECs with exogenous IFN- . The effect of IFN- was Madison, WI also measured on virus titer preinfection and postinfec- tion.

RESULTS. Rhinovirus-16 infection induced ICAM-1 (inter- IL-19 Induced Th2 Cytokines and Was Up- cellular adhesion molecule-1), IL-6 (interleukin-6), and regulated in Asthma Patients RANTES (regulated upon activation, normal T cells ex- Liao SC, Cheng YC, Wang YC, et al. J Immunol. 2005; pressed and secreted) expression equally in BECs from 173:6712–6718 asthmatic and healthy subjects. Viral RNA expression, lactate dehydrogenase activity, and virus titers all signif- PURPOSE OF THE STUDY. Interleukin-10 (IL-10) has been icantly increased in asthmatic versus healthy subjects’ shown to inhibit allergen-induced airway hyperrespon- BECs. The percentage of viable cells was 63% in asth- siveness and inflammation. This study evaluates matic versus 80% in healthy subjects’ BECs, whereas whether IL-19, a member of the IL-10 family, is associ- apoptosis increased 1.4-fold in asthmatic and 2.2-fold in ated with asthma. control subjects’ BECs (P ϭ .02). Caspase activity in- STUDY POPULATION. The authors investigated IL-19 levels in creased significantly more in the control versus asth- 100 asthmatic patients, aged 3 to 12 years, as well as 50 matic subjects’ BECs postinfection. Induction of apopto- healthy adults and 50 age-matched children. A dust sis in the healthy controls was inhibited by treatment of mite–induced mouse model of asthma was also used to BECs with ZVD-fmk, and in a similar experiment, viral study the association of IL-19 with asthma. titers increased in the control BECs posttreatment and closely approximated the titers seen in infected asth- METHODS. Cytokine levels were quantified by enzyme- matic subjects’ BECs. Induction of IFN-␤ messenger RNA linked immunosorbent assay. IL-19 levels were mea- and IFN-␤ production were both significantly greater in sured in all study subjects, but among asthmatic patients, the control versus the asthmatic subjects’ BECs. The the levels of IL-4 and IL-13 were analyzed in the 27 effect of IFN-␤ on induction of apoptosis was evaluated: patients with the highest and 25 patients with the lowest although apoptosis increased with posttreatment, there IL-19 levels. By using a dust mite–sensitized murine

PEDIATRICS Volume 118, Supplement 1, August 2006 S25 Downloaded from www.aappublications.org/news by guest on September 28, 2021 asthma model, IL-19 levels were measured in asthmatic STUDY POPULATION. There were 25 patients aged 14 to 55 and control mice. To test whether IL-19 upregulates whose asthma was being treated only with a short-acting ␤ T-helper 2 (Th2) cytokines, IL-19 complementary DNA 2 agonist as needed and who experienced a fall in FEV1 was injected into healthy mice using intramuscular elec- of Ն15% after an exercise challenge. troporation, and serum levels of IL-4, IL-5, IL-10, and METHODS. Induced sputum was obtained at baseline and IL-13 were later monitored. After injection of IL-19 into 30 minutes after exercise challenge. In a randomized, asthmatic mice, IL-13 and immunoglobulin E (IgE) lev- double-blind crossover study, the cysteinyl leukotriene els were measured. To determine if IL-19 could induce antagonist montelukast and antihistamine loratadine, or Th2 cytokine production in vitro, IL-19 was incubated 2 matched placebos, were administered for 2 doses be- with CD4ϩ T cells and IL-4, IL-5, IL-10, and IL-13 levels fore exercise challenge. were quantified in the cell-culture supernatant. RESULTS. The percentage of columnar epithelial cells in RESULTS. Among asthmatic patients, the serum level of induced sputum at baseline was associated with the IL-19 was twice that of healthy controls, and those with severity of EIB. After exercise challenge, histamine, a high level of IL-19 also had high levels of IL-4 and tryptase, and cysteinyl leukotrienes significantly in- IL-13. In the murine asthma model, asthmatic mice also creased in the airways, and there was an increase in had IL-19 levels twice that of healthy control mice. columnar epithelial cells in the sputum. The concentra- Injection of the IL-19 gene into healthy mice induced tion of columnar epithelial cells was associated with the production of IL-4, IL-5, and IL-10 but not IL-13. IL-19 levels of histamine and cysteinyl leukotrienes. Treat- upregulated IL-13 in asthmatic mice and also upregu- ment with montelukast and loratadine inhibited the re- lated IgE production. In vitro, IL-19 was associated with lease of cysteinyl leukotrienes and histamine but did not increased IL-4, IL-5, IL-10, and IL-13 production by inhibit the release of columnar epithelial cells. activated cells. CONCLUSION. Epithelial cells, mast cell mediators, and eico- CONCLUSIONS. IL-19 upregulates production of Th2 cyto- sanoids are released into the airways during EIB, sup- kines in activated T cells and may be an important mol- porting an inflammatory basis for EIB. ecule in the pathogenesis of asthma. REVIEWER COMMENTS. “Exercise-induced asthma” (EIA) is not REVIEWER COMMENTS. The Th2 cytokines upregulated by a disease unto itself. As the authors point out, “[EIB] is IL-19 play crucial roles in the pathogenesis of asthma. a highly prevalent condition present in approximately IL-13 regulates airway hypersensitivity and mucus hy- half of patients with asthma.” Most such patients, if persecretion; IL-4 is critical for IgE antibody switching; questioned carefully, will admit to symptoms under cir- and IL-5 plays a key role in eosinophil maturation. The cumstances other than exercise, such as with upper re- findings from this study suggest that IL-19 is another spiratory infections or irritant or allergen exposures. It is potentially important molecule in asthma pathogenesis better to consider EIB a very common phenomenon and may be responsible, at least in part, for upregulation among patients with asthma. There are 2 competing of Th2 cytokines that are critical to the development of hypotheses of the mechanism of EIB: (1) loss of heat allergic disease. leads to vascular engorgement as the airways rewarm URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900PP after exercise, initiating bronchoconstriction; and (2) loss of water leads to a change in airway osmolarity that Hemant Sharma, MD initiates epithelial cell and mast cell activation, leading to Elizabeth Matsui, MD Baltimore, MD the release of inflammatory mediators in the airways that cause bronchoconstriction. These 2 theories are not necessarily mutually exclusive, and the former theory may apply more to the minority of patients who com- plain of symptoms only after they finish exercising (ie, Inflammatory Basis of Exercise-Induced when they stop breathing through an open mouth). If Bronchoconstriction the number of desquamated epithelial cells before exer- Hallstrand TS, Moody MW, Wurfel MM, Schwartz LB, cise is taken as an indication of the level of ongoing Henderson WR Jr, Aitken ML. Am J Respir Crit Care airway inflammation, this study would suggest that pa- Med. 2005;172:679–686 tients with worse baseline inflammation would have PURPOSE OF THE STUDY. To establish whether epithelial cell worse EIB. Also of note is that the combination of the and mast cell activation with release of inflammatory cysteinyl leukotriene antagonist and antihistamine did mediators occurs during exercise-induced bronchocon- not inhibit the desquamation. For patients in whom a ␤ striction (EIB) and how histamine and cysteinyl leuko- short-acting 2 agonist does not prevent EIB or who triene antagonists alter the airway events occurring dur- have any abnormality on baseline spirometry, a truly ing EIB. and broadly antiinflammatory medication (ie, inhaled

S26 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 corticosteroids) would seem to be the most appropriate challenge with the first antigen (ovalbumin); (2) the treatment for EIB. differentiation of naive CD4ϩ T cells to Th2 cells required trafficking of naive CD4ϩ T cells to bronchial lymph URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900QQ nodes and required interleukin-4 produced by ovalbu- John M. Kelso, MD min-activated Th2 cells; and (3) a TLR9 agonist inhibited San Diego, CA phenotype spread and experimental asthma by decreas- ing the production of chemokines involved in the traf- ficking of activated Th2 and naive CD4ϩ T cells to re- gional lymph nodes. Induction and Inhibition of the Th2 Phenotype Spread: Implications for Childhood CONCLUSIONS. Th2 phenotype spread is the mechanism by Asthma which allergic sensitization to inhaled allergens is ex- Hayashi T, Gong X, Rossetto C, et al. J Immunol. 2005; panded in an already Th2-primed host. It occurs in re- 174:5864–5873 gional lymph nodes and is mediated by interleukin-4 produced by activated Th2 cells. PURPOSE OF THE STUDY. T-helper 2 (Th2) phenotype spread refers to the concept that an established antigen-specific REVIEWER COMMENTS. Studies have suggested that initial ex- Th2 immune response may promote a Th2 response to a posure to aeroallergens, the development of Th2 mem- neoantigen. This study used a mouse model to investi- ory against them, and the associated clinical allergic gate the requirements for induction and inhibition of manifestations occur during early childhood. Th2 phe- phenotype spread to ragweed, a clinically relevant aller- notype spread may be the mechanism by which the gen. allergic/asthmatic phenotype develops in early child- hood. This study offers an animal model for further METHODS. To induce and characterize phenotype spread, study of the inhibition of Th2 phenotype spread, which BALB/c mice were first immunized by a series of subcu- may lend insight to immunomodulatory interventions taneous injections of egg ovalbumin and then chal- that could curb phenotype spread in early childhood, lenged intranasally with ovalbumin, ragweed, or both thereby attenuating or halting the allergic march. simultaneously. Mice were finally challenged intrana- sally with ragweed alone to assess allergic response URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900RR (Th2-mediated lung inflammation, ragweed-specific im- Hemant Sharma, MD munoglobulin E). To study the effect of time interval Elizabeth Matsui, MD between the first and second antigens, the above-de- Baltimore, MD scribed experiment was repeated with ragweed being given either simultaneously with ovalbumin or 8, 24, or Self-Organized Patchiness in Asthma as a 48 hours after ovalbumin challenge. To investigate the Prelude to Catastrophic Shifts role of activated Th2 cells in the induction of phenotype Venegas JG, Winkler T, Musch G, et al. Nature. 2005; spread, severe combined immunodeficient (SCID) mice 434:777–782 received ovalbumin-specific Th2 cells and naive CD4ϩ T cells intravenously and were initially challenged with PURPOSE OF THE STUDY. To reveal self-organized small airway ovalbumin and ragweed and then challenged later with constriction contributing to large ventilation defects in ragweed and assessed for allergic response. To evaluate asthmatics. whether trafficking of naive CD4ϩ T cells to bronchial STUDY POPULATION. Mild and moderate asthmatics. lymph nodes is required for the induction of phenotype spread, these cells were labeled and treated with an METHODS. Ventilation defects in asthmatics were studied inhibitor of chemotaxis before the adoptive transfer ex- during methacholine bronchoprovocation by using se- periments in the SCID mice. The effect on phenotype rial dynamic positron emission tomography with a spread of immunostimulatory sequence-oligodeoxy- positron-emitter nitrogen-13 tracer and a single termi- nucleotide (ISS-ODN), a Toll-like receptor 9 (TLR9) ag- nal-airway model. onist, was first assessed in BALB/c mice by using the RESULTS. Heterogeneity of ventilation defects in asthmatics protocol described above, with injection of ISS-ODN be- was demonstrated. In this model, constriction of termi- fore intranasal ovalbumin and ragweed challenge. ISS- nal bronchioles was the main feature of bronchocon- ODN was also tested in the SCID adoptive-transfer striction, contributing to nonuniform ventilation defects. model to study its effect on trafficking to regional lymph Consequently, on the basis of the mechanical interde- nodes. pendence in expansion between airways and surround- RESULTS. The experiments yielded the following results: ing parenchyma, clusters of constricted terminal bron- (1) Th2 phenotype spread to the neoallergen (ragweed) chioles fed by a common tree branch developed and led was induced only within the first 8 hours after bronchial to large ventilation defects.

PEDIATRICS Volume 118, Supplement 1, August 2006 S27 Downloaded from www.aappublications.org/news by guest on September 28, 2021 CONCLUSION. Clustered groups of self-organized terminal for Chlamydia by culture. Of the positive BAL samples, 28 bronchiolar constriction, not large airways obstruction, (74%) of 38 PCR-positive and 14 (64%) of 22 culture- contribute to large ventilation defects in acute asthma. positive samples were from children with asthma. Cul- ture-positive blood samples were found in 24 (34%) of REVIEWER COMMENTS. The nature of functional changes of 70 respiratory patients and 8 (11%) of 70 nonrespiratory both small and large airways affecting ventilation during controls. In the blood culture–positive respiratory group, acute asthma attacks has been unclear. Previously, MRIs 17 (71%) of 24 were from children with asthma. Ele- of asthmatic lungs during bronchoprovocation suggested vated total serum IgE was associated with BAL culture– large-airway obstruction as a major cause of large ven- positive results, and this relationship was stronger than tilation defects (eg, J Allergy Clin Immunol. 2003;111: total IgE and asthma diagnosis. 1205–1211). In this study, Venegas et al demonstrated the role of clustered terminal bronchiolar constriction CONCLUSIONS. Viable C pneumoniae organisms are fre- resulting in ventilation defects in acute asthma. On the quently present in the lung lavage in a cohort of pre- basis of this model, inhaled bronchodilators could be dominately asthmatic pediatric patients. ineffective because the inhaled form might reach only REVIEWER COMMENTS. Results from this study suggest that well-ventilated regions and could further impede lung infectious C pneumoniae may be common in BAL fluid of expansion of problematic regions and exacerbate re- children with asthma. Historically, C pneumoniae has gional ventilation defects. The concept of catastrophic been associated with exacerbation and increased inci- shifts might account for sudden, unexplained, and se- dence of respiratory conditions in adults, but studies to vere asthma attacks in some patients. Systemic broncho- examine similar associations in children have not been dilators may be needed in some asthmatics to bypass this performed. This is the first investigation to report viable problem. This line of investigation is further elucidated and infectious C pneumoniae in the BAL fluid of children elsewhere (J Appl Physiol. 2005;99:2388–2397). with asthma. These findings are intriguing and should URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900SS encourage investigators to examine the clinical implica- Akaluck Thatayatikom, MD tions of Chlamydia infection among pediatric patients Bangkok, Thailand with asthma.

