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Pediatrics- allergy/asthma

Primary Care Corner with Geoffrey Modest MD: Thumb Sucking and Immunity

25 Jan, 17 | by EBM

By Dr. Geoffrey Modest

Another microbiome article (I realize this is the third in a series of two, but can’t help myself). This one looked at the “hygiene hypothesis”, which is basically that kids exposed to more microbes early in life have fewer allergies or asthma. This article looked at thumb-sucking, nail-biting and atopic sensitization, also finding that the more the fingers went into the mouth, the fewer had atopic sensitization (see DOI: 10.1542/peds.2016-0443).

Details:

  • The Dunedin Multidisciplinary Heath and Development Study, a population-based birth cohort study of 1037 people (52% male) born in Dunedin (the second largest city in the South Island of New Zealand with 120,000 inhabitants), with follow-up at ages 3,5,7,9,11,13,15,18,21,26,32, and 38
  • At age 5,7,9,11 the parents were asked about the kid’s thumb-sucking and nail-biting, along with an estimate of frequency
  • Skin-prick testing was done at age 13 on 724 of the 1031 kids (70%), including testing for house dust mites, grass, cat, dog, horse, aspergillus, penicillium, and a few others; a positive test was a wheal >2mm larger than the negative saline control
  • Detailed respiratory reviews were done since age 9
  • The researchers controlled for potential confounders of sex and parental history for asthma or hayfever; breastfeeding; exposure to cat or dog in childhood (a prior analysis of this cohort showed that this exposure led to lower risk of atopic sensitization); parental smoking history, household crowding (total number of kids divided by number of rooms), socioeconomic status

Results:

  • Overall 31% of children were frequent thumb-suckers or nail-biters at age >1yo
    • Nail-biting or thumb-sucking were each found in 20% of girls and 17% of boys
  • Incidence of atopy:
    • ​Atopic sensitization in 38% of girls/52% of boys age 13; 58% of girls/61% of boys at age 32
    • ​Asthma in 10% of girls/16% of boys age 13; 18% of girls/18% of boys at age 32
    • ​Hayfever in 28% of girls/32% of boys age 13; 42% of girls/37% of boys at age 32
  • For atopic sensitization, as compared to those without thumb-sucking or nail-biting:
    • At age 13:
      • There was an adjusted 36% lower likelihood of atopic sensitization: OR 0.64 (0.45-0.90) for either thumb-sucking or nail-biting
      • A 36% lower likelihood if only thumb-sucking, OR 0.64 (0.42-0.97)
      • A 30% lower likelihood if only nail-biting, OR 0.70 (0.47-1.10), nonsignificant
    • At age 32:
      • There was a 38% adjusted lower likelihood of atopic sensitization: OR 0.62 (0.45-0.86) for either thumb-sucking or nail-biting
      • A 31% lower likelihood if only thumb-sucking, OR 0.69 (0.47-1.00), borderline significant
      • A 29% lower likelihood if only nail-biting, OR 0.71 (0.49-1.02), nonsignificant
    • The only significant difference for specific allergens was for house dust mites in those aged 32, though all of the others had trends that were almost significant
  • For asthma or hayfever:
    • None were significantly associated, at either ages 13 or 32
  • A dose-response curve (doing both thumb-sucking and nail-biting vs either one of them) was only evident at age 13

Commentary:

  • This study further supports the “hygiene hypothesis”, though it was notable that the dramatic difference in atopy was only in the objective measurement of sensitization (but, one might argue that these clinical manifestations of atopy are what really matters….). Why not with asthma or hayfever?
  • Is it just that these were by report and therefore less “reliable” than the objective measure of atopic sensitization?
  • Asthma, also, is more complicated, given that atopy is only part of the issue playing into it
  • Or, my guess, is that they were looking at kids who were already too old (there were no data on thumb-sucking and nail-biting during the preschool years), that immune tolerance largely develops earlier in life, and other studies showing a relationship between “hygiene” and atopic conditions (e.g. hayfever or asthma) included much younger children (see blogs listed below)
  • The study does support the results of a prior study finding that in kids using pacifiers, there seemed to be fewer allergies later in life when the mothers sucked the pacifiers to clean them
  • The proposed mechanism here is that exposure to bacteria and other microorganisms early changes the gut microbiome (and, see blog below about the respiratory microbiome); and the microbiome can change the function of helper T cell (TH) subsets, increasing the helper T cell type 1 (TH-1, which produce interferon-g, IL-2, TNF-b and leads to cell-mediated immunity) and decreasing helper T cell type 2 (TH-2, which produces a slew of interleukins which lead to strong antibody responses), with these changes promoting the development of immune tolerance to allergen exposures.
  • But overall this study does support the concept that early exposure to some microbes leads to more immune tolerance. And thumb-sucking or nail-biting certainly increases exposure to a diverse variety of microbes.

