Too Much, Too Early or Too Late

Transcription

1 Too Much, Too Early or Too Late Prenatal & Perinatal Exposures Charles (Chip) Webb, M.D. The Allergy Group 1

2 Disclosure I have no relevant disclosures 2

3 1. Hygiene Hypothesis 2. Epigenetics 3. Climate Change/Dual Exposure J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 4 3

4 J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 4 1. Hygiene Hypothesis 2. Epigenetics 3. Climate Change/Dual Exposure 4

5 Hygiene Hypothesis Proposed that lower incidence of infection in early childhood could be an explanation for the rapid 20th century rise in allergic diseases such as asthma and hay fever. In 2003, the "old friends hypothesis was developed Argued that the vital microbial exposures are not colds, influenza, measles and other common childhood infections Rather the microbes present during mammalian and human evolution, that persist and are tolerated in carrier states. Humans have become so dependent on these "old friends" that their immune systems neither develop properly nor function properly without them. Strachan, D. (2000). "Family size, infection and atopy: The first decade of the 'hygiene hypothesis'". Thorax. 55 (90001): 2S. doi: /thorax.55.suppl_1.s2 5

6 Infections and Hygiene Hypothesis NEJM 2002; 347:

7 B a c t e r i a N Engl J Med 2011; 364: Bacteria on Farms N Engl J Med 2011; 364:

8 Amish LancasterPA.com Amish in America Amish adhere to simple living, plain dress, and a traditional lifestyle They eschew modern conveniences and technology Dairy farming is a desirable lifestyle and avocation for Amish family The Amish in America emigrated from the Swiss region of Europe J Allergy Clin Immunol 2015;136:

9 America Rural Farmers Amish Swiss Europe Farm vs. Non-Farm Asthma 5.2% Hay Fever 0.6% Atopic Eczema 1.3% Sensitization 7.2% Asthma 6.8 and 11.2% Hay Fever 3.1% and 11.6% Atopic Eczema 7.6% and 12.1% Sensitization 25.2% and 44.2% J Allergy Clin Immunol 2015;136:860-5 Amish in America The theory that asthma and allergy were relatively uncommon in the past and proper immune development requires protective antimicrobial responses to environmental allergens moves away from atopy. Other lifestyle difference between modern metropolitan living and that characteristic of Amish farming families. The Amish families averaged 6 children per family which was double the Swiss farmers and non-farmers. 9

10 Hitterite stpopular&mediatype=photography&phrase=hutterite Amish & Hutterite Study The Amish of Indiana and the Hutterites of South Dakota Lifestyles are similar with respect to most of the factors known to influence the risk of asthma: large sibship size, high rates of childhood vaccination, diets rich in fat, salt, and raw milk, low rates of childhood obesity, long durations of breast-feeding, minimal exposure to tobacco smoke and air pollution, and taboos against indoor pets. Amish practice traditional farming, live on single family dairy farms, and use horses for fieldwork and transportation, Hutterites live on large, highly industrialized, communal farms. 10

11 N Engl J Med 375; Amish & Hutterite Study N Engl J Med 375;

12 N Engl J Med 375; Amish & Hutterite Study Key Findings: The median endotoxin levels in Amish house dust was 6.8 times higher Prevalence of asthma in Amish versus Hutterite schoolchildren is 5.2% versus 21.3% Prevalence of allergic sensitization is 7.2% versus 33.3% N Engl J Med 375;

13 Pacifier Study Pacifier Study PEDIATRICS Volume 131, Number 6, June

14 Pacifier Study PEDIATRICS Volume 131, Number 6, June 2013 Pacifier Study PEDIATRICS Volume 131, Number 6, June

15 1. Hygiene Hypothesis 2. Epigenetics 3. Climate Change/Dual Exposure The cause for the allergy epidemic or is it?! 15

16 Charles Darwin Jean-Baptiste Lamarck Evolution Unlike most other people at that time, Darwin and Lamarck both thought that life had changed gradually over time and was still changing Darwin and Lamarck also agreed that life evolved from fewer, simpler organisms to many, more complex organisms 16

