Damir Dabranin

Tomatoes, Cucumbers, and Fish Protect Against Childhood Wheeze and Atopy CME/CE Kliknite

News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD

Complete author affiliations and disclosures, and other CME information, are available at the end of this activity.
Release Date: September 18, 2007; Valid for credit through September 18, 2008
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September 18, 2007 — A diet rich in fish and fruity vegetables, such as tomatoes and cucumbers, has a protective effect against childhood wheeze and atopy, according to the results of a cross-sectional analysis published in the September issue of Pediatric Allergy Immunology.

"Epidemiological studies have shown inverse associations of asthma symptoms with fish, vegetable, and fruit intake," write Leda Chatzi, MD, PhD, from the University of Crete in Heraklion, Greece, and colleagues. "We evaluated the association between several dietary factors with wheeze and atopy among children in Menorca, a Spanish Mediterranean island."

At age 6.5 years, 460 children underwent skin prick tests with 6 common aeroallergens, and parents completed a questionnaire on the child's respiratory and allergic symptoms and a 96-item food frequency questionnaire.

These children had a relatively high average daily intake of fruits (177 g) and fish (54 g) and a moderate intake of vegetables (59 g). Intake of more than 40 g/day of fruity vegetables (tomatoes, eggplants, cucumber, green beans, zucchini) was associated with beneficial effects on current wheeze (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.15 - 0.95; P < .05) and atopic wheeze. When intake of fruity vegetables was increased, there was a significant decreasing trend for wheeze (OR, 0.19; 95% CI, 0.04 - 0.95; P for trend = .04).

Wheeze and atopy prevalence were not significantly associated with dietary intake of other fruits or vegetables. Fish intake of 60 g/day or greater was inversely associated with atopy (OR, 0.43; 95% CI, 0.21 - 0.90; P < .05). Adjustment for energy intake and maternal diet during pregnancy did not abolish the significance of these associations.

Study limitations include cross-sectional design precluding assessment of causal relationships, possible confounding effect, and reliance on parental reports of children's diet and symptoms, which could result in information bias.

"Our results support a potential protective effect of fruity vegetables and fish intake during childhood on wheeze and atopy respectively," the authors write. "The biological mechanisms underlying the observed associations need to be further investigated."

The Instituto de Salud Carlos III red de Grupos Infancia y Media Ambiente, the Fundacio La Caixa, the Instituto de Salud Carlos III, red de Centros de Investigacion en Epidemiologia y Salud Publica, and the EU supported this study.

Pediatr Allergy Immunol. 2007;18:480-485.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

  1. Report the association between dietary intake and wheezing in children.
  2. Report the association between dietary intake and atopy in children.
Clinical Context

Dietary intake appears to affect the development of atopy and asthma symptoms, but the results are inconsistent. Intake of fruits and vegetables has been noted to protect against asthma-related symptoms in children, according to Chatzi and colleagues in the August 2007 issue of Thorax. According to Farchi and colleagues in the November 2003 issue of the European Respiratory Journal, fish intake was not beneficial in preventing asthma-related symptoms.

But in the April 2007 issue of Clinical and Experimental Allergy, Romieu and colleagues reported that maternal fish intake during pregnancy decreased the risk for atopy and atopic wheeze (wheezing plus atopy) in the offspring at 6.5 years of age. This cross-sectional study evaluates the association between dietary intake and respiratory and allergic symptoms and skin prick test results in the children of the mothers who participated in the previous study by Romieu and colleagues of maternal fish intake.

Study Highlights
  • 507 women were enrolled in previous study during a 12-month period.
  • Of 482 enrolled children, 468 had data at 6.5 years of age.
  • Exclusion criteria included total energy intake less than 800 or more than 3000 kcal/day.
  • Parental traits included the following: 65% of mothers never smoked, 56% of fathers and 50% of mothers had primary school education, 93% had no maternal asthma, and 64% had no maternal atopy.
  • Traits of children included the following: 50.4% male sex, 83% breast-feeding, 68% normal body mass index, 18% overweight, 14% obese, and 60% with 1 sibling.
  • Follow-up assessment at age 6.5 years included report of medical events in prior year, 96-item food frequency questionnaire, growth measurements, and skin prick testing.
  • 412 (89.6%) children had skin prick testing at 6.5 years of age with Dermatophagoides pteronyssinus, grass pollen, olea europea, mixed graminae, parietaria, and cat epithelium.
  • Positive skin prick test result was defined by wheal diameter at least 2 mm more than response to control.
  • The prevalence of current wheeze, defined by at least 1 episode of "whistling or wheezing from the chest, but not noisy breathing from the nose" in prior year, was 8.7%.
  • The prevalence of atopy, diagnosed by at least 1 positive skin prick test result, was 5.8%.
  • The prevalence of atopic wheeze, defined by current wheeze and atopy, was 17.0%.
  • The prevalence was 8.7% for current wheeze, 5.8% for atopic wheeze, and 17.0% for atopy.
  • Food categories included dairy products; meat, poultry, and fish; vegetables and legumes; fruits and nuts; breads and cereals; sweets; oils and fats; and beverages.
  • Parents reported frequency of intake for each food item for prior year, ranging from "less than 1 per month" to "6 or more per day."
  • Estimated daily intake in grams was based on standard portion sizes.
  • Vegetables were divided into subgroups, excluding potatoes, legumes, and vegetable juices:
    • Leafy: lettuce, green salad, and spinach.
    • Fruity: tomatoes, green beans, eggplant, zucchini, and cucumber.
    • Root: carrots and beetroot.
    • Cabbages: cabbage, cauliflower, and broccoli.
  • Fish intake greater than 60.5 g/day vs up to 38.7 g/day was inversely associated with atopy (P < .05).
  • Fruity vegetable intake greater than 40 g/day vs up to 17.1 g/day was inversely associated with atopic wheeze (P < .05).
  • There were no significant associations between atopy or wheezing and other food groups: vegetables or nonfruit vegetable subgroups, fruits and fruit subgroups, dairy products, cereals, legumes, meat and poultry, sweets and sugar, and lipids.
  • Multivariate logistic regression analysis adjusted for possible confounders, including sex, parental asthma or atopy, maternal smoking, body mass index at age 6.5 years, parental education and social class, breast-feeding, fish intake during pregnancy, and number of siblings at age 6.5 years:
    • Fruity vegetable intake greater than 40 g/day was associated with less risk for current wheeze (OR, 0.38; P < .05).
    • Increasing intake of fruity vegetables was associated with decreasing risk for atopic wheeze (OR, 0.19; P = .04).
    • Fish intake greater than 60.5 g/day was negatively associated with atopy (OR, 0.43; P < .05).
Pearls for Practice
  • Daily fruity vegetable intake of more than 40 g appears to be associated with less wheeze alone and less wheeze with atopy in children.
  • Daily fish intake of at least 60.5 g appears to reduce the risk for atopy in childhood.
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Target Audience

