bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination Therapy With Desmopressin and an Anticholinergic Medication for Nonresponders to Desmopressin for Monosymptomatic Nocturnal Enuresis: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Austin Paul F. , Ferguson Genoa , Yan Yan , Campigotto Mary J. , Royer Michele E. , Coplen Douglas E.
Published: October 2008

OBJECTIVE. Desmopressin is an approved medical therapy for the treatment of monosymptomatic primary nocturnal enuresis. In cases of limited response to desmopressin, we have added anticholinergic therapy to desmopressin (combination therapy). To evaluate this treatment strategy, we examined the efficacy of combination therapy for primary nocturnal enuresis in desmopressin-nonresponders.

METHODS. Only patients with primary nocturnal enuresis refractory to the maximal dosage of desmopressin were enrolled. Children with lower urinary tract symptoms or bowel dysfunction were excluded, on the basis of a 3-day, 24-hour, frequency-volume chart and elimination record. Children continued to take desmopressin and were assigned randomly, in a double-blind manner, to receive either extended-release anticholinergic medication or placebo. Patients were reassessed after 1 month of therapy, with a 1-week nocturnal record.

RESULTS. Forty-one desmopressin-nonresponders were enrolled, and 7 patients were excluded because of noncompliance. The treatment groups were equally matched with respect to age, gender, functional bladder capacity, and number of wet nights per week. After 1 month of treatment, there was a significant reduction in the mean number of wet nights in the combination therapy group, compared with the placebo group. With a generalized estimating equation approach, there was a significant 66% decrease in the risk of a wet episode, compared with the placebo group.

CONCLUSIONS. This study represents the first prospective, placebo-controlled trial examining the effect of desmopressin in combination with long-acting, anticholinergic, bladder-relaxing therapy for monosymptomatic primary nocturnal enuresis.
Mortality and Morbidity by Month of Birth of Neonates Admitted to an Academic Neonatal Intensive Care Unit
Authors: Soltau Thomas D. , Carlo Waldemar A. , Gee Jonathan , Gould Jeffrey , Ambalavanan Namasivayam
Published: October 2008

BACKGROUND. Clinical expertise and skill of pediatric housestaff improve over the academic year, and performance varies despite supervision by faculty neonatologists. It is possible that variation in clinical expertise of housestaff affects important clinical outcomes in infants in ICUs.

OBJECTIVE. Our goal was to test the hypothesis that there is a decrease in morbidity and mortality in infants admitted to an NICU over the course of the academic year.

DESIGN/METHODS. A retrospective analysis was conducted using data on infants with birthweight 401 to 1500 g and ≥24 weeks’ gestation (n = 3445) and infants with birth weights >1500 g (n = 7840) admitted to a regional NICU from January 1991 to June 2004. All infants were cared for by pediatric and neonatal housestaff supervised by neonatologists. Analysis of mortality and morbidity (intraventricular hemorrhage grades 3–4/periventricular leukomalacia, necrotizing enterocolitis ≥ Bell stage 2, and bronchopulmonary dysplasia) over time were performed by repeated measures analysis of variance and the χ2 test.

RESULTS. Mortality rate in the 401 to 1500 g cohort, as well as the >1500 g cohort did not decrease over time during the academic year and was similar between the first (July–December) and second (January–June) halves of the academic year. There were no differences noted over the academic year for any of the morbidities.

CONCLUSIONS. Morbidity and mortality in infants admitted to an academic NICU did not change significantly over the academic year. These observations suggest that the quality of care of critically ill neonates is not decreased early in the academic year.
Needle Pain in Children: Contextual Factors
Authors: Walco Gary A.
Published: October 2008

Pediatric pain experiences result from a complex interplay of genetic, experiential, and developmental factors. These elements, as they relate to needle-stick procedures and other relevant painful phenomena, are explored in this article so that the context of possible interventions may be more fully appreciated. Clinical implications are discussed incorporating ethical perspectives. Pediatrics 2008;122:S125-S129
Pharmacologic Approaches for Reducing Venous Access Pain in Children
Authors: Zempsky William T.
Published: October 2008

A variety of pharmacologic options are available to clinicians who want to provide effective and safe topical local anesthesia to children undergoing venous access procedures. These options can be distinguished on the basis of how they deliver active drug through the impermeable outer layer of skin, the stratum corneum, to pain receptors located in the dermis and epidermis. Three general methodologies are typically used to bypass the stratum corneum: direct injection of local anesthetics, usually via a small-gauge hypodermic syringe; passive diffusion from topical creams or gels; and active needle-free drug strategies that enhance the rate of drug passage into the dermis and epidermis. Examples of the latter mechanisms include heat-enhanced diffusion, iontophoresis, sonophoresis, laser-assisted transdermal passage, and pressurized gas delivery of powdered drug particles. Pharmacologic options in this setting can also be distinguished on the basis of the time to onset of full anesthetic effect. Several available agents induce significant local anesthesia within 1 to 3 minutes of administration, or faster, allowing easy integration into the skin preparation and subsequent venous access procedure. In combination with nonpharmacologic approaches, these agents can be used to dramatically lessen this significant source of pediatric pain.
Increased Mortality Rates of Young Children With Traumatic Injuries at a US Army Combat Support Hospital in Baghdad, Iraq, 2004
Authors: Matos Renée I. , Holcomb John B. , Callahan Charles , Spinella Philip C.
Published: October 2008

OBJECTIVE. The objective of this study was to determine whether age ≤8 y is an independent predictor of mortality in noncoalition trauma patients at a US combat support hospital.