See http://blogs.bmj.com/ebm/2016/09/19/primary-care-corner-with-geoffrey-modest-md-microbiome-and-type-1-diabetes-etc/​ which includes an article on the microbiome and type 1 diabetes, and two more on the “hygiene hypothesis”: one on the increased incidence of autoimmune disease in kids in those born in North Karelia Finland (more automated, advanced technologically) vs the Russian side (same gene pool but more natural environment/exposures); and the other being the recent NEJM article finding the same type of difference for asthma in the Hutterites (industrialized farming) vs the Amish (traditional farming)​

See http://blogs.bmj.com/ebm/2015/11/09/primary-care-corner-with-geoffrey-modest-md-gi-microbiome-in-little-kids-and-development-of-asthma/ which is a Canadian longitudinal study finding that early infancy microbiome changes increase the risk of childhood asthma; or http://blogs.bmj.com/ebm/2014/08/13/primary-care-corner-with-geoffrey-modest-md-asthma-and-early-exposure-to-allergens/ which looks at 4 US cities and similarly finding that early allergen exposure leads to more asthma

There was a blog I sent out 8/27/2014 (which did not make it into the BMJ blogs) which looked at the lung microbiome, showing that diet leads to changes in the TH1 and TH2 cells in the lung itself (i.e., there is more than one microbiome, not just the gut one). For the article, see doi:10.1038/nm.3444. With regards to asthma: there is evidence of increased prevalence of chlamydia and mycoplasma with asthma exacerbations. Also, the respiratory microbiome is different in asthmatic vs nonasthmatic patients, even in asymptomatic asthmatic patients, with abundance of Proteobacteria. There is also some evidence that airway hyperresponsiveness tracks with bacterial diversity and composition (esp. increase in Proteobacteria).

Primary Care Corner with Geoffrey Modest MD: Errors in Inhaler Usage

13 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent systematic review looked at articles on patient inhaler technique over the past 40 years, finding that 1/3 of users had poor technique, and that number has not changed over these 4 decades (see Sanchis J. Chest 2016; 150(2): 394).

Details:

  • 144 articles from 1975-2014 reported on 54,354 subjects performing 59,584 observed tests of technique, from 31 countries around the world
  • 54 studies reported on asthma, 14 on COPD, and 76 on both or unspecified.
  • Mean age of adults was 54, and of children was 9.

Results for most frequent errors:

  • Metered-dose inhalers (MDI): problems with full expiration in 48%, coordination 45%, speed and/or depth of inspiration 44%, and no postinhalation breath-hold in the 5-10 second range 46%
  • Breath-activated MDIs: problems with full expiration in 32%, speed and/or depth of inspiration 33%, and no postinhalation breath-hold 39%
  • MDI plus inhalation chambers: problems with preparation/shaking in 33%; exhale/seal chamber 34%; actuate/slow deep breath/breath-hold 38%
  • Dry-powder inhalers (DPI): problems with full expiration in 46%; postinhalation breath-holding 37%; preparing the inhaler 29%
  • The overall prevalence of correct technique was 31%; of acceptable, 41%; and of poor, 31%.
  • There were no significant differences between incorrect inhaler usage comparing the first and second 20-year periods of scrutiny

Commentary:

  • These results were actually better than I expected (this may be because these were from studies, where the patients may have received more rigorous training than in many offices or health centers). Even my patients who are smokers and used to inhaling and holding their breaths some (even those who smoke marijuana) mostly do terribly with inhalers.
  • MDIs had the worst outcomes, even if adding holding chambers (though there were pretty few studies on this, and there is lots of variability in sizes and functions of these chambers)
  • There were more limited studies on kids: mostly for MDI with inhalation chambers, and the children tended to do better: adults with errors in the 34-49% range, kids in the 21-31% range
  • There are a few other studies suggesting that correctly used MDIs are as beneficial as nebulizers, but i do have several patients who just can’t use their inhalers correctly despite education/review. So in some, nebulizers do work better…
  • The bottom line: inadequate technique in using inhalers is really common, apparently with all types of inhalers but worse with MDIs and without much improvement with inhalation chambers or over time. It makes sense to me that we have the patient regularly bring in their inhalers to their appointments and that we review their usage.

Primary Care Corner with Geoffrey Modest MD: Microbiome and Type 1 Diabetes, etc

19 Sep, 16 | by EBM

By Dr. Geoffrey Modest

The NY Times had a recent story looking at the role of the microbiome (sorry to those microbiome-phobic) in the development of type 1 diabetes (T1D), see http://www.nytimes.com/2016/06/05/opinion/sunday/educate-your-immune-system.html?smprod=nytcore-iphone&smid=nytcore-iphone-share . This article was based on a recent clinical study (see doi.org/10.1016/j.chom.2015.01.001).