Andrew H. Liu, MD URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900TT Denver, CO Tamara T. Perry, MD Little Rock, AR

The Bronchial Lavage of Pediatric Patients With Asthma Contains Infectious Chlamydia Repeat Exercise Normalizes the Gas-Exchange Webley WC, Salva PS, Andrzejewski C, et al. Am J Impairment Induced by a Previous Exercise Respir Crit Care Med. 2005;171:1083–1088 Bout in Asthmatic Subjects PURPOSE OF THE STUDY. To examine the frequency of Chlamydia Haverkamp HC, Dempsey JA, Miller JD, et al. J Appl pneumoniae infections in pediatric patients with asthma. Physiol. 2005;99:1843–1852

STUDY POPULATION. Seventy pediatric patients undergoing PURPOSE OF THE STUDY. To determine the effects of a second flexible fiber-optic bronchoscopy as a part of their ongo- exercise bout on the gas-exchange impairment caused ing clinical care. by an initial exercise-induced bronchospasm (EIB) re- sponse in asthmatic subjects. METHODS. Bronchoaveolar lavage (BAL) fluid and blood were examined for the presence of C pneumoniae by STUDY POPULATION. Twenty-one subjects with a known his- smear examination and culture. The BAL and blood tory of asthma participated after meeting at least 1 in- samples were cultured on human or mouse macro- clusion criteria: (1) Ն12% increase in the forced expira- ␤ phages to determine infectivity. Polymerase chain reac- tory volume in 1 second (FEV1) after -agonist inhalation, Ն tion (PCR) amplification of BAL samples was performed (2) 10% decrease in FEV1 after exercise test to exhaus- to confirm specificity of the culture technique. Blood tion, or (3) a provocative concentration Յ4.0 mg/mL of was examined for total immunoglobulin E (IgE). Blood methacholine causing a 20% decrease in FEV1. samples from 70 matched, nonrespiratory control pa- METHODS. The subjects performed 2 submaximal work- tients were cultured for Chlamydia. loads for 3 minutes. After 3 to 5 minutes of rest, constant RESULTS. Forty-two patients undergoing bronchoscopy work-rate exercise was performed until exhaustion at had asthma and 28 had various other respiratory dis- 90% of maximal O2 uptake (EX1). Arterial blood and eases. Thirty-eight (54%) BAL samples were positive for expired gases were collected at 3 (early recovery) and 35

Chlamydia by PCR and 22 (31%) samples were positive (late recovery) minutes after EX1. Subjects then per-

S28 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 formed a second bout of exercise to exhaustion at 100% PURPOSE OF THE STUDY. To determine if variations in clinical

of maximal O2 uptake (EX2). Pulmonary-function tests asthma phenotypes are the result of differences in un- were repeated at 5-minute intervals after EX1 and EX2. derlying T-cell immune responses to inhalant allergens. ϩ Ͼ RESULTS. Subjects classified as EIB ( 10% FEV1 decrease STUDY POPULATION. One hundred forty-seven children (aged Ϫ 5–10 minutes after EX1) and EIB had similar baseline 8.6–13.5 years) and 25 of their siblings (aged 7.4–17.4 lung function. In the EIBϩ group, the inspiratory pul- years) were recruited from 194 members of a birth co- Ϯ monary resistance (RLi) peaked at 4.2 3.2 cm H2O/L hort studied prospectively for asthma development. Ͻ per second above baseline (P .05) 4 minutes after EX1 METHODS. Wheeze and asthma were defined by parental and dropped back to baseline during EX2. The RLi did Ϫ questionnaire. Atopy was defined as at least 1 positive not change significantly in the EIB group. After EX1, ϩ skin-prick test for environmental or food allergens. In- the EIB group showed a sustained decrease in FEV 1 creased bronchial hyperreactivity (BHR) was defined as (2.8 Ϯ 0.66 L versus baseline, 3.97 Ϯ 0.47 L; P Ͻ .05), Ն whereas the EIBϪ group did not (3.60 Ϯ 0.56 L versus a 20% drop in forced expiratory volume in 1 second ␮ baseline, 3.72 Ϯ 0.53 L). In the EIBϩ group, the alveolar- after inhaled histamine up to 7.8 mol/L. T-cell re- sponses to allergens and mitogens, blood eosinophils, to-arterial PO difference (A-aDO ) remained greater 2 2 and immunoglobulin E (IgE) were measured and com- than baseline during early recovery after EX1 and wid- ened to 14.1 mm Hg above baseline (P Ͻ .001) during pared with clinical phenotypes. Ϫ late recovery. In the EIB group, the A-aDO2 returned to RESULTS. Ninety-five (55.2%) of the children were atopic, baseline during early recovery and increased to 18.1 Ϯ sensitized predominantly to house dust mite (42.4%). 9.1 mm Hg above baseline during late recovery. In both Asthma was present in 26 (15.1%) children, of whom 22 groups, the RLi, FEV1, and A-aDO2 were similar during (85%) were atopic; BHR was present in 62 (35.9%) ϩ EX1 and EX2. In the EIB group, sputum histamine children, of whom 45 (73%) were atopic. Atopy was increased after exercise (61.2 Ϯ 42.0 ng/mL versus base- associated with T-helper 2 (Th2) cytokine responses (in- line 34.6 Ϯ 25.9 ng/mL; P Ͻ .05) and was correlated terleukin-4 [IL-4], IL-5, IL-9, IL-13), whereas Th1 re- ϭ ϭ with the A-aDO2 (r 0.68; P .02) during EX1. sponses (IL-10, interferon-␥ [IFN-␥], tumor necrosis fac- ␣ CONCLUSIONS. In asthmatic patients, late gas-exchange dis- tor- [TNF]) occurred in all children. Skin-prick test turbance after exercise occurs independently of de- wheal size was positively associated with house dust mite allergen-induced IL-5 (P Ͻ .0001) and IFN-␥ (P ϭ creased FEV1 or increased pulmonary resistance. Gas exchange normalizes with a second bout of exercise, .003) and negatively associated with IL-10. Asthma was likely because of bronchodilation. associated with eosinophilia and elevated house dust mite–specific IL-5, IL-9, IL-13, and IgE. BHR was asso- REVIEWER COMMENTS. A new finding from this study is the ciated with eosinophilia, elevated allergen-specific IL-5 gas-exchange impairment seen after exercise in asth- and IgE, increased total IgE, and a polyclonal cytokine matic patients without measurable disturbance in FEV1 response (IL-5, IL-13, IFN-␥, and TNF-␣). In atopics, or pulmonary resistance after exercise; this late-recovery current asthma or wheeze was associated with house impairment of gas exchange may be a result of periph- dust mite allergen-specific IL-5 and IL-13; BHR was as- eral airway abnormalities that take time to develop. As sociated with IL-5 and IgE. In nonatopics, BHR was expected, sputum inflammatory mediators were in- associated with increased house dust mite allergen-spe- creased in patients with EIB. One of the goals of asthma cific and polyclonal IL-10 and polyclonal IFN-␥ and management is to avoid restrictions on activity and ex- TNF-␣. ercise, and the normalization of lung function and gas exchange seen in most subjects with a second bout of CONCLUSIONS. In atopic and nonatopic children, distinctive exercise offers some reassurance to asthmatic patients immune-response patterns were identified for asthma involved in repetitive, intense physical activity. and BHR. Immunologic Th1 and Th2 hyperresponsive- ness was identified as a hallmark of BHR. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900UU Elinor Simons, MD REVIEWER COMMENTS. Modification of T-cell responses has Albany, NY become an increasingly important focus in the investi- gation of treatments for atopic disease. Although this study further highlights the prominence of Th2-driven An Immunoepidemiological Approach to responses in atopic individuals, the results also demon- Asthma: Identification of in-Vitro T-Cell strate allergen-specific and polyclonal Th1 responses as- Response Patterns Associated With Different sociated with BHR in atopic and nonatopic children. Wheezing Phenotypes in Children These findings suggest a nonantagonistic interaction be- Heaton T, Rowe J, Turner S, et al. Lancet. 2005:365: tween Th1 and Th2 pathways in the production of 142–149 asthma symptoms. Further understanding of the associ-

PEDIATRICS Volume 118, Supplement 1, August 2006 S29 Downloaded from www.aappublications.org/news by guest on September 28, 2021 ations between T-cell response patterns and clinical who never wheezed and those with late-onset wheezing wheezing phenotypes in children may lead to future (P ϭ .43). Among the subgroup of children who had asthma therapies in this population. wheezed by age 3, the risk of persistent wheeze in- creased markedly with increasing sRAW values. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900VV Elinor Simons, MD CONCLUSIONS. Children with persistent wheeze have re- Albany, NY duced lung function at 3 and 5 years compared with other wheeze phenotypes. In children who wheezed during the first 3 years of life, reduced lung function at age 3 predicted persistent wheezing. However, reduced Wheeze Phenotypes and Lung Function in lung function at age 3 did not predict late-onset wheeze Preschool Children in those who had not wheezed previously. Lowe LA, Simpson A, Woodcock A, et al. Am J Respir Crit Care Med. 2005;171:231–237 REVIEWER COMMENTS. It would be useful to be able to predict whether wheezing early in life will be transient or per- PURPOSE OF THE STUDY. To determine the relationship be- sistent. This study augments the findings of the similarly tween wheeze phenotypes in childhood and lung func- sized, longitudinal, Tucson Children’s Respiratory Study tion at age 3 and 5 years and determine if lung function by suggesting that (1) poor lung function at age 3 is a at 3 years of age predicts the development or persistence predictor of persistent symptoms in those with a history of wheeze. of early wheezing, but for individuals the measurement STUDY POPULATION. A population-based cohort of 874 chil- has limited predictive value; (2) children with transient dren from the Manchester Asthma and Allergy Study. early wheezing have increased airflow resistance at age 5 Subjects were recruited prenatally and followed up at 3 compared with those who never wheezed; and (3) those and 5 years of age. with persistent wheeze and transient early wheeze both have airflow obstruction compared with the group who METHODS. Subjects were assigned to categories on the basis never wheezed. At age 5, the group with persistent of parental report of wheezing: “no wheezing” was de- wheeze also had lower postbronchodilator lung function fined as no wheezing by age 5; “transient early wheez- than the group with no wheeze, indicating that factors ing” was defined as wheezing before age 3 but none in other than smooth muscle contraction are present early the year before the 5-year follow-up; “late-onset wheez- in life. Additional studies are needed to determine the ing” was defined as no wheezing before age 3 but factors contributing to poor lung function early in life wheezing in the 12 months before the 5-year follow-up; and to identify measures that would predict persistent and “persistent wheezing” was defined as wheezing be- wheezing in individuals. fore age 3 and in the year before the 5-year follow-up. Specific airway resistance (sRAW) was measured at age URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900WW 3 and 5 by body plethysmography when subjects were Kricia P. Palmer, MD symptom-free. Postbronchodilator lung function was Scott D. Nash, MD measured as sRAW after albuterol inhalation. Larry W. Williams, MD Durham, NC RESULTS. The 530 (60.6%) subjects successfully perform- ing sRAW at age 3 were distributed as: 248 never wheezed, 115 had transient early wheeze, 22 had late- onset wheezing, and 78 had persistent wheezing. The Asthma Phenotypes, Risk Factors, and 730 children successfully performing sRAW at 5 years Measures of Severity in a National Sample of old were distributed as: 384 never wheezed, 162 had US Children transient early wheeze, 40 had late-onset wheeze, 104 Kelley CF, Mannino DM, Homa DM, Savage-Brown A, had persistent wheeze, and 40 were not classifiable. At 3 Holguin F. Pediatrics. 2005;115:726–731 years of age, the only significant differences in sRAW between groups was an increased resistance in those PURPOSE OF THE STUDY. To determine if there are differences with persistent wheeze compared with children with in risk factors and measures of severity between children late-onset wheeze (P ϭ .04) and those who never with different asthma phenotypes. wheezed (P Ͻ .001). At 5 years of age, sRAW was STUDY POPULATION. The authors reviewed data from children elevated in children with persistent wheeze compared aged 6 to 16 years derived from the Third National with those with transient early wheeze (P ϭ .02) and Health and Nutrition Examination Survey. those who never wheezed (P Ͻ .001). Also, sRAW was significantly higher in those with transient-early wheez- METHODS. The authors used questionnaire and skin-prick– ing compared with those who never wheezed (P ϭ .01), testing data to separate children into the following cat- but there was no significant difference between those egories: atopic asthma, nonatopic asthma, resolved asthma,

S30 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 frequent respiratory symptoms with no asthma diagno- were enrolled in the study during an acute asthma at- sis, and normal. Multivariate regression was used to tack. determine if demographic or potential risk factors varied METHODS. Spacer devices used by 62 asthmatic children between phenotypes and whether measures of severity were examined. Swabs taken from the inner surface of varied by phenotype. the reservoirs and face masks were cultured. Parents RESULTS. A total of 4.8% of children had atopic asthma, were interviewed regarding their spacer-cleaning and 1.9% had nonatopic asthma, 3.4% had resolved asthma, -disinfection routines. and 4.3% had frequent respiratory symptoms. Mean RESULTS. Bacterial contamination was noted in 22 reser- BMI was higher among children with nonatopic asthma, voirs (35.5%) and 16 masks (25.8%). Pseudomonas whereas prenatal maternal smoking was a risk factor for aeruginosa was isolated from 21.0% of the reservoirs and resolved asthma. Atopic and nonatopic asthma were 14.5% of the face masks, Klebsiella pneumoniae from similar for most measures of asthma severity (eg, med- 6.5% and 4.8%, and Staphylococcus aureus from 9.7% and ication use and lung function), and relatively few chil- 8.1%, respectively. Only 34 parents (54.8%) reported dren in either group were receiving inhaled corticoste- that they received cleaning and maintenance instruc- roids (5%–10%). Patients with resolved asthma had tions from the medical staff at initiation of spacer use by fewer symptoms but lung-function impairment similar their child, and only 38 (61.8%) cleaned the device after to that seen with current asthma, whereas children with each use. frequent respiratory symptoms but no asthma diagnosis had normal lung function. CONCLUSIONS. Bacterial contamination is common in spacer devices. This study demonstrates that contamination CONCLUSIONS. The authors conclude that asthma risk fac- rates are significantly lower when parents clean and tors and measures of severity vary between children actually dry (preferably with an air blower) spacer de- with different asthma phenotypes. vices after each use. Spacer device maintenance should REVIEWER COMMENTS. Studies of children and adults have be emphasized in education programs for managing identified several unique phenotypes of asthma that asthma. share the feature of chronic and/or recurrent airflow REVIEWER COMMENTS. This study underscores the need for obstruction. Accurate categorization is crucial in efforts pediatricians and families to be educated about the to define genetic and environmental risk factors for proper care of spacer devices and the potential risks asthma, and this work uses a very large national data- associated with improper cleaning. In particular, simple base to help establish environmental correlates to cleansing techniques can lessen or eliminate the number asthma subgroups in children. Notably, resolved asthma of nosocomial infections introduced by poor care of was linked to prenatal exposure to tobacco smoke and these devices. The benefit of metered-dose inhalers used also to persistent impairment in lung function. Because with spacers and a face mask is high, and it is worthwhile environmental and lifestyle factors are almost certainly to ensure that patients and health care workers use these behind the rise in asthma prevalence, this line of re- devices properly and to their best advantage. search is clearly valuable from a public health perspec- tive. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900YY Troy Leo, MD URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900XX Harvey L. Leo, MD James E. Gern, MD Ann Arbor, MI Madison, WI

Clinical Use of Noninvasive Measurements of DIAGNOSIS AND MANAGEMENT Airway Inflammation in Steroid Reduction in Children Bacterial Contamination of Spacer Devices Zacharasiewicz A, Wilson N, Lex C, et al. Am J Respir Used by Asthmatic Children Crit Care Med. 2005;171:1077–1082 Cohen HA, Cohen Z, Pomeranz AS, Czitron B, Kahan PURPOSE OF THE STUDY. To examine the clinical utility of non- E. J Asthma. 2005;42:169–172 invasive measures of airway inflammation as predictors PURPOSE OF THE STUDY. To investigate bacterial contamination for successful inhaled corticosteroid (ICS) dose reduction in spacer devices used by asthmatic children and the in children with asthma. device-maintenance procedures practiced by parents. STUDY POPULATION. Forty children (aged 6–17 years) with STUDY POPULATION. The study group consisted of 62 consec- stable asthma on a constant ICS dose and eligible for utive children (aged 2–5 years) attending a clinic. All steroid dose reduction.

PEDIATRICS Volume 118, Supplement 1, August 2006 S31 Downloaded from www.aappublications.org/news by guest on September 28, 2021 METHODS. Children were followed prospectively every 8 The Influence of Pulmonary Function Testing weeks with noninvasive measures of airway inflamma- on the Management of Asthma in Children tion including exhaled nitric oxide (eNO), sputum in- Nair SJ, Daigle KL, DeCuir P, Lapin CD, Schramm CM. duction with bronchial hyperreactivity testing, and ex- J Pediatr. 2005;147:797–801 haled breath condensate. Physicians who were unaware of the results of inflammatory measures made reduc- PURPOSE OF THE STUDY. Seventy-five percent of the asthma tions in the steroid dose on the basis of clinical assess- care in the United States is provided by primary care ment and spirometry. Multiple logistic-regression mod- generalists. The National Asthma Education and Preven- els were used to determine the usefulness of noninvasive tion Program guidelines recommend spirometry to as- inflammatory markers in predicting successful steroid sess management once the peak flow has stabilized. The reduction. purpose of this study was to assess how pulmonary- function tests (PFTs) performed during a patient en- RESULTS. Seventy-five percent of patients tolerated a re- counter influence management decisions beyond the duction in steroid dose for at least 2 months; however, history and physical examination alone. 15 (38%) of the 40 patients’ conditions subsequently failed ICS dose reduction and experienced an asthma STUDY POPULATION. A total of 367 asthmatic patients were exacerbation. All children with absence of sputum eo- enrolled during their visit to a pediatric pulmonary sinophils successfully tolerated dose reduction. Increased clinic. The patients were 4 to 18 years old (mean: 10.4 eNO Ն22 ppb (odds ratio: 6.3; 95% confidence interval: years), and 60% were male. Patients were excluded if 3.75–10.58) and increased sputum eosinophils Ն3% PFTs could not be performed on them, if they had a (odds ratio: 1.38; 95% confidence interval: 1.06–1.81) pulmonary diagnosis other than asthma, or if they had used albuterol within 4 hours. were significant predictors of failed ICS dose reduction.