METHODS. A retrospective chart review was conducted of 1132 noncoalition trauma patients who were admitted to a combat support hospital between December 2003 and December 2004. Data on age, severity of injury indices, and in-hospital mortality rates were analyzed. All variables that were associated with death on univariate analysis were analyzed by multivariate logistic regression to determine independent associations with mortality.

RESULTS. There were 38 young pediatric patients (aged ≤8 years) and 1094 older pediatric and adult patients (aged >8 years). Penetrating trauma accounted for 83% of all injuries. Young pediatric patients compared with older pediatric and adult patients had increased severity of injury indicated by decreased Glasgow Coma Scale score; increased incidence of hypotension, base deficit, and serum pH on admission; red blood cell transfusion amount; and increased injury severity scores on admission. Young pediatric patients compared with older pediatric and adult patients also had increased ICU lengths of stay (median 2 [interquartile range 0–5] vs median 0 [interquartile range 0–2] days) and in-hospital mortality rate (18% vs 4%), respectively. Multivariate logistic regression indicated that base deficit, injury severity score of ≥15, Glasgow Coma Scale score of ≤8, and age of ≤8 years were independently associated with mortality.

CONCLUSIONS. Young children who present to a combat support hospital have increased severity of injury compared with older children and adults. In a population with primarily penetrating injuries, after adjustment for severity of injury, young children may also have an independent increased risk for death compared with older children and adults. Providing forward-deployed medical staff with pediatric-specific equipment and training in the acute care of young children with severe traumatic injuries may improve outcomes in this population.
Health Risk Behaviors in Adolescents With Chronic Conditions
Authors: Surís Joan-Carles , Michaud Pierre-André , Akre Christina , Sawyer Susan M.
Published: October 2008

OBJECTIVE. The objective of this study was to compare the frequency of risk behaviors and to measure the extent of co-occurrence of these behaviors in chronically ill and healthy adolescents.

METHODS. Data were drawn from the 2002 Swiss Multicenter Adolescent Survey on Health database, a nationally representative survey of 7548 adolescents in postmandatory school aged 16 to 20 years. There were 760 subjects who reported a chronic illness and/or a disability. The comparison group consisted of 6493 subjects who answered negatively to both questions. We defined 8 risk behaviors: daily smoking, alcohol misuse, current cannabis use, current use of any other illegal drug, early sexual debut, eating disorder, violent acts, and antisocial acts. We analyzed each behavior and the sum of behaviors, controlling for age, gender, academic track, parents' education level, depression, and health status. Results are given as adjusted odds ratios using the comparison group as the reference category.

RESULTS. Youth with a chronic condition were more likely to smoke daily, to be current cannabis users, and to have performed violent or antisocial acts. Youth with a chronic condition were also more likely to report 3 or ≥4 risk behaviors.

CONCLUSIONS. These results indicate that having a chronic condition carries additional risks for engaging in health risk behaviors and emphasize the importance of health risk screening and preventive counseling for young people in general and among those suffering from chronic conditions in particular.
Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents
Authors: Wagner Carol L. , Greer Frank R. ,   and the Section on Breastfeeding and Committee on Nutrition
Published: October 2008

This Clinical Report was retired October 2012.

Rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continues to be reported in the United States. There are also concerns for vitamin D deficiency in older children and adolescents. Because there are limited natural dietary sources of vitamin D and adequate sunshine exposure for the cutaneous synthesis of vitamin D is not easily determined for a given individual and may increase the risk of skin cancer, the recommendations to ensure adequate vitamin D status have been revised to include all infants, including those who are exclusively breastfed and older children and adolescents. It is now recommended that all infants and children, including adolescents, have a minimum daily intake of 400 IU of vitamin D beginning soon after birth. The current recommendation replaces the previous recommendation of a minimum daily intake of 200 IU/day of vitamin D supplementation beginning in the first 2 months after birth and continuing through adolescence. These revised guidelines for vitamin D intake for healthy infants, children, and adolescents are based on evidence from new clinical trials and the historical precedence of safely giving 400 IU of vitamin D per day in the pediatric and adolescent population. New evidence supports a potential role for vitamin D in maintaining innate immunity and preventing diseases such as diabetes and cancer. The new data may eventually refine what constitutes vitamin D sufficiency or deficiency.
Adverse Effects of Inhaled Corticosteroids in Funded and Nonfunded Studies
Authors: Adinoff Allen
Published: October 2008

Nieto A, Mazon A, Pamies R, et al. Arch Intern Med. 2007;167(19):2047–2053

PURPOSE OF THE STUDY. Evidence regarding the safety profile of drugs may vary depending on study sponsorship. The authors aimed to evaluate differences between studies funded by the pharmaceutical manufacturer of the drug (PF) and those with no pharmaceutical funding (NoPF) regarding the finding and interpretation of adverse effects of inhaled corticosteroids.

METHODS. The authors assessed the safety reporting of inhaled corticosteroids in 275 PF and 229 NoPF studies identified by a Medline search using prespecified criteria.