  • 33 infants genetically predisposed to T1D through specific HLA alleles, following changes in their gut microbiota frequently
  • Though microbiota varied greatly between individuals, it remained stable throughout infancy in each individual
  • After 3 years, 4 of the children developed T1D
  • At the time of T1D diagnosis, there was a marked 25% drop in diversity of the microbiome occurring after anti-islet cell autoantibody development/seroconversion (not found in those who did not seroconvert) but 1 year before clinical T1D, along with spikes in inflammation-favoring organisms, gene functions and serum plus stool metabolites.

Commentary:

  • Initial colonization of the human gut begins in utero, is influenced by microbial exposure at birth, then gets gradual increase in diversity in part related to the introduction of table foods. The microbiome largely stabilizes at approximately 3 years of age
  • T1D: an autoimmune disorder resulting from T cell-mediated destruction of insulin-producing pancreatic b-cells. 70% of T1D cases carry HLA high risk alleles for T1D, yet only 3-7% of children with those alleles develop T1D. The incidence of T1D has been increasing rapidly over the past few decades. All of this suggests that there are important non-genetic factors influencing the development of clinical T1D. In Finland, the incidence of T1D is particularly high: 1 in 120 children develop T1D before age 15 (the US is about 1 in 300).
  • Mouse data show that in those susceptible to T1D, changing the gut microbiota can lead to protection from T1D.
  • Other studies have found a decreased intestinal microbial diversity in children with long-lasting b-cell autoimmunity, as well as in inflammatory bowel disease and C difficile-associated diarrhea (in mice, decreased diversity is associated with increased in IgE levels and predisposition to immune-mediated disorders).
  • The probability of progression to T1D after positivity of 2 islet autoantibodies is >80% after 15-year followup, though there is significant variability as to when this happens. so even though in the above study the microbiome seemed to influence the development of clinical T1D but not the autoantibody seroconversion, it does suggest that the effect of an adverse microbiome is associated at least with earlier development of clinical disease.

——————————————————————————————————————————————————————————————————–

A follow-up of the above but now larger study looked the “hygiene hypothesis” in general, which posits that early exposure to specific microorganisms/parasites in infancy benefits the development of the immune system, leading to protection from the development of allergic and immunologic disease. This study looked at microbiome changes in North Karelia, Finland, where those from the same genetic pool but living on the Russian side have about 1/5 the development of early-onset autoimmune diseases as the European side, and noting important microbiome changes, which might explain these clinical differences (see Vatanen T. Cell 2016; 165: 842).

  • Background:
    • Several studies have shown that improved sanitation seems to be associated with increased incidence of type 1 diabetes (T1D), multiple sclerosis, and early childhood infections
    • Rates of asthma, hayfever and allergic sensitization are decreased in kids growing up on traditional farms
    • Mice with their gut colonized by with protective microbiota have decreased risk of autoimmune diabetes and allergies
    • There is a 2- to 6-fold increase in allergies and 5- to 6-fold increase in T1D and other autoimmune disorders in the Finnish vs Russian sides of North Karelia; in nearby Estonia, the incidence of T1D and atopy are transitioning with economic development from rates historically similar to the Russian side to the Finnish side
  • The study:
    • Approx 1000 infants in the three areas (Russian Karelia, Finnish Karelia, and Estonia) were followed from birth to 3 yo with monthly stool samples, with metagenomic characterization of 785 gut microbial communities. These 3 areas have similar genetic makeup as well as similar climate and latitude.
    • 74 kids were selected from each country based on similar HLA risk class distribution and gender, getting monthly stool samples and information on breastfeeding, diet, allergies, infections, family history, etc.
  • Results:
    • The resident country was the major source of variation of gut microbiome, especially during the first year of life. The diversity of the microbiome overall increased with age. The specific microbiome findings below are corrected for major confounding factors or birth mode, breastfeeding and other dietary factors, antibiotic use and age
    • The Finnish and Estonian kids harbored more Bacteroides species and enrichment in lipopolysaccharide (LPS) biosynthesis-encoding genes; Russian kids had more Bifidobacterium species (esp B. bifidum)
    • The abundance of Bacteroides correlated with serum insulin autoantibody levels
    • More lipopolysaccharides (endotoxins) were produced in Finnish and Estonian kids,
    • This LPS differed from that in the Russian kids, which developed almost exclusively from E coli. (And, the Bacteroides LPS inhibits immune stimulation and inflammatory cytokine responses to E coli LPS in human cells.) This Russian-side LPS, unlike that from Bacteroides as in the Finnish and Estonian kids, elicits endotoxin tolerance (further studies in mice of the specific endotoxins found that the LPS from E coli, as in the Russian kids, also increased their immune tolerance and decreased diabetes): i.e., different LPS produce different constituents in the human gut microbiome, with either stimulatory or inhibitory activity on components of the immune system (though, of note, the specific LPS differences are quite different in mice and human gut microbiomes)
    • Assessment of T1D anti-b cell autoantibody seropositivity revealed a gradient: 16 in Finland, 14 in Estonia and 4 in Russia

