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|
Received: 17 April 2021    Accepted: 31 July 2021

DOI: 10.1111/all.15046

E A ACI P OSITION PAPER

Dangerous liaisons: Bacteria, antimicrobial therapies, and

allergic diseases

Gerdien  Tramper-­Stranders1,2  | Dominika Ambrożej3,4 | Alessandra Arcolaci5 |

Marina  Atanaskovic-­Markovic6  | Cristina Boccabella7  | Matteo Bonini7,8 |
Aspasia Karavelia9 | Ervin Mingomataj10  | Liam O' Mahony11 |
Milena Sokolowska12  | Eva Untersmayr13  | Wojciech Feleszko3  | the EAACI Task
Force on Conscious and Rational use of Antibiotics in Allergic Diseases
1
Department of Pediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
2
Department of Neonatology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands
3
Department of Pediatric Pneumonology and Allergy, Medical University of Warsaw, Warsaw, Poland
4
Doctoral School, Medical University of Warsaw, Warsaw, Poland
5
Immunology Unit, University of Verona and General Hospital Borgo Roma Hospital, Verona, Italy
6
Faculty of Medicine, University of Belgrade, University Children's Hospital, Belgrade, Serbia
7
Department of Cardiovascular and Thoracic Sciences, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli –­IRCCS, Rome,
Italy
8
National Heart and Lung Institute (NHLI), Imperial College London, London, UK
9
Department of Ear-­Nose-­Throat surgery, General Hospital of Kozani, Kozani, Greece
10
Department of Allergology & Clinical Immunology ‘Mother Theresa’ School of Medicine, Tirana, Albania
11
Departments of Medicine and Microbiology, APC Microbiome Ireland, National University of Ireland, Cork, Ireland
12
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Zurich, Switzerland
13
Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

Correspondence
Gerdien Tramper-­Stranders, Department
of Pediatrics, Franciscus Gasthuis
& Vlietland, Kleiweg 500, 3045 PM
Rotterdam, the Netherlands.
Email: g.tramper@franciscus.nl
Funding information
Outside the budget from the EAACI for
the task force, no funds were granted to
this project
Abstract
Microbiota composition and associated metabolic activities are essential for the edu-
cation and development of a healthy immune system. Microbial dysbiosis, caused by
risk factors such as diet, birth mode, or early infant antimicrobial therapy, is associated
with the inception of allergic diseases. In turn, allergic diseases increase the risk for
irrational use of antimicrobial therapy. Microbial therapies, such as probiotics, have
been studied in the prevention and treatment of allergic diseases, but evidence re-
mains limited due to studies with high heterogeneity, strain-­dependent effectiveness,
and variable outcome measures.
In this review, we sketch the relation of microbiota with allergic diseases, the over-
use and rationale for the use of antimicrobial agents in allergic diseases, and current
knowledge concerning the use of bacterial products in allergic diseases. We urgently
recommend 1) limiting antibiotic therapy in pregnancy and early childhood as a method
contributing to the reduction of the allergy epidemic in children and 2) restricting an-
tibiotic therapy in exacerbations and chronic treatment of allergic diseases, mainly

© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

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3276    
wileyonlinelibrary.com/journal/all Allergy. 2021;76:3276–3291.