17 Lamarck Changes during life in order to adapt to environment, are passed on to offspring He cited examples of blindness in moles The presence of teeth in mammals and the absence of teeth in birds Change is made by what the organism wants or needs Lamarck For example, Lamarck believed that elephants all used to have short trunks. When there was no food or water that they could reach with their short trunks, they stretched their trunks to reach the water and branches, and their offspring inherited long trunks amarck/lamarck/lamarck_lamarck.html 17

18 Lamarck believed that giraffes stretched their necks to reach food. Their offspring and later generations inherited the resulting long necks. amarck/lamarck/lamarck_lamarck.html Darwin Desires of animals have nothing to do with how they evolve Changes in an organism during its life do not affect the evolution of the species Organisms, even of the same species, are all different and those which happen to have variations that help them to survive in their environments survive and have more offspring. The offspring are born with their parents' helpful traits, and as they reproduce, individuals with that trait make up more of the population. Other individuals, that are not so well adapted, die off amarck/darwin/lamarck_darwin.html 18

19 Darwin Most elephants used to have short trunks, but some had longer trunks. When there was no food or water that they could reach with their short trunks, the ones with short trunks died off, and the ones with long trunks survived and reproduced. Eventually, all of the elephants had long trunks. amarck/lamarck/lamarck_lamarck.html Who do we believe? Darwin's theory has been supported by a lot of evidence Lamarck's Theory of Inheritance of Acquired Characteristics has been disproved If a dog's ears are cropped short, its puppies are still born with long ears If someone exercises every day, runs marathons, eats well, and is generally very healthy, the fitness is not passed on and the person's children still have to work just as hard to get that fit and healthy. We know that the only way for traits to be passed on is through genes, and that genes can not be affected by the outside world The only thing that can be affected is which gene sets there are in a population, and this is determined by which individuals die and which ones live amarck/webelieve/lamarck_webelieve.html 19

20 Epigenetics and The Rest of the Story No simple answer for the rapid rise in allergy Since 1950 s a 50% rise in prevalence of allergic disease each decade Gene Changes/Hygiene hypothesis/processed foods, and etc does not seem to answer all the questions What about Epigenetics Drosophila melanogaster Normal Embryo raised in higher temperature (35 instead of 25 degrees Celsius) If these flies are again crossed, the following generations are partly red-eyed without further temperature treatment even though only white-eyed flies are expected according to the rules of genetics htm 20

21 Polyphenism More than one phenotype for one genotype Current Biology Volume 21, Issue 18, 27 September 2011, Pages R738-R749 21

22 You can think of the fat yellow mice as looking different because they have an epigenetic "mutation When researchers fed pregnant yellow mice a methylrich diet, most of the resulting pups were brown and healthy and stayed that way for life. These results indicate that an individual's adult health is heavily influenced by early prenatal factors. In other words, our health is not only determined by what we eat, but also what our parents ate Current Biology Volume 21, Issue 18, 27 September 2011, Pages R738-R749 22

23 DNA Methylation Non-permanent modification of the genome (Like turning on and off a light, genes can be turned on and off as well) A methyl group ( CH3) is attached to a specific cytosine residue. The bulky methyl group attached to the DNA blocks the transcription machinery, so a methylated gene is effectively silenced. Methylation is strongly associated with the environment Evidence is slowly accumulating that methylated genes can be transmitted from one generation to the next 23

24 Histone Acetylation Acetylation brings in a negative charge that acts to neutralize the positive charge on the histones Condensed chromatin is transformed and associated with greater gene transcription Relaxation of chromatin can be reversed by histone deacetylation This is not thought to be passed on to future generations m Micro RNAs Post-transcriptional regulators that bind to complementary sequences on target messenger RNA Micro RNA result in translational repression and gene silencing Human genome encodes over 1000 micro RNAs which may target about 60% of mammalian genes 24