Commentary

  • This article and the NY Times commentary reinforce that the microbiome is a major mediator of the environment into human disease. Colonization by different bacteria in the first year of life leads to changes in attendant lipopolysaccharides, which seem to have a direct effect on immune tolerance/susceptibility, and seems to be related to diabetes autoantibody seropositivity (not found in the first study) and potentially to the increased incidence in T1 diabetes in certain areas. One of the important components of this study is that the potential genetic differences between these communities is pretty much mitigated, since they all derive from a common gene pool and only recently had such dramatic differences in environmental exposures.
  • Again, this type of study reinforces that what seems intuitive: it makes sense that being brought up in a natural environment with natural exposures, as in farming, allows for evolutionary adaptation; recent human changes, which do not allow for evolutionary accommodation, in farming and hygiene have the potential to disrupt the complex interaction between us and nature.
  • Some unresolved issues: is it just the microbiome? Are there undetected viruses which either promote or protect from T1D development? Is it when one is exposed to the virus (e.g. it seems that several diseases such as EBV seem to confer less likelihood of developing MS if the EBV infection happens earlier. same with the clinical results from polio infection). Though the very well-controlled mice experiments seem to suggest an important role for the microbiome itself, and the effect of specific bacterial changes.
  • This does not mean that modernization has no benefits: Russian Karelia has life expectancy 66.6 years, 13 yrs less than Finns.
  • The hygiene hypothesis does not mean personal cleanliness. It refers to specific environmental exposures. So, eating food off the ground is not necessarily protective….

—————————————————————————————————                                     The Amish of Indiana and the Hutterites of South Dakota are groups of farmers who emigrated from Europe in the 1700s and 1800s during the Prostestant Reformation, have similar genetic ancestries, but very different prevalences of asthma: the Amish schoolchildren have a prevalence of 5.2% vs 21.3% in the Hutterites; and the prevalence of allergic sensitization is 7.2% vs 33.3%. This is despite similarities in many of the risk factors for asthma, including: large sibship size; high rates of childhood immunization; diets rich in fat, salt and raw milk; low rates of childhood obesity; long duration of breast-feeding; minimal exposure to tobacco and air pollution; and taboos against indoor pets. But they have very different farming styles: the Amish practice traditional farming using horses for fieldwork and transportation, and live on single-family dairy farms; the Hutterites live on large communal industrialized farms. The current study (see Stein MM. N Engl J Med 2016; 375:411) assessed environmental exposures, genetic ancestry, and immune profiles of 60 Amish and Hutterite children, measuring levels of antigens and endotoxins, and the microbial composition of indoor dust samples. They also looked at the effect of dust extracts from each grouping on the immune and airway responses in a mouse model of experimental allergic asthma. Results:

  • Of the 30 children from each group, mean age 11, 30% girls, 14 sibs, but they found: no asthma in the 30 Amish kids and 6 cases in the Hutterites, similarly much higher allergen-specific IgE  and total serum IgE levels in the Hutterites. No other immunoglobulin differences. Also decreased peripheral eosinophils in the Amish children
  • Genome-wide SNPs revealed “remarkable genetic similarities” between the 2 groups of children (confirming that these groups are from similar genetic backgrounds)
  • Median endotoxin levels were 6.8 times as high in the Amish house dust; common allergens (cats, dogs, house dust-mites, cockroaches) were 4 times as high in the Amish homes
  • There were profound differences in the microbial composition of mattress dust samples
  • There were profound differences in the proportions, phenotypes, and functions of innate immune cells of the 2 groups of kids
  • Intranasal instillation of dust extracts from Amish but not Hutterite houses significantly inhibited airway hyperreactivity and eosinophilia in the mice

Commentary:

  • Unfortunately they did not assess microbiome changes (both in the gut and in the respiratory tract) in these children. This study does suggest that there are profound effects of the environment (likely related to the differing farming techniques) which translate into quite dramatic differences in immune responses and ultimately into clinical allergic asthma.
  • The tie-in with microbiome is a bit opaque (at least translucent) in this article, but was addressed in a Canadian study, which looked at the effect of microbiome changes associated with antibiotic exposure and the development of asthma, along with comments on other studies about T1D, gluten-sensitivity, etc. (see prior blog http://blogs.bmj.com/ebm/2015/11/09/primary-care-corner-with-geoffrey-modest-md-gi-microbiome-in-little-kids-and-development-of-asthma/)
  • So, the bottom line: there are pretty clearly very important associations between the human microbiome and an array of disorders (see http://blogs.bmj.com/ebm/category/microbiome/); the microbiome is sometimes referred to as the “missing organ”, but seems quite susceptible to external/environmental stimuli. Preserving a healthy microbiome relies on a healthy diet and exercise (and reducing the barriers to them…). And there are even some data finding that stress itself leads to changes in the microbiome and conversely that changes in the microbiome lead to changes in how the body reacts to stress through the hypothalamic-pituitary axis (e.g. see Gur TL. Front Psychiatry 2015; 6:1, or the whole issue of Science from June 08, 2012, including the article by Nicholson JK. Science. 2012; 336: 1262). So, to me, this issue really does reinforce some of the current initiatives: reducing the use of antibiotics both in humans and especially in farming where farm animals get antibiotics to increase their weight; and increasing a healthier lifestyle with better nutrition, exercise, and decreasing stress (though these last ones are not really getting better….).

 

 

Primary Care Corner with Geoffrey Modest MD: GI Microbiome in Little Kids and Development of Asthma

9 Nov, 15 | by EBM

By Dr. Geoffrey Modest

A rather striking article came out recently finding early infancy microbiome changes are associated with increased risk of childhood asthma, further feeding my interest/concern with changes in the microbiome and disease (see  Sci Transl Med 2015; 307 (Sept 30): 307ra152). In humans, it seems pretty clear that there are genetic factors which predispose individuals to asthma/allergies, but the dramatic recent increase in incidence confirms an environmental component. The hypothesis is that early life events alter the microbiome, including such things as pre and peri-natal antibiotics, delivery by C-section, urban vs farm living, and formula feeding (see http://blogs.bmj.com/ebm/2014/08/13/primary-care-corner-with-geoffrey-modest-md-asthma-and-early-exposure-to-allergens/  for prior blog on this). Mouse and some human studies show that there is an early-life critical window when gut microbial dysbiosis affects subsequent immune function development. Mice given antibiotics perinatally have increased airway inflammation, prevented by replacing the gut with healthy microbial flora. The current study was derived from the multicenter longitudinal prospective CHILD Study (Canadian Healthy Infant Longitudinal Development), which followed a birth cohort until 5 yo.

Details:

  • 319 kids had stool microbiome analysis at age 3 mos and 1 year, including 87 with atopy (A), 136 with wheezing (W), 22 with both (AW), and 74 controls. The AW infants were ultimately at the highest risk of developing asthma based on the Asthma Predictive Index (API) and clinician diagnosis of asthma by age 3. [API is a validated clinical tool for predicting active asthma at school age (age 6-13). A positive API is recurrent wheezing between 2-3 yo along with other criteria such as positive family history of asthma or MD-diagnosed atopic dermatitis. A positive API in 3yo’s has a 77% chance of developing asthma at school age, a negative API is associated with a 3% chance].
  • There was clinical assessment of the kids at age 1, 3, and 5 yo for atopic dermatitis, rhinitis, or asthma. And there was standardized assessment of  inhalant and common food allergens

Results:

  • ​Kids at 1 yo with AW were 21.5x more likely to have a diagnosis of asthma than controls, 3.9x more likely than the A group and 5.4x more likely than the W group. (i.e., AW kids had a really high likelihood of developing clinical asthma]
  • Of the risk factors for GI microbial dysbiosis, antibiotic exposure in the first year of life increased the likelihood of AW at 1 year (OR 5.6) as did atopic dermatitis (OR 6.4). Caesarian birth, exclusive breast-feeding, and antibiotic exposure in infancy (though these can affect the microbiome) only displayed a nonsignificant trend to developing AW
  • Decreases in 4 bacterial genera were found in the AW group (Faecalibacterium, Lachnospira, Veillonella, and Rothia, or FLVR)
  • There are functional correlated to these changes in microbiota: there are decreases in lipopolysaccharide levels as well as changes in short chain fatty acid levels. And these changes are associated with proinflammatory cytokines (IFN-g, TNF, IL-17A, IL-6)
  • Mice with a sterile GI tract were inoculated with stool from an AW patient (who later developed asthma) vs the same innoculum with added live FLVR. They then looked at the subsequent generation of mice, finding that the fecal microbiota in the offspring tracked whether they received the FLVR or not, and that those with FLVR had much less lung inflammation (those without FLVR had “severe lung inflammatory response” to a stimulus), confirming that the changes in the microbiome were associated with strong imunomodulatory effects
  • The intestinal microbiota of the AW children at 1 yo was only minimally different from controls

 

So, what does this all mean???

