1. Role of probiotics in allergic
disease prevention in children
益生菌在兒童過敏疾病預防
所扮演的角色
高雄榮總 兒童醫學部
兒童過敏免疫風濕科
邱益煊
1/95
2. 前言
➢ Allergic diseases (including atopic dermatitis, respiratory
allergies and food allergies) are increasing in prevalence
worldwide, affecting up to 30% of the world population,
and pose a significant impacts on the quality of life in
atopic individual and on society, both economically and
psychosocially.
➢ Allergic diseases are now classified as the 4th most
common global disease by the World Health Organization.
➢ Allergic diseases are also the earliest onset non
communicable diseases (NCDs) and a clear manifestation
of the vulnerability of the immune system to modern
environmental changes.
➢ 根據研究報告顯示,過敏性疾病可能發生於不同年齡
,若發生時間愈早,其嚴重性就愈大,因此,預防過
敏的工作應盡早開始,才能將影響降到最低。
10. Life style and environment
➢ These allergic conditions linked to environmental and lifestyle
changes driving the dysfunction of three interdependent
biological systems: microbiota, epithelial barrier, and immune
system.
➢ Dietary changes are of particular interest in the altered
establishment and maturation of the microbiome, including the
associated profile of metabolites that modulate immune
development and barrier function.
➢ The primary prevention of allergic airway diseases focuses on
offspring’s gestational and childhood environment, such as
maternal smoking and diet during pregnancy and breast feeding
as well as exposure to environmental microbes and irritants.
➢ Rapid action needs to be taken to restrain smoking among
children and adolescents in order to prevent burden of allergic
airway diseases.
➢ Exposure to pollution and environmental issues concerning
hygiene and lifestyle would also need to be actively addressed.
10Nutrients 2019, 11, 1841
Curr Treat Options Allergy (2018) 5:347–355
37. the Canadian Healthy Infant Longitudinal Development (CHILD)
Study
嬰兒早期微生物及代謝改變影響兒童哮喘的風險
38. 嬰兒早期微生物及代謝改變影響兒童哮喘的風險
The relative abundance of the
bacterial genera Lachnospira,
Veillonella, Faecalibacterium, and
Rothia was significantly decreased
in children at risk of asthma
45. Seventeen studies from PubMed, Embase and Cochrane Library were
searched for randomized controlled trials evaluating the use of probiotics
during pregnancy or early infancy for prevention of allergic diseases,
reporting data from 4755 children (2381 in the probiotic group and 2374 in
the control group), were included in the meta-analysis.
17篇針對懷孕期及早期嬰兒使用益生菌預防過敏性疾病的研究,共收案4755名兒
童(2381名為益生菌組,2374名為對照組)進行資料分析
益生菌應用於預防兒童過敏性疾病
Allergy Eur J Allergy Clin Immunol 2015;70:1356-1371
46. 補充益生菌組的孩子和對照組相比,較少發展成濕疹(672 [28.22%]
vs 847 [35.67%], respectively).顯示補充益生菌可顯著降低濕疹的發
生率(RR 0.78 [95% CI 0.69–0.89], P = 0.0003)
Forest plot showing the association between probiotics and eczema
森林圖顯示益生菌和濕疹間之關聯性
Fewer children in the probiotic group developed eczema compared
to those in the control group (672 [28.22%] vs 847 [35.67%],
respectively). The RR was significantly lower in children treated with
probiotics (RR 0.78 [95% CI 0.69–0.89], P = 0.0003)
47. Forest plot showing the association between
probiotics and eczema in the studies which used
森林圖顯示益生菌和濕疹間之關聯性
A). Lactobacillus
P =0.18
B). Bifidobacterials
P =0.23
48. Forest plot showing the association between
probiotics and eczema in the studies which used
森林圖顯示益生菌和濕疹間之關聯性
C). Probiotics mixture with Lactobacillus
and Bifidobacteria
Test for overall effects Z =5.34
(P < 0.00001)
49. < 12 mon,
p =0.008
< 24 mon,
p =0.008
> 2 yrs,
p =0.13
50. No significant difference in terms of prevention of asthma
(RR 0.99 [95% CI: 0.77–1.27], P = 0.95), wheezing (RR 1.02
[95% CI: 0.89–1.17], P = 0.76) or rhinoconjunctivitis (RR
0.91 [95% CI: 0.67–1.23], P = 0.53) was documented
The results of the present meta-analysis show that
probiotic supplementation prevents infantile eczema, thus
suggesting a new potential indication for probiotic use in
pregnancy and infancy.
本結果顯示,益生菌補充劑可預防嬰兒濕疹,建議在懷孕期和嬰
兒期即可補充益生菌
Allergy Eur J Allergy Clin Immunol 2015;70:1356-1371
51. ➢ 29 randomized-controlled trials that examined probiotic
supplementation in pregnant women, breastfeeding mothers,
infants, and children.
