Michael D. Cabana

Role of the gut microbiota in defining human health

The human superorganism is a conglomerate of mammalian and microbial cells, with the latter estimated to outnumber the former by ten to one and the microbial genetic repertoire (microbiome) to be approximately 100-times greater than that of the human host. Given the ability of the immune response to rapidly counter infectious agents, it is striking that such a large density of microbes can exist in a state of synergy within the human host. This is particularly true of the distal gastrointestinal (GI) tract, which houses up to 1000 distinct bacterial species and an estimated excess of 1 × 1014 microorganisms. An ever-increasing body of evidence implicates the GI microbiota in defining states of health and disease. Here, we review the literature in adult and pediatric GI microbiome studies, the emerging links between microbial community structure, function, infection and disease, and the approaches to manipulate this crucial ecosystem to improve host health.

Effects of Asthma Education on Children's Use of Acute Care Services: A Meta-analysis

OBJECTIVE. National Heart, Lung, and Blood Institute clinical practice guidelines strongly recommend that health professionals educate children with asthma and their caregivers about self-management. We conducted a meta-analysis to estimate the effects of pediatric asthma education on hospitalizations, emergency department visits, and urgent physician visits for asthma. PATIENTS AND METHODS. Inclusion criteria included enrollment of children aged 2 to 17 years with a clinical diagnosis of asthma who resided in the United States. Pooled standardized mean differences and pooled odds ratios were calculated. Random-effects models were estimated for all outcomes assessed. RESULTS. Of the 208 studies identified and screened, 37 met the inclusion criteria. Twenty-seven compared educational interventions to usual care, and 10 compared different interventions. Among studies that compared asthma education to usual care, education was associated with statistically significant decreases in mean hospitalizations and mean emergency department visits and a trend toward lower odds of an emergency department visit. Education did not affect the odds of hospitalization or the mean number of urgent physician visits. Findings from studies that compared different types of asthma education interventions suggest that providing more sessions and more opportunities for interactive learning may produce better outcomes. CONCLUSIONS. Providing pediatric asthma education reduces mean number of hospitalizations and emergency department visits and the odds of an emergency department visit for asthma, but not the odds of hospitalization or mean number of urgent physician visits. Health plans should invest in pediatric asthma education or provide health professionals with incentives to furnish such education. Additional research is needed to determine the most important components of interventions and compare the cost-effectiveness of different interventions.

Indices for Continuity of Care: A Systematic Review of the Literature

This article systematically reviews published literature on different continuity of care (COC) indices that assess the physician-patient relationship and the applicability of such indices to pediatric and chronic-disease patient populations. Frequency and visit type may vary for pediatric and chronically ill patients versus healthy adult patients. Two investigators independently examined 5,070 candidate articles and identified 246 articles related to COC. Forty-four articles were identified that include 32 different indices used to measure COC. Indices were classified into those that calculated COC primarily based on duration of provider relationship (n = 2), density of visits (n = 17), dispersion of providers (n = 8), sequence of providers (n = 1), or subjective estimates (n = 4). The diversity of COC indices reflect differences in how this measure is conceptualized. No index takes into account the visit type. A unique index that reflects continuity in the physicianpatient relationship for pediatric and chronic disease populations is needed.

Impact of physician asthma care education on patient outcomes.

OBJECTIVE. We evaluated the effectiveness of a continuing medical education program, Physician Asthma Care Education, in improving pediatricians’ asthma therapeutic and communication skills and patients’ health care utilization for asthma. METHODS. We conducted a randomized trial in 10 regions in the United States. Primary care providers were recruited and randomly assigned by site to receive the program provided by local faculty. The program included 2 interactive seminar sessions (2.5 hours each) that reviewed national asthma guidelines, communication skills, and key educational messages. Format included short lectures, case discussions, and a video modeling communication techniques. We collected information on parent perceptions of physicians’ communication, the child’s asthma symptoms, and patients’ asthma health care utilization. We used multivariate regression models to determine differences between control and intervention groups. RESULTS. A total of 101 primary care providers and a random sample of 870 of their asthma patients participated. After 1 year, we completed follow-up telephone interviews with the parents of 731 of the 870 patients. Compared to control subjects, parents reported that physicians in the intervention group were more likely to inquire about patients’ concerns about asthma, encourage patients to be physically active, and set goals for successful treatment. Patients of physicians that attended the program had a greater decrease in days limited by asthma symptoms (8.5 vs 15.6 days), as well as decreased emergency department asthma visits (0.30 vs 0.55 visits per year). CONCLUSIONS. The Physician Asthma Care Education program was used in a range of locations and was effective in improving parent-reported provider communication skills, the number of days affected by asthma symptoms, and asthma health care use. Patients with more frequent asthma symptoms and higher health care utilization at baseline were more likely to benefit from their physician’s participation in the program.

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.

Human gut microbiota and its relationship to health and disease

Probiotics are live microorganisms that confer a health benefit on the host when administered in appropriate amounts. Over 700 randomized, controlled, human studies have been conducted with probiotics thus far, with the results providing strong support for the use of probiotics in the clinical prevention or treatment of gastrointestinal tract disorders and metabolic syndrome. The present review is based on webinar presentations that were developed by the American Gastroenterological Association (AGA) in partnership with the International Scientific Association for Probiotics and Prebiotics (ISAPP) and the North American branch of the International Life Sciences Institute (ILSI North America). The presentations provided gastroenterologists and researchers with fundamental and current scientific information on the influence of gut microbiota on human health and disease, as well as clinical intervention strategies and practical guidelines for the use of probiotics and prebiotics.