  • As a perspective, the human microbiome is a coevolution of the human host and microbiota over eons, in a mutually beneficial way, and is vertically transmitted from mothers to kids through the birth canal and breast milk (the infant gut is sterile, but quickly develops its own microbiome from the mother)
  • Lots of stuff we do to infants changes that microbiome significantly, and in this study the primary villain was early antibiotic use (the other concerns about c-sections, maternal perinatal antibiotics, formula feeding all showed trends to being implicated but did not reach statistical significance)
  • These changes seem to be time sensitive: the microbiome is changed dramatically at age 3 months (and not so much later), suggesting that there is a window in which there are profound differences in the developing immune system, and that changing the microbiota leads to important clinical changes in the immune system long-term (with kids have AW at 1 year and much higher risk of asthma at 3 years of age)

 

So, bottom line, there is, I think, increasing evidence that what we do as clinicians and in society overall has profound effects. We clearly see the more immediate effects of antibiotics, e.g. infections get better, but there may be long-term and unappreciated sequelae of these changes. I think we need to be increasingly circumspect about our interventions. Clearly one of the most positive changes over the past decade or so is the decreasing use of antibiotics. The problem is that we tend to treat kids under 3 yo with fevers pretty aggressively with antibiotics to prevent real potentially fatal outcomes, and this seems to be a critical time in microbiome changes. Our approach has been an increasingly less invasive over time, though data as from this study should be incorporated into the risk/benefit analysis. As a side note, this study on antibiotic-induced microbiome changes dovetails nicely with all of the studies suggesting that asthma is associated with “too clean” an environment, finding that kids brought up on farms, in rural areas, etc. (and with altered microbiomes) have less asthma.

See http://blogs.bmj.com/ebm/category/microbiome/ for more blogs on the microbiome

 

Interesting article in Sunday New York Times on celiac disease (see http://www.nytimes.com/2013/02/24/opinion/sunday/what-really-causes-celiac-disease.html?ref=todayspaper&_r=0 ). A few points:

  1. Breast-feeding may protect kids
  2. Intestinal bacteria may play an important role
  3. There is a pretty clear genetics/environment interaction (e.g. 30% of people from European ancestry carry one of the predisposing genes, yet <5% get the disease)
  4. Interesting area in Finnish/Russian border, in north Karelia (where lots of epidemiologic studies have been done over the decades), an area which includes ethnic Finns and Russians. Russians have far fewer cases of celiac dz (or type 1 diabetes, which is also correlates with celiac dz), though eat more gluten.
  5. But there are interesting microbial differences: more microbes on the Russian side of the city (harkens back to the larger studies of asthmatics and apparent protection from early microbial exposure). Turns out that some microbes intensify intestinal inflammation (e.g. e coli) and some decrease inflam/protect the intestines and lead to tolerance (e.g. bifidobacteria). Bifidobacteria occur naturally in breast milk (with some interindividual variations).
  6. In Sweden 30 years ago, they encouraged mothers to wait till kids were 6 months old to introduce gluten into the diet, and coincidentally that was the time that they typically stopped breast-feeding. Kids were given a pretty big bolus of gluten at that time. Result: tripling of celiac dz.  Incidence decreased when they changed their guidelines: keep breast-feeding but introduce gluten slowly and in small aliquots. (Am acad of pediatrics recommends that infants start eating gluten while still breast-feeding)
  7. Spanish cohort of 117 children with celiac-assoc genotypes: fewer bifidobacteria in their guts, but those who breast-fed had boosted bifidobacteria counts.
  8. Researcher at children’s hosp (Fasano) followed 17 at-risk kids, checked their gut microbes over time, and found that 2 of them developed dz (1 celiac, 1 type 1 dm), assoc with falling lactobacillus counts.
  9. So, complex interaction between genes and environment, it seems. genes seem to be assoc with changes in the microbial environment, as does diet, breast milk, antibiotics, etc. also turns out that breast-milk varies in its effects on the microbial environment: higher bifidobaceria in mothers living in microbially-enriched environment (such as farmers)

Pursuant to the above, a discover magazine article discussed the extensive microbial collection in our bodies and reinforces the conception that we are part of a large microbiome (i.e., the conceptual antithesis to the predominantly held belief that we need to fight germs tooth-and-nail-and-with-lots-of-antibiotics….  — a path which has not only led to the development of untreatable superbugs, but perhaps to the increasing development of asthma and perhaps other allergic/autoimmune diseases. Also lends credence to the concept, however distasteful, of stool transplant for c. diff (i.e., either sending the stuff down an n-g tube or up through a colonoscope or enema) see http://discovermagazine.com/2013/jan-feb/3-a-census-of-your-insides#.USt_XDDql8E

Primary Care Corner with Geoffrey Modest MD: Vitamin D and atopic dermatitis in kids