This article is intended for primary care clinicians, pulmonologists, allergists, and other specialists who care for children at risk for asthma and allergy.


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Increased Risk of Childhood Asthma From Antibiotic Use in Early Life Kliknite

Anita L. Kozyrskyj; PhD, Pierre Ernst, MD; Allan B. Becker, MD
CHEST.  2007;131(6):1753-1759.  ©2007 American College of Chest Physicians
Posted 07/20/2007

Abstract and Introduction

Background: To address the major methodological issues of reverse causation and selection bias in epidemiologic studies of antibiotic use in early life and the development of asthma, we undertook a cohort study of this association in a complete population of children.
Methods: Using the health-care and prescription databases of Manitoba, Canada, this longitudinal study assessed the association between antibiotic prescription use during the first year of life and asthma at age 7 years in a 1995 birth cohort of 13,116 children.
Results: Independent of well-known asthma risk factors, asthma was significantly more likely to develop in children who had received antibiotics in the first year of life at age 7 years. The association with asthma was observed for antibiotic use in non-respiratory tract infections (adjusted odds ratio [OR], 1.86; 95% confidence interval [CI], 1.02 to 3.37). The risk of asthma was highest in children receiving more than four courses of antibiotics (adjusted OR, 1.46; 95% CI, 1.14 to 1.88), especially among rural children, and in the absence of maternal asthma or a dog in the birth year. Broad-spectrum (BS) cephalosporin use was more common in these subpopulations of children.
Conclusions: Antibiotic use in early life was associated with the development of childhood asthma, a risk that may be reduced by avoiding the use of BS cephalosporins.


Asthma is one of the most common chronic diseases worldwide, significantly impacts quality of life, and represents a significant cost to the health-care system.[1-3] The increasing prevalence of asthma in the industrialized world over the last quarter century has produced several theories on its origins.[4] In particular, the "hygiene hypothesis" postulates that growing up in a more hygienic environment with less microbial exposure may promote the fetal immune response, which is skewed in the atopic T-helper (Th) type 2 direction, whereas microbial pressure would drive the immune system toward a balanced Th-1 and Th-2 immunity.[5,6] Studies[7] of farmer children have suggested that exposure early in life to endotoxin from Gram-negative bacteria may be the key element of less hygienic environments, which results in a lower prevalence of allergy and asthma. However, many researchers have argued[8] that the regulation of the immune response is not likely to be dependent on external microbial exposure and have proposed the "microflora hypothesis" of allergic disease. This theory posits that the maturation of the mucosal immune system during infancy, namely, the development of immunologic tolerance via regulatory T cells, requires the presence of commensal microbial flora in the GI tract.[9] Evidence for this thesis comes from epidemiologic studies[10-12] that link variations in GI microflora and probiotic administration with less allergy and asthma, and from murine models[13-15] that document that antibiotic administration causes altered intestinal flora, impaired barrier function, diminished Th-1 immune responses, and allergic airway disease.
To date, the findings from epidemiologic studies have supported[16-22] and refuted[23-25] an association between antibiotic use in early life and the development of asthma. Since oral antibiotics are frequently prescribed for upper and lower respiratory tract infections in children,[26,27] an understanding of the relation between antibiotic use and asthma is critical to clinicians and health-care policymakers worldwide. Previous attempts to assess whether the relationship between antibiotic use in early life and asthma is causal have been hampered by cross-sectional or retrospective study design, in which it is difficult to discern whether the association is subsequent to antibiotic use for wheeze-related respiratory illnesses that precede asthma. A recent metaanalysis[28] of antibiotic use in the first year of life has reported a twofold increased risk of childhood asthma following antibiotic use, but no association among studies conducted prospectively. Further, some studies have been limited to high-risk cohorts[23,24] or to urban populations.[25] We examined the association between oral antibiotic use in the first year of life and asthma at age 7 years in a large cohort of children who were followed up from birth and were living in urban and rural environments with universal access to health-care insurance. As a secondary objective, we tested this association in subgroups of antibiotics and subgroups of children. Preliminary findings from this research have been published in an abstract.[29]