RESULTS. Overall, the finding of statistically significant differences for adverse effects was significantly less frequent in PF (34.5%) than in NoPF (65.1%) studies (prevalence ratio [PR]: 0.53 [95% confidence interval (CI): 0.44–0.64]). This association became nonsignificant (PR: 0.94 [95% CI: 0.77–1.15]) after controlling for design features (such as dose or use of parallel groups) that tended to be associated with less-frequent findings of adverse effects and were more common in PF studies. Among studies that found a statistically significant increase in adverse effects associated with the study drug, the authors of PF articles concluded that the drug was “safe” more frequently than the authors of NoPF studies (PR: 3.68 [95% CI: 2.14–6.33]).

CONCLUSIONS. The type of funding may have determinant effects on the design of studies and on the interpretation of findings: funding by the industry is associated with design features less likely to lead to finding statistically significant adverse effects and with a more favorable clinical interpretation of such findings. Disclosure of conflicts of interest should be strengthened for a more balanced opinion on the safety of drugs

REVIEWER COMMENTS. Okay, so maybe this is not a real big shock to most of us. What was surprising to me was the extent that this bias exists with a variety of other drugs including hypertensive agents, pain medications, and cancer treatments. This seems to be related to the study design of the protocols, suggesting that the whole system is “rigged.” The investigator physicians have no clue how the studies are set up or how the data are manipulated. So where is the Food and Drug Administration in all of this?
Esophageal Subepithelial Fibrosis in Children With Eosinophilic Esophagitis
Authors: Geaney Casey
Published: October 2008

Chehade M, Sampson H, Morotti R, Magid M. J Pediatr Gastroenterol Nutr. 2007;45:319–328

PURPOSE OF THE STUDY. To determine the prevalence and specificity of esophageal fibrosis in children with eosinophilic esophagitis (EE) and to correlate its presence with clinical presentation and additional pathologic features.

STUDY POPULATION. This was a retrospective review of 1099 upper endoscopy specimens from pediatric patients presenting over a 6-year period with upper gastrointestinal complaints suspicious for possible EE. Patients with known infectious disease, parasitic disease, celiac disease, or inflammatory bowel disease were excluded. Fifty-one patients were included: 21 with EE, 7 with eosinophilic gastroenteritis, 6 with gastroesophageal reflux disease, and 17 controls.

METHODS. A normal pattern and extent of collagen and elastin fiber composition in the esophageal lamina propria was established in the control specimens. Extent of fibrosis was determined on trichrome-stained specimens. Fibrosis was defined as abnormally increased collagen deposition. Hematoxylin and eosin staining, and immunohistochemical staining for tryptase and major basic protein and were used to determine intraepithelial and lamina propria maximum eosinophil counts and extent of eosinophilic degranulation at 400 high-power field as well as mast cell presence and extent of degranulation. Basal thickness and lymphocyte and plasma cell infiltration were also determined.

RESULTS. Subepithelial fibrosis was present in 57% of the patients with EE, 1 patient with eosinophilic gastroenteritis, 0 patients with gastroesophageal reflux disease, and 1 control patient. Dysphagia was present in 42% of the patients with fibrosis. Dysphagia was not observed in the absence of fibrosis. Fibrosis was not influenced by increasing eosinophil or mast cell counts; however, fibrosis was significantly associated with eosinophilic degranulation in the epithelium.

CONCLUSIONS. Subepithelial fibrosis is both common in EE and specific for this disease in children. There is a strong association between dysphagia and fibrosis in children with EE. The extent of eosinophilic activation seems to be influenced by the degree of fibrosis.

REVIEWER COMMENTS. This article provides additional insight into the pathology of EE, an inflammatory disorder that is often associated with food allergy. Although a strong relationship was seen between fibrosis and dysphagia in this study, its impact on motility in this specific disease would be an interesting additional determination. Nevertheless, fibrosis preceded the dysphagia in this study, and it may serve as an early marker of more-severe disease. Fibrosis was associated with eosinophilic activation, which may also serve as a maker for more-severe disease. The presence of 1 or both may indicate a need for more aggressive treatment.
Childhood Overweight Increases Hospital Admission Rates for Asthma
Authors: Randolph Christopher
Published: October 2008

Carroll CL, Stoltz P, Raykov N, Smith SR, Zucker AR. Pediatrics. 2007;120(4):734–740

PURPOSE OF THE STUDY. To determine if childhood overweight increases the risk of hospitalization for asthma among children presenting to an emergency department with an asthma exacerbation.

STUDY POPULATION. Children who were >2 years old and presented to the emergency department of a Connecticut children's hospital with an asthma exacerbation in 2005 were included in the study.

METHODS. A retrospective chart review was completed. Children were classified as overweight (>95th weight-for-age percentile) or nonoverweight (≤95th weight-for-age percentile). Children with chronic medical conditions other than asthma were excluded.

RESULTS. There were 884 visits for 813 children. Overall, 238 (27%) were admitted to the hospital, and 33 (4%) were admitted to the ICU. Overweight children (202 [23%]) were significantly more likely to be older (8.5± 4.4 vs 7.3 ± 4.3 years) and to inhabit an impoverished area (37% vs 28%). Overall, hospital admission was associated with higher clinical asthma score but not with age, gender, or poverty status. Despite similar asthma scores and therapeutic management in the emergency department, hospital and ICU admission was significantly more likely for overweight than nonoverweight children (odds ratio: 1.76 [95% confidence interval: 1.23–2.51]; P = .002).