CONCLUSIONS. Noninvasive measures of airway inflamma- METHODS. History of asthma symptoms was obtained, and tion may be useful tools in optimizing treatment of chil- a physical examination was performed. Spirometry was dren with asthma. performed before the provider assessment. Peak expira- tory flow rate (PEF) was also obtained. The results of the REVIEWER COMMENTS. These findings suggest that noninva- PFTs were not known to the provider at the time of the sive measures of airway inflammation are potential ad- assessment and initial decision-making. The provider junctive tools that can be used in pediatric patients who then reviewed the spirometry results and revised the appear clinically stable. However, their clinical useful- initial recommendations if necessary. Changes in man- agement were analyzed with respect to demographic ness may be limited by several factors. Sputum induction data and spirometry. The diagnostic accuracy of PEF to was not successfully performed in 25% of the children, detect abnormal lung function was determined. and some measures including bronchial hyperreactivity and breath condensate did not prove to be useful pre- RESULTS. Eight percent of the patients had mild intermit- dictors in this study. In addition, criteria for predicting tent asthma, 21% mild persistent asthma, 57% moder- failure were met in 6 (21%) of 28 and 19 (39%) of 49 ate persistent asthma, and 14% severe persistent occasions for sputum eosinophil and eNO cutoffs, re- asthma. Spirometry results were normal in 55% of the spectively, when the child was successfully weaned on visits. Abnormal spirometry occurred equally in boys the basis of clinical judgment. Conversely, use of non- and girls. Sixty percent of the abnormal results were new invasive markers would have prevented an attempt to compared with previous baseline measurements. The wean steroids on Ͼ70% of occasions when patients likelihood of an abnormal PFT increased with increasing subsequently experienced an exacerbation. Inflamma- severity classification. Ten percent of those in the group tory markers as sole predictors of success or failure will with mild intermittent asthma had abnormal PFTs, com- likely result in both significant undertreatment and pared with 74% of those with severe persistent asthma. overtreatment with ICSs. Treatment algorithms that in- PFT results changed management in 15% of the visits. clude noninvasive airway inflammatory markers in con- When spirometry did not change the treatment, the junction with clinical markers are likely the best ap- providers were more likely to have already decided to proach to optimize therapy in children who appear maintain therapy (58%). When spirometry did change clinically stable. treatment, providers were more likely to increase med- ications (75%). PEF was moderately inaccurate in de- tecting abnormal spirometry. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900ZZ Tamara T. Perry, MD CONCLUSIONS. In a clinical setting, even asthma care experts Little Rock, AR tended to overestimate the degree of asthma control as

S32 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 measured by airway obstruction. Spirometry results in CONCLUSION. In children with asthma, 1 year of steroid this study were just as likely to be abnormal in patients titration on FeNO did not result in higher steroid doses with a normal history and physical examination. and did improve airway hyperresponsiveness and in- flammation. REVIEWER COMMENTS. The next logical question is: Does de- REVIEWER COMMENTS. I am still not sure what to make of cision-making enhanced by spirometry result in better eNO. If monitoring FeNO and making treatment deci- outcomes such as decreased symptoms, improved func- sions on the basis of the values leads to better asthma tioning and sleep, fewer exacerbations requiring steroid outcomes, then it would be a useful tool. Because the rescue, and less use of urgent asthma care services? FeNO group did not end up receiving a higher cumula- When assessing asthma control, one should always con- tive ICS dose, we have to assume that they got more sider comorbidities and adherence issues before stepping when they needed it and less when they did not. How- up therapy. ever, the clinical results seem inconsistent. I suppose it is

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900AAA a good thing to have a higher methacholine PD20 (the dose provoking a 20% fall in FEV1) and a lower FeNO, Michael S. Kaplan, MD but I would have been happier to see a difference in Los Angeles, CA FEV1 and symptom scores, or if the difference in the number of episodes requiring prednisone courses had been statistically significant. Although I am not sure that I can share the authors’ conclusion that “the time has Titrating Steroids on Exhaled Nitric Oxide in come to introduce FeNO in to the routine assessment of Children With Asthma: A Randomized, children with asthma,” I believe we should pay attention Controlled Trial to future studies on FeNO monitoring and clinical Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. asthma outcomes. Am J Respir Crit Care Med. 2005;172:831–836 URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900BBB PURPOSE OF THE STUDY. To evaluate whether titrating inhaled John M. Kelso, MD corticosteroids (ICSs) on the fraction of nitric oxide in San Diego, CA exhaled air (FeNO) improves asthma management in children.

STUDY POPULATION. A total of 85 children (aged 6–18 years) Use of Exhaled Nitric Oxide Measurements to with asthma who had been using ICSs at a constant dose Guide Treatment in Chronic Asthma for at least 3 months. Smith AD, Cowan JO, Brassett KP, Herbison GP, METHODS. Children were randomly allocated to 1 of 2 Taylor DR. N Engl J Med. 2005;352:2163–2173 groups stratified for baseline FeNO and dose of ICSs. In PURPOSE OF THE STUDY. To determine if measurement of ex- one group, ICS doses were determined by FeNO and haled nitric oxide (FeNO) adds to guideline-driven symptoms according to an algorithm; in the other group, asthma management for patients with chronic asthma. only symptoms influenced ICS dosing. The study dura- tion was 12 months, with 5 visits at 3-month intervals. STUDY POPULATION. A total of 110 patients (aged 12–75 FeNO was measured at each visit, and the ICS dose was years) with chronic asthma on inhaled corticosteroids then adapted to FeNO and/or symptom scores that were (ICSs) for at least 6 months using stable doses for 6 recorded during the previous 2 weeks. weeks were initially evaluated. Exclusion criteria in- cluded Ն4 courses of oral prednisone in the previous 12 RESULTS. The cumulative ICS dose was not different be- months, admission to the hospital because of asthma in tween groups. Within the FeNO group, no significant the previous 6 months, ICU admission at any time in the change in FeNO was found, whereas in the symptom past, or Ͼ10 pack-years (an average of 1 pack of ciga- group there was a significant increase in FeNO (P ϭ rettes smoked per day for Ͼ10 years) of cigarette smok- .035). In the FeNO group, hyperresponsiveness im- ing. proved more than in the symptom group (2.5 vs 1.1 METHODS. This was a single-blind, placebo-controlled methacholine doubling dose; P ϭ .04). Eight prednisone study. In phase 1 the ICS dose was adjusted on the basis courses were prescribed for 7 patients in the FeNO group of FeNO or guidelines-based algorithms. When the op- versus 18 courses in 10 patients in the symptom group, timal dose was determined, patients were managed for but this difference was not statistically significant (P ϭ 12 months. .60). There was no difference between groups in forced expiratory volume in 1 second (FEV1) or symptom RESULTS. There were 46 patients in the FeNO group and 48 scores. patients in the guideline group who completed the

PEDIATRICS Volume 118, Supplement 1, August 2006 S33 Downloaded from www.aappublications.org/news by guest on September 28, 2021 study. The final ICS dose for fluticasone was 370 ␮g/day auscultation were noted in both patients. Resolution of (95% confidence interval [CI]: 263–477 ␮g) in the FeNO symptoms and pulmonary-function values occurred af- group and 641 ␮g/day (95% CI: 526–756 ␮g; P ϭ .003) ter administration of albuterol. Neither patient had a in the guideline group. The rate of exacerbations per decrease in FEV1 after placebo. Neither patient had a patient per year was 0.49 (95% CI: 0.31–1.49) in the history of ibuprofen use before study enrollment. Two

FeNO group, compared with 0.9 (95% CI: 0.31–1.49; additional patients had a decrease in FEV1 of 15% (with P ϭ .27) in the guideline group. There was no difference no change after placebo) but remained asymptomatic in the number, frequency, or time of first exacerbation with normal physical examinations. between groups. There was no significant difference in CONCLUSIONS. In this study of children ages 6 to 18 years nighttime awakenings, bronchodilator use, percent with mild or moderate persistent asthma, the prevalence symptom-free days, or number of oral corticosteroid of ibuprofen-induced bronchospasm was 2%. This is courses. There also was no difference in percent sputum much lower than previous estimates (9%–28%) of aspi- eosinophils or pulmonary-function tests. rin-sensitive asthma in children. CONCLUSIONS. With the use of FeNO, control of asthma can REVIEWER COMMENTS. Use of inhaled corticosteroids by 70% be obtained with a lower ICS dose. of study subjects and exclusion of patients with severe REVIEWER COMMENTS. The values for FeNO differ from other asthma and those using leukotriene receptor antagonists studies because a flow rate of 250 mL/second was used may have resulted in an underestimate of the prevalence instead of 50 mL/second. The control group had down- of ibuprofen-sensitive asthma. However, given the wide- ward titration of dose on the basis of symptoms, which spread use of ibuprofen as an over-the-counter analgesic was achieved only in a minority of patients. This may and antipyretic, pediatricians should be aware of the have magnified the observed difference in the ICS dose. possibility of ibuprofen-induced asthma exacerbations. This and subsequent studies suggest that markers of airway inflammation are becoming accepted as impor- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900DDD tant surrogate markers of asthma control. John E. Duplantier, MD Indianapolis, IN URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900CCC Bradley E. Chipps, MD Sacramento, CA Patterns of Quick-Relief and Long-term Controller Medication Use in Pediatric Asthma The Prevalence of Ibuprofen-Sensitive Asthma Walders N, Kopel SJ, Koinis-Mitchell D, McQuaid EL. in Children: A Randomized Controlled J Pediatr. 2005;146:177–182 Bronchoprovocation Challenge Study PURPOSE OF THE STUDY. To simultaneously examine adher- Debley JS, Carter ER, Gibson RL, Rosenfeld M, ence to long-term controller and quick-relief medica- Redding GJ. J Pediatr. 2005;147:233–238 tions and to contrast patterns of medication use in chil- PURPOSE OF THE STUDY. To determine the prevalence of ibu- dren with asthma. profen-sensitive asthma in school-aged children with STUDY POPULATION. There were 75 children aged 8 to 16 years mild or moderate persistent asthma. diagnosed with persistent asthma and prescribed quick- STUDY POPULATION. Children (n ϭ 100) between the ages of relief and long-term medications by metered-dose inhaler. 6 and 18 years with a 2-year history of asthma. Participants were a subsample of a larger adherence study.

METHODS. Ibuprofen (10 mg/kg) was administered via a METHODS. This was a cross-sectional, 1-month follow-up randomized, double-blind, placebo-controlled crossover study. The primary outcome measure was adherence to trial. At 0.5, 1, 2, and 4 hours postingestion, spirometry both medications as measured by electronic monitoring and physical examinations were performed. Children devices. A classification framework for contrasting ad- taking leukotriene receptor antagonists or with a known herence patterns between medication classes was devel- sensitivity to aspirin or ibuprofen sensitivity were ex- oped to identify cases for individual analysis. cluded. RESULTS. High levels of nonadherence to long-term con- RESULTS. Two subjects (2%) had bronchospasm after ad- troller medications (median: 46% of prescribed doses ministration of ibuprofen, with decreases in the forced taken) and variable patterns of quick-relief medication expiratory volume in 1 second (FEV1) of 35% and 25%, use (range: 0–251 doses over the month) were docu- respectively. The maximal drop in FEV1 occurred 1 hour mented, but consistent relationships between patterns of after ibuprofen administration in both subjects. Clinical medication use across both classes were not found. In- manifestations of shortness of breath and wheezing on dividual cases identified by the classification scheme il-

S34 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 lustrated the complexity and clinical utility of contrast- ment visit), Ն2 outpatient diagnoses, or use of asthma- ing adherence patterns. related medications. High-risk asthma was defined as an admission for asthma, an emergency department visit, CONCLUSIONS. Monitoring long-term controller medication long-term use of oral steroid, or use of Ն3 short-acting ␤ adherence may be more predictive of morbidity than agonists per year. quick-relief medication use except in outlier cases, in which monitoring both medication types may be valu- METHODS. Invasive pneumococcal disease was defined as able for clinical and empirical purposes. isolation of strep pneumonia from a normally sterile site (eg, blood, cerebrospinal fluid, pleural fluid, surgical as- REVIEWER COMMENTS. Medication adherence has long been pirate, joint fluid, and/or bone). The organisms were identified as a key factor in overall asthma outcome. For serotyped. example, self-reporting quick-relief and long-term con- troller medication use, canister weighing, pharmacy RESULTS. A total of 635 patients with invasive pneumococ- records, and electronic monitoring have all been used to cal disease and 6350 controls were identified. A total of assess medication adherence. Of these methods, elec- 18% (114 patients) with asthma had an invasive infec- tronic monitoring, which is the most costly and techno- tion compared with 8.1% (516 patients) in the control logically complex, is generally accepted as the most ac- group. Patients with asthma had increased risk of inva- curate method for monitoring adherence. Inadequate sive disease (odds ratio: 2.4; 95% confidence interval: daily medication adherence has been widely docu- 1.9–3.1). In patients with high-risk asthma, the annual mented in patients with asthma and has been linked to risk for invasive disease was 4.2 of 10 000 compared morbidity and increased health care costs. Although it with 2.3 of 10 000 in the low-risk asthma group and 1.2 was not surprising that nonadherence to long-term con- of 10 000 in the control group. troller medications was common in this investigation, it CONCLUSIONS. Asthma is an independent risk factor for in- was very interesting that no statistically significant rela- vasive pneumococcal disease. tionship was found between adherence with quick-relief and long-term controller medication classes. For exam- REVIEWER COMMENTS. The risk of invasive disease did not de- ple, the investigators’ hypothesis that quick-relief and pend on comorbid conditions or advancing age. This is the long-term controller medication use would demonstrate first study to show the association and, if upheld with an inverse relationship (eg, higher long-term controller further data, will significantly affect our recommended im- medication use corresponding to lower reliance on munization strategy for patients with asthma. quick-relief medications) was not confirmed. The inves- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900FFF tigators suggest that novel strategies to enhance appro- priate medication use, such as better tracking the use of Bradley E. Chipps, MD long-term controller medications and providing feed- Sacramento, CA back regarding actual use, may be effective in improving adherence in asthma patients. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900EEE Exercise-Induced Dyspnea in Children and John James, MD Adolescents: If Not Asthma Then What? Fort Collins, CO Abu-Hasan M, Tannous B, Weinberger M. Ann Allergy Asthma Immunol. 2005;94:366–371

PURPOSE OF THE STUDY. Exercise-induced asthma (EIA) is the Asthma as a Risk Factor for Invasive most commonly recognized cause of exercise-induced Pneumococcal Disease dyspnea (EID) in children and adolescents. However, Talbot TR, Hartert TV, Mitchel E, et al. N Engl J Med. EID in otherwise healthy children and adolescents may 2005;352:2082–2090 have other causes besides asthma. The purpose of this study is to report the outcome of evaluations for EID PURPOSE OF THE STUDY. To determine if asthma is a risk factor when other signs and symptoms of asthma were absent for invasive pneumococcal disease. or there was no response to previous use of an inhaled ␤ STUDY POPULATION. Patients 2 to 49 years of age in a Ten- 2 agonist. nessee Medicaid program (TennCare) with Ͼ1 year of STUDY POPULATION. One hundred forty-two patients, 6 to 21 continuous enrollment during the study period (1995– years old (mean: 14 years), with EID were studied. 2002). For each patient with invasive pneumococcal disease, 10 age-matched controls were chosen. A total of METHODS. In this retrospective study, investigators re- 11 counties in Tennessee with a population of 2.8 mil- viewed the results of all exercise tests performed in lion participated in the study. Asthma was defined as Ն1 otherwise healthy patients with EID between 1996 and inpatient diagnoses (admission or emergency depart- 2003. Physiologic measures assessed included preexer-

PEDIATRICS Volume 118, Supplement 1, August 2006 S35 Downloaded from www.aappublications.org/news by guest on September 28, 2021 cise and postexercise spirometry with the addition of STUDY POPULATION. Parents of children aged 2 to 18 years oxygen uptake, carbon dioxide production, continuous being discharged after asthma treatment in a pediatric ED. oximetry, and electrocardiogram monitoring during METHODS. Parents were surveyed by coordinators and de- most tests. EIA was diagnosed if treadmill exercise re- scribed their child’s asthma history and perceived bene- sulted in reproduction of symptoms in association with a fits and barriers to making a PCP follow-up visit. Biva- decrease in forced expiratory volume in 1 second of at riate tests and multivariable logistic regression were used least 15%. Endoscopy was performed if stridor and/or to determine association with completion of a follow-up decreased maximal inspiratory flow were present. Crite- visit within 4 weeks of the ED visit. ria were established for restrictive abnormalities, physi- cal conditioning, exercise-induced hyperventilation, and RESULTS. A total of 278 subjects (n ϭ 278) were enrolled; normal physiologic limitation. 55% saw their PCP within 4 weeks of the ED visit. Baseline factors that were associated with an increased RESULTS. EID was present in the subjects for an average of likelihood of follow-up included a recent hospitalization, 30.2 months (range: Ͻ1 to 192 months) before evalua- Ͼ1 ED visit for asthma in the past year, the parent’s tion, and in 98 patients the symptoms were attributed to assessment that the child had “very severe” asthma, and asthma. Symptoms of EID were reproduced during ex- current daily use of a controller medication. Parental ercise testing in 117 patients. EIA was identified as the beliefs that taking daily asthma medications and finding cause of EID in only 11 of the 117. Seventy-four dem- out about the causes of asthma attacks were also asso- onstrated only normal physiologic exercise limitation; 48 ciated with increased PCP follow-up rate. Parents were of the 74 had normal-to-high cardiovascular condition- less likely to follow-up if they reported a lack of conve- ing, and 26 had poor conditioning. Other diagnoses for nient appointments or prolonged waits in the PCP office. reproducible EID included restrictive abnormalities in A multivariable model including clinical factors, parental 15, vocal cord dysfunction in 13, laryngomalacia in 2, beliefs, and the study intervention predicted the likeli- primary hyperventilation in 1, and supraventricular hood of follow-up. tachycardia in 1. CONCLUSIONS. Parental beliefs about asthma severity, the CONCLUSIONS. The diagnoses of EIA should be questioned benefits of controlling asthma, and organizational barri- as the etiology of EID in children and adolescents who ers to seeing a PCP were associated with follow-up after do not have other symptoms of asthma and who do not ␤ a pediatric ED visit for asthma. respond to pretreatment with a 2 agonist. REVIEWER COMMENTS. Many children receive their first and REVIEWER COMMENTS. Although asthma is the most common subsequent follow-up visits for acute asthma attacks in cause of EID, this article demonstrates the important the ED. Unfortunately, this is an inefficient and cost- point that not all EID is caused by asthma. Patients who prohibitive method of managing asthma. This study at- experience EID but not other signs or symptoms of tempted to identify parental perceptions of their child’s asthma or who do not benefit from pretreatment with disease and the barriers to proper follow-up. These issues an inhaled ␤ agonist clearly can benefit from a treadmill 2 are paramount for the pediatrician caring for these chil- test with cardiac and respiratory physiologic monitoring. dren. Addressing parental concerns and removing barri- A large portion of these patients demonstrated normal ers to follow-up can improve asthma control and allow physiologic limitation associated with reproduction of for more cost-effective management and proper utiliza- symptoms. Routine treatment of EID as asthma can lead tion of health care resources. Both the acute treating to both unnecessary medication and frustration on the physician and practicing pediatrician can influence the part of the patients and their families. possibility of appropriate follow-up and care.