Materials and Methods

This was a longitudinal study (known as the Study of Asthma, Genes and the Environment) of a cohort of 13,980 children born in Manitoba in 1995 and continuously registered with the Manitoba Health Services Insurance Plan (MHSIP) until 2003. The likelihood of asthma at age 7 years according to antibiotic prescription use during the first year of life was determined. Data sources were the complete health-care administrative records for the cohort, including all physician visits, hospitalizations, and prescription drugs collected by MHSIP in the provision of universal health insurance to Manitoba residents. MHSIP databases are reliable and valid data sources.[30,31] Database record linkages were achieved through anonymized personal identifiers. A family registration number permitted linkage of maternal and child records. This study was approved by the Health Research Ethics Board at the University of Manitoba and the Health Information Privacy Committee.
Current asthma at age 7 years was defined as at least two physician visits for asthma, one asthma hospitalization, or two prescriptions for any asthma drug (eg, ß-agonists, inhaled corticosteroids, cromones, or leukotriene receptor antagonists) in the year following the seventh birthday. This definition was chosen from a validation study[32] in a subset of 539 cohort children who were recruited for clinical assessment by an allergist, on the basis of a high positive predictive value (94%; 95% confidence interval [CI], 82 to 99%) and high specificity (92%; 95% CI, 78 to 98%).
Antibiotic use during the first year of life was categorized by the number of oral antibiotic prescriptions (zero, one to two, three to four, and five or more courses, as classified in other publications[25] testing the association between antibiotic use and asthma development). Penicillin, cloxacillin, cephalexin, cefadroxil, and erythromycin were defined as narrow-spectrum (NS) antibiotics. The remaining antibiotics fell into the category of broad-spectrum (BS) antibiotics. Physician visits for childhood infections were classified by the number of lower respiratory tract infections (eg, bronchitis, bronchiolitis, and pneumonia), upper respiratory tract infections (eg, otitis media, pharyngitis, and sinusitis), and non-respiratory tract infections (eg, genitourinary infections, cellulitis, and impetigo). Risk and protective factors for asthma, which were derived from health-care administrative records, included gender, urban location (municipality population, > 40,000) or rural location, neighborhood income, total number of siblings at age 7 years, the number of health-care visits made during the first year of life, and maternal history of asthma (at least one physician visit or hospitalization for asthma or one prescription for an asthma drug).
In order to control for reverse causation, 864 children who had received asthma diagnoses during the first year of life were excluded from the study. In a subset of 2,859 children, health-care database records were linked to parental reports of the presence of pets in the home during the birth year of their child. This information was obtained from a mail survey of the 1995 cohort on health and home environmental exposures.
Multivariate logistic regression analysis was conducted with a statistical software package (SAS; SAS Institute; Cary, NC). Variables were retained in models at the 95% level of confidence. Separate multivariate models were tested by antibiotic type (ie, NS and BS antibiotics), and for children living in urban and rural areas, for children with and without a maternal history of asthma, and for children exposed and not exposed to dogs at birth. Although the stratified analyses were based on a priori questions, the interaction term for antibiotic use and the stratum was tested for statistical significance. The type of antibiotic and the timing of its administration were compared among these subpopulations of children.


In the study cohort of 13,116 children at age 7 years, 50% were male, 57% lived in urban areas, 24% were from low-income families, 90% had siblings, 6% had current asthma at age 7 years, and 5% had a maternal history of asthma; 65% of children had received at least one antibiotic prescription during the first year of life, 3% of children had received NS antibiotics and no BS antibiotics, 52% of children had received BS antibiotics and no NS antibiotics, and 10% of children had received both types of antibiotics. The majority of children (55%) had received at least one prescription for a BS penicillin, 9% had received a BS cephalosporin, and 1% had received a BS macrolide (Fig 1). The linkage of a physician diagnosis with an antibiotic prescription dispensed within 7 days following the physician visit showed that 40% of children received antibiotics for otitis media, 28% for other upper respiratory tract infections, 19% for lower respiratory tract infections, and 7% for non-respiratory tract infections.
Figure 1. 
Frequency of children receiving antibiotics in the first year of life by drug class.
Following adjustment for gender, maternal history of asthma, number of siblings, urban/rural location, and the number of health-care visits (model 1 in Table 1 ), antibiotic use in the first year of life (vs no use) was significantly associated with greater odds of the development of asthma at age 7. This likelihood increased with the number of antibiotic courses, as confirmed by analyses that treated antibiotic use as a continuous variable (odds ratio [OR], 1.09; 95% CI, 1.06 to 1.12). Children who had received more than four courses of antibiotics were almost twice as likely to have asthma develop. Separate adjustments for the number of lower respiratory tract infections and non-respiratory tract infections reduced but did not eliminate the association with asthma.
In a model that adjusted for all risk factors for asthma ( Table 2 ), asthma was significantly more likely to develop in children receiving antibiotics in a dose-dependent manner. The multivariate model included all of the factors tested, with the exceptions of neighborhood income and the number of upper respiratory tract infections, which were not significantly associated with asthma at age 7 years. The highest risk of asthma occurred among children receiving more than four courses of antibiotics (OR, 1.46; 95% CI, 1.14 to 1.88). The association between asthma and the use of BS antibiotics was statistically significant (OR, 1.50; 95% CI, 1.16 to 1.93), but this was not the case for NS antibiotics (OR, 1.35; 95% CI, 0.29 to 6.23), although the ORs were not appreciably different from each other.
Asthma at age 7 years was almost twice as likely (OR, 1.86; 95% CI, 1.02 to 3.37) in children receiving one or more antibiotic prescriptions for non-respiratory tract infections in comparison to children who had not received antibiotics. These analyses were adjusted for maternal history of asthma, number of health-care visits, number of siblings, household income, urban/rural location, and gender. A total of 148 children had received antibiotics for non-respiratory tract infections only (33 children had urinary tract infections and the remainder had skin infections), as determined from the linkage of the antibiotic prescription to the preceding physician visit. This risk for asthma following antibiotic use in treating non-respiratory tract infections was greater than that use in treating non-respiratory tract infections alone (OR, 1.15) [ Table 2 ].
The interaction term for antibiotic use and presence/absence of maternal asthma was statistically significant (p = 0.03), as was the interaction term for antibiotic use and urban/rural location (p = 0.04). Limiting the analysis to 7,517 children living in urban areas reduced the association with antibiotic use to nonsignificance ( Table 3 ). However, in 5,599 rural children the association remained among children receiving more than four courses of antibiotics (OR, 1.88). Antibiotic use was associated with asthma in children with no history of maternal asthma, especially in children who had received multiple courses of antibiotics (OR, 1.57). The interaction term for antibiotic use and the presence/absence of a dog during the birth year was also statistically significant (p = 0.03). The absence of a dog in the home at birth increased the strength of the association between more than four courses of antibiotics and the development of asthma (OR, 2.02).
The time to the receipt of the first antibiotic was shorter in rural children than in urban children (p = 0.06) [ Table 4 ]. While 100% of children in each subpopulation received BS antibiotics, there were differences in the use of BS cephalosporins (eg, cefixime, cefprozil, and cefuroxime). In comparison to urban children, a significantly higher proportion of rural children received BS cephalosporins. The percentage of use of BS cephalosporins was higher, but not statistically significant, in children with no history of maternal asthma or no dog exposure vs their counterparts. No other group differences in antibiotic type were observed.