CONCLUSIONS. Overweight children with an acute episode of asthma seen in an emergency department are significantly more likely to be admitted than their nonoverweight counterparts. Overweight status clearly impacts asthma management and health in children.

REVIEWER COMMENTS. The limitations of this study include its retrospective nature and the failure to use BMI because of lack of height data. However, the weight-for-age percentiles used in this study are most commonly used in practice. When children younger than 5 years, in which asthma diagnosis is difficult, are excluded, the conclusion still holds with overweight children ≥5 years old being significantly more likely to be admitted than nonoverweight children (33% vs 24%; P = .03). Whether the results reflect comorbidity, differences in lung mechanics, differences in response to therapy, more severe asthma, or socioeconomic or behavioral factors remains to be determined.
STAT3 Mutations in the Hyper-IgE Syndrome
Authors: Bonilla Francisco A.
Published: October 2008

Holland SM, DeLeo FR, Elloumi HZ, et al. N Engl J Med. 2007;357(16):1608–1619

PURPOSE OF THE STUDY. To identify the genetic defect underlying the hyper–immunoglobulin E (IgE) (Job) syndrome.

STUDY POPULATION. Patients with hyper-IgE syndrome were ranked by a clinical scoring system. Fifty patients over the age of 16 years who had the highest scores (most features of the disease) were selected. Forty-eight family members also underwent genetic analysis.

METHODS. The authors used a combination of microarray screening of gene expression and analysis of cytokine production in vitro from lymphocytes subjected to various stimuli.

RESULTS. Lymphocytes from patients were found to have diminished response to the cytokine interleukin 6. The authors systematically analyzed the intracellular signaling molecules involved in the response to interleukin 6 and found that patients carried a mutation in 1 of the 2 copies of the gene encoding signal transducer and activator of transcription 3 (STAT3). They confirmed the biological importance of the mutations by showing that the STAT3 protein did not function normally within the cell.

CONCLUSIONS. STAT3 mutations are the genetic basis of the hyper-IgE syndrome.

REVIEWER COMMENTS. The first clinical description of hyper-IgE syndrome as a distinct entity was published in 1966. It was given the eponym “Job syndrome” as a biblical allusion because of the many severe skin abscesses that afflict patients with the condition. This report is the culmination of >40 years of investigation by many groups around the world to find the molecular basis of this disease. A similar report was published by another group around the same time (Minegishi Y, Saito M, Tsuchiya S, et al. Nature. 2007;448[7157]:1058–1062). We are reminded again of the power of modern molecular biological methods and the tremendous insights we gain when such diseases are finally understood at their “source.”
Population Prevalence of Diagnosed Primary Immunodeficiency Diseases in the United States
Authors: Bonilla Francisco A.
Published: October 2008

Boyle JM, Buckley RH. J Clin Immunol. 2007;27(5):497–502

PURPOSE OF THE STUDY. To measure the prevalence of primary immunodeficiency diseases (PIDs) in the United States.

STUDY POPULATION. A random sample of 10 005 American households (26 657 people) was included in the study.

METHODS. Households were selected by random-digit dialing stratified according to time zone. Calls were placed by trained interviewers with computer assistance. Eighty percent of the households contacted completed the interview. Respondents were asked, “Has anyone in your household ever been diagnosed with a primary immunodeficiency disease such as common variable immunodeficiency, IgA [immunoglobulin A] deficiency, IgG subclass deficiency, or any other immunodeficiency? (This is not acquired immunodeficiency—AIDS).” If they replied “yes,” they were further questioned with details of the diagnosis and limited demographic information about the affected individual(s).

RESULTS. Twenty-three individuals in 18 households were identified as having a specific PID (including common variable immunodeficiency, IgA deficiency, IgG subclass deficiency, X-linked agammaglobulinemia, severe combined immunodeficiency, and chronic granulomatous disease). The calculated prevalence of diagnosed immunodeficiency was 1 in 2000 children, 1 in 1200 people of all ages, and 1 in 600 households. The 95% confidence limits for the estimate for all individuals were between 1 in 824 and 1 in 1956. Several of the identified individuals with primary immunodeficiency were not receiving therapy that is standard of care for their diagnoses (γ-globulin replacement).

CONCLUSIONS. Quoting the authors, “The current study suggests that these conditions are sufficiently common that primary care physicians are likely to see patients with underlying primary immunodeficiency disorders in their practice and should test for these disorders in patients with recurring, unusual or serious infections. In the absence of routine screening, physician awareness of the relative frequency of these disorders is critical to early diagnosis and treatment.”