25 Micro RNA inheritance Obese fathers may pass their obesity to children and grandchildren (Source: The University of Adelaide) Molecular cell biology has long been dominated by a protein-centric view. But the emergence of small, non-coding RNAs challenges this perception. These plentiful RNAs regulate gene expression at different levels, and have essential roles in health and disease 1. Hygiene Hypothesis 2. Epigenetics 3. Climate Change/Dual Exposure 25

26 Environment/Dual Exposure The Food We Eat? Travel 5,674 children with early travel history 2/3 travel outside of Germany in 1 st 2 years of life No association with travel frequency or distance Clin Exp Allergy: 2017;

27 Prophylactic Moisturization for Atopic Dermatitis Emerging evidence suggests that the use of moisturizers on newborns and infants (ie, from birth to 6 months of age) is potentially helpful in preventing the development of atopic dermatitis JAMA Pediatr. 2017;171(2) Moisturizing Newborns Can Prevent Eczema and Allergies 118 newborns into two groups of 59 each, applying an emollient a glycerine-based overthe-counter moisturiser to one group of babies for 32 weeks and no treatment to the other group. As a result, 19 in the intervention group developed atopic dermatitis eczema against 28 in the control group. The study, which the researchers said was a global first, tentatively shows moisturising reduces the risk of developing eczema by 30 percent. JAMA Pediatr. 2017;171(2) 27

28 Long-Chain n-3 Polyunsaturated Fatty Acids Journal of Allergy and Clinical Immunology 2017; 139:

29 Journal of Allergy and Clinical Immunology 2017; 139: Journal of Allergy and Clinical Immunology 2017; 139:

30 Journal of Allergy and Clinical Immunology 2017; 139: Journal of Allergy and Clinical Immunology 2017; 139:

31 Long-Chain n-3 Polyunsaturated Fatty Acids Maternal supplementation with fish oil might have prophylactic potential for longterm prevention of asthma in offspring. 31

32 Food Allergies Parentally-perceived food allergy is common with up to 1/3 of parents reporting one or more adverse food reactions Most food allergy is acquired in 1 st to 2 nd year of life with a peak prevalence of 6-8% at one year of age Food Allergy is increasing (The prevalence of food allergy in children (0-17 years) has increased from 3.4% in 1997 to 5.1% in 2009) Food allergy in Children - UpToDate - current Jan 2015 U. S. FDA 2004 Food Labeling Law Law requires imported and domestic food labels that contain any protein derived from the eight most common food allergens be identified 160 foods can cause allergic reactions 90 percent of food allergic reactions were caused by 8 foods: 1) Milk 2) Egg 3) Fish 4) Shellfish 5) Tree Nuts 6) Peanuts 7) Wheat 8) Soybeans Food allergies: what you need to know - FDA

33 An Australian Consensus on Infant Feeding Guidelines to Prevent Food Allergy: Outcomes From the Australian Infant Feeding Summit J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER

34 Deaths From Food Anaphylaxis* 63% Peanut *JACI 2001;107:191-3 All Other Anaphylaxis Attributed to Foods (USA and UK) 47% Peanut All Other Foods 34

35 Peanut Anaphylaxis Severity 81% Arch Allergy Immunology 1999;119: Avoidance the primary therapeutic strategy 237 peanut allergic patients Accidental exposures An annual rate of accidental exposure was 9.7% (95% CI, 6.3% to 14.2%) About 10% RXN/YR Accidental ingestions in children with peanut allergy; JACI 2006; 2; 118;

36 Avoidance Often Fails 36

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38 Primary Prevention Clinical practice guidelines recommended exclusion of allergenic foods from the diets of infants and their mothers Studies show these measures failed to prevent food allergy 2008 Avoidance recommendations withdrawn Peanut Consumption in Infants at Risk for Peanut Allergy: NEJM Feb 2015 Exposure to peanuts in utero and in infancy and the development of sensitization to peanut allergens in young children Mothers who consumed peanuts more than once a week during pregnancy were more likely to have a peanut-allergic child than mothers who consumed peanuts less than once a week (odds ratio=3.97, 98% confidence interval ) Peanuts or peanut butter was introduced into the child's diet from a significantly younger age in the peanut-allergic subjects (p<0.03) Exclusive breast feeding did not protect against the development of peanut sensitization It is more likely to occur if mothers eat peanuts more frequently during pregnancy and introduce it early to the infant's diet Pediatr Allergy Immunol 1999; Vol10,