➢ Of the 29 studies, 15 trials (n = 3509) evaluated probiotic use
during pregnancy. Exploration of the data showed a reduced risk
of eczema in infants (RR 0.72; 95% CI: 0.61–0.85) with probiotic
use during pregnancy.
➢ Thirteen studies (n = 1595) evaluating the use of probiotics in
breastfeeding mothers also revealed a reduced risk of eczema
(RR 0.61; 95% CI: 0.50–0.74).
➢ Fifteen trials (n = 3447) evaluating the use of probiotics in infants
reported a reduced risk of eczema (RR 0.81;95% CI: 0.70–0.94).
J. Allergy Clin. Immunol. 2015, 136, 952–961.
52. Results: Currently available evidence does not indicate that probiotic
supplementation reduces the risk of developing allergy in children. However,
considering all critical outcomes in this context, the WAO guideline panel
determined that there is a likely net benefit from using probiotics resulting
primarily from prevention of eczema.
The WAO guideline panel suggests:
世界過敏組織指南建議
a) using probiotics in pregnant women at high risk for having an allergic child;
過敏高遺傳性懷孕婦女可使用益生菌
b) using probiotics in women who breastfeed infants at high risk of developing
allergy
有過敏兒之哺乳婦女可使用益生菌
c) using probiotics in infants at high risk of developing allergy.
高過敏危險之嬰兒可使用益生菌
All recommendations are conditional and supported by very low quality evidence
53. ➢ A total of 28 studies met the inclusion criteria.
➢ Compared with controls, probiotic treatment was associated with
a reduced risk of AD (OR 0.69;95% CI 0.58-0.82, P < 0.0001).
➢ The use of probiotics during both the prenatal and the postnatal
period significantly reduced the incidence of AD (OR 0.67; 95% CI 0.54-0.82)
➢ Analysis of studies of probiotics given prenatally or postnatally only
did not reach statistical significance.
➢ Conclusions: Our meta-analysis showed that probiotic
supplementation during both the prenatal and the postnatal
period reduced the incidence of AD in infants and children.
➢ Our findings suggest that starting probiotic treatment during
gestation and continuing through the first 6 months of the
infant's life may be of benefit in the prevention of AD 53
54. ➢ A recent mini-review by Mennini et al. highlights that in asthma,
MMP9 levels were significantly increased, and treatment with
LGG was shown to decrease MMP9 expression in lung tissue and
inhibit inflammatory cell infiltration.
➢ Furthermore, in OVA-sensitized mice, LGG suppressed the airway
hyper-responsiveness to methacholine and reduced the number
of infiltrating inflammatory cells and Th2 cytokines in
bronchoalveolar lavage fluid and serum.
➢ LGG has previously been reported to reduce the concentration of
exhaled nitric oxide among 4- to 7-year-olds in pediatric asthma
54
Front. Pediatr. 2017, 5:1–5
Children 2019, 6:24
55. Current evidence does not support the use
of probiotics in the prevention of asthma
➢ Azad M.B., a meta-analysis including nine different trials and a
total of 3257 children showed an RR of 0.99 (95% CI: 0.81–1.21)
of asthma in children receiving probiotics.
➢ The previously described randomized-controlled trial by Cabana
et al. evaluated probiotics and the incidence of asthma at 5
years of age as a secondary outcome.
– The study did not show a significant reduction in asthma development
following the use of probiotics, with an incidence of asthma at 17.4% in
the control arm (n = 92) and 9.7% in the LGG arm (n = 92) (HR 0.88; 95%
CI: 0.41–1.87; log rank p = 0.25)
➢ Zuccottti et al. and Cuello-Garcia et al., which also did not show
any significant effect of probiotics on asthma
55
1. BMJ 2013, 347, f6471
2. Pediatrics 2017, 140, 1–9.
3. Allergy Eur. J. Allergy Clin. Immunol. 2015, 70, 1356–1371
4. J. Allergy Clin. Immunol. 2015, 136, 952–961
56. Probiotics in allergic rhinitis
➢ Allergic rhinitis affects between 10 and 30% of the population,
and the management of this disease is costly, both in the amount
spent on medications and in the loss of time away from work.
➢ Currently, there is no strong evidence that probiotics have an
effect on the development of allergic rhinitis.
➢ Peldan et al. administered questionnaires to the parents of their
study patients (at the time between 5 and 10 years of age)
investigating the presence of atopy, including allergic rhinitis, in
those children.