REVIEWER COMMENTS. This is an extremely important message for all primary care physicians. These patients are in your practices now. The authors also pointed out that several studies have shown that many cases of PID are diagnosed late or are “mild” enough that they are never diagnosed and that patients suffer excess morbidity and mortality as a result. Some severe cases may be missed because children die before they are diagnosed. Thus, the true prevalence of PID is likely to be higher than what was found in this study. I found it discouraging that two thirds of the people who should have been receiving γ globulin were not.
Pulse Oximetry Coupled With Spirometry in the Emergency Department Helps Differentiate an Asthma Exacerbation From Possible Vocal Cord Dysfunction
Authors: Williams Larry W.
Published: October 2008

Nolan PK, Chrysler M, Phillips G, Goodman D, Rusakow LS. Pediatr Pulmonol. 2007;42(7):605–609

PURPOSE OF THE STUDY. These investigators sought to determine if they could find evidence for vocal cord dysfunction (VCD) in asthmatic adolescents whose condition failed to respond adequately to treatment in the emergency department (ED) for a presumptive asthma exacerbation.

STUDY POPULATION. Subjects with wheezing presenting to the ED of an urban children's hospital were recruited. Inclusion criteria were age 12 to 21 years, failure to respond to treatment for wheeze sufficiently to allow discharge, and pulse oximetry reading of ≥97%. Exclusion criteria were having other cardiac or pulmonary disease, inability to perform spirometry, or need for endotracheal intubation.

METHODS. Spirometry with standard techniques was performed by using a computer-linked pneumotachygraph and appropriate software to capture both expiratory and inspiratory flow volume curves. Spirometric results were classified as small airway obstruction, variable extrathoracic airway obstruction (consistent with VCD), a combination of the 2 previous findings, or normal airflow.

RESULTS. Twenty ED encounters with 17 subjects were studied. Only 5 (25%) of the encounters included spirometric evidence of small airway obstruction, but 12 of 20 had evidence for VCD (ie, variable extrathoracic airway obstruction on the inspiratory loop). These 12 included 3 that also had evidence for small airway obstruction. There were 6 encounters with no abnormality on spirometry.

CONCLUSIONS. Spirometry may identify presumptive refractory asthma exacerbations that, instead, are episodes of VCD.

REVIEWER COMMENTS. Several years ago we treated an 8-year-old boy who had been admitted to the hospital for status asthmaticus 4 times in 1 month but never had an oxygen requirement. A videotape of the boy when he was symptomatic (provided by the parents) showed obvious stridor, not wheezing. Similarly, in this study the cardinal observation was refractory “wheeze” without arterial desaturation. Computerized spirometry is not universally available in the ED, and in addition, not all such units have software capable of displaying the inspiratory limb of the flow-volume loop. However, in busy ED environments with large asthmatic populations, availability of this measurement should greatly aid the classification of wheezing events. Pediatricians need to be more aware that VCD may present symptoms that mimic asthma.
Specific Oral Tolerance Induction in Food Allergy in Children: Efficacy and Clinical Patterns of Reaction
Authors: Keet Corinne A. , Wood Robert A.
Published: October 2008

Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Allergy. 2007;62(11):1261–1269

PURPOSE OF THE STUDY. To evaluate the efficacy of oral tolerance induction as a treatment for cow's milk and egg allergies.

STUDY POPULATION. Forty-seven children aged 0.6 to 12.9 years with positive double-blind, placebo-controlled food challenges to milk or hen's egg were included in this German study. Children with severe eczema were excluded.

METHODS. Subjects were randomly assigned to specific oral tolerance induction or continued avoidance. Treatment involved home escalation over at least 67 days from a dose of 1 drop of cow's milk to 250 mL or from 5 mg of lyophilized hen egg powder to 3500 mg. Subjects continued home dosing for a median of 21 months total, after which time they underwent a secondary period of avoidance for 2 months followed by a food challenge.

RESULTS. At follow-up challenge, 9 (36%) of 25 children in the specific-oral-tolerance-induction group showed permanent tolerance, 3 (12%) of 25 were tolerant with regular intake, 4 (16%) of 25 were partial responders, and 9 (36%) of 25 did not complete the treatment because of adverse effects. In the control group, 7 (35%) of 20 children were tolerant at the study end. Allergen-specific IgE levels decreased in children who developed tolerance both in the control (P < .05) and treatment (P < .001) groups.

CONCLUSIONS. Specific oral tolerance induction may be a valid treatment option for patients with persistent food allergy. However, only a minority of patients had evidence of persistent tolerance once treatment was stopped, with some unable to tolerate the therapy and others seeming to be only transiently desensitized.

REVIEWER COMMENTS. Allergen-specific immunotherapy with injected extracts has proven too dangerous to be a viable treatment method for food allergy. Sublingual or oral immunotherapy, as described here, is a promising alternative to strict avoidance. Although one third of the patients in this study had to withdraw because of adverse effects, the remaining patients were able to incorporate the allergen into their diet at some level. This treatment modality is highly promising, but it is still experimental, carries the potential for significant risk, and requires close monitoring by experienced physicians. Several studies of oral and sublingual immunotherapy for food allergy are ongoing in the United States and Europe.
Functional Patterns of HIV-1-Specific CD4 T-Cell Responses in Children Are Influenced by the Extent of Virus Suppression and Exposure
Authors: Church Joseph A.
Published: October 2008

Correa R, Harari A, Vallelian F, et al. AIDS. 2007;21(1):23–30

PURPOSE OF THE STUDY. HIV-specific CD4+ T cells seem to play a critical role in antiretroviral immunity and particularly in maintaining cytotoxic T-cell responses. The objective of this study was to evaluate the function of HIV-specific T cells in antiviral treated, HIV-infected children.