In a cohort of 13,116 children born in Manitoba in 1995, we found an association between antibiotic use in the first year of life and asthma at age 7 years. Children receiving more than four courses of antibiotics were at 1.5 times the risk of having asthma develop than were children not receiving antibiotics. Our analysis was adjusted for reverse causation, health-care utilization bias, and many well-known risk factors for asthma, and used a health-care database definition of asthma with a high positive predictive value for allergist-diagnosed asthma.[33,34] Moreover, the association was observed for antibiotic use in the treatment of children for non-respiratory tract infections, for which the risk of asthma was doubled.
While our findings are consistent with many retrospective surveys and some prospective health-care database studies, they do not agree with a similar database study conducted by Celedon et al.[25] These authors reported no association for asthma until age 5 years in children receiving multiple course of antibiotics. We speculate that the discrepant findings are related to differences in the populations studied. Almost half of our cohort of children lived in rural areas, while the study by Celedon et al[25] drew its data from an urban population. We also did not find an association with antibiotic use in urban Manitoba children, but the risk was twofold greater in rural children receiving multiple courses of antibiotics.
Similar to its distribution worldwide, asthma prevalence was lowest in our rural children,[35] which may be attributed to the protective effect of endotoxin exposure in farming communities in Manitoba.[7,36,37] Urban-rural differences in allergy and asthma are also supported by the microflora hypothesis. The gut microbiota of infants in more rural countries has higher levels of anaerobic bacteria, such as lactobacilli or bifidobacteria, and lower levels of Clostridium difficile.[11,38] These same patterns of gut colonization are more common in nonallergic infants than in allergic infants.[39,40] Antibiotics may alter the protective effect of gut flora in rural children but have little effect on the gut flora of urban children, who are already predisposed to the development of atopic disease. Of interest, Voor et al[41] also reported an association between antibiotic use and atopy in Estonian children and not in more urbanized Swedish infants.
An alternate explanation for the increased risk of asthma from antibiotic use in rural children may be related to the type of antibiotic used, which has not been investigated in intestinal microflora studies of infants.[38,39,40] All antibiotics decrease anaerobic microflora in infants, but use of the BS cephalosporins leads to the significant suppression of lactobacilli and bifidobacteria, and to the overgrowth of C difficile.[42,43,44] The microflora existing in rural Manitoba children may be subject to the more potent effect of BS cephalosporins. Voor and colleagues[41] have offered a similar account for their findings of increased atopy following antibiotic use in Estonian children, but not in Swedish children; the former children were more likely to have received BS antibiotics. Still another explanation for the increased risk of the development of asthma among the rural children in our study may be related to the earlier administration of antibiotics following birth.[45]
Children who have received therapy with multiple antibiotics and were born to women without a history of asthma were at greater risk of the development of asthma than those who did not receive antibiotics. No antibiotic effect was observed in the presence of maternal asthma, which is consistent with findings from high-risk cohort studies.[24] An increased sensitivity to antibiotics in the absence of maternal asthma may be analogous to the protective effects of dog ownership in children with no parental history of asthma.[46] Postnatal maturation of Th-1 immunity is faster in genetically low-risk children vs high-risk children, so low-risk children are potentially more susceptible to the effects of antibiotic administration on intestinal microflora early in life than are high-risk children,[47] in whom changes in microflora have already occurred.[48] Alternatively, as with our rural children, the increased use of BS cephalosporins may explain the increased occurrence of asthma among children with no maternal history of asthma.
Lack of dog exposure during the birth year also increased the association of antibiotic use with the development of asthma among children receiving multiple courses of antibiotics. This concentration of risk for atopy with antibiotic use in children who were exposed to fewer pets in the first year of life has been reported by others.[45] We hypothesize that lesser contact with dogs during infancy results in a lower microbial load and makes infants more vulnerable to the effects of antibiotics, especially if they are BS cephalosporins.
The strongest evidence against reverse causation in our study is the finding of an association between asthma and antibiotic use for the treatment of non-respiratory tract infections. The majority of non-respiratory infections were skin infections, which may represent misdiagnosed atopic dermatitis. Atopic dermatitis in early life is a major risk factor for asthma, as between 50% and 80% of children with atopic dermatitis will have asthma in childhood.[49] It is the earliest disease manifestation of future allergic asthma. However, recent findings[50] on the immunogenetics of asthma and atopic dermatitis have identified the epithelium as a common pathway for the development of both of these diseases. It is plausible that skin infections early in life are manifestations of an impaired barrier function of the epithelium, including the GI epithelium, which leads to allergen penetration and subsequent inflammation. Antibiotic disruption of intestinal microflora may further increase this inflammation by preventing immunologic tolerance via regulatory T cells.[8] This is suggested in our findings of a greater risk of asthma following antibiotic use in children with non-respiratory tract infections than in those with non-respiratory tract infections alone.
Our population-based study of a 1995 cohort of children identified antibiotic use as a risk factor for the development of asthma at age 7 years. While we have constructed our study to diminish the likelihood of reverse causation and confounding bias, and have implemented a validated definition of childhood asthma, we can neither confirm nor refute the causative role of antibiotics in the development of asthma. However, our study has yielded some interesting findings in subpopulations of children, which we postulate are due to the use of BS cephalosporins or to increased sensitivity to the antibiotic effect among children with a genetic predisposition to impaired barrier function of the epithelium. Further large-scale studies are required to determine the longitudinal associations between the composition of intestinal microflora, antibiotic use, and atopic dermatitis during infancy, and the development of asthma in low-risk and high-risk children. In the interim, it would be prudent to avoid the unnecessary use BS antibiotics in the first year of life when other antibiotics are available.