➢ Analysis of the lifetime prevalence of allergic rhinitis was the
same in both placebo and probiotic group; however, the
prevalence of allergic rhino-conjunctivitis at age 5–10 years was
greater in the probiotic group compared to the placebo group
(36.5% versus 29.0%, OR: 1.43, 95% CI:1.06–1.94, p = 0.03). 56
Clin. Exp. Allergy 2017, 47, 975–979.
61. Safety of probiotics
➢ Probiotics are generally considered safe; however,
they may not be completely innocuous. While there
are some probiotic products that are considered
medicinal, most are classified as commercial
food/dietary supplements or natural health
products.
➢ The authors rightfully recommend that patients
should always read labels closely and use commercial
probiotics with caution.
61
63. ➢ Hassan, a more recent systematic review examining the efficacy
and safety of probiotics in people with cancer included 25 studies
(n = 2242 participants) in their safety analysis.
– Five case reports were identified involving probiotic-associated infections
including bacteremia and fungemia. Two deaths were reported in patients
receiving probiotics; however, these were not attributed to the probiotic
intervention.
➢ Brunser reports of sepsis due to lactobacillus or bifidobacterium,
these species are generally not considered pathogenic. Relevant
case reports are usually associated with an underlying comorbidity
resulting in immunocompromise.
➢ Overall, the risk with probiotic administration appears low in non-
immunocompromised patients, but good clinical judgment is still
important in making the decision of whether to administer
probiotics or not in different clinical settings. 63
Safety of probiotics
Care Cancer 2018, 26, 2503–2509.
Rev. Chil. Pediatr. 2017, 88, 534–540
64. Conclusion
➢ Current evidence does not support the routine use of probiotics
as an intervention for preventing any form of allergic disease,
with the exception of eczema in high-risk infants (World Allergy
Organization WAO recommendation)
➢ The WAO does favor probiotic supplementation in
pregnant/lactating women and in infants with a family history of
allergic disease
➢ As a result of the previously studies, lack of homogeneity in
specific probiotic strains, many trials are now carefully recording
the specific strains of probiotics that are being used
➢ However, research in this area is ongoing and will hopefully
provide better insights into how probiotics may contribute to the
prevention or treatment of atopic diseases.
➢ The optimal strains, dosages, timing, and duration of probiotic
administration remain unknown. 64
69. Smoking
➢ Smoking during pregnancy is common, and estimated
rates vary from 17 to 30%.
➢ Cigarette smoking is the single largest modifiable risk
for all pregnancy-related morbidity and mortality.
➢ Numerous studies have confirmed the effect of
external tobacco smoke on the risk of asthma and also
on the severity of bronchial inflammation.
➢ This risk may be even transmitted by possible
epigenetic mechanisms over the generation from
grandmothers to grandchildren.
69
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70. ➢ A recent meta-analysis found that on adults, active smoking did
not increase risk of AR, but increased the risk for rhinitis.
➢ In children and adolescents, both active and passive smoking
increased the incidence of AR.
➢ The study group estimated that 14% of the AR is due to active
smoking, therefore eliminating smoking among young and
children, every seventh case of AR could be prevented.
➢ Reduction of smoking remains the easiest and one of the most
concrete ways of practical asthma prevention.
➢ Studies have shown that maternal smoking during pregnancy
increases the risk for wheezing in childhood or asthma among
offspring during early childhood [19], in preschool-age children,
in adolescents, and in adults.
➢ Conclusion: encourage women of childbearing age and parents
having children to permanently cease smoking in order to
decrease AR and asthma risk of offspring.
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Smoking
71. Allergen avoidance as
prevention of airway allergy
➢ It is not clear whether airway allergy can be prevented by
allergen avoidance in families having risk for allergic diseases.
➢ Most studies aiming to reduce risk of asthma or allergy
through controlling environmental exposure to allergens are
inconsistent and have failed.
➢ The Isle of Wight study examined the effect of diets and
extensive measures to reduce exposure to house dust mite
(HDM). This study with a relatively small number of children
(n = 120) considered at high risk for allergic disorders is the
only trial which has shown reduction of mite sensitization and
asthma persisting until the age of 18 years.
➢ The much larger and more comprehensive Manchester study
reported an opposite effect on mite sensitization. 71
Curr Treat Options Allergy (2018) 5:347–355
72. ➢ An impaired lung function was shown to develop on
children with high exposure to indoor allergens early
in life compared to children without sensitization.
➢ High amount of viral upper respiratory tract
infections in the first years of life may reduce the
onset of asthma later in life.
➢ It is clear that if an anaphylaxis has happened, then
avoidance is recommendable. Also, in secondary
prevention, avoidance seems to have a role.
72
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Allergen avoidance as
prevention of airway allergy
73. Inhaled indoor factors
➢ HDM has been the most studied of indoor air particles in
association with AR prevention.