Vitamin D Insufficiency and Severe Asthma Exacerbations in Puerto Rican Children

RATIONALE Vitamin D insufficiency (a serum 25(OH)D <30 ng/ml) has been associated with severe asthma exacerbations, but this could be explained by underlying racial ancestry or disease severity. Little is known about vitamin D and asthma in Puerto Ricans. OBJECTIVES To examine whether vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, and time outdoors. METHODS A cross-sectional study was conducted of 560 children ages 6-14 years with (n = 287) and without (n = 273) asthma in San Juan, Puerto Rico. We measured plasma vitamin D and estimated the percentage of African racial ancestry among participants using genome-wide genotypic data. We tested whether vitamin D insufficiency is associated with severe asthma exacerbations, lung function, or atopy (greater than or equal to one positive IgE to allergens) using logistic or linear regression. Multivariate models were adjusted for African ancestry, time outdoors, atopy, and other covariates. MEASUREMENTS AND MAIN RESULTS Vitamin D insufficiency was common in children with (44%) and without (47%) asthma. In multivariate analyses, vitamin D insufficiency was associated with higher odds of greater than or equal to one severe asthma exacerbation in the prior year (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.9; P = 0.001) and atopy, and a lower FEV(1)/FVC in cases. After stratification by atopy, the magnitude of the association between vitamin D insufficiency and severe exacerbations was greater in nonatopic (OR, 6.2; 95% CI, 2-21.6; P = 0.002) than in atopic (OR, 2; 95% CI, 1-4.1; P = 0.04) cases. CONCLUSIONS Vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, or markers of disease severity or control.

Consequences of the delayed diagnosis of ataxia-telangiectasia

Objectives. Ataxia-telangiectasia (AT) is a rare, autosomal recessive neurodegenerative disorder in which the diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests. The purpose of this study is to identify factors responsible for delays in the diagnosis of AT. Design. The records of all patients seen at the Ataxia-Telangiectasia Clinical Center from July 1, 1995 to April 1, 1997 were reviewed to determine age of onset of gait abnormality, recognition of telangiectasia, and diagnosis. Results. In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months). In the majority of cases (34/48), telangiectasia appeared before the diagnosis was established. The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. Conclusions. The term AT, although a concise and memorable label for the disorder, is also a barrier to early diagnosis. We recommend the use of routine serum α-fetoprotein testing for all children with persistent ataxia.

Lactobacillus casei abundance is associated with profound shifts in the infant gut microbiome.

Colonization of the infant gut by microorganisms over the first year of life is crucial for development of a balanced immune response. Early alterations in the gastrointestinal microbiota of neonates has been linked with subsequent development of asthma and atopy in older children. Here we describe high-resolution culture-independent analysis of stool samples from 6-month old infants fed daily supplements of Lactobacillus casei subsp. Rhamnosus (LGG) or placebo in a double-blind, randomized Trial of Infant Probiotic Supplementation (TIPS). Bacterial community composition was examined using a high-density microarray, the 16S rRNA PhyloChip, and the microbial assemblages of infants with either high or low LGG abundance were compared. Communities with high abundance of LGG exhibited promotion of phylogenetically clustered taxa including a number of other known probiotic species, and were significantly more even in their distribution of community members. Ecologically, these aspects are characteristic of communities that are more resistant to perturbation and outgrowth of pathogens. PhyloChip analysis also permitted identification of taxa negatively correlated with LGG abundance that have previously been associated with atopy, as well as those positively correlated that may prove useful alternative targets for investigation as alternative probiotic species. From these findings we hypothesize that a key mechanism for the protective effect of LGG supplementation on subsequent development of allergic disease is through promotion of a stable, even, and functionally redundant infant gastrointestinal community.

Partially hydrolyzed 100% whey protein infant formula and reduced risk of atopic dermatitis: a meta-analysis.

Objective: A reduced risk of atopic dermatitis (AD) among healthy infants who received 100% whey protein partially hydrolyzed formula (PHF-W) compared with intact protein cows milk formula (CMF), has been reported in several studies. To validate these observations and estimate the magnitude of this potential association with greater statistical precision, we conducted a meta-analysis of clinical trial and intervention studies. Materials and Methods: A total of 18 articles representing 12 independent study populations met our inclusion criteria. Results: A statistically significant 44% (summary relative risk estimate [SRRE] = 0.56, 95% confidence interval 0.40–0.77) reduced risk of atopic manifestations, which included AD, was found among infants receiving PHF-W compared with infants receiving CMF. In a subanalysis of 4 studies that reported results specifically for AD and that were considered of superior methodological quality, the incidence of AD was reduced by 55% (SRRE = 0.45, 95% confidence interval 0.30–0.70). Conclusions: Regardless of study design, infant population, follow-up time, or study location, individual study findings were consistent because a reduced incidence of AD was reported in all of the reviewed studies. Exclusive breast-feeding should be encouraged as the standard for infant nutrition in the first months of life. For infants who are not exclusively breast-fed, feeding with PHF-W instead of CMF reduces the risk of AD in infants, particularly in infants with a family history of allergy.