STUDY POPULATION. The researchers evaluated 23 HIV-infected children who were treated with antiretroviral therapy for a mean of 7 years.

METHODS. Flow-cytometric analysis was used to measure the ability of HIV-specific T cells to secrete interleukin 2 (IL-2) and interferon γ (IFN-γ) after stimulation of patient cells with p55 gag protein.

RESULTS. Three patterns of intracellular cytokine generation were identified: in 10 subjects, antigen-specific cytokine production was characterized by IL-2 production, 8 subjects’ CD4+ T cells expressed IL-2 and IFN-γ, and 5 subjects’ T cells expressed IFN-γ alone. These 3 groups were then analyzed for factors that might explain the different patterns. The patterns correlated with viral load at the time of functional analysis and over the previous 2 years. The group with dominant IFN-γ responses had high viremia levels, a pattern similar to that observed in patients with uncontrolled viral replication. Patients with combined IL-2 and IFN-γ production had relatively lower viral loads but had experienced viral “blips” over the 2 years before analysis. This pattern was similar to adults who were long-term nonprogressors or those whose conditions continued to progress despite antiretroviral therapy. The subjects with a dominant IL-2 response had very low levels of viremia and had not experienced viral “blips” over the previous 2 years. This pattern was similar to that generally observed in individuals who have cleared the infecting agent. It is important to note that this pattern has not been observed in HIV-infected adults.

CONCLUSIONS. Children with HIV have a higher frequency of HIV-specific CD4+ T cells compared with adults, and their recovery of an IL-2–secreting T-cell pattern indicates a greater capacity for immune restoration in children than adults.

REVIEWER COMMENTS. This elegant study provides a biological rationale for the clinical observation that young children started on antiretroviral therapy have the capacity for remarkable reconstitution of immune functions relative to those reported in adults and older children who have been infected for prolonged periods before antiretroviral therapy. Perhaps it is unfair to compare these results with findings in adults that included patients who were infected for many years before their initiation of therapy. A more appropriate comparative adult group would be those treated within 6 months of their diagnosis. Most importantly, this study demonstrates that children are “different” and that treatment early in infection allows excellent immune reconstitution if viral replication is completely controlled.
Proteinuria in Children Infected With the Human Immunodeficiency Virus
Authors: Church Joseph A.
Published: October 2008

Chaparro AI, Mitchell CD, Abitbol CL, et al. J Pediatr. 2008;152(6):844–849

PURPOSE OF THE STUDY. Proteinuria is a common feature of HIV infection and a potential complication of therapy in adult patients. This study was performed to determine the prevalence of proteinuria in a group of children infected with HIV and to assess this process over time and the impact of antiretroviral therapy on it.

STUDY POPULATION. HIV-infected children (N = 286) were studied from 1998 through 2006.

METHODS. Proteinuria was determined by random urine protein/creatinine ratios, with “normal” defined as <0.2 and “nephrotic” defined as >1.0.

RESULTS. A total of 94 (33%) of the children had proteinuria at baseline. Of these, 32 had urine protein range ratios of ≥1.0. Clinically, the mortality rate was higher in those patients with proteinuria. It is important to note that 55 of the 94 patients with baseline proteinuria showed a good response to antiretroviral therapy, as indicated by a decrease in HIV viral load and a substantial reduction in the number of subjects who had proteinuria.

CONCLUSIONS. Control of HIV viremia with antiretroviral therapy reduces progression of HIV-associated proteinuria and improves the survival rate of infected children.

REVIEWER COMMENTS. Proteinuria is a common feature of HIV infection in children. Two features of this patient population may affect the generalizability of the study findings: 85% of the patients were African American or African Caribbean, and the number of individuals with complicating hepatitis B or C was not indicated. Renal disease is more prevalent in HIV-infected black people than white people, particularly with respect to HIV-associated nephropathy. Chronic viral hepatitis may also cause secondary renal disease, likely secondary to an immunocomplex-associated inflammatory process. Regardless of these caveats, the authors’ conclusion is very much warranted: “surveillance of quantitative proteinuria with imaging and chemical indicators of renal dysfunction is very much warranted” for children with HIV infection.
Drug Allergy Claims in Children: From Self-reporting to Confirmed Diagnosis
Authors: Huang Faith , Nowak-Wegrzyn Anna
Published: October 2008

Rebelo Gomes E, Fonseca J, Araujo L, Demoly P. Clin Exp Allergy. 2008;38(1):191–198

PURPOSE OF THE STUDY. To assess the prevalence of self-reported adverse drug reactions and drug allergy in a pediatric population and confirm the diagnosis in children with suspected drug allergy.

STUDY POPULATION. Patients (n = 1426) responded to an initial cross-sectional survey. A total of 60 of 67 patients with reported drug allergy were evaluated at an allergy clinic.

METHODS. The first phase included a cross-sectional survey that assessed the life occurrence of adverse drug reactions and self-reported drug allergy in the outpatient clinic of a pediatric hospital. The second phase involved a diagnostic workup in children with parent-reported drug allergy, including detailed clinical history and in vitro and in vivo investigations. Specific immunoglobulin E (IgE) level determination for β-lactams, prick and intradermal skin testing for β-lactams, local anesthetics and sulfonamides, and patch tests (if a delayed reaction was reported) were performed. If all other investigations were inconclusive and a provocation test was not contraindicated, this test was performed.