TRAMPER-­S TRANDERS et al.
concerning asthma and atopic dermatitis. Future research should be aimed at antibi-
otic stewardship implementation strategies and biomarker-­guided therapy, discerning
those patients that might benefit from antibiotic therapy.
KEYWORDS
allergy, antibiotics, bacterial lysates, microbiota, probiotics
1  |  I NTRO D U C TI O N
Antibiotics are one of the most frequently prescribed medications
and their rational use has become an essential topic in clinical care,
mainly because of emerging antimicrobial resistance, which is a
threat to global health. A healthy interaction between the human
microbiota and the developing immune system, especially in the
gut, can be disturbed by the use of antibiotics in infancy. Several
studies have shown the association between the use of antibiot-
ics early in life and the development of allergic diseases. In aller-
gic diseases, the microbiome profile is associated with disease type
and severity. In turn, patients with allergic diseases such as asthma
have an increased risk of being prescribed antibiotics for infections
compared to the general population, despite the uncertainty about
clinical benefit. In fact, there are no clear data supporting antibiotic
prescriptions for acute exacerbations; and clinical and/or laboratory
criteria are lacking. Therefore, initiatives to evaluate and ensure the
appropriate use of antibiotics in patients with allergic diseases, and
guidelines to protect patients from antibiotic overprescription are
urgently needed. This narrative review aims to sketch the current
setting and describe the relation of microbiota with allergic diseases,
the rationale for the use of antimicrobial agents in allergic diseases,
and current knowledge concerning the use of microbial products in
allergic diseases.
2  |  M E TH O D S
The European Academy of Allergy & Clinical Immunology (EAACI)
Task Force “Conscious and rational use of antibiotics in allergic dis-
eases” was initiated in 2020 to address questions about the use of
antibiotics and their risk-­benefit ratio in allergic diseases. It received
a mandate to propose answers to frequently asked clinical ques-
tions and present practical, consensus-­based management sugges-
tions focused on published data. The Task Force consists of experts
in pediatrics, pulmonology, allergy, immunology, microbiology, and
evidence-­based medicine from 10 European countries (A, AL, CH,
GR, I, IRL, NL, PL, SRB, UK).
For this review, the Task Force has used existing literature and
systematic reviews to propose its clinical statements. Three key
questions were addressed: (i) What is the role of early antibiotic
prescriptions on dysbiosis and allergy inception? (ii) What is the ev-
idence for antibiotic prescriptions in allergy (asthma, atopic derma-
titis)? (iii) Are there any non-­antibiotic antimicrobial strategies that
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      3277
may be used for the prevention or exacerbations of allergic diseases?
This narrative review assessed all three questions.
The evidence was harvested through a thorough review of the
field finding problem-­specific systematic reviews. For those prob-
lems where the relevant systematic reviews were lacking, Task Force
members independently performed systematic literature searches
using PubMed, Cochrane, and EMBASE databases. The literature
searches were compared, duplicates were eliminated, and articles
were assessed for suitability.
3  |  TH E RO LE O F BAC TE R I A I N A LLE RG I C
DISEASES
3.1  |  Asthma and asthma exacerbations
Until 2010, when the first paper about the lung microbiome in
asthma and healthy controls was published, the lower airways were
regarded as sterile.1-­3 Since that time, many studies have been per-
formed comparing the microbiome between different asthma phe-
notypes and during a stable or uncontrolled clinical condition. In fact,
the lower airways are continuously exposed to aerosols with bacte-
ria and oral flora. Some bacterial strains or microbiome composition
has been postulated to contribute to asthma inception and exacer-
bations,4 while others confer a more protective role.5 The gut and
respiratory microbiome profiles of infants as young as 1 month old
are associated with the later development of wheezing and asthma.6
Infant upper respiratory tract colonization with Haemophilus influ-
enza, Moraxella catharralis, and Streptococcus spp. shows associations
with childhood asthma; increased ex vivo Th2 cytokine production
(IL-­5, IL-­13, and IL-­17) was observed already during infancy.7-­9
Before the availability of 16s sequencing methods, severe asthma
had been associated with the presence of Mycoplasma pneumoniae
and Chlamydophila pneumoniae.10 Together with Chlamydia tracho-
matis, Staphylococcus aureus, and Proteobacteria such as H. influenza,
all have been identified as possible contributors to more severe
asthma and asthma exacerbations, independent of inhaled cortico-
steroid use. In contrast, increased airway microbiota diversity and