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900GGG URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900HHH Helen Skolnick, MD Harvey L. Leo, MD Princeton, NJ Ann Arbor, MI

Use of Asthma Guidelines by Primary Care Predictors of Primary Care Follow-up After a Providers to Reduce Hospitalizations and Pediatric Emergency Visit for Asthma Emergency Department Visits in Poor, Zorc JJ, Scarfone RJ, Li Y. J Asthma. 2005;42:571–576 Minority, Urban Children Cloutier MM, Hall CB, Wakefield DB, Bailit H. PURPOSE OF THE STUDY. To identify predictors associated with J Pediatr. 2005;146:591–597 primary care pediatrician (PCP) follow-up in children evaluated for acute asthma in a pediatric emergency PURPOSE OF THE STUDY. To determine if a standardized city- department (ED). wide asthma management program delivered by pri-

S36 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 mary care providers (PCPs) would increase adherence the idea that improving asthma management relies not with the National Asthma Education and Prevention only on patient adherence but also physician review and Program guidelines and whether this would improve faithful implementation of the current guidelines. PCPs medical service utilization. managing asthma in low-income, urban, minority chil- dren would benefit the community by participating in STUDY POPULATION. Children between 6 months and 18 such standardized programs that are focused on diagno- years of age (n ϭ 8324) who presented for care at any of sis and treatment. This not only decreases the morbidity 6 primary care clinics in Hartford, Connecticut, between related to asthma in these children but also alleviates the 1998 and 2002 and had enrolled in either Medicaid or financial burden involved in excessive utilization of the State Children’s Health Insurance Plan (SCHIP). medical services. METHODS. Enrollment in the Easy Breathing asthma man- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900III agement program for PCPs included completing a survey Saba Sharif, MD regarding the child’s clinical history, provider assessment Michael S. Kaplan, MD of asthma severity, and a written asthma treatment plan Los Angeles, CA for the caregiver. Providers underwent training in the Easy Breathing curriculum. Data regarding demograph- ics for enrolled patients were obtained from the survey and compared with all resident children in Hartford. A Multisite Randomized Trial of the Effects of Claims data were obtained. Utilization of medical ser- Physician Education and Organizational vices and prescriptions was examined. Children were Change in Chronic Asthma Care: Cost- continuously enrolled in the program during the 4-year effectiveness Analysis of the Pediatric Asthma analysis period. Relative rates of utilization (in event/ Care Patient Outcomes Research Team II child-months) were compared for the same children (PAC-PORT II) before and after enrollment. Sullivan SD, Lee TA, Blough DK, et al. Arch Pediatr Adolesc Med. 2005;159:428–434 RESULTS. Of the 1799 children with persistent asthma, only 38% were treated with antiinflammatory therapy PURPOSE OF THE STUDY. To estimate the cost-effectiveness of 2 before Easy Breathing; after enrollment, this improved different asthma care interventions: a peer leader–based to 96%, with 85% of those treated specifically with an physician behavior-change intervention (PLE) and a inhaled corticosteroid. After enrollment in Easy Breath- practice-based redesign called the planned asthma care ing, the rate of hospitalization for all children with intervention (PACI). Ͻ asthma decreased 35% (P .006), and the decrease was STUDY POPULATION. Participants were 638 children (aged sustained over 3 years. There was a 27% overall de- 3–17 years) with mild-to-moderate asthma. More than crease in emergency department (ED) visits for asthma half of the subjects were on maintenance medication. (P Ͻ .01) and less seasonal variation in hospitalizations. Adjusted relative rates for total and asthma-specific ED METHODS. This was a 3-arm cluster-randomized trial con- and hospital visits decreased significantly for children ducted in 42 primary care practices. These practices were ϭ ϭ with persistent asthma. Decreases in adjusted rates of randomly assigned to PLE (n 226), PACI (n 213), or ϭ outpatient visits after enrollment were also found for usual care (n 199). The PLE strategy involved training children overall (19%; P Ͻ .0001). This was true for a pediatrician at each of the practice sites as an asthma children with intermittent asthma (22%; P Ͻ .001) and expert and champion. This leader provided support, ed- persistent asthma (18%; P Ͻ .001). ucation, and feedback to the other members of the prac- tice with regard to asthma management. The PACI strat- CONCLUSIONS. Adherence to National Asthma Education egy included all the components of the PLE arm and also and Prevention Program guidelines by PCPs managing included scheduled asthma care visits with an asthma asthma for low-income minority children decreased nurse, who provided standardized assessments, care their total number of hospitalizations and asthma-spe- planning, coordination with the primary care physician, cific ED visits and outpatient visits. The authors believe and self-management tools. Practices in the usual-care that contributors to the success of the program include arm received copies of the National Asthma Education the standardized approach to therapy, including inhaled and Prevention Program Expert Panel Report 2 and pa- corticosteroids when indicated, as well as the develop- tient-information handouts 12 months into the study. ment of a written, individualized asthma treatment plan. The subjects were followed for 2 years. The primary The benefits of the program continued through the 3 outcome was symptom-free days (SFDs). Costs included years. asthma-related health care utilization and intervention.

REVIEWER COMMENTS. Despite a few limitations (nonrandom- RESULTS. Patients in the usual-care arm of the study had in ized, use of claims data), this study strongly reinforces increase in SFDs of 14.8 per year. Patients in the PLE and

PEDIATRICS Volume 118, Supplement 1, August 2006 S37 Downloaded from www.aappublications.org/news by guest on September 28, 2021 PACI arms had an additional gain of 6.5 and 13.3 SFDs trol arm of the study, primary care providers were not per year, respectively, compared with the usual-care contacted. Interviewers then contacted the parents 3 to arm. When the costs of development were excluded, the 6 months later to determine if preventive actions were cost for SFDs gained compared with usual care was $18 taken. for PLE and $68 for PACI. RESULTS. Children in the provider-notification group were CONCLUSIONS. It is possible to increase SFDs in children and not more likely to receive a preventive medication ac- to move organizations toward guideline recommenda- tion than children in the control group (21.9% vs 26%). tions for asthma management. However, the improve- Additional preventive measures such as encouraging ments were associated with an increase in the costs compliance with medications, recommending environ- associated with asthma care. mental modifications, and referrals to specialty care also REVIEWER COMMENTS. This trial was designed to provide cost did not differ between the 2 groups. The only factors that analyses to both health care providers and health main- significantly predicted the occurrence of a preventive tenance organizations. It is difficult, however, to estab- action were acute visits for asthma and baseline use of lish a threshold for cost-effectiveness. The authors cite preventive medications. At the end of the study, 52.4% other trials to provide a context for this question. For of children in both groups with no medications change example, the cost-effectiveness of inhaled corticosteroids were still experiencing symptoms. in the treatment of children ranges from $7 to $12 per SFD gained. A social worker–based intervention had a CONCLUSIONS. School-based asthma screening identified cost-effectiveness ratio of $9 per SFD gained. What is it many symptomatic children in need of medication mod- worth to patients, their families, and their health care ification, but notification of their primary care providers providers to have an extra SFD? did not improve preventive care.

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900JJJ REVIEWER COMMENTS. Asthma is a complex disease, and there Brian A. Smart, MD are many barriers to effective care. These barriers in- Glen Ellyn, IL clude steroid phobia, cost of medication, denial of the presence or severity of the disease, access to health care, exposure to asthma triggers, and poor adherence to treatment. It is concerning that another barrier to effec- A Randomized Trial of Primary Care Provider tive care of asthma, as illustrated by this study, is a poor Prompting to Enhance Preventive Asthma response of health care providers to supportive educa- Therapy tion, such as treatment guidelines. In an effort to better Halterman JS, McConnochie KM, Conn KM, et al. understand this deficit, the authors queried the provid- Arch Pediatr Adolesc Med. 2005;159:422–427 ers: “Was the information in the original notification helpful?” Only 27 of 73 providers responded: 10 said the PURPOSE OF THE STUDY. To determine if systematic school- information was helpful (7 changed medications); 9 re- based asthma screening, coupled with primary care pro- plied that their patients had mild, intermittent asthma vider notification of asthma severity, would prompt pro- and did not need changes; 4 replied that their patients viders to prescribe a new preventive medication or already were on preventive medications; and 4 replied change a current dose. that they were unable to contact their patients for fol- STUDY POPULATION. The study included 151 children (aged low-up. 3–7 years) with mild persistent to severe asthma living in an urban setting. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900KKK Brian A. Smart, MD METHODS. A routine school health-and-development form Glen Ellyn, IL was sent to parents of schoolchildren. When asthma was indicated on this form, the parents were contacted by telephone. To be eligible for the trial, the child’s parent needed to report that a physician had diagnosed their Asthma-Related Health Care Resource Use child as having asthma, and the child’s symptoms Among Asthmatic Children With and Without needed to be consistent with mild persistent asthma or Concomitant Allergic Rhinitis worse according to National Heart, Lung, and Blood Thomas M, Kocevar VS, Zhang Q, Yin DD, Price D. Institute guidelines. The intervention arm of the study Pediatrics. 2005;115:129–134 involved notification of the primary care providers via fax of the child’s symptoms and recommendations for PURPOSE OF THE STUDY. To determine the incremental effect action on the basis of national criteria. Confirmation of of allergic rhinitis on health care resource use in children receipt was received from 90% of providers. In the con- with asthma.

S38 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 STUDY POPULATION. Children (aged 6–15 years) with asthma STUDY POPULATION. Parents of asthmatic children seen in a and Ͼ1 asthma-related encounter with a general prac- tertiary care pediatric allergy and immunology clinic. titioner (GP) during a 12-month follow-up period were METHODS. Caregivers completed the Visual-Aural-Read/ included from the United Kingdom medical plus gener- Write-Kinesthetic (VARK) questionnaire anonymously, al-practice database, including 2 million office patient and the responses were evaluated on the basis of previ- visits per year to Ͼ500 GPs. ously validated scoring instructions. METHODS. This was a population-based historical cohort RESULTS. Analysis of 98 respondents showed that 42% had investigation. Asthma and allergic rhinitis were deter- a single learning-modality preference, and the remain- mined by diagnosis codes and drug codes for appropriate ing 58% were multimodal learners. Of those who re- medications. ported a single mode of learning, 61% preferred kines- RESULTS. Of 9522 children with asthma, 1879 (19.7%) had thetic, 27% preferred reading/writing, and Ͻ1% each allergic rhinitis recorded in the GP medical charts. Com- preferred aural or visual stimuli. Of all 98 caregivers, pared with children with asthma alone, children with 82% included kinesthetic as a learning preference, 59% comorbid allergic rhinitis experienced more GP visits included reading/writing, 50% included aural stimuli, (4.4 vs 3.4) and more of them were hospitalized for and 41% included visual stimuli. asthma (1.4% vs 0.5%) during the 12-month follow-up CONCLUSIONS. The majority of caregivers preferred the kin- period. In multivariable regression analyses, comorbid esthetic learning method, whether as a single learning allergic rhinitis was an independent predictor of hospi- preference or in combination with other approaches. talization for asthma (odds ratio: 2.34; 95% confidence Incorporating kinesthetic methods of learning, such as interval [CI]: 1.41–3.91) and was associated with in- role playing and problem-solving case scenarios, into creases in the number of asthma-related GP visits (mean standardized asthma education curricula may be bene- increase: 0.53; 95% CI: 0.52–0.54) and asthma drug ficial to patients and families in terms of understanding costs (mean increase [British pounds]: £6.7; 95% CI: and using their regimen. £6.5–£7.0). The association between allergic rhinitis and higher costs of prescriptions for asthma drugs was inde- REVIEWER COMMENTS. This is a novel study that attempted to pendent of asthma severity, measured indirectly by the improve asthma care by identifying the learning prefer- intensity of use of asthma drugs. ences of the caretakers of asthmatic children. Asthma regimens can be complex, and simplification and under- CONCLUSIONS. Children with comorbid allergic rhinitis in- standing of these regimens can improve overall adher- curred greater prescription drug costs and experienced ence. Individual caretakers demonstrate multiple modes more physician visits and hospitalizations for asthma than of learning preference, and the current educational did children with asthma alone. A unified treatment strat- modules should focus on role playing and other visual egy for asthma and allergic rhinitis, as recommended by modalities to enhance the understanding of the caretak- the Allergic Rhinitis and Its Impact on Asthma initiative, ers’ asthma knowledge. Streamlining and improving might reduce the costs of treating these conditions. these educational methods could result in significant REVIEWER COMMENTS. This is a useful study emphasizing the improvement in medication adherence, symptom recog- impact of allergic rhinitis on asthma, with implications for nition, and appropriate utilization of medical care. better therapeutic approaches. The study may have actu- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900MMM ally underestimated the impact of allergic rhinitis, because the data are retrospective and diagnosed allergic rhinitis Harvey L. Leo, MD Ann Arbor, MI was estimated at only 19.7%, compared with rates as high as 50% among children with asthma in other studies.

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900LLL Racial and Ethnic Differences in Asthma Christopher Randolph, MD Diagnosis Among Children Who Wheeze Waterbury, CT Akinbami LJ, Rhodes JC, Lara M. Pediatrics. 2005;115: 1254–1260

Learning Preferences of Caregivers of PURPOSE OF THE STUDY. To determine if racial and ethnic dif- Asthmatic Children ferences in documented pediatric asthma prevalence re- Dinakar C, Adams C, Brimer A, Silva MD. J Asthma. late to true prevalence differences or a different proba- 2005;42:683–687 bility of receiving the diagnosis.