➢ A Cochrane review was conducted in 2010, in which
seven reports concluded that HDM load can be reduced
with combination of acaricides and bedroom
environmental control programs. Reduction of AR
symptoms is poorly assessed in these reports, and more
specific studies are in request.
➢ Also, other factors as excessive moisture and volatile
organic compounds may play a role in airway allergy, but
taken together, controversial knowledge exists of the
effect of indoor particles to development of AR or
asthma.
73
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74. Outdoor environment factors
➢ Climate change and air pollution is one of the main reasons for
increase of allergic diseases. Especially, sulfur dioxide (SO2) is
shown to increase AR.
➢ In a cross-sectional questionnaire study, the authors concluded
that increase in the levels of SO2 increased the prevalence in AR
in Taiwanese school children.
➢ Also, exposure to traffic-related pollutant during pregnancy is
shown to increase the incidence of AR, as well as asthma and
eczema.
➢ Exposure to extreme heat has speculated to increase the
incidence of hay fever.
➢ Taken together, evidence exists that outdoor air pollution is
associated with airway allergy.
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75. Outdoor environment factors
➢ Several studies reported nearly 20 years ago that children grown
up in farm environment develop less asthma and allergies. This
effect is now contributed to contact with farm animals and their
microbes.
➢ The most recent studies from Amish and Hutterite populations
demonstrated that Amish children have much lower prevalence
of asthma than Hutterite children, despite the similarities in
ancestry and most lifestyle factors associated with asthma risk.
➢ At the moment, the data suggest that airborne substances likely
derived from animals and their microbes shape innate immune
pathways to finally produce protection from asthma.
➢ Several trials are now underway to examine whether for example
bacterial lysates could prevent development of asthma.
75
76. Vit D and obesity
➢ In a recent systematic review, the role of vitamin D in
primary prevention of allergic diseases was assessed
in four populations: pregnant and breastfeeding
mothers, infants, and older children. No clear
association between D vitamin and prevention of
airway allergy was found.
➢ There is lacking knowledge of the association
between obesity and AR.
➢ In a Chinese survey study (n = 4132), the prevalence
of allergic rhinitis and atopic dermatitis was higher
among obese children compared to children with
normal weight . 76
77. Perinatal dietary factors
➢ During the breastfeeding-period and first months of life,
nutrition of the baby is regarded as a major factor in
development of allergic diseases.
➢ There is not enough evidence on AR with dietary
consumption of the mom during the pregnancy or the
breastfeeding period.
➢ It is shown that if milking is not sufficient, highly
hydrolyzed formulas of cow milk decrease the incidence
of atopic eczema, but not asthma or AR.
➢ Polyunsaturated fatty acids (omega-3- and 6) were
tested in a randomized controlled trial in Australia and
no significant difference on allergic disease onset was
found between the study groups. 77
78. Perinatal dietary factors
➢ Numerous follow-up cohorts have addressed the
significance of breastfeeding on development of
asthma. The results have been often inconsistent and
the studies are often confounded by selection bias and
reverse causality.
➢ Even several meta-analysis studies done over the years
have not been able to solve the dilemmas and do not
demonstrate a consistent protection from asthma.
➢ It is, however, obvious that breastfeeding should be
recommended in all guidelines for many other health
benefits.
78
79. Maternal nutrition
➢ The nutrition of mothers during pregnancy: dietary patterns
and selective supplementation as well as levels of iron,
vitamin D, folic acid, and other nutrients may have protective
as well as adverse effects on the evolution of atopic diseases
in the offspring.
➢ However, only one published trial on nutritional intervention
of mothers has been able to show a clear decrease in asthma
risk.
➢ In a Danish study, pregnant mothers received fish oil or
placebo and their offsprings were followed for 3 years. The
risk of the children’s persistent wheeze and infections of the
lower respiratory tract infections was reduced by
approximately one third.
79
80. Conclusions
➢ Current knowledge of primary prevention of allergic
airway diseases is limited, except for smoking
cessation.
➢ Childhood AR and asthma risk are increased by
exposure to smoking. Hence, asthma and AR
offspring could be reduced and airway health could
be improved by encouraging parents to permanently
cease smoking.
➢ There is limited or controversial knowledge of other
environmental factors and their effect on airway
allergies
80
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81. Future needs
➢ Western urbanization and lifestyle changes are claimed
to be the main reason for the increase of airway
allergy.
➢ There is a global need of prevention of the current
epidemics of chronic allergic respiratory diseases.
Studies on prediction and prevention of allergic
diseases are needed.
➢ Programs of better education and successes of
children and adults in the case of the prevalence and
burden of allergic airway diseases are needed, such as
allergy programs.
➢ This would increase airway health and also general
health and wellbeing. 81
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