the abundance of Actinobacteria were linked with improvement and
better asthma control.11 However, in other studies, increased diver-
sity was associated with more symptoms, depending on coloniza-
tion.12,13 It is essential to realize that the comparison of these studies
might be difficult because of different respiratory sampling sites (eg,
nasopharynx versus bronchi).
 |
3278      TRAMPER-­S TRANDERS et al.
Evidence exists that allergy and asthma undermine M.  pneu-
moniae clearance, suggesting that there is a feedback between the
host and organism.14 Recurrent M. pneumoniae infections are asso-
ciated with increased expression of non-­t ype 2 pro-­inflammatory
cytokines (including IL-­17, TNF-­α , and IL-­6), proposing that chronic
low-­level exposures result in mucosal inflammatory responses in
14
asthma patients. A similar pattern was found for C. pneumoniae
and H. influenzae, where the active infection is uncommon, and col-
onization is associated with IL-­17 expression, neutrophilic inflam-
mation, and chronic immune reaction.15 Taken together, the role of
biologic factors driving these non-­t ype 2 patients are very poorly
understood but may lead to sustained colonization of the airways
by specific microbial species, which could promote neutrophilic
inflammation. However, these phenomena seem to have minimal
impact on the direct pathogenesis of asthma exacerbations, and
any antimicrobial therapy in these circumstances is superfluous,
leading to unnecessary hospitalizations and antibiotic-­related side
16
effects.
Alternatively, several phyla that have been found in the respi-
ratory flora of asthmatics and non-­asthmatics exert an immune-­
modulating effect upon mucosal immunity, probably contributing
to asthma prevention. For example, non-­asthmatics are predom-
inantly colonized with beneficial phyla, including Firmicutes and
Actinobacteria. At the same time, asthmatics have a greater abun-
dance of Proteobacteria.12 Proteobacteria are associated with worse
asthma control.11 Neutrophilic asthma is associated with decreased
airway microbial diversity and increased airway Moraxella and
Haemophilus taxa.17 Figure  1 shows the differences in respiratory
microbiome composition between healthy controls and patients
with asthma. Concerning fecal samples, patients with severe asthma
show a reduction in Akkermansia muciniphila levels.18 Taking this into
account, one should promote airway microbial diversity and limit the
use of antibiotics as a potential prevention method.
13989995, 2021, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15046 by Cochrane Mexico, Wiley Online Library on [26/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
3.2  |  Atopic dermatitis
The skin microbiota is the most diverse microbial population in the
human body, hosting more than 1000 different bacterial species
from 19 different phyla.3,19 The composition of these microbiota de-
pends on physiology and mostly varies by individual and body site. 20
Although the skin microbiota is relatively stable over the years,
as seen in healthy adults, this microbial community structure vastly
expands and diversifies in infants. 21,22 The role of exogenous fac-
tors, such as mode of delivery, remains open for discussion with re-
cent evidence that their impact, if perceptible, is only transient after
birth.
In the light of an intensive maturation of the immune system
during early childhood, active host-­commensal cross-­t alk seems to
be an essential mechanism in establishing the antigen-­specific tol-
erance to skin microflora. The insufficient induction of regulatory T
cells, that prevent a following inflammatory response to these bacte-
ria, appears to play a role in determining the future development of
atopic dermatitis (AD). It has been found that colonization with both
reduced commensal staphylococci (eg, S.  epidermidis) and abundant
S. aureus precedes the onset of AD in infancy. 21,23
Patients with AD are remarkably more often colonized with
S. aureus than healthy controls. The prevalence of S. aureus coloniza-
tion in AD is estimated at 70% for lesional skin, 39% for non-­lesional
skin, and associated with disease severity. 24 S. aureus has developed
multiple sophisticated mechanisms—­displaying adhesion, barrier
dysfunction, and pro-­inflammatory features—­to enable it to survive
in demanding conditions of the healthy skin. 25
Type 2 cytokines such as IL-­4 and IL-­13 reduce filaggrin, lipids,
and antimicrobial peptides required to control S.  aureus growth,
thereby allowing S. aureus to proliferate and reach high numbers in
atopic skin with significant barrier dysfunction. 26 S. aureus found in
individuals with AD is often resistant to fusidin and arises through
F I G U R E 1  Respiratory bacterial
colonization patterns in asthma and
healthy subjects. 2 Legend: This figure
summarizes respiratory microbiome
patterns found in healthy subjects and
asthmatics. The microbiome composition
is also influenced by other factors next
to the disease condition, as shown in the
lower text box