PURPOSE OF THE STUDY. To determine the learning styles of STUDY POPULATION. The study population was 3- to 17-year- the caregivers of asthmatic children seen in a pediatric old children of non-Hispanic white, non-Hispanic black, allergy and immunology clinic. Puerto Rican, and Mexican ethnicity taken from a con-

PEDIATRICS Volume 118, Supplement 1, August 2006 S39 Downloaded from www.aappublications.org/news by guest on September 28, 2021 tinuous survey administered by the National Center for STUDY POPULATION. A total of 291 healthy children aged 2 Health Statistics. weeks to 3 years. These children were recruited from a primary care center that provides care to a low-income METHODS. The results for children aged 3 to 17 years in the 1999 National Health Interview Survey were analyzed population. Exclusion criteria included history of birth at Ͻ for those with reported wheezing. Asthma diagnosis was 36 weeks’ gestation, asthma, other chronic pulmonary evaluated for racial and ethnic differences while control- disease, or cardiac disease. ling for age, gender, parental education, single-parent METHODS. The primary caregivers of the children in the household, residence, insurance, health care, and par- study filled out a questionnaire that included items on ent-reported severity of symptoms. demographics, smoking status of individuals living in the RESULTS. Among those reported to have wheezed in the children’s homes, number of cigarettes smoked per day, past year (n ϭ 946), 83% of Puerto Rican, 71% of and the locations in which individuals smoked. Primary non-Hispanic black, and 65% of Mexican children were caregivers also gave samples of their own and their diagnosed with asthma compared with 57% of non- children’s hair for measurement of levels of cotinine. Hispanic white children. Using non-Hispanic white chil- RESULTS. A total of 7 subjects (2%) had hair cotinine levels dren as the reference group, the approximate adjusted of Ͻ0.01 ng/mg, 99 subjects (34%) had levels of Ͻ0.3 relative risk for physician diagnosis of asthma given wheezing in the past year was 1.43 (95% confidence mg/ng, 68 (23%) had midrange levels of 0.3–0.7 ng/mg, Ͼ interval [CI]: 1.04–1.63) for Puerto Rican, 1.22 (95% CI: and 124 (43%) had levels of 0.7 mg/ng. Factors asso- 1.03–1.37) for non-Hispanic black, and 1.19 (95% CI: ciated with higher cotinine levels included maternal 0.94–1.39) for Mexican children. Minority children smoking, the presence of other smokers in the home, were reported to have greater severity of wheezing and where persons other than the mothers smoke (ie, in symptoms. Even after accounting for this increased se- the home or outside the home). Interestingly, the re- verity, children in racial and ethnic minority groups ported location of mothers’ smoking (indoors versus were as or more likely to have a reported asthma diag- outdoors) was not associated with cotinine levels in the nosis than non-Hispanic white children. hair. The investigators used this information to create a model questionnaire to predict ETS exposure. Three CONCLUSIONS. These findings do not support the hypothesis questions were selected: does the mother smoke, do that symptomatic minority children are underdiagnosed others in the home smoke, do others who smoke remain with asthma compared with non-Hispanic white chil- dren. To the contrary, among currently symptomatic inside the home or go outside. Using this model, children children, minority children were more likely to be diag- of mothers who smoke and are also exposed to others who nosed than non-Hispanic white children even after ac- smoke inside the home have an 81% chance of having counting for the higher wheezing severity among mi- high exposure to ETS. In contrast, children of mothers nority children. who do not smoke and are not exposed to others who smoke have a 64% chance of low exposure to ETS. REVIEWER COMMENTS. This study suggests that minority chil- dren with wheezing severity measured by National CONCLUSIONS. It was possible to derive a simple and valid Health Interview Survey guidelines are not underdiag- screening tool to identify children at risk for ETS expo- nosed. These results suggest that public health endeavors sure, but this tool still needs to be tested prospectively. should be directed toward better management and con- REVIEWER COMMENTS. We all struggle with our patients’ ex- trol. posure to ETS in the home. Part of the struggle has to do URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900NNN with obtaining accurate information about exposures. Christopher Randolph, MD The screening tool described in this study needs to be Waterbury, CT tested prospectively, but it may prove to be highly useful. Of interest is the finding that it did not matter, in terms of levels of cotinine in children’s hair, whether their mothers smoked indoors or reported that they limited themselves Screening for Children’s Exposure to to outdoor smoking. We may speculate that this finding Environmental Tobacco Smoke in a Pediatric has to do with inaccurate reporting (shame about smok- Primary Care Setting ing indoors) or to the large amount of particulate residue Groner JA, Hoshaw-Woodard S, Koren G, Klein J, that remains on smokers after they smoke. Castile R. Arch Pediatr Adolesc Med. 2005;159:450–455 URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900OOO PURPOSE OF THE STUDY. To develop a brief screening tool to accurately predict environmental tobacco smoke (ETS) Brian A. Smart, MD exposure. Glen Ellyn, IL

S40 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 MEDICAL THERAPIES Safety of Budesonide Inhalation Suspension in Infants Aged Six to Twelve Months With Mild Daily Versus As-Needed Corticosteroids for to Moderate Persistent Asthma or Recurrent Mild Persistent Asthma Wheeze Boushey HA, Sorkness CA, King TS, et al. N Engl Berger WE, Qaqundah PY, Blake K, et al. J Pediatr. J Med. 2005;352:1519–1528 2005;146:91–95

PURPOSE OF THE STUDY. To determine the effectiveness of as- PURPOSE OF THE STUDY. To compare the safety of budesonide needed versus regular controller therapy in adults with inhalation suspension (BIS) with placebo. mild persistent asthma. STUDY POPULATION. Infants (aged 6–12 months) with mild- STUDY POPULATION. A total of 225 adults with symptom to-moderate persistent asthma or recurrent wheeze. criteria for mild persistent asthma and forced expira- tory volume in 1 second (FEV ) Ͼ70% predicted with 1 METHODS. A multicenter, randomized, double-blinded, Ͼ 12% reversibility or PC20 (provocative concentra- parallel-group, placebo-controlled study, in which 141 tion causing a 20% decrease in FEV1) methacholine at infants received 0.5 mg of BIS (n ϭ 48), 1.0 mg of BIS Յ16 mg/mL. (n ϭ 44), or placebo (n ϭ 49) once daily for 12 weeks. The primary variable was adrenal function, which was METHODS. Patients were assigned to 1 of 3 treatment based on cosyntropin-stimulated plasma cortisol levels. groups: budesonide DPI 200 ␮g twice daily (BUD), oral Spontaneous adverse events and clinical laboratory find- zafirlukast 20 mg twice daily (ZAF), or placebo. The ings were monitored. study was double-blind, double-dummy. At the begin- ning and the end of the study, all patients were treated RESULTS. Overall, the types and frequencies of adverse with 0.5 mg/kg per day of prednisone, 800 ␮g twice a events reported during the study were comparable across day of budesonide, and 20 mg twice a day of zafirlukast treatment groups. The response to cosyntropin stimulation plus as-needed albuterol. Evaluation was accomplished was similar across treatment groups, with no significant by assessing asthma symptoms followed by pulmonary- difference between BIS treatment and placebo. function testing and gathering information on, albuterol use and exacerbations over the 1-year study. CONCLUSIONS. The safety profile of BIS was similar to that of placebo, with no suppressive effect on adrenal func- RESULTS. For both of the primary efficacy outcomes, tion in patients 6 to 12 months of age with mild-to- morning peak expiratory flow rate and exacerbations, moderate persistent asthma or recurrent wheeze. there were no differences between the groups. Several outcomes were superior for the BUD group, including REVIEWER COMMENTS. Inhaled corticosteroids remain the pre- prebronchodilator FEV , bronchial reactivity, symp- 1 ferred choice for the long-term management of persis- tom scores, exhaled nitric oxide, asthma control score, tent asthma in pediatric patients. In addition, because and symptom-free days (26 more). Postbronchodilator BIS has become available for clinical use, more and more FEV and quality of life were not different between the 1 infants and young children with persistent asthma groups. The as-needed group took budesonide, on aver- age, for only one-half week during the study. and/or recurrent episodes of wheezing have been man- aged with this inhaled antiinflammatory medication. In turn, appropriate questions have arisen from caregivers CONCLUSIONS. Adults with mild persistent asthma can be managed with high-dose budesonide on an intermit- and providers about the overall safety of this therapy in tent basis. However, greater improvement in markers these very young patients. Although the safety and ef- of airway inflammation and more symptom-free days ficacy of nebulized BIS have been confirmed in well- (26 per year) occurred with regular use of low-dose designed investigations in patients 6 months to 8 years of budesonide. age, controlled clinical studies addressing the safety and efficacy of inhaled corticosteroids exclusively in the in- REVIEWER COMMENTS. This is an adult study that focused on fant age range have been lacking. This current investi- short-term outcomes, which may not translate to chil- gation provides very useful safety data for BIS in this dren. It is not known if similar results would be seen understudied infant population. The data demonstrate with a longer-term study. that once-daily administration of BIS, 0.5 or 1.0 mg, was not associated with a decrease in adrenal function, URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900PPP which was based on cosyntropin-stimulated plasma cor- Bradley E. Chipps, MD tisol levels. This information should be very useful to Sacramento, CA health care providers who prescribe this medication for

PEDIATRICS Volume 118, Supplement 1, August 2006 S41 Downloaded from www.aappublications.org/news by guest on September 28, 2021 young infants with mild-to-moderate persistent asthma ing a severe asthma-related event but also that budes- or recurrent wheeze. onide has very little risk of causing any significant adverse events. One of the most difficult, yet very im- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900QQQ portant tasks as a physician is to educate the patient that John James, MD inhaled corticosteroids are not the enemy, but rather Fort Collins, CO that the patient’s health is at greater risk from asthma itself. Clearly, early intervention is safe and effective. This study provides valuable information and should Long-term Safety of Once-Daily Budesonide in help patients and their families to feel comfortable with Patients With Early-Onset Mild Persistent long-term inhaled corticosteroids use in asthma. Asthma: Results of the Inhaled Steroid URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900RRR Treatment as Regular Therapy in Early Asthma (START) Study Helen Skolnick, MD Princeton, NJ Sheffer AL, Silverman M, Woolcock AJ, Diaz PV, Lindberg B, Lindmark B. Ann Allergy Asthma Immunol. 2005;94:48–54 Budesonide/Formoterol Combination Therapy PURPOSE OF THE STUDY. Inhaled corticosteroids are the recom- as Both Maintenance and Reliever Medication mended treatment for all patients with persistent in Asthma asthma. The aim of this study was to evaluate the safety O’Byrne PM, Bisgaard H, Godard PP, et al. Am J Respir and tolerability of long-term treatment of patients with Crit Care Med. 2005;171:129–136 mild persistent asthma with once-daily budesonide. PURPOSE OF THE STUDY. Previous studies have shown that the STUDY POPULATION. Seven thousand two hundred twenty- combination of inhaled corticosteroids (ICSs) with long- two patients (aged 5–66 years) with mild persistent acting ␤ agonists improves asthma control and reduces asthma diagnosed within 2 years of study entry, with 2 exacerbations. The authors hypothesized that in patients wheeze, cough, dyspnea, or chest tightness weekly and already receiving daily budesonide/formoterol (B/F), re- demonstration of reversible airway obstruction, were placing conventional short-acting ␤ agonist (SABA) res- enrolled into the study. 2 cue with the B/F combination drug would increase an- METHODS. This was a prospective, double-blind, placebo- tiinflammatory therapy while simultaneously giving controlled study. Patients were divided into 2 groups rapid relief of symptoms. The investigators reasoned that according to age. Those patients younger than 11 years using the B/F combination drug in this manner might received 200 ␮g of budesonide via a dry-powder inhaler reduce asthma exacerbations and improve asthma con- or placebo, and patients 11 years and older received 400 trol compared with other possible regimens. ␮g of budesonide via dry-powder inhaler or placebo. All STUDY POPULATION. Subjects were 2760 patients with asthma treatments were administered for 3 years and in addition (aged 4–80 years), all previously on ICSs. to the patients’ usual asthma therapy. METHODS. A double-blind parallel-group study was per- RESULTS. Overall, 21 520 adverse events were reported formed with subjects randomly assigned to 3 groups: B/F (10 850 in the budesonide group and 10 670 in the (80 mg/4.5 ␮g) twice daily for maintenance and also for placebo group). The most commonly reported events rescue; B/F (80 mg/4.5 ␮g) twice daily with terbutaline were respiratory infections such as rhinitis, pharyngitis, 0.4 mg for rescue; or budesonide 320 ␮g twice daily with bronchitis, viral infections, and sinusitis. Oral candidiasis terbutaline 0.4 mg for rescue. Pediatric patients (11%– was more common in the budesonide group (1.2%) 13% of each group) received half of the above-stated than in the placebo group (0.5%); the frequencies of doses for maintenance. The primary outcome was time other adverse effects previously reported to be associated to first severe exacerbation, defined as asthma symptoms with inhaled corticosteroids (skin disorders, psychiatric requiring an emergency department visit or hospitaliza- disorders, and allergic reactions) were similar between tion; an increase in ICS dose; use of oral steroids; or a the 2 groups. The number of deaths and serious adverse morning peak expiratory flow rate Յ70% of baseline on events were similar for children and adults in both treat- 2 consecutive days. ment groups. RESULTS. Multiple positive outcomes were seen in the CONCLUSIONS. Three-year treatment with budesonide (200 group using B/F for maintenance and rescue: a signifi- or 400 ␮g) is safe and well tolerated in both children and cant increase in the time to the first severe and mild adults who have recent onset of mild persistent asthma. exacerbations (P Ͻ .001); a 45% to 50% decrease in the REVIEWER COMMENTS. This study shows not only that budes- number of severe exacerbations; significant decreases in onide dramatically reduces the overall risk of experienc- the use of rescue medication, nighttime symptom score,

S42 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 and the number of nighttime awakenings; and fewer the preceding 4 weeks and improvement in forced ex- Ն courses of oral steroids per year. The average daily dose piratory volume in 1 second (FEV1)of 12% after max- of ICS received per patient was lower in the 2 B/F imal bronchodilation or methacholine PC20 (provocative Յ groups. All of the medications were well tolerated. Pe- concentration causing a 20% decrease in FEV1)of 12.5 diatric subjects receiving B/F demonstrated greater lin- mg/mL. Children with severe asthma were excluded, ear growth than those on higher-dose budesonide. as were those with recent use of corticosteroid or LTRA. CONCLUSIONS. Use of B/F for both maintenance and rescue is associated with a lower asthma-exacerbation rate and METHODS. After a 5- to 10-day characterization phase, par- an improvement in several other indicators of asthma ticipants were randomly assigned to 1 of 2 crossover control. In addition, subjects using B/F in this manner treatment sequences with 8-week periods of either ac- have a decreased exposure to oral steroids and require tive ICS (fluticasone 100 ␮g twice daily) or an age- less use of rescue medication. The authors suggest that appropriate dose of montelukast. During the active- the timing of the increase in ICS use for asthma exacer- treatment period for one drug, the participant received a bations, rather than the total ICS dose administered, placebo for the alternative drug. Baseline-only charac- provides the greater improvement in efficacy. terization included various asthma biomarkers. The pri- ␤ REVIEWER COMMENTS. The rapid onset of action of the 2- mary outcome measure was percentage change in pre- agonist formoterol suggests that it could be used as a bronchodilator FEV1 from baseline to the end of the rescue medication, although this is not a licensed indi- treatment period. “Response” was defined as improve- cation. Use of the B/F combination as controller and ment in FEV1 of at least 7.5%. rescue presents an attractive option because of the de- crease in asthma morbidity compared with either B/F RESULTS. Fifty-five percent of the 126 participants showed and SABA or ICS and SABA. Even with the use of B/F no response to either drug, whereas 23% responded to for rescue, the mean dose of ICS received was lower than fluticasone alone, 17% responded to both, and 5% re- in the ICS-and-SABA group (240 vs 640 ␮g/day in the sponded to montelukast alone. Compared with those adults) and only slightly higher than in the B/F-and- who responded to neither drug, those who responded to SABA group (240 vs 160 ␮g/day in the adults). This fluticasone alone had higher exhaled nitric oxide, serum combination product is not yet licensed in the United immunoglobulin E, serum eosinophilic cationic protein, States, but if approved, B/F used in this fashion will offer and total eosinophil count, along with lower methacho- a novel treatment alternative for asthmatic patients. In line PC20 and lower pulmonary function. Favorable re- addition, B/F maintenance and rescue therapy may pro- sponse to montelukast alone was associated with vide a significant benefit for patients for whom adher- younger age and shorter disease duration. Greater dif- ence to 2 separate drugs may present serious difficulties ferential response to fluticasone over montelukast was or confusion. associated with higher bronchodilator use and response,

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900SSS along with higher exhaled nitric oxide and serum eosin- ophilic cationic protein levels and lower methacholine Ivan N. Chinn, MD PC and pulmonary function. Mary Dell Railey, MD 20 Larry W. Williams, MD CONCLUSIONS. Responses to fluticasone and montelukast Durham, NC vary. Children with low pulmonary function or high levels of biomarkers should start with ICSs. In children with less severe disease, it would be reasonable to start Characterization of Within-Subject Responses with either ICSs or LTRAs. Asthma therapy might soon to Fluticasone and Montelukast in Childhood move from the current approach, which is based on Asthma mean responses in populations, to one predicated on a Szefler SJ, Phillips BR, Martinez FD, et al. J Allergy Clin given person’s asthma phenotype and genotype. Immunol. 2005;115:233–242 REVIEWER COMMENTS. The vast majority of asthmatic pa- PURPOSE OF THE STUDY. Asthmatic individuals vary in their tients in a primary care practice can maintain excel- responses to inhaled corticosteroids (ICSs) and leukotri- lent control with one or the other of the above-men- ene antagonists (LTRAs). The authors of this study tioned drugs as simple monotherapy. History is sought to determine if responses are concordant for both paramount in assessing asthma severity, especially be- types of drugs and sought markers for responses. cause the above-described biomarkers are largely un- STUDY POPULATION. Children (aged 6–17 years) with mild- available to the pediatrician. It is tantalizing to con- to-moderate asthma. They had asthma symptoms or sider a time when we will be able to more accurately bronchodilator use on average at least 3 days/week over target successful treatment in advance.