Table 1. Risk of Asthma at Age 7 Years Following Antibiotic Use in the First Year of Life, Adjusted for Respiratory and Nonrespiratory Infections*

Variables (Reference Group)

Model 1 Model 2 Model 3 Model 4

Courses of antibiotics (none)

  1–2 1.27 (1.06–1.53) 1.25 (1.04–1.51) 1.27 (1.05–1.53) 1.23 (1.02–1.48)
  3–4 1.41 (1.12–1.76) 1.36 (1.08–1.70) 1.40 (1.10–1.78) 1.35 (1.07–1.69)
  > 4 1.74 (1.37–2.22) 1.64 (1.29–2.10) 1.72 (1.27–2.34) 1.56 (1.22–2.00)
Each lower respiratory tract infection†   1.05 (1.02–1.09    
Each upper respiratory tract infection†     1.00 (0.98–1.03)  
Each non-respiratory tract infection‡       1.15 (1.11–1.19)

*Values are given as OR (95% CI). All models were adjusted for gender, urban/rural location, maternal history of asthma, number of health-care visits, and number of siblings.
† For example, zero vs one infection, one vs two infections, two vs three infections, etc.
‡ For example, skin vs urinary tract infection.

Tabele 2. Risk of Asthma at Age 7 Years Following Antibiotic Use in the First Year of Life, Final Model*


Variables (Reference Group) All Children (n = 13,116)
Courses of antibiotics (none)
  1–2 >1.21 (1.01–1.46)
  3–4 1.30 (1.04–1.63)
  > 4 1.46 (1.14–1.88)
Each lower respiratory tract infection† 1.06 (1.02–1.09)
1.15 (1.12–1.19)
Maternal history of asthma 2.21 (1.73–2.81)
No. of health-care visits during first year 1.01 (1.00–1.02)
No. of siblings 0.82 (0.76–0.87)
Urban location 1.65 (1.40–1.94)
Male gender 1.75 (1.50–2.04)

*Values are given at OR (95% CI), adjusted for all variables in model.
† For example, zero vs one infection, one vs two infections, two vs three infections, etc.
‡ For example, skin vs urinary tract infection.

Table 3. Risk of Asthma at Age 7 Years Following Antibiotic Use in the First Year of Life in Specific Childhood Environments*


Childhood Environments Courses of Antibiotics (Reference Group = None)
1–2 3–4 > 4
Urban† 1.17 (0.94–1.45) 1.29 (0.99–1.68) 1.22 (0.89–1.69)
Rural 1.30 (0.91–1.85) 1.21 (0.78–1.89) 1.88 (1.23–2.88)
Maternal asthma‡ 1.11 (0.60–2.07) 1.34 (0.67–2.67) 0.95 (0.42–2.13)
No maternal asthma 1.21 (1.00–1.48) 1.28 (1.00–1.63) 1.57 (1.20–2.04)
Dog exposure§ 1.67 (0.82–3.37) 1.68 (0.69–4.07) 0.72 (0.20–2.53)
No dog exposure 1.04 (0.69–1.55) 1.01 (0.60–1.72) 2.02 (1.20–3.38)

*Values are given as OR (95% CI).
† Adjusted for respiratory/nonrespiratory infections, maternal asthma, number of health-care visits, number of siblings, and gender.
‡ Adjusted for respiratory/nonrespiratory infections, urban/rural location, number of health-care visits, number of siblings, and gender.
§ Adjusted for respiratory/nonrespiratory infections, maternal asthma, urban/rural location, number of siblings, and gender.