RESULTS. The prevalence of self-reported adverse drug reactions and drug allergy were 10.2% and 6.0%, respectively. The frequency of a medical diagnosis of drug allergy was 3.9%. The majority of the suspected allergic reactions were nonimmediate cutaneous events attributed to β-lactam antibiotics in younger children. Of 60 patients evaluated in the allergy clinic, 39 patients had a plausible clinical history, and additional investigation including a skin test, IgE-level measurement, and possible provocation tests were conducted. Drug allergy was diagnosed in 3 children on the basis of positive responses in skin (n = 1) and oral provocation (n = 2) tests.

CONCLUSIONS. Although adverse drug reactions and suspected drug allergy are frequently reported in children, after a complete evaluation, only a few of these reactions can be attributed to immediate and nonimmediate drug allergy. Overall, 94% of the patients could tolerate the initially suspected drug.

REVIEWER COMMENTS. This study underscores a serious problem: patients who experience or perceive a drug reaction are often classified as being truly allergic when this may not be the case. Such overdiagnosis and misdiagnosis may result in suboptimal medication choices. These results show that only 6% of the patients with initially suspected drug allergy were truly allergic. This study demonstrates the importance of a complete and detailed history, with consideration of additional testing including skin-prick tests, specific IgE-level determination, and provocation tests. It should be noted that for nonimmediate drug allergy, an oral provocation test may require prolonged treatment to observe for symptoms. Such provocation tests would not be undertaken for severe previous reactions (eg, toxic epidermal necrolysis).
Pollen Grains Induce a Rapid and Biphasic Eczematous Immune Response in Atopic Eczema Patients
Authors: Maloney Jennifer M.
Published: October 2008

Eyerich K, Huss-Marp J, Darsow U, et al. Int Arch Allergy Immunol. 2008;145(3):213–223

PURPOSE OF THE STUDY. To investigate the relationship between eczematous reactions in subjects with immunoglobulin E–mediated allergy to pollen grains.

STUDY POPULATION. Two populations were evaluated: one population included subjects with atopic eczema who were sensitized to grass or birch pollen and who had a positive atopy patch test, and the second population included subjects without atopic eczema or atopy but who had a positive atopy patch test to nickel. In addition, as control populations, healthy volunteers and atopic subjects with eczema and sensitization to grass or birch but without a positive atopy patch test were included.

METHODS. Atopy patch tests with native pollen grains were performed to delineate the effect of native pollen grains on human skin of healthy and atopic individuals. A nickel patch test served as an established model of contact dermatitis. Skin-site samples were taken for biopsy 6 to 96 hours after allergen application and investigated immunohistochemically.

RESULTS. Histology of positive patch tests showed an influx of mononuclear cells (predominantly CD4+, CD25+, and CD45RO+). This influx was detected earlier in the pollen patch-test reactions compared with the immune response to nickel. A biphasic cytokine response could be detected in skin samples from the pollen patch test: interleukin 5 dominated in the early phase, and interferon γ dominated in the late phase. The nickel patch test was continuously dominated by interferon γ.

CONCLUSIONS. Pollen grains induce eczematous reactions in susceptible individuals. This reaction seems clinically and immunohistochemically similar to the contact hypersensitivity reaction to nickel but follows a faster kinetic and a biphasic course: T-helper 2 and immunoglobulin E in the early (24-hour) phase and T-helper 1 predominance in the late (96-hour) phase.

REVIEWER COMMENTS. This article highlights the importance of understanding that type 1 allergy-inducing antigens such as pollens can exacerbate atopic eczema in susceptible individuals. Physicians should remember to discuss this with their atopic patients before the start of pollen season.
Impact of Interview Mode on Accuracy of Child and Parent Report of Adherence With Asthma Controller Medication
Authors: Kaplan Michael S.
Published: October 2008

Bender BG, Bartlett SJ, Rand CS, Turner C, Wamboldt FS, Zhang L. Pediatrics. 2007;120(3). Available at: www.pediatrics.org/cgi/content/full/120/3/e471

PURPOSE OF THE STUDY. To examine the effect of different modes of reporting adherence on the accuracy of self-administration of inhaled corticosteroids in asthmatic children under conditions mimicking a clinical trial.

STUDY POPULATION. A total of 104 asthmatic children, 8 to 18 years old, who were being treated for asthma with regular use of inhaled corticosteroids were studied. One parent was required to participate with each child.

METHODS. Each parent/child pair was assigned to 1 of 3 self-reporting modes: audio computer-assisted self-interview (ACASI), face-to-face interview with a member of the study staff, or self-administered paper-and-pencil questionnaire. The same mode was administered at each study visit for any given parent/child pair: baseline and at 1, 2, 3, and 4 months. Corticosteroid metered-dose inhalers were fitted with an electronic chronometer that captured the time and date of metered-dose inhaler dispensing, freshly initialized at baseline and at each study visit. Adherence was determined by dividing the number of puffs recorded by the number of puffs prescribed. Self-assessment of adherence was determined similarly for the 3 modes. The recall time frames were 1 week and 1 day. The primary outcome was self-reporting discrepancy (percent adherence recorded minus percent self-adherence self-reported). A positive discrepancy score represented underreporting, a negative score represented overreporting, and zero represented exact reporting. Adequate accuracy was considered when the discrepancy score was ±25%.