PEDIATRICS Volume 118, Supplement 1, August 2006 S43 Downloaded from www.aappublications.org/news by guest on September 28, 2021 URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900TTT inhaled corticosteroids should be considered first-line James R. Banks, MD therapy in this age group. Timothy Andrews, MD URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900UUU Arnold, MD John E. Duplantier, MD Indianapolis, IN

Comparative Efficacy and Safety of Low-Dose Fluticasone Propionate and Montelukast in Montelukast, Compared With Fluticasone, for Children With Persistent Asthma Control of Asthma Among 6- to 14-Year-Old Ostrom N, Decotis B, Lincourt W, et al. J Pediatr. 2005; Patients With Mild Asthma: The Mosaic Study 147:213–220 Garcia Garcia ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P. Pediatrics. 2005;116:360–369 PURPOSE OF THE STUDY. To evaluate efficacy, safety, health out- comes, and cost-effectiveness of fluticasone propionate PURPOSE OF THE STUDY. Per current asthma guidelines, mon- (FP) versus montelukast in children with asthma telukast is considered a suitable alternative to inhaled corticosteroids (ICSs) for the treatment of mild persistent STUDY POPULATION. Children aged 6 to 12 years with persis- asthma, and this study was conducted to evaluate the tent asthma. use of oral montelukast compared with inhaled flutica- sone in children with mild asthma. METHODS. Multicenter, randomized, double-blind, double- STUDY POPULATION. Children (aged 6–14 years) with mild dummy, parallel-group study of 342 children with per- persistent asthma participating in the Montelukast Study sistent asthma. Children received either FP 50 ␮g twice of Asthma in Children (MOSAIC) study. daily via Diskus or montelukast 5 mg once daily for 12 weeks. The primary efficacy variable was percent change METHODS. In this 12-month, multicenter, randomized, in morning predose forced expiratory volume in 1 sec- double-blind, noninferiority comparison study, patients ond at the end point. were randomly assigned to receive oral montelukast 5 mg once a day (n ϭ 495) or inhaled fluticasone 100 ␮g RESULTS. Compared with montelukast, children treated twice a day (n ϭ 499) after an appropriate run-in period. with FP experienced a significantly greater increase in After baseline evaluations, patients were evaluated at mean percent forced expiratory volume in 1 second, 4-month intervals with spirometry and review of an mean morning peak expiratory flow rate, and mean asthma diary card. The primary end point, the percent- evening peak expiratory flow rate. Children treated age of asthma rescue-free days (RFDs), included days with FP also experienced significantly greater reduc- with no rescue-medication use and no asthma-related tions in total supplemental albuterol use, mean night- primary care or urgent care visits or hospitalizations. time albuterol use, and mean nighttime symptom Secondary end points included forced expiratory volume scores compared with children treated with monte- in 1 second (FEV1), use of additional asthma medica- lukast. There were no significant differences between tions, asthma attacks, ␤-agonist use, and peripheral the groups for daytime asthma symptom scores, day- blood eosinophil levels. time albuterol use, percent symptom-free days, or adverse events. Parent and physician satisfaction rat- RESULTS. The mean percentage of RFDs was 84% in the ings were significantly higher for FP treatment. The montelukast group compared with 86.7% in the flutica- daily total asthma-related cost per patient in the FP sone group. The least-squares means difference was Ϫ Ϫ Ϫ group was approximately one third of the cost in the 2.8% (95% confidence interval: 4.7% to 0.9%), Ͻ montelukast group. which represents a difference of 1 day/month. Both montelukast and fluticasone were associated with im-

CONCLUSIONS. FP was significantly more effective than provement in FEV1 (percent predicted) from baseline as montelukast in improving pulmonary function, asthma well as reduction in the percentage of days with ␤-ago- symptoms, and rescue albuterol use. Both therapies had nist use, reduction in blood eosinophils, and improve- similar safety profiles. ment in patient-perceived asthma control and asthma quality-of-life scores; however, fluticasone was signifi- ␤ REVIEWER COMMENTS. Comparative studies in adults and ad- cantly favored in terms of FEV1, -agonist use, asthma olescents have previously shown greater efficacy with control, and quality of life. Montelukast was associated inhaled corticosteroids versus leukotriene receptor an- with the increased use of systemic corticosteroids tagonists. This 12-week study reports similar findings for (17.8% vs 10.5%; P Յ .001) and a higher percentage of children 6 to 12 years of age with persistent asthma. patients with an asthma attack (32.2% vs 25.6%) com- Based on efficacy, cost, and safety profiles, low-dose pared with fluticasone.

S44 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 CONCLUSIONS. Montelukast was not inferior to fluticasone with 2.34 in the placebo group, for a 31.9% rate reduc- in terms of asthma RFDs; however, the use of monte- tion (P Յ .001). Other end points with significant differ- lukast was associated with more asthma attacks and ences favoring the montelukast group included time to ␤ ϭ more systemic steroid use. FEV1, -agonist use, and first exacerbation (median: 206 vs 147 days; P .0024), quality of life improved significantly better for those in rate of inhaled corticosteroid use (39.8% rate reduction; the fluticasone group. P ϭ .027), and proportion of patients with asthma epi- sodes (45% vs 56%; P ϭ .008). There were no statisti- REVIEWER COMMENTS. This study represents the first direct cally significant differences in rates of oral corticosteroid comparison between montelukast and an ICS measuring use, average duration and severity of exacerbations, or differences in multiple parameters of asthma control in proportion of patients who missed time from day care or children with mild persistent asthma. This study estab- school. Both groups experienced more exacerbations in lishes the noninferiority of montelukast compared with the fall and fewer in the summer. Montelukast was well fluticasone in terms of RFDs; however, in terms of FEV , 1 tolerated, and no patient discontinued therapy because systemic corticosteroid use, number of asthma attacks of a drug-related adverse event. and ␤-agonist use, fluticasone was significantly superior to montelukast. This study underscores the fact that CONCLUSIONS. The authors concluded that once-daily mon- asthma control cannot be determined with just one mea- telukast significantly reduces asthma exacerbations sec- sure and confirms the role of montelukast as an alter- ondary to respiratory tract infections compared with native to ICSs as suggested by the current guidelines. placebo among 2- to 5-year-old children with intermit- The role of montelukast in future asthma guidelines is tent asthma and also reduces time to first exacerbation currently under investigation. Future studies are needed and need for ␤-agonist or inhaled corticosteroid therapy. for evidence-based clinical application. There was no difference in severity or duration of epi-

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900VVV sodes, although the authors argue that the study was not specifically designed to detect differences in these end Jeremy D. Bufford, MD points. Mark H. Moss, MD Madison, WI REVIEWER COMMENTS. This study attempts to address the question of whether a controller medication may be useful in young children who wheeze with colds but are Montelukast Reduces Asthma Exacerbations otherwise categorized as mild intermittent or even in 2- to 5-Year-Old Children With Intermittent symptom-free. Asthma guidelines do not endorse use of Asthma preventive medications for such children, yet this study Bisgard H, Zielen S, Garcia-Garcia ML, et al. Am J suggests that daily montelukast during the respiratory Respir Crit Care Med. 2005;171:315–322 viral season may be useful to reduce exacerbations (al- though it did not reduce oral steroid use or severity of PURPOSE OF THE STUDY. To evaluate the role of montelukast in exacerbations). Montelukast during specified times prevention of viral-induced asthma exacerbations might be a good option for many young children with among 2- to 5-year-old children with a history of inter- intermittent asthma, but the cost/benefit ratio of chronic mittent asthma. use is unclear, because the number of wheezing episodes STUDY POPULATION. A total of 549 children aged 2 to 5 years per child was low even in the placebo group. Investiga- (from 68 sites in 23 countries) with a history of intermit- tion of episodic use of montelukast with upper respira- tent wheezing associated with upper respiratory infections. tory infections would be of interest.

METHODS. This was a multicenter, double-blind, parallel- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900WWW group randomized trial comparing once-daily oral monte- Todd D. Green, MD lukast (4- or 5-mg chewable tablets) with placebo for 12 Larry W. Williams, MD months. Subjects were required to have been free of symp- Durham, NC toms and ␤-agonist use in a typical week over the 3 months before enrollment. An asthma exacerbation was defined as any 3 consecutive days with daytime symptoms and at least 2 ␤-agonist treatments per day; rescue use of oral/ A Meta-analysis on Intravenous Magnesium inhaled corticosteroids during Ն1 days; or a hospitalization Sulphate for Treating Acute Asthma because of asthma. The primary efficacy end point was Cheuk DK, Chau TC, Lee SL. Arch Dis Child. 2005;90: number of exacerbation episodes over 1 year. Numerous 74–77 secondary outcomes were also measured. PURPOSE OF THE STUDY. To evaluate the effectiveness of intra- RESULTS. Patients in the montelukast group experienced a venous magnesium sulfate in the treatment of acute mean of 1.60 asthma-exacerbation episodes, compared asthmatic attacks in children.

PEDIATRICS Volume 118, Supplement 1, August 2006 S45 Downloaded from www.aappublications.org/news by guest on September 28, 2021 STUDY POPULATION. Pediatric patients (n ϭ 182) with mod- CONCLUSION. Intravenous magnesium sulfate probably pro- erate-to-severe asthmatic attacks in the emergency de- vides additional benefit in moderate-to-severe acute partment in 5 randomized, placebo-controlled trials asthma in children treated with bronchodilators and comparing intravenous magnesium sulfate to placebo, steroids. with co-therapies of inhaled ␤ agonists and systemic 2 REVIEWER COMMENTS. Meta-analyses are useful when multi- steroids. ple previous studies have shown inconsistent results. METHODS. Meta-analysis that evaluated outcomes of hos- They may not, however, be the final answer, because pitalization, short-term pulmonary-function tests, and subsequent large trials can alter the conclusion of a symptom scores. meta-analysis. Nonetheless, the data to date considered in this meta-analysis seem quite convincing. Also, the RESULTS. Magnesium sulfate was effective in preventing treatment is inexpensive and well tolerated, and the hospitalization (odds ratio: 0.29; 95% confidence inter- number needed to treat is small (you would need to give val: 0.143–0.589). The number needed to treat was 4 this therapy to only 4 children to keep 1 out of the (95% confidence interval: 3–8). Secondary outcomes of hospital). short-term pulmonary-function tests and clinical symp- tom scores also showed significant improvement. The URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900XXX therapy was well tolerated with only minor adverse John M. Kelso, MD effects reported. San Diego, CA

S46 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 Immunodeficiency Presenting Phenotype in 100 Children With the 22q11 Deletion Syndrome Oskarsdottir S, Persson C, Eriksson BO, Fasth A. Eur J Pediatr. 2005;164:146–153 PRIMARY IMMUNODEFICIENCY PURPOSE OF THE STUDY. To describe the clinical presentations Development of Population-Based Newborn of individuals having deletion of the 22q11 region. Screening for Severe Combined Immunodeficiency STUDY POPULATION. The first 100 individuals Ͻ20 years old Chan K, Puck JM. J Allergy Clin Immunol. 2005;115: presenting to the Queen Sylvia Children’s Hospital 391–398 (Go¨teborg, Sweden) and found to have 22q11 deletion (from 1993–2002). PURPOSE OF THE STUDY. To evaluate analysis of T-cell devel- opment as a potential population-screening method for METHODS. All diagnoses were confirmed by fluorescence in severe combined immunodeficiency (SCID). situ hybridization. Clinical data collected at diagnosis STUDY POPULATION. Twenty-three infants with SCID, 2 pa- included age and clinical findings in 8 categories (1, tients without SCID, 245 randomly selected infants, and cardiac defects; 2, thymus size, infection history, auto- several healthy adults. immune disease; 3, hypocalcemia; 4, feeding difficulties; 5, cleft lip/palate, speech/language impairment; 6, de- METHODS. DNA was extracted from dried blood spots on velopmental delay, learning difficulties, behavioral ab- standard newborn screening (Guthrie) cards. The DNA normalities; 7, other malformations/deformities; 8, was subjected to polymerase chain reaction (PCR) to dysmorphic features). Those features that led (in par- amplify and quantitate the number of T-cell receptor ticular) to the consideration of the diagnosis were excision circles (TRECs), a marker of T-cell development distinguished. in the thymus. For comparison, the ␤-actin gene was also amplified by PCR. RESULTS. The largest number was diagnosed by cardiolo- gists (39) at a median age of 0.5 years old, with cleft RESULTS. None of the SCID patients’ blood spots contained palate or speech pathology specialists second (22) at a detectable TRECs, whereas the infants without SCID had median age of 8 years, and neurologists or psychia- normal TRECs. Healthy adults had normal TRECs, and trists third (19) at a median age of 11.2. Note that 68 intentional depletion of T cells led to the disappearance of the 74 children diagnosed after age 2 were born of TRECs in simulated blood spots. Approximately 3% of before the fluorescence in situ hybridization test was randomly collected blood spots did not contain measur- routinely available. The main findings are summarized ␤ able TRECs but did contain -actin. in Table 1. CONCLUSIONS. Measurement of TRECs by PCR can accu- CONCLUSIONS. The authors offer diagnostic guidelines for rately identify infants with SCID. The relatively high testing for 22q11 deletion (for infants: any typical car- percentage (3%) of screened spots having the SCID pro- diac defect or 2 of the features in categories 2 through 5, file indicates the need for further refinement of the 7, or 8; for preschool-aged children and adolescents: any method before a larger population study. 2 of the 8 categories either present currently or in the REVIEWER COMMENTS. Newborn screening for SCID is desir- past medical history). able because of the rapidly fatal nature of this disease REVIEWER COMMENTS. 22q11 deletion leads to a spectrum of and because of the good outcomes that may be obtained phenotypes most commonly called velocardiofacial syn- with the earliest possible diagnosis. The minimum esti- drome and/or DiGeorge syndrome. Occurring in ϳ1in mate of the incidence of SCID is Ͼ1 per 100 000 births, 3000 to 4000 live births, it is among the most common comparable to other diseases that are already part of syndromes associated with primary immunodeficiency. newborn screening programs. Almost all patients with Serious infection occurs but is relatively rare. Early di- SCID lack detectable TRECs. The ability to accurately agnosis is most desirable to prevent or mitigate morbid- measure them in dried blood spots represents a tremen- ity arising from developmental and psychiatric compli- dous advance toward the possibility of effective newborn cations in childhood and adolescence. Of the major screening for this genetically very heterogeneous group clinical manifestations, the symptoms arising from velo- of disorders. If the specificity of the analysis can be pharyngeal insufficiency (poor suck, nasal reflux) and improved, this may soon be implemented in newborn various associated malformations seem to be signifi- screening programs. cantly overlooked. The fact that all patients had subtle URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900YYY characteristic dysmorphisms that did not contribute very Francisco A. Bonilla, MD, PhD much to diagnosis shows how much our vision improves Boston, MA with the aid of molecular genetic glasses.

PEDIATRICS Volume 118, Supplement 1, August 2006 S47 Downloaded from www.aappublications.org/news by guest on September 28, 2021 TABLE 1 Clinical Features (Category) % Diagnosed at % Diagnosed at Overall Ͻ2yr(n ϭ 26) Ͼ2y(n ϭ 74) 1. Cardiac defects (eg, ventricular septal defect, tetralogy of Fallot, truncus arteriosus) 92a 54a 64a 2. Hypoplastic thymus 91a Unknown 2. Infections (mainly upper and lower respiratory tract bacterial infections) 8 85a 65 2. Autoimmunity 066 3. Hypocalcemia/hypoparathyroidism 58a 1a 16a 4. History of feeding difficulty (poor suck, nasal reflux) Not recorded 74 5. Cleft lip/palate 15a 28 25 5. Speech/language impairment N/A 85a 6. Developmental delay, learning difficulties, psychiatric problems N/A 96a 7. Other malformations (most common was inguinal or umbilical hernia; many others 42 45 44 were noted) 8. Characteristic subtle dysmorphic features (mildly abnormal ears, broad nasal tip, 100 100 100 small arched mouth, long slender fingers, etc) a Elements of the presentation that led to diagnosis.