Table 4. Antibiotic Characteristics in Children With More Than Four Prescriptions in the First Year of Life by Urban/Rural Status, Maternal Asthma Status, and Presence of Dog*


Characteristics Children, No. Time to First Antibiotic BS Cephalosporins
Days p Value % p Value
Rural residence 728 119 0.06 47.0 - / - 0.0001 - / -
Urban residence 773 126   32.1  
No maternal asthma 1,381 123 NS 39.8 NS
Maternal asthma 120 122   33.3  
No dog in birth year 208 134 NS 37.5 NS
Dog in birth year 72 124   33.3  
* NS = not significant.
Aspirin Prophylaxis for Heart Patients May Be Less Effective in Women Kliknite

Reuters Health Information 2007. © 2007 Reuters Ltd.

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NEW YORK (Reuters Health) May 11 - Women with coronary artery disease (CAD) appear to be more resistant to aspirin's anti-platelet effects than men, according to new study results. However, the clinical relevance of aspirin resistance has yet to be determined, Dr. Susan S. Smyth and colleagues report in the May issue of the Annals of Pharmacotherapy.
Despite their use of aspirin, many patients experience atherothrombotic events, prompting the concept of aspirin resistance. The original goal of this study was to see if patients with a prior MI while on aspirin therapy were more likely to be aspirin resistant than patients with CAD and no history of prior MI.

Aspirin resistance was determined by an instrument, the VerifyNow Aspirin Assay (Accumetrics; San Diego), to measure platelet aggregation in whole blood samples. Aspirin resistance was defined as at least 550 ARU (aspirin responsive units, range 350 to 680), which represents less than 40% of inhibition of arachidonic acid-mediated platelet aggregation.

The study cohort comprised 100 patients with stable CAD who were on aspirin prophylaxis, of whom 50 had a past history of MI. Fourteen patients were classified as "biologically aspirin resistant."

Dr. Smyth, from the Gill Heart Institute in Lexington, Kentucky, and colleagues observed that aspirin resistance did not differ significantly between cases and control subjects (eight versus six, p = 0.566).
In univariate analysis, female sex was the only factor that was significantly associated with aspirin resistance (64.3%, p = 0.011).
Other factors - age, history of revascularization, history of cerebrovascular accident, current smoking, or diabetes - were not associated with aspirin resistance.

However, Dr. Smyth and her associates report that only one of the 14 patients classified as aspirin-resistant was taking the higher dose of 325 mg; the other 13 were on 81 mg/day. When six of those with resistance switched to the higher dose, their ARU score fell below the 550 cutpoint, thereby fulfilling the definition of aspirin responsiveness.

Thus, their evidence suggests that increasing the daily dose of aspirin would improve biologic aspirin sensitivity. But until research establishes the clinical significance of their findings Dr. Smyth's team does not advocate changes in aspirin dosing based on their small study.
Ann Pharmacotherapy 2007.

Anorexia Nervosa in Adolescents Kliknite
The Pediatric Academic Societies meeting took place in Toronto, Ontario, May 5-8, 2007. Among some of the most popular sessions at the meeting are the invited science presentations, where experts review research findings on topics chosen by the program committee. This report focuses on the "Eating Disorders Among Adolescents: Recent Advances in Management and Treatment" Mini Course, jointly sponsored by the Lawson Wilkins Pediatric Endocrine Society, Society for Adolescent Medicine and the Pediatric Academic Societies.[1]

Dr. Debra Katzman of the Hospital for Sick Children and the University of Toronto chaired the session.[1] Speakers covered topics that included the epidemiology of anorexia nervosa, the effects of anorexia nervosa on bone health, management principles, and outcomes of anorexia nervosa. Because some of the speaker topics overlapped, I have combined presentations by topic area, with particular topics covered by each speaker in parentheses. Although the mini-course reviewed all eating disorders, the majority of the material presented related to anorexia nervosa, so that disorder is the focus of this report.

Epidemiology of Anorexia Nervosa

Dr. Richard Kreipe, of the University of Rochester School of Medicine, Golisano Children's Hospital at Strong University, began the session by providing an overview of anorexia nervosa (AN), including definition, epidemiology, and an overview of outcomes.[2]

Dr. Kreipe reviewed 2 publications that provide a great deal of guidance to practitioners treating adolescents with eating disorders. In 1996, the American Academy of Pediatrics published the Classification of Child and Adolescent Mental Diagnoses in Primary Care: Diagnostic and Statistical Manual for Primary Care (DSM-PC), providing a primary-care oriented definition of anorexia nervosa.[3] In addition, he suggested becoming familiar with a 2006 report published by the Agency for Healthcare Quality and Research entitled Management of Eating Disorders, a more than 1200-page report reviewing the evidence surrounding AN and other eating disorders.[4] AN is an eating disorder characterized by low body weight (< 85% of ideal body weight), a profound alteration of body perception so that patients continue to feel that they are too heavy despite abnormally low weight, and behaviors (both eating and activities) that facilitate weight loss or avoiding weight gain (see below).

Criteria for Anorexia Nervosa (307.10), Adapted From DSM-PC[3]

A. Refusal to maintain body weight at or above a minimally normal weight for age and height. Weight loss or failure to gain weight leads to maintenance of body weight at < 85% of that expected.

B. Intense fear of gaining weight or becoming fat, even though underweight.

C. Disturbance in the way in which one's body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight.

D. In postmenarchal girls, amenorrhea is present as defined by absence of at least 3 consecutive cycles.

There are other criteria for diagnosing AN, but the central components of AN are similar in all diagnostic schemata.[4] Other diagnostic approaches subcategorize patients with AN into "restricting" and "binge/purge" types, but these subtypes will not be reviewed as part of this report.

Dr. Kreipe reported that the prevalence of AN has slowly increased since mid-century, with rates in the United States hovering at around 5 per 1000 (0.5%).[5] It has also become evident that 5% to 10% of eating disorders occur in males, and there have been recent efforts to better understand AN in males and minorities of both genders.[5] There is a potentially even larger group of adolescents that have partial symptoms of an eating disorder, suggesting that like many disorders, AN exists as a spectrum of symptoms.