RESULTS. Children and parents overrepresented adherence for both the 1-week and 1-day monitoring periods. Adherence discrepancy was the greatest in the ACASI mode (adequate accuracy for children and parents, respectively, was 32% and 27% for 1-day recall and 47% and 38% for 1-week recall). The best accuracy was for the 1-day recall in children interviewed face-to-face (50% adequate). Larger discrepancies were observed in both children and parent with the other modes.

CONCLUSIONS. Self-reporting of adherence was insufficient even under the best of circumstances regardless of the mode of self-reporting used in this study.

REVIEWER COMMENTS. The recently updated National Asthma Education and Prevention Program report underscored the need to address adherence when considering a step up in asthma medication. Inaccurate accounting for adherence may taint clinical trials that examine treatment outcomes and on which guidelines are based. Several studies have used electronic chronologs to monitor adherence. Even then, dose dumping (dispensing several puffs in the air over a short period to boost the number of dispensings recorded) has been reported. You can lead a patient to an inhaler, but you can’t make them inhale.
The Neglected Role of Antibody in Protection Against Bacteremia Caused by Nontyphoidal Strains of Salmonella in African Children
Authors: Shreffler Wayne G.
Published: October 2008

MacLennan CA, Gondwe EN, Msefula CL, et al. J Clin Invest. 2008;118(4):1553–1562

PURPOSE OF THE STUDY. To investigate whether specific antibody protects against nontyphoidal Salmonella (NTS) bacteremia.

POPULATION STUDIED AND METHODS. Admissions for NTS bacteremia during 1 year were reviewed (N = 352). Sera from 65 healthy Malawian children (median age, 24 months: range, 3–107 months) was used for in vitro NTS-killing assays. Purified immunoglobulin G (IgG) from patient sera was used to delineate the role of antibody versus complement. Immunoglobulin and complement deposition on bacteria was also assessed by flow cytometry. Complement dependency was tested by heat inactivation and by using C9-deficient serum.

RESULTS. Overall, 82% of the children with NTS bacteremia were <36 months old, but there was a nonuniform distribution with fewer-than-expected cases in children <4 months old (actual: 9.7% vs 16.7%), suggesting a role for passive humoral immunity. From healthy donors, 9 of 25 children <16 months of age had serum with normal in vitro killing, whereas 40 of 40 children >16 months of age did so. NTS killing in vitro was complement and membrane attack complex dependent. Effective killing corresponded to a specific IgG or IgM Salmonella titer of 1.5 U and was associated with the deposition of complement (C3 and C9) measured by flow cytometry. Resistance to killing by alternative complement activation was mediated by long-chain lipopolysaccharide and the rck gene product.

CONCLUSIONS. Salmonella-specific antibody that overcomes the complement resistance of NTS develops by 2 years of life in Malawian children and is mediated by specific IgG or IgM antibody.

REVIEWER COMMENTS. NTS is the most common cause of bacteremia in Malawi and much of tropical Africa and is associated with high rates of mortality even with appropriate culture facilities and access to antibiotics. The finding that specific antibody is protective against this invasive, facultative intracellular pathogen supports the importance of vaccine development for this pathogen.
Children's Respiratory Health and Mold Levels in New Orleans After Katrina: A Preliminary Look
Authors: Petersen Maureen M. , Mikita Cecilia P.
Published: October 2008

Rabito FA, Iqbal S, Kiernan MP, Holt E, Chew GL. J Allergy Clin Immunol. 2008;121(3):622–625

PURPOSE OF THE STUDY. To study indoor air mold levels, lung function, and respiratory symptoms in a sample of children returning to live in New Orleans, Louisiana, immediately after Hurricane Katrina.

STUDY POPULATION. Participants were children aged 7 to 14 years currently residing in greater New Orleans with no plans to move. All study participants were recruited from a private primary school in the Garden District of New Orleans.

METHODS. Parents of all study participants completed a respiratory health symptom questionnaire during February/March and April/May 2006. During these defined study points, the children performed spirometry, and indoor and outdoor air sampling was performed. All data were statistically analyzed to determine if indoor mold levels correlated to the children's respiratory health.

RESULTS. Average indoor and outdoor mold concentrations decreased during the study, although only the reduction in outdoor mold levels reached statistical significance. Pulmonary function of all study participants was >80% of predicted at both study points. Participants were stratified according to asthma history and flooding status, but no lung-function decrements were observed with stratification. A trend was seen in which respiratory symptoms increased after the hurricane and seemed to improve during the study. This difference, however, was only statistically significant for lower respiratory tract symptoms.

CONCLUSIONS. Indoor mold levels were low and pulmonary function in a sample of children living in New Orleans was normal >6 months after Hurricane Katrina.

REVIEWER COMMENTS. The Children's Respiratory Health Study is the first published study to evaluate pediatric respiratory health and indoor mold in the post–Hurricane Katrina environment. Although a small sample size was evaluated, this study provides practitioners with objective, reassuring findings. This study, however, included children who were exposed to limited flood damage. This possible selection bias should not allow us to ignore respiratory symptoms in the pediatric population returning to the more damaged neighborhoods. We look forward to further research studying this at-risk pediatric population.