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900ZZZ tions could cause disease in both the heterozygous and Francisco A. Bonilla, MD, PhD homozygous conditions. Patients’ cells had diminished Boston, MA binding to TACI ligands and showed diminished re- sponses (immunoglobulin production) to TACI agonists in vitro. The clinical characteristics of the patients in- Mutations in TNFRSF13B Encoding TACI Are cluded hypogammaglobulinemia and impaired antibody Associated With Common Variable responses, recurrent bacterial sinopulmonary infections, Immunodeficiency in Humans autoimmune disease (anemia, thyroiditis, positive anti- Salzer U, Chapel HM, Webster AD, et al. Nat Genet. nuclear antibody), lymphoproliferative disease, and ma- 2005;37:820–828 lignancy (B-cell lymphoma, gastric carcinoma). CONCLUSIONS. Approximately 8% to 20% of patients with severe combined immunodeficiency or IGAD may have TACI Is Mutant in Common Variable heterozygous or homozygous mutation in TACI. This Immunodeficiency and IgA Deficiency genetic alteration should be sought in patients with Castigli E, Wilson SA, Garibyan L, et al. Nat Genet. these disorders. 2005;37:829–834 REVIEWER COMMENTS. CVID and IGAD are among the most PURPOSE OF THE STUDIES. To search for mutations of TACI prevalent humoral immunodeficiencies at all ages. These (transmembrane activator and calcium modulator and studies represent important descriptions of defined mu- cyclophilin ligand interactor; also TNFRSF13B) in pa- tations in patients with CVID and IGAD occurring in a tients with common variable immunodeficiency (CVID) significant fraction of these patients in 2 relatively ge- and immunoglobulin A deficiency (IGAD). netically disparate populations. The ability to clearly de- fine the underlying cause of disease in these patients will STUDY POPULATIONS. Salzer et al screened 162 unrelated in- immediately lead to greater accuracy and confidence in dividuals with CVID. Castigli et al studied 19 unrelated diagnosis, earlier and more aggressive therapy, and, individuals with CVID and 16 with IGAD. Healthy indi- hopefully, improved outcomes. viduals (100 and 50, respectively) served as controls. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900AAAA METHODS. Genomic DNA from patients was subjected to Francisco A. Bonilla, MD, PhD reverse transcription and polymerase chain reaction se- Boston, MA quencing analysis of the 5 exons of the gene encoding TACI. Binding of mutant TACI to ligands and stimula- tion of immunoglobulin production in vitro with TACI Gene Therapy of X-Linked Severe Combined agonists in patients was also studied. Immunodeficiency by Use of a Pseudotyped Gammaretroviral Vector RESULTS. Salzer et al identified 13 individuals with CVID Gaspar HB, Parsley KL, Howe S, et al. Lancet. 2004; who had mutations in TACI. Castigli et al identified 4 364:2181–2187 individuals with CVID and 1 with IGAD and TACI mu- tations. None of the 150 controls studied had any of the PURPOSE OF THE STUDY. To investigate the application of so- identified TACI mutations. Interestingly, TACI muta- matic gene therapy for X-linked severe combined immu-

S48 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 nodeficiency (SCID-X1) in patients without an HLA- including enhancer-mediated activation of the T-cell matched donor for bone marrow transplant. protooncogene LMO-2. Additional longitudinal studies will help to determine the duration of reconstitution and STUDY POPULATION. All 4 children with SCID-X1 resulting quantify the risk of adverse events. from a ␥-c chain mutation and without an HLA-identical sibling referred to Great Ormond Street Hospital (Lon- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900BBBB don, United Kingdom) between July 2001 and Decem- Elinor Simons, MD ber 2002 were offered and consented to receive gene Albany, NY therapy.

METHODS. The complete coding region of human ␥-c was cloned into a pMFG gammaretroviral vector and trans- Pediatric Hypereosinophilic Syndrome (HES) fected into bone marrow CD34ϩ stem cells for reinfusion Differs From Adult HES into the patients. T-cell function was assessed by re- Katz HT, Haque SJ, Hsieh FH. J Pediatr. 2005;146:134– sponses to mitogens, Candida antigen, and mixed lym- 136 phocyte reactions. T-cell receptor (TCR) repertoires were PURPOSE OF THE STUDY. To highlight specific differences be- assessed by direct immunofluorescence with fluoro- tween pediatric and adult patients with hypereosino- ␤ chrome-conjugated antibodies to TCRV- . Somatic hy- philic syndrome (HES). permutation was expressed as the fraction of ␬ light- chain polymerase chain reaction product with mutations STUDY POPULATION. The case report involved a 15-year-old preventing cleavage by Fnu4HI. male who presented with abdominal pain, diarrhea, and a 10-lb weight loss. Colonoscopy revealed colitis. A non- RESULTS. At reinfusion, 27% to 58% of cells were CD34- productive cough, night sweats, and a diffuse pruritic, ␥ positive and -c–positive. In all patients, natural killer papular rash developed. His initial absolute eosinophil cells appeared 2 to 4 weeks postinfusion and remained at count was 1890/mm3 (reference: Ͻ400/mm3), which Ϫ ϩ low-normal levels. Naive CD45RO , CD27 T cells ap- increased to 52 000/mm3. Additional laboratory studies peared at 10 to 30 weeks. Two patients developed nor- included: immunoglobulin E, 8561 U/mL (7–110 U/mL); mal numbers of CD3, CD4, and CD8 cells, allowing alkaline phosphatase, 1149 U/mL (reference: 50–280 discontinuation of prophylactic medications. One of U/mL); ␥-glutamyl transpeptidase, 193 (reference: 0–50 these patients developed a maculopapular rash on the U/mL); and serum tryptase, 4.7 ␮g/L (reference: 1.9– palms and soles after CD4 T-cell recovery. Another pa- 13.5 ␮g/L). Ultrasound of the liver revealed an abnormal tient had gastrointestinal bleeding resulting from rejec- parenchymal pattern with dilated bile ducts. Molecular tion of engrafted maternal cells. The eldest patient, who analysis of the patient’s peripheral blood for the Fip1- received gene therapy at 33 months of age, had slower like-1 platelet-derived growth factor receptor ␣ chain lymphocyte recovery. All patients developed normal T- (FIP1L1-PDGFRA) fusion tyrosine kinase associated cell–proliferative responses to mitogens, antigens, and with HES in adults was negative. Open lung biopsy mixed lymphocyte reactions. One year after treatment, revealed patchy interstitial and intra-alveolar inflamma- all patients showed normal TCRV-␤ usage and poly- tion with a predominance of eosinophils. A skin biopsy clonality within individual V-␤ families. Two patients showed acute neutrophilic folliculitis with perivascular maintained normal immunoglobulin levels after discon- dermatitis with eosinophils. Bone marrow biopsy dem- tinuing replacement, and normal serologic responses to onstrated a hypercellular marrow with predominantly vaccines were documented in 1 patient. Somatic mutation eosinophils, which is consistent with idiopathic HES. demonstrated by mutated V-␬ A27 transcripts increased from Ͻ2.0% to 5.3% to 23.3% by 1 to 2 years after gene METHODS. The investigators compared this case report of therapy. No pathologic clonal expansions or insertions near pediatric HES and additional published cases of pediatric and adult patients with HES. the T-cell protooncogene LMO-2 were detected. RESULTS. Pediatric HES has only a slight male predomi- CONCLUSION. After somatic gene therapy, all 4 patients with nance (55.3% male vs 44.7% female), whereas adult SCID-X1 had significant improvement in clinical and HES is reported to be more common among males than immunologic function without serious adverse events. females, with a ratio of 9 to 1. In adults, the frequencies REVIEWER COMMENTS. Morbidity and mortality are high in of symptoms found on presentation are: fatigue (26%), patients with SCID-X1 for whom an HLA-matched fam- cough (24%), dyspnea (16%), rash (12%), and fever ily donor is not available. This small study suggests that (12%). Fever (58.8%), arthralgias (23%), and rash substantial, prolonged immunologic recovery is possible (23.5%) were more common in pediatric cases. As with with somatic gene therapy; however, recovery of thy- adults, involvement of the cardiovascular system is the mopoiesis may be compromised in older patients. Previ- major source of morbidity and mortality. Pediatric HES is ous studies have shown more serious adverse events, commonly associated with chromosomal abnormalities,

PEDIATRICS Volume 118, Supplement 1, August 2006 S49 Downloaded from www.aappublications.org/news by guest on September 28, 2021 and in ϳ40% of the cases, it has been associated with indicating that ongoing reactivation of latently infected, acute leukemia. As opposed to the vast majority of adult resting CD4ϩ T cells may occur in these patients. HES cases, no pediatric case with the FIP1L1-PDGFRA CONCLUSIONS. Continual replenishment of the CD4ϩ T-cell fusion gene has been reported. reservoir occurs despite prolonged periods of plasma CONCLUSION. There are several distinct features of pediatric, aviremia. compared with adult, HES. REVIEWER COMMENTS. It is only with the elimination of viral REVIEWER COMMENTS. Most of the published information on reservoirs that HIV infection can be “cured.” Resting T the HES has focused on adult patients. This report com- cells harboring proviral DNA do not live forever. How- pares a pediatric case report of HES and a review of ever, the rate of viral replenishment in this cell compart- published pediatric cases of this condition to adult pa- ment at least equals the natural decline in their num- tients with this syndrome. This is an insightful clinical bers. Eliminating this cell reservoir will be a daunting report that should be useful in the overall workup of task. pediatric patients who present with dramatic eosino- URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900DDDD philia (Ͼ1500/mm3) for Ͼ6 months’ duration without other known causes of eosinophilia and who have evi- Joseph A. Church, MD Los Angeles, CA dence of organ involvement that might be attributable to HES.

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900CCCC Emergence of Drug Resistant HIV-1 After John James, MD Intrapartum Administration of Single-Dose Fort Collins, CO Nevirapine Is Substantially Underestimated Johnson JA, Li JF, Morris L, et al. J Infect Dis. 2005; 192:16–23 HUMAN IMMUNODEFICIENCY VIRUS PURPOSE OF THE STUDY. An inexpensive, effective regimen to HIV-Infected Individuals Receiving Effective prevent perinatal HIV transmission in the developing Antiviral Therapy for Extended Periods of world is highly desirable. Nevirapine, a nonnucleoside Time Continually Replenish Their Viral reverse transcriptase inhibitor, seems to provide such an Reservoir intervention. However, drug-resistance mutations have Chun TW, Nickle DC, Justement JS, et al. J Clin Invest. been identified in up to 40% of women shortly after 2005;115:3250–3255 they received a single intrapartum nevirapine dose as part of a transmission-prevention strategy. This study PURPOSE OF THE STUDY. Latently infected, resting CD4ϩ T cells was undertaken to reexamine the incidence of drug- provide a reservoir for HIV, and the persistence of these resistant HIV-1 after single-dose nevirapine. cells prevents the eradication of HIV even in patients who have received highly active antiretroviral therapy STUDY POPULATION. Fifty South African women infected (HAART) for prolonged periods. The purpose of this with HIV subtype C. study was to examine the underlying mechanisms by METHODS. Sensitive, real-time polymerase chain reaction which HIV persists in CD4ϩ T cells in individuals treated assays were sequentially performed for nonnucleoside effectively for up to 9 years. reverse transcriptase inhibitor–resistance mutation, METHODS. Eleven HIV-infected subjects were studied. K103N and Y181C. These individuals had received effective therapy for an RESULTS. Resistance mutations emerged in 65% of women average of 8 years (range: 7.16–9.1 years). None of the after a single dose of nevirapine. patients had experienced detectable plasma viremia after initial suppression. Peripheral blood cells were obtained CONCLUSIONS. Single-dose nevirapine as used in the devel- sequentially on all individuals and studied for the pres- oping world for prevention of perinatal HIV transmission ence of replication-competent virus. results in the development of resistance mutations in a very high percentage of women who receive this inter- RESULTS. All infected subjects carried replication-compe- vention. tent HIV in their CD4ϩ T cells despite having received prolonged, effectively suppressive antiviral therapy. REVIEWER COMMENTS. Although single-dose nevirapine has Contrary to current thinking, substantial higher levels of been successfully implemented as a strategy to prevent HIV proviral DNA were found in circulating activated perinatal HIV transmission, it is increasingly apparent CD4ϩ T cells when compared with the resting subset. that the women who are treated with this regimen more Sequence analysis revealed evidence for cross infection often than not develop resistance mutations to nevirap- between the resting and activated T-cell compartments, ine. The clinical implications are clear: Will nevirapine

S50 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 work for future perinatal interventions for individual circulating HIV-infected resting CD4ϩ T cells. There were women with drug-resistance mutations? Will women no complications of the additional treatments except for with these drug-resistance mutations fail to respond to the expected injection-site reactions to enfuvirtide. nevirapine as part of a highly active retroviral therapy CONCLUSIONS. Combination therapy with an HDAC inhibi- intervention when they need treatment for their own tor and very potent antiretroviral therapy accelerated HIV disease? In the same issue of The Journal of Infectious the reduction in HIV-infected resting T cells. This sug- Diseases, Flys et al (J Infect Dis. 2005;192:24–29) demon- gests a new approach to the management of HIV that strated that drug-resistance variants of HIV may persist eventually may result in clearance of HIV from infected for Ͼ1 year in this situation. In addition, Lee et al (J Infect individuals. Dis. 2005;192:1260–1264) showed that women who de- veloped drug-resistant HIV after exposure to single-dose REVIEWER COMMENTS. This study received a fair amount of nevirapine shed drug-resistant HIV in their breast milk. media coverage at the time it was published. It begs the This increases the risk of transmission of resistant virus question, can HIV be cured? A 75% reduction in the to uninfected infants. Together, these studies demon- resting T-cell reservoir seems impressive. However, this strate that single-dose nevirapine, although an effective was a very short-term study, and the kinetics and degree strategy for reducing maternal-child transmission of to which the resting T-cell reservoir was replenished HIV, also predisposes treated women to the development after discontinuation of valproic acid was not reported. of drug-resistant virus as well as the potential for trans- In addition, valproic acid, a widely used anticonvulsant, mitting drug-resistant virus to their infants via breast- is potentially highly toxic and has “black-box” warnings feeding. for hepatotoxicity, teratogenicity, and pancreatitis. De- spite the authors’ optimistic conclusions, “this finding, URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900EEEE though not definitive, suggests that new approaches will Joseph A. Church, MD allow the cure of HIV in the future,” use of the “C word” Los Angeles, CA is likely premature.

URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900FFFF

Depletion of Latent HIV-1 Infection in Vivo: A Joseph A. Church, MD Los Angeles, CA Proof-of-Concept Study Lehrman G, Hogue IB, Palmer S, et al. Lancet. 2005; 366:549–555

-PURPOSE OF THE STUDY. Resting CD4ϩ T cells are a primary Paradoxical CD4؉ T-Cell Decline in HIV reservoir for HIV. In these cells the HIV is in a latent form Infected Patients With Complete Virus and not a target of current antiviral agents. The chroma- Suppression Taking Tenofovir and Didanosine tin-remodeling enzyme histone deacetylase 1 (HDAC1) Barrios A, Rendon A, Negredo E, et al. AIDS. 2005;19: maintains latency of integrated HIV. This study tested 569–575 the hypothesis that an inhibitor of HDAC1, valproic acid, PURPOSE OF THE STUDY. Tenofovir and didanosine are adeno- would result in depletion of latently infected resting sine analogs commonly used in highly active antiretro- CD4ϩ T cells. viral therapy combinations. Although virologically effec- STUDY POPULATION. Four human volunteers with HIV receiv- tive, this combination is theoretically associated with ing highly active antiretroviral therapy. pharmacokinetic interactions and increased risks of pan- creatitis and hyperglycemia. The study examined the METHODS. The individual subjects’ antiretroviral therapies CD4ϩ T-cell effects of the use of these 2 drugs as part of were intensified with enfuvirtide, a fusion inhibitor, to a highly active antiretroviral therapy regimen. minimize the spread of HIV during potential release from latency. The subjects then were treated with oral val- METHODS. Data from 570 individuals were analyzed retro- proic acid, 500 to 750 mg twice daily, in addition to their spectively according to the nucleoside analog “back- antiretroviral therapy, and they were followed for 3 bone” of protease inhibitor–containing regimens: teno- months. Latently infected resting T cells were quantified fovir ϩ didanosine in 298 subjects, didanosine in 88, before and after augmentation of treatment with limit- tenofovir in 44, and neither didanosine nor tenofovir in ing-dilution culture of resting cells after ex vivo activa- 140. tion. RESULTS. Significant CD4ϩ T-cell declines were noted in RESULTS. The frequency of resting CD4ϩ T-cell infection patients taking the combination of tenofovir ϩ di- was stable before the addition of enfuvirtide and valproic danosine relative to all other nucleoside analog combi- acid but declined thereafter. This decline was significant nations including didanosine or tenofovir only. Patients in 3 or 4 patients, with a mean reduction of 75% in exposed to higher didanosine doses showed a more pro-

PEDIATRICS Volume 118, Supplement 1, August 2006 S51 Downloaded from www.aappublications.org/news by guest on September 28, 2021 nounced CD4ϩ T-cell decline, and plasma levels of di- METHODS. Eight rhesus macaque monkeys were infected danosine correlated with the extent of T-cell loss. with a pathogenic strain of SIV. Plasma and tissue sam- ples were collected at various time points by biopsy and CONCLUSIONS. Although patients receiving tenofovir ϩ di- necropsy. Lymphocyte subsets were analyzed with stan- danosine–based combinations generally achieved excel- dard flow cytometry, and T-cell–associated viral DNA lent viral suppression, their CD4ϩ T cells often paradox- was measured by a highly sensitive quantitative poly- ically declined. This effect generally progressed over merase chain reaction assay. time. It is hypothesized that the use of these 2 agents together results in a condition that metabolically resem- RESULTS. This study demonstrated that in this monkey bles purine nucleoside phosphorylase deficiency, a rare model, memory CD4ϩ T cells are depleted in multiple but well-described primary immunodeficiency syn- tissues during acute SIV infection. In addition, the loss of drome. these cells is explained by a massive infection of these cells by the virus. Specifically, ϳ50% of these cells REVIEWER COMMENTS. Tenofovir and didanosine frequently throughout the body are infected by SIV at the peak of are the only nucleoside analog agents available to pa- infection, and most of the infected cells disappear within tients with drug-resistant virus. This combination with several days. Alternative mechanisms are not required. either a nonnucleoside reverse transcriptase inhibitor or This depletion occurs to a similar extent in all tissues. a protease inhibitor is often effective in suppressing virus in patients with limited options. However, the paradox- CONCLUSIONS. Acute immunodeficiency virus infection re- ical decline in T-cell numbers is of great concern. Pa- sults in the loss of ϳ50% of all memory T cells within tients on this regimen must be monitored carefully for days of infection. This and other studies strongly suggest this potential complication. that this loss, at least in adult animals and humans, is irreversible. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900GGGG Joseph A. Church, MD REVIEWER COMMENTS. This study confirms and extends previ- Los Angeles, CA ous findings demonstrating massive memory T-cell loss during acute HIV or SIV infection. The extent to which this loss is recoverable is likely to be very limited. Most interesting is that these authors also noted that naive T -Massive Infection and Loss of Memory CD4؉ T cells are highly resistant to SIV infection. These obser Cells in Multiple Tissues During Acute SIV vations are particularly important for infants infected Infection with HIV. Young infants have fewer memory CD4ϩ T Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin cells, and, therefore, their loss may not be as critical in M, Roederer M. Nature. 2005;434:1093–1097 newborns. In addition, the thymus in young children may be more capable of reconstituting memory T-cell PURPOSE OF THE STUDY. It was recently established that both functions if HIV is completely suppressed early. Similar acute HIV and its simian counterpart, simian immuno- studies should be performed on infant laboratory ani- deficiency virus (SIV), are accompanied by dramatic and mals to determine the extent to which recovery is likely selective loss of memory CD4ϩ T cells. This loss has been in infected children. shown to primarily occur in mucosal tissues. The extent and mechanisms underlying this depletion have not URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900HHHH been defined. The purpose of this study was to investi- Joseph A. Church, MD gate these questions in a simian model. Los Angeles, CA

S52 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 Infectious Disease for those with asthma vs 62% for those with other HRCs) would have been achieved. Telephone interviews with parents revealed lack of physician recommendation, low Missed Opportunities for Influenza perceived susceptibility to influenza, and misconception of Vaccination in Children With Chronic Medical the risks of vaccination as the primary reasons. Conditions Daley MF, Beaty BL, Barrow J, et al. Arch Pediatr CONCLUSIONS. Missed opportunities for influenza immuni- Adolesc Med. 2005;159:986–991 zation are common among children with asthma and other HRCs, particularly at non-WCC visits and later in PURPOSE OF THE STUDY. To assess the frequency and charac- the influenza season, and contribute to the persistently teristics of missed opportunities for influenza immuni- low influenza-immunization rate in this population. zation in children with chronic medical conditions, and among unimmunized children in that group, to explore REVIEWER COMMENTS. As illustrated in this study, parents of- parent-reported reasons for not vaccinating their child. ten rely on their child’s heath care provider to advise them about preventive health care measures. Therefore, STUDY POPULATION. A cohort of 926 children (aged 6 to 72 it is important for providers to identify the patients at risk months) who were identified from October 1, 2002, (existence of HRC), recognize the indications for influenza through January 31, 2003, as having Ն1 high-risk con- immunization, and discuss the pros and cons of influenza ditions (HRCs). A total of 594 (64%) were male, and 734 immunization with the parents and patients. (79%) were between 24 and 72 months of age. The children were insured privately (84%) or publicly (12%) URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900IIII or uninsured (3%). Diagnoses included asthma only Sally Joo Bailey, MD (89%), cardiac conditions (3%), immunosuppressive New York, NY conditions or therapies (2%), chronic nonasthma pul- monary conditions (2%), and other HRCs (2%).

METHODS. Data were obtained from shared billing and im- Identification of a Universal Group B munization registry databases of 4 private pediatric prac- Streptococcus Vaccine by Multiple Genome tices in metropolitan Denver, Colorado, during the Screen 2002–2003 influenza season. Study sites had 5 to 8 Maione D, Margarit I, Rinaudo CD, et al. Science. 2005; pediatricians and 2 to 6 nonphysician providers per prac- 309:148–150 tice. The method of HRC identification through billing data using set diagnostic codes was documented to have PURPOSE OF THE STUDY. To apply comparative genomic tech- a sensitivity of 72%, specificity of 95%, and an overall niques for the development of a universally protective accuracy of 90% compared with medical charts. The group B Streptococcus (GBS) vaccine. billing system contained data for individual patient de- METHODS. The genome sequences of 8 GBS strains were mographics, diagnostic codes, procedural codes for im- compared to identify shared and strain-restricted genes. munizations, and type of visit distinguished as well-child Computer algorithms were used to identify putative sur- care (WCC) visit or not (non-WCC visit). Telephone face or secreted proteins. Candidates were cloned and surveys of randomly selected parents of children not expressed recombinantly in Escherichia coli. Purified pro- given influenza vaccine were conducted in April to May teins initially alone and then in combination were used 2003. to immunize groups of female mice. Immunized animals RESULTS. In children with asthma only (820), of all vac- were then mated, and resulting offspring were chal- Ͻ cine-eligible visits (881), 78% resulted in missed oppor- lenged at 48 hours of age with virulent GBS. Protec- tunities. Missed opportunities occurred at 62% of WCC tion was also correlated with specific antibody binding. visits and 86% of non-WCC visits (difference of 24%; RESULTS. Genomic analysis identified 1811 shared genes 95% confidence interval: 16%–31%). The rate of influ- representing ϳ80% of the genome of each strain. Of enza immunization was 43% among subjects with vac- these, 589 proteins were predicted to be surface or se- cine-eligible WCC visits compared with 18% for those creted proteins (396 shared, 193 variable), and 312 of without a vaccine-eligible WCC visit. In children with them were successfully expressed as soluble fusion pro- other HRCs (106), the rates of missed opportunities were teins from E coli. Systemic screening of all 312 of these similar to those children with asthma only. The rate of proteins revealed that 4 were capable of significant pro- influenza immunization was also similar at 40% with tection of GBS-challenged offspring of immunized vaccine-eligible WCC visits; however, the rate of immu- mothers. One of these 4, Sip, was a previously described nization for those without a vaccine-eligible WCC visit shared gene, whereas 3 were variably present in the was higher at 28%. If the subjects were immunized at genomes from different strains. As expected, in experi- their first opportunity, similar rates of immunization (61% ments with single-antigen vaccination, there was no

PEDIATRICS Volume 118, Supplement 1, August 2006 S53 Downloaded from www.aappublications.org/news by guest on September 28, 2021 protection when challenged with strains that lack the traumbilical-cord, or intra-amniotic doses were admin- gene encoding the vaccine protein. However, protection istered if evidence of persistent fetal involvement was was also variable and even absent in some strains when present on ultrasound. Women with CMV-positive am- the gene was known to be present. However, using all 4 niotic fluid who declined to receive hyperimmune-glob- antigens in combination, the authors demonstrated pro- ulin infusions were followed as a comparison group. tection against a panel of 12 challenge strains represent- Those in the prevention group, consisting of women ing all 9 major pathogenic GBS serotypes ranging from with a recent primary infection before 21 weeks’ gesta- 59% to 100%. tion or who declined amniocentesis, were offered monthly hyperimmune globulin (100 U/kg intrave- CONCLUSIONS. Multistrain genome analysis and screening nously). Pregnant women who declined monthly ad- represents an effective new approach for the identifica- ministration of hyperimmune globulin were followed as tion of vaccine candidates that single-strain analysis a comparison group. would miss. RESULTS. In the therapy group, 31 women received hyper- REVIEWER COMMENTS. Vaccine strategies taking into account immune globulin, only 1 (3%) of whom gave birth to an the enormous variability at the genomic and proteomic infant with symptomatic CMV disease, compared with 7 levels that many pathogens have evolved are the best (50%) of 14 women who did not receive hyperimmune hedge against a mere “arms race” in which temporary globulin. Thus, hyperimmune-globulin therapy was as- vaccine efficacy gives way to the emergence of antigenic sociated with a significantly lower risk of congenital variants. This is a novel application of such a rational CMV disease (adjusted odds ratio: 0.02; 95% confidence strategy. However, the extent of the challenge is under- interval: Ϫϱ to 0.15; P Ͻ .001). In the prevention group, scored by the identification of only 4 targets despite a 37 women received hyperimmune globulin, 6 (16%) of comprehensive approach. Furthermore, 3 of 4 are not whom had infants with congenital CMV infection, com- part of the “core” conserved genome and are, therefore, pared with 19 (40%) of 47 women who did not receive likely to be nonessential. It remains unproven whether hyperimmune globulin. Thus, hyperimmune-globulin targeting of so few surface proteins of an encapsulated therapy was associated with a significantly lower risk of organism would prove to be a good long-term strategy. congenital CMV infection (adjusted odds ratio: 0.32; Nevertheless, this approach seems likely to be at least 95% confidence interval: 0.10 to 0.94; P ϭ .04). No complementary to efforts directed to polysaccharides for adverse effects resulted from CMV-specific hyperim- encapsulated organisms. mune globulin administration. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900JJJJ CONCLUSIONS. Treatment of pregnant women with CMV- Wayne G. Shreffler, MD, PhD specific hyperimmune globulin is safe, and the findings New York, NY of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may be appropriate. Passive Immunization During Pregnancy for Congenital Cytomegalovirus Infection REVIEWER COMMENTS. The risk of congenital CMV infection is Nigro G, Adler SP, La Torre R, Best AM; Congenital high after primary maternal CMV infection. Although Cytomegalovirus Collaborating Group. N Engl J Med. the majority of congenitally acquired CMV infections are 2005;353:1350–1362 asymptomatic, symptomatic infections result in signifi- cant morbidity and possible mortality. The implementa- PURPOSE OF THE STUDY. To investigate the effectiveness of cy- tion of CMV-specific hyperimmune globulin may reduce tomegalovirus (CMV)-specific hyperimmune globulin or prevent the devastating effects of symptomatic con- for primary CMV infection during pregnancy as a pre- genital CMV. ventive therapy for fetal CMV infection. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900KKKK STUDY POPULATION. One hundred fifty-seven pregnant Jennifer M. Maloney, MD women from 8 Italian cities with a primary CMV infec- Scott H. Sicherer, MD tion diagnosed via serologic testing. New York, NY METHODS. Women were placed in 1 of 2 groups. The ther- apy group comprised women who underwent amnio- centesis and whose amniotic fluid contained either CMV Information Leaflet and Antibiotic Prescribing detected by culture or CMV DNA detected by polymer- Strategies for Acute Lower Respiratory Tract ase chain reaction. The group was offered intravenous Infection: A Randomized, Controlled Trial CMV-specific hyperimmune globulin at a dose of 200 U Little P, Rumsby K, Kelly J, et al. JAMA. 2005;293: per kg of maternal weight. Additional intravenous, in- 3029–3035

S54 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 PURPOSE OF THE STUDY. Acute lower respiratory tract infection confidence interval: Ϫ0.37–1.88; immediate prescrip- is the most common condition treated in primary care. tion, 0.11 days; 95% confidence interval: Ϫ1.01–1.24) Many physicians still prescribe antibiotics; however, sys- or other primary outcomes. Compared with those in the tematic reviews of the use of antibiotics are small and immediate-antibiotic group, slightly fewer patients in have diverse conclusions. This study evaluated the effec- the delayed-prescription and control groups used anti- tiveness of 3 prescribing strategies and an information biotics (96%, 20%, and 16%, respectively; P Ͻ .001), leaflet for acute lower respiratory tract infection. fewer patients were “very satisfied” (86%, 77%, and ϭ STUDY POPULATION. A randomized, controlled trial con- 72%, respectively; P .005), and fewer patients be- ducted from August 18, 1998, to July 30, 2003, of 807 lieved in the effectiveness of antibiotics (75%, 40%, and Ͻ patients presenting to a primary care setting with acute 47%, respectively; P .001). There were lower reatten- uncomplicated lower respiratory tract infection. Patients dances within a month with antibiotics (mean atten- were assigned to 1 of 6 groups by a factorial design: dances for no antibiotics: 0.19; delayed prescription: leaflet or no leaflet and 1 of 3 antibiotic groups (imme- 0.12; immediate prescription: 0.11; P ϭ .04) and higher diate antibiotics, no offer of antibiotics, and delayed attendance with a leaflet (mean attendances for no leaf- antibiotics). let: 0.11; mean attendances for leaflet: 0.17; P ϭ .02).

METHODS. Three strategies, immediate antibiotics (n ϭ CONCLUSIONS. No offer or a delayed offer of antibiotics for 262), a delayed antibiotic prescription (n ϭ 272), and no acute uncomplicated lower respiratory tract infection is offer of antibiotics (n ϭ 273), were prescribed. Approx- acceptable, associated with little difference in symptom imately half of the patients in each group received an resolution, and is likely to considerably reduce antibiotic information leaflet (129 for immediate antibiotics, 136 for use and beliefs in the effectiveness of antibiotics. delayed antibiotic prescription, and 140 for no antibiotics). REVIEWER COMMENTS. This is good that we do not need yet RESULTS. A total of 562 patients (70%) returned complete another patient-information leaflet. I have always liked diaries, and 78 (10%) provided information about both the “delayed-offer” approach, because it is a compromise symptom duration and severity. Cough rated at least “a to the patient, and most of the time they get better and slight problem” lasted a mean of 11.7 days (25% of the never need the drug. patients had a cough lasting Ն17 days). An information leaflet had no effect on the main outcomes. Compared URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0900LLLL with no offer of antibiotics, other strategies did not alter Allen Adinoff, MD cough duration (delayed prescription, 0.75 days; 95% Denver, CO

PEDIATRICS Volume 118, Supplement 1, August 2006 S55 Downloaded from www.aappublications.org/news by guest on September 28, 2021 The PREVASC Study: The Clinical Effect of a Multifaceted Educational Intervention to Prevent Childhood Asthma Wanda Phipatanakul Pediatrics 2006;118;S9 DOI: 10.1542/peds.2006-0900P

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/118/Supplement_1/S9.1 References This article cites 1 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/118/Supplement_1/S9.1 #BIBL Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 The PREVASC Study: The Clinical Effect of a Multifaceted Educational Intervention to Prevent Childhood Asthma Wanda Phipatanakul Pediatrics 2006;118;S9 DOI: 10.1542/peds.2006-0900P

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/118/Supplement_1/S9.1

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 28, 2021