Factors Contributing to Anorexia Nervosa

Dr. Richard Kreipe also spoke about the increased emphasis on the genetics of AN. Current evidence suggests that there may be genetic "potential" for developing AN, but there also appears to be strong evidence that this genetic potential requires an environmental "trigger" for a patient to develop AN. In many children, retrospective review of medical and behavioral histories does not suggest that one could have identified who might develop the disorder. Certainly, cultural expectations play a role, with higher rates of AN in more industrialized countries.[5]

A study by Becker and co-authors noted that exposure to Western media was associated with increased rates of eating disorders in Fiji, an island nation that historically did not have high adolescent exposure to Western media and body habitus expectations.[6] In addition, adolescents with perfectionist tendencies, depressed adolescents, and adolescents with mood and anxiety disorders also have higher rates of AN.[4,7]

Potential precipitating events can include pubertal hormonal changes. Klump and co-investigators have conducted longitudinal studies of 510 female twins. In cross-sectional analyses, nearly 100% of prepubertal variation in disordered eating was attributable to "environmental" origin. However, in older adolescent twins, 44% of the variation in disordered eating was attributable to "genetic" factors, with reduced influence of shared environmental influences.[8]

These data support the hypothesis that pubertal hormonal changes are potential triggers of the genetic predisposition. Social transitions, such as divorce, school changes, moving, and peer pressure are also thought to be triggers. These transitions lead to a decreased sense of control by the adolescent, and AN may be a way to re-exert control over one's life. In addition, the perception of the patient that he or she is "in control" of eating may be a perpetuating factor making treatment more difficult, rendering the adolescent loathe to give up control over this facet of his or her life.

Primary Care Provider Identification of Anorexia Nervosa

Dr. Kreipe emphasized that the following signs and symptoms should serve as "red flags" for the primary care clinician (PCP) in identifying someone with AN:
Red flags for PCPs to recognize signs of anorexia:

  • Abnormally low weight or fluctuations in weight;
  • Purging for weight loss;
  • Persistent and intense concerns with weight;
  • Amenorrhea; and
  • Social withdrawal and isolation from food activities.

Metabolic and Bone Effects of Anorexia Nervosa

Some of the most profound physical effects of AN are those on growth and metabolism, especially bone growth and bone density. Dr. Madhusmita Misra of Massachusetts General Hospital reviewed both her work and the research of others regarding the effects of AN on bone health.[9]

Humans reach peak bone mass during adolescent years. The peak bone mass of childhood and adolescence correlates inversely with fracture risk when we are elderly.[4,10]

In a study published in 2000, Grinspoon and colleagues demonstrated that 92% of adult women with AN had reduced bone mineral density in at least one area.[11] Adolescents with eating disorders miss out on a great deal of bone mass accumulation, and Dr. Misra's own studies have examined the prevalence of decreased bone mineral density in adolescents with AN.

In a study comparing bone densities, hormonal levels, and other clinical parameters between 60 adolescent girls with AN and 58 normal controls, Dr. Misra and co-authors found that 41% of the AN girls had bone mineral densities (by Z score, a standardized measure comparing to "normal") that were Z -1, and another 11% had Z -2 bone mineral density (more severe reduction in density) in at least 1 site.[12]

The comparison rates for normal controls were 19% with Z -1 bone mineral density in at least 1 site and 2% with Z -2 scores. Fractures, even at a mean age of approximately 15 years, were more likely in girls with AN (32%) than girls without AN (26%).
Dr. Misra also expressed the concern that the lost accrual of bone mineral density in girls with AN can't be "made up" even with later weight gain. She referenced her own unpublished data (study still underway) that suggests that weight gain alone has not improved bone mineral density by a concurrent amount. However, she notes that the data are still preliminary and have relatively short follow-up of only 1 year.

The hormonal disruptions that occur with AN have a direct effect on bone mineral accrual. Dr. Misra's 2004 study demonstrated that girls with AN had lower levels of luteinizing hormone, estradiol, and insulin-like growth factor-1 (IGF-1).[12] While use of oral contraceptives may help replace hormone levels in AN girls, the 'supra-normal' levels of hormones in contraceptives may down-regulate IGF-1, contributing to poor accrual of bone density.[13,14]

In addition, girls with AN will increase production of growth hormone, but IGF-1 levels remain low, suggesting that the mediating effects of IGF-1 may be the more critical for bone mineralization. Finally, girls with AN also have increased cortisol levels, and cortisol inhibits bone formation.[15]

In summary, Dr. Misra emphasized that reduced bone mineral density is prevalent in patients with AN, residual bone mass remains impaired even with weight recovery, and the hormonal alterations that accompany AN may play a more critical role in the poor bone outcomes than dietary restrictions in AN.

Management of Anorexia Nervosa

Management of AN requires a multidisciplinary team, but the PCP should be aware of the basic tenets of management. First, early detection of AN should be the goal of any clinician, especially in that outcomes are generally better for AN of short duration compared to long duration.[16] Dr. Kreipe suggested using the Guidelines for Adolescent Preventive Services (GAPS) materials developed by the American Medical Association as a screening tool. Along with other questions, the GAPS asks questions specific to eating disorders, such as eating habits, dieting habits, and body image (see http://www.ama-assn.org/ama/upload/mm/39/periodic.pdf).

This tool can help the PCP identify at-risk teens for further interview. Once AN is suspected by the PCP, one must engage a multispecialty team that would include behavior specialists, nutritional support, and psychiatric support.