12 May, 15 | by EBM

By: Dr. Geoffrey Modest

Atopic dermatitis (AD) is pretty common in kids (up to 25%), typically occurring early on (45% of cases begin within first 6 months of life, 60% within first year), and 70% remit spontaneously by adolescence. In those with AD there are significant immunologic changes (increase in Th2 cells and decrease in Th1 cells in their skin, though there are differences in these T-cell subsets in the acute AD phase, with Th2 cells and their associated cytokines of IL-4, IL-5, IL-13 predominating, but in the chronic phase the Th1 cells and their associated IFN-g, IL-5,IL-12 predominate. Vitamin D receptors are all over the body, including in the skin and in the immune system, and a small RCT in AD patients randomized to vitamin D 1,600 IU/d found clinical improvement after 60 days. The current study looked further into the immunologic changes and clinical effects of vitamin D supplementation in AD patients (see Arch Allergy Immunol 2015;166:91–96​).

Atopic_dermatitis_child

Details:

–39 children with chronic AD (mean age 4, 38% with family history of asthma, 87% family history of allergies, 33% of the kids had asthma and 33% had rhinitis; 8% had mild AD/46% moderate and 46% severe; 90% with total IgE increased and 23% had documented food allergy, 21% for inhalants only; 38% tested positive for dust mite allergen and 44% for eggs. overall skin test positivity was present in 79%). These AD patients were compared with 20 nonallergic healthy controls.​

— baseline cytokine (IL-2, IL-4, IL-6, IFN-g, TNF-a) and vitamin D levels were assessed, along with SCORAD (an AD clinical scoring system) index.

–then the patients were treated with vitamin D (1,000 IU/day) for 3 months.

–Families of AD patients were asked not to use topical steroids (6 did use them sporadically) or oral steroids (none used)

Results:

–all cytokines except TNF-a were elevated in the AD kids
–baseline vitamin D levels in the AD and control patients were similar (23 ng/ml in AD group and 20 ng/ml in controls)

–after vitamin D supplementation, the vit D levels increased from 23 ng/ml to 29 ng/ml

–the altered cytokines  (IL-2, IL-4, IL-6, IFN-g) were all statistically significantly and dramatically reduced after the vitamin D supplementation, and were within the range of the normal kids

–the SCORAD index decreased from 46.13 +/- 15.68 to 22.57 +/- 15.28, p<0.001) — a SCORAD index of 25-50 reflects moderate AD

In terms of the role of helper T cell subsets, in brief Th1 cells are moere involved in immunity to intracellular pathogens and in autoimmunity; Th2 more with defense against parasites and with atopic diseases. the balance of Th1/Th2 may be important in terms of disease progression. People with higher ratios and HIV infection have slower disease progression. The most significant initial cytokine associated with Th1 is IL-12, and also IFN-g. Th2 is most strongly associated with IL-4.

Although there was no formal control in this study, they did find that those kids who did not adhere to the vitamin D supplementation or did not have much of a bump in their vitamin D levels did not have a significant change in their SCORAD index or cytokine levels. So, given the data that vitamin D may well be important in immune function in general and the results in this and the other study cited above, it certainly seems reasonable to me to check vitamin D levels and supplement in kids with atopic dermatitis.

Primary Care Corner with Geoffrey Modest MD: Food Diversity in Young Kids and Subsequent Allergy

10 Jun, 14 | by EBM

as perhaps a complementary article to the blog last week on soluble fiber, changes in the microbiome, and asthma, this article also came out finding that increased variety of foods introduced in the first year of life led to decreased asthma, food allergy and food sensitization, as well as several biological markers of allergy (see doi.org/10.1016/j.jaci.2013.12.1044). this was a birth cohort study of 856 children from rural Europe with parents reporting monthly food diaries during the first year of life (which should decrease likelihood of reverse causality). they also assessed environmental factors and the development of allergic diseases up til the kids were 6 years old. results:

–51.5% of kids grew up on farms, 53.6% had at least one allergic parent (note: this may affect generalizability of results) –dose-response effect: each additional food item introduced into the diet was associated with 26% decreased likelihood of developing asthma, with similar effect on food allergy and food sensitization. –this inverse relation between increased complementary foods and asthma did not change after if parents avoided food because of presumed allergy. the relation between numbers of foods and allergies was independent of whether the kids grew up on farms or had allergic parent(s) –in terms of specific foods, strong negative association with milk products (eg yogurt and butter) or with in the first year of life and subsequent allergies –also increased expression of marker for regulatory Tcells in those on diverse diets –this same research group previously reported similar findings with atopic dermatitis