39 An Increasing Problem United States and United Kingdom: Prevalence might have tripled in past years Nearly 100,000 new cases annually 1:50 primary school-aged children Consensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants: JACI 2015; 136: Primary Prevention Jewish children in UK had 10X the risk of their Jewish counterparts in Israel Similar ancestory UK children typically do not consume peanut-based foods in first year of life Israel children have peanut-based products introduced by 7 months of age Hypothesis early peanut is protective Peanut Consumption in Infants at Risk for Peanut Allergy: NEJM Feb

40 t and Randomization. Du Toit G et al. N Engl J Med DOI: /NEJMoa months to 11 months of age Had to have severe eczema, egg allergy, or both (markers for risk of food allergy) Peanut Consumption in Infants at Risk for Peanut Allergy: NEJM Feb

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42 Intervention Assigned to peanut consumption who had a positive response to the oral food challenge administered at baseline were instructed not to eat peanuts but were included in the intention-to-treat analysis Only participants who adequately adhered to treatment were included in the per-protocol analysis. Adequate adherence to treatment was defined in the peanut-avoidance group as consumption of less than 0.2 g of peanut protein (the equivalent of one peanut) on any occasion and less than 0.5 g over a single week in the first 2 years of life In the peanut-consumption group, adequate adherence was defined as consumption of at least 2 g of peanut protein on at least one occasion in both the first and second years of life and of at least 3 g of peanut protein (25 g of Bamba [a snack food made from peanut butter and puffed maize] or 12 g of peanut butter) per week for at least 50% of the weeks during which data were recorded mary Outcome. Du Toit G et al. N Engl J Med DOI: /NEJMoa

43 86.1% relative reduction in the prevalence of peanut allergy Peanut Consumption in Infants at Risk for Peanut Allergy: NEJM Feb 2015 Early environmental exposure (through the skin) to peanut may account for early sensitization early oral introduction of peanuts could prevent allergy in high-risk, sensitized infants and nonsensitized infants Peanut Consumption in Infants at Risk for Peanut Allergy: NEJM Feb

44 Eat Peanuts Baby! LEAP-ON Study 556 of LEAP participants enrolled (88.5%) Avoid peanut for one year Challenge with peanut Avoidance group % peanut allergy Consumption group % peanut allergy P< Conclusion: benefit of early introduction is enduring NEJM 2016; 374:

45 EAT Study 1,303 unselected 3 month olds Introduction of cow s milk, cooked egg, peanut, sesame, whitefish, and wheat breast feeding alone until 6 months of age Eat Study 32% adherence to 2 grams of protein two times a week 2 oz plain yogurt ½ boiled egg 1/3 oz fish 2 tsp peanut butter 7 tsp cream of wheat or pasta 3 tsp sesame seeds (tahini) 45

46 EAT continued Failure to adhere: Questions incomplete Parental QOL Eczema Protocol Adherent Children (32%) Allergy to at least one food 7.3% of breast fed only X 6 months 2.4% of early introduction Decreased risk for peanut and egg No significant difference in sesame, milk, wheat & fish Heap Study (Hen s Egg Allergy Prevention) 4-6 month of age infants Negative IgE to Hen s Egg Given Egg or Rice Powder (control) Ate it 3 times per week for up to 12 months of age 23/406 infants developed IgE to Egg 16/17 had a positive food challenge 11 had anaphylaxis Journal of Allergy and Clinical Immunology 2017; 139:

47 Heap Study (Hen s Egg Allergy Prevention) 5.6% of the egg white group sensitized 2.6% of the rice powder group became sensitized 2.1% of the egg white group developed egg allergy Conclusions: Early introduction of Hen s Egg does not decrease the risk of sensitization or the risk of Egg Allergy Journal of Allergy and Clinical Immunology 2017; 139: STEP Study (Starting Time of Egg Protein) Patient Selection: 820 infants of high risk mothers. Children 4-6 months of age Infants with eczema were excluded (primary prevention study) Infants were given Egg powder or Rice Powder Followed to 12 months of age Journal of Allergy and Clinical Immunology 2017; 139:

48 STEP Study (Starting Time of Egg Protein) Infants in Egg ingestion group had higher levels of IgG4 No difference in egg allergy at 12 months of age Conclusions: Early egg introduction does not decrease the risk of egg allergy at 12 months of age Journal of Allergy and Clinical Immunology 2017; 139: Beating Egg Trial Patient Selection: 4-8 months of age with 1 or more 1 st degree relatives with allergies Skin prick to egg was negative ¼ of the patients had eczema Given egg powder or rice powder At 12 months of age, skin prick was performed Journal of Allergy and Clinical Immunology 2017; 139:

49 Beating Egg Trial 11% sensitized for egg ingestion group 20% for the rice powder group Risk reduction of 9.8% Journal of Allergy and Clinical Immunology 2017; 139: Guideline Addendum Severe Eczema or egg allergy or both Peanut IgE <0.35 do home or office feeding >0.35 refer to allergist for skin testing or challenge testing Skin prick testing 0-2mm home or office feeding 3-7mm office feeding or graded challenge >7mm probably allergic, avoid 49

50 Optimal Exposure to Allergens The cornerstone of the change is high-level, RCT-based evidence that inclusion of allergens (peanuts) in the diet during the first year of life reduces the risk of food allergy. Summit participants agreed common allergens (such as peanut, egg, wheat, and cow's milk) should be included in an infant's diet during the first year of life. This is consistent with the NHMRC 2012 Infant Feeding Guidelines, and consistent with WHO recommendations encouraging food diversity in the weaning diet. It was agreed that practical guidelines on appropriate textures of infant foods are required (specifically use of nut meal or paste rather than whole nuts in the early diet to reduce the risk of choking). J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017 Optimal Exposure to Allergens Practical and economic issues were noted if allergy screening was to be recommended for infants at a higher risk of food allergies (including infants with severe eczema and/or diagnosed egg allergy). The HealthNuts study identified that families at high risk of developing food allergy are less likely to introduce egg and peanut into their infant's diets compared with lowrisk families.26 Potential means of targeting families who are more likely to benefit from early introduction of allergens were discussed, including education at diagnosis. J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER

51 Other Ideas Besides Prevention? 51

52 Eat Peanuts Baby! Peanut Immunotherapy 12 patients with peanut allergy 6 received IT, 6 untreated in open study All 6 of active group achieved maintenance dose of 0.5 ml 1:100 wt/vol extract by RIT All 6 achieved increased tolerance to oral challenge Systemic reactions common during both RIT and maintenance (mean 7.7 reactions/patient during RIT and 13.2 reactions/patient during maintenance) JACI 1997;99:

53 Peanut Immunotherapy Only 3 of 6 patients remained tolerant of full maintenance dose These patients demonstrated threshold doses of mg of peanut (~5-10 peanuts) Partial to complete loss of protection in the 3 who did not tolerate full maintenance dose Concluded: high rate of systemic reactions makes this form of treatment with the currently available peanut extracts unacceptable JACI 1997;99: Food Oral Immunotherapy Has been shown to provide protection against life-threatening reactions during therapy (desensitization) Potential for tolerance when therapy is discontinued Still limited availability Food Allergy: A practice Parameter update 2014 JACI 53

54 VIASKIN PEANUT Viaskin 18.5% of patients were able to consume at least 10-fold more peanut 0% in the placebo group (p=0.05) increase in: of peanut-specific IgE (immunoglobulin E) (p= 0.036) peanut-specific IgG4 (immunoglobulin G4) (p<0.0001). 54

55 However, after all this work Avoidance is still the primary strategy when prevention fails Read all labels Education: Internet (i.e. Foodallergy.org) Wear Medical Alert Bracelet Carry 2 epinephrine autoinjectors Have a plan of action 55