The treatment phase generally begins with an inpatient admission to stabilize the patient medically and to begin to restore weight.[16] In life-threatening malnutrition, the weight gain goal would be 0.3-0.4 lb/day. In fact, studies suggest that discharging a patient before they have reached a stable weight is associated with worse outcomes.[16]

Weight restoration and later maintenance then proceeds in the outpatient setting. Throughout the treatment, the focus of the PCP should be on restoring health. Dr. Kreipe uses a "what is your body telling me?" approach, focusing on unpleasant physical findings or changes of AN (eg, cold intolerance) as a potential method to gain the buy-in of the patient and provide motivation to get better. This approach also makes it clear to the patient that weight gain is NOT the only goal.

Drs. Kreipe and Lock both recommended an authoritative approach that empowers the parents -- weight restoration is the parents' responsibility. Education of the patient is also a cornerstone of treatment with meal planning, and education with a dietician is imperative. Finally, addressing mental health symptoms is also an integral component of treatment. The goal here is to present mental health treatment as a way to help the patient, not to label them with a mental health diagnosis. Like many illnesses, avoiding stigmatization with AN is crucial.

It has long been recognized that some parents enable adolescents with AN; therefore, one may have the impulse to remove the family from the treatment regimen. However, involvement of parents, and indeed requiring parents to be involved, is a cornerstone of current best practices for treating AN. There are many parent-related issues to consider.

Parents must be able to discuss their guilt or feelings of blame they might have openly with the patient and with caregivers. Caregivers must be careful not to allow blame to perpetuate, however. This can be addressed in part by attempting to orient the family toward the future and the goals for the patient, not dwelling on past blame or guilt. Often, roles within the family need to be re-aligned. The parents must realize that they are not 'friends' to the patient but are instead parents with a duty to help the patient make the transition from adolescence to adulthood. Finally, the parents must empower, not undermine, healthcare workers. This is where keeping the parents focused on the future may be most valuable.

Dr. James Lock of Stanford University School of Medicine and Lucile Salter Packard Children's Hospital at Stanford described the general approach to treatment used in his hospital and also reviewed his outcomes research.[17] The first phase of treatment is weight restoration, and the parents again have the central role to play in this. The second phase includes transfer of control over eating to the adolescent in a supervised manner. The third phase is when the team focuses on other issues of adolescent development that are particular to the patient. Depression, anxiety, obsessive behaviors, and other comorbid psychological and social issues must be dealt with intensively for the treatment plan to succeed, especially given that patients with comorbid disorders have worse long-term outcomes in longitudinal studies.[18]


In discussing outcomes, Dr. Kreipe encourages optimism. His own outcome studies, as well as those by Steiner and Nussbaum suggest that most patients either don't change or get better. It is a minority of patients who will get worse.[19-22]

Dr. Lock lamented that only 8 randomized, controlled trials have been completed in adolescents with AN between 1987 and 2006. The total number of patients involved in these trials was less than 300! So, outcomes of patients with AN are still largely based on small case numbers.

One of the first questions that should be answered is, "What constitutes 'getting better'?" In a 2006 article by Couturier and Lock, they suggested that a combination of attaining > 85% Ideal Body Weight and improvement in 'Eating Disorder Examination' scale scores seem to be the most reproducible measures of improvement.[23] Interestingly, in their study, mean time to weight recovery was 11.3 months, but the mean time to recovery of Eating Disorder Examination scores (all scores on subscales within 2 standard deviations of normal) was 22.6 months, reinforcing the long-term nature of recovery efforts for both the patient and parents and healthcare team.

Dr. Lock reviewed a study by Russell and colleagues from 1987, notable for being the first study to demonstrate a treatment effect for patients with AN.[24] That study enrolled 21 adolescents and compared individual therapy to family therapy. The family therapy group had a higher rate of attainment of 90% ideal body weight, and the relatively better outcomes of patients who received family therapy persisted at 5 years of follow-up. Robin and co-investigators published their comparison of individual therapy vs family therapy in 1999.[25] That study included 37 adolescents and demonstrated that both modes of therapy appear effective, although patients who underwent family therapy did slightly better. Two-thirds of the all subjects had reached their respective target weights at the end of the active treatment period. The family therapy patients also resumed menstruation more quickly, but this difference was not present at the 1-year follow-up point.

Finally, Dr. Lock's own data, published in 2006, demonstrated similar overall improvement.[26] After a hospitalization period to render the patients medically stable, that 1999-2002 study randomized 86 subjects between to 2 groups -- 6 months vs 12 months of family therapy. The 2006 publication detailed the follow-up of 71 patients who agreed to participate. The groups had similar outcomes at approximately 4 years (mean) follow-up with mean body mass indexes (BMIs) of approximately 20.5%, with 88.7% having gained to at least 90% of ideal body weight and 62% having a BMI greater than 20. Seven percent had BMIs less than 17.5, and this rate was similar between the 2 groups. Overall, Drs. Kreipe and Lock both emphasized the need for optimism in that the majority of patients either get better or at least don't get worse, but the long-term nature of treatment can't be overemphasized.


In summary, PCPs have a central role in identifying and treating patients with AN. Use of screening tools such as the GAPS and being aware of 'red flags' can help the PCP improve identification of adolescents with eating disorders. The PCP has a central role in supporting the patient, parents, and the specialty healthcare team by gaining the trust of the patients and helping the patient and parent 'orient to health.' PCPs may also be very helpful in identifying and helping to address other comorbid conditions that complicate anorexia. The long-term nature of most primary care settings make PCPs ideal partners in treating eating disorders.