one link with the last study is that the infant gut develops its microbiome early which may be affected by different foods ingested. studies have found an inverse relation between bacterial diversity of the gut microbiota in the first month of life and later development of eczema. prior pediatric feeding guidelines have recommended food allergy avoidance/delayed introduction of foods to prevent allergic diseases, but no clear benefit has been evident and there has been a clear increase in allergic diseases — hence newer guidelines have changed (eg, see doi: 10.1097/MPG.0b013e3181615cf2, or see below). as in the previous blog on asthma and the microbiome, the current study again challenges our model of health and disease. had we been “protecting” our kids too much by overly regulating/constraining what they eat? (perhaps similar to the studies finding that kids in “cleaner environments” at an early age are more allergic later on).  have the recommendations by various societies (pediatrics, nutrition), which seem to be based on logic (better to have kids in clean surroundings, or old guidelines to avoid potentially allergy-inducing foods…) been myopic/ looking only short-term? we have certainly been through a prolonged strong recommendation by the am heart assn and various nutrition societies that low fat/high carb diets were good for the heart (and perhaps the resulting dramatic increase in obesity/diabetes)… the issue, as always, is to develop our models of disease with our best understanding of physiology, etc, but then to continually test and challenge them. here is prior blog on nutrition recs for kids: There were recent recommendations from the American Academy of of Allergy, Asthma, and Immunology regarding the primary prevention of allergic disease in infants through nutritional interventions (see doi: 10.1016/j.jaip.2012.09.003).  These recommendations were specifically for prevention of allergy and not for kids who already have allergic disorders.  In brief, through their literature review which is current as of August 2012, they suggest the following:

— maternal avoidance during pregnancy of essential foods such as milk and eggs is not recommended.  The data are mixed and inconclusive for peanut ingestion during pregnancy and the subsequent development of peanut allergy in children, so no recommendation is made. (Given the severity of peanut allergy and data suggesting that maternal ingestion of peanuts more than a few times a week may be associated with peanut sensitization in infants, it still might be prudent to minimize peanut ingestion to less than twice a week.  My suggestion.)

— maternal avoidance of highly allergenic foods during lactation is not recommended at this time.

— they recommend exclusive breast-feeding for at least 4 months and up to 6 months of age,which may possibly reduce the subsequent development of atopic dermatitis in kids younger than the age of two years and to reduce early-onset wheezing before age 4 years, as well as to reduce the incidence of cow’s milk allergy but not food allergy in general for the first two years of life. the data are however not conclusive

— for infants that have increased risk of allergic disease (eg lots of fam members with allergic diseases, though this definition varies considerably from one study to another) and cannot be exclusively breast fed for the first 4 to 6 months of life, hydrolyzed formula appears to offer advantages to prevent allergic disease and cow’s milk allergy.  An extensive casein or whey hydrolysate formula may be slightly more beneficial than the partial whey hydrolysate formula. There does not seem to be any advantage to soy based formulas.

— as I mentioned in my e-mail on celiac disease, there has been a major rethinking of introduction of complementary foods in infants.  The gist of these studies, which are observational, is that delayed introduction of  cereal grains, cow’s milk, eggs, and even peanut butter may lead to more allergic problems.  The report details these observational studies, which are quite impressive, and notes that there need to be interventional studies done.  But they do state that the studies support the general notion that highly allergenic foods may be introduced earlier in the diet as complementary foods.  They do note that it is important to start solid foods by 6 months of age to support growth, though different societies very a bit on this recommendation. (see DOI: 10.1053/j.gastro.2013.04.051, which suggested more specifically that gluten-containing foods be added after 6 months of age in small quantities at first and while breastfeeding at the same time)

— guidelines on food introduction have basically not changed, with the introduction of a single ingredient foods between 4 to 6 months of age at a rate not faster than one new food every 3 to 5 days.  Complementary foods are typically rice or oat cereal, yellow/orange vegetables, fruits, green vegetables, and then age-appropriate staged foods with meats.  They do not recommend delaying the introduction of acidic fruits, though they can cause localized perioral reactions on contact with the skin.  These do not usually result in systemic reactions and therefore should not be delayed.  Highly allergenic food should not be the first complementary food introduced, however once a few typical complementary foods are tolerated, highly allergenic foods may be introduced.  Whole cow’s milk as the infant’s main drink or other cow’s milk-based products such as cheese and yogurt are safe before the age 1, but should be minimized because of increased solute load and low iron content.

— children who have one underlying food allergy are at risk for other food allergies.  Referral to an allergist is recommended.  Children with siblings with peanut allergy have a 7% risk of peanut allergy themselves.  They feel that these children can have peanuts at home, in the form of peanut butter to avoid choking. they suggested the first introduction to peanuts be at home as opposed to in daycare.  Parents should be told that the initial reaction to such foods as peanuts typically happen after the initial ingestion but that fatal reactions have not been reported on a first exposure.

geoff

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