TRAMPER-­S TRANDERS et al.
distinct genetic mechanisms when compared with healthy controls
27
carrying fusidin-­resistant S. aureus.
During an AD flare, the bacterial diversity moreover lowers, with
decreases in the genera Streptococcus, Corynebacterium, Cutibacterium,
and the phylum Proteobacteria shifting toward the Staphylococcus
25
dominance. Figure  2 shows factors associated with the develop-
ment of atopic dermatitis and (anti) microbial treatment options.
3.3  |  Food allergy
Findings from 16S rRNA sequencing-­based studies have shown
that children with food allergies (mainly studies for cow's milk and
egg) have distinct gut microbiome compositions compared to those
without food allergies. Furthermore, results suggest that the gut
microbiota can differ by individual food allergy. 28 Early-­infancy gut
microbiota development studies, as well as murine models, show
richness and composition associated with clinical allergy and/or sen-
sitization. 29,30 At a later age, these associations disappeared. Thus, a
diverse microbiota early in life is required to inhibit IgE induction.31
Several studies suggest a relationship between antibiotic ex-
posure and the development of food allergies. A recent systematic
review by Netea et al32 has addressed this issue, finding a multifac-
torial association between antibiotics and food allergies. Antibiotics
have been found to strongly influence the microbiome, and espe-
cially broad-­spectrum (in contrast to narrower-­spectrum) antibiotics
are plausible to have a significant influence on the development of
the immune system and allergic disease. There is no clear definition
of broad-­spectrum antibiotics; usually, a broad-­spectrum antibiotic
covers both Gram-­positive and -­negative bacteria. Examples of
broad-­spectrum antibiotics are certain beta-­lactam antibiotics (such
as amoxicillin [with or without clavulanic acid], cephalosporins, and
carbapenems) and macrolide antibiotics (such as azithromycin).
4  |  A NTI B I OTI C S , TH E D E V E LO PM E NT,
A N D TR E ATM E NT O F A LLE RG I C D I S E A S E S
4.1  |  Infant antibiotic prescriptions and the
development of allergic diseases
As previously mentioned, the use of antibiotics during pregnancy
or early childhood may have several effects on the neonatal mi-
crobiome, leading to an increased risk to develop childhood atopy,
asthma, and allergy.33,34 Adjusted hazard ratios for allergic condi-
tions after antibiotic prescription during the mentioned lifespan
range between 1.20 and 2.10, with the highest risk for asthma.35-­38
In some countries, the routine use of antibiotics for cesarean section
is practiced. Notably, multiple prescriptions of broad-­spectrum anti-
biotics (macrolides, cephalosporins, penicillins, etc.), especially dur-
ing the final pregnancy semester and in early infancy, or a familiar
history for asthma reveals a more significant association, reaching
an odds ratio up to ~3 for asthma and allergies.39-­41 A recent study
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      3279
on a European birth cohort (PASTURE) has identified antibiotic ex-
posure in utero as significantly and positively associated with atopic
dermatitis and food allergy.40 Infant antibiotic use is associated with
increased odds of childhood asthma in a dose-­dependent manner,
with a 20% increase in odds for each additional antibiotic prescrip-
tion filled.42,43 This pattern also applies to food allergy, with children
having three or more antibiotic prescriptions being at higher risk of
milk-­ and other food allergies.44 A meta-­analysis summarizing the
literature on infant antimicrobial agent use correlating with the de-
velopment of food allergy did indicate noticeable evidence, although
not homogeneously among all the collected data.32
The association of allergic diseases with prenatal and postnatal
antibiotic exposure is generally attributed to an altered composition
of resident bacteria (dysbiosis).45,46 In murine studies, the disrupted
colonization and cross-­t alk with colonizing bacteria in the devel-
oping neonatal intestine suppressed the infant's initial adaptation
to extra-­uterine life, particularly in acquiring immune homeostasis
which protects against allergy expression later in life.
Healthy bacterial colonization is essential to skew the newborn's im-
mune response away from the allergy-­favoring type 2 response toward a
regulatory T-­cell and type 1 immune response.47 An experimental study
in mice demonstrated that deliberate alteration of commensal bacterial
populations via oral antibiotic treatment resulted in elevated serum IgE
concentrations, increased steady-­state circulating basophil populations,
and exaggerated basophil-­mediated type 2 cell responses as well as aller-
gic inflammation.48 Another study on the experimental model of dysbiosis
and intra-­tracheal house dust mite sensitization revealed an augmented
eosinophilic airway infiltration, bronchial hyper-­responsiveness (BHR) to
methacholine challenge and goblet cell hyperplasia.49
The successful experimental microbial therapy with pro-­
tolerogenic bacteria, such as certain Clostridial species, reinforces
the role of bacterial colonization in the healthy balance of the intes-
tinal and extra-­intestinal immune response.50-­52
Finally, a very recent systematic review with meta-­analysis eval-
uating the association between antibiotic use during pregnancy and
childhood allergy demonstrated that maternal antibiotic exposure
in pregnancy was associated with 1.3 increased risk of childhood
asthma/wheeze and 1.6 increased risk of eczema/atopic dermatitis,
but not food allergy.53 This review underscores the critical role of
the appropriate use of antibiotics during pregnancy. It paves the way
to recommendations directing healthcare professionals to be selec-
tive when prescribing antibiotics for pregnant women to reduce the
risk of allergic diseases in children.
Children developing asthma seem to be prone to viral infections
in their first years of life because of their increased susceptibility
with, consequently, an augmented prescription of empiric therapies
including antibiotics. Therefore, the association between antibiotics
and asthma might arise through a complex confounding by indication
and maybe a consequence of bias rather than causal relation.54,55
However, infants who received antibiotic therapy during infancy
for viral respiratory infection experienced more severe wheeze or
asthma exacerbation after antibiotic prescription than those with-
out antibiotics.54 In a mouse model, experimental antibiotic therapy
 |
3280      TRAMPER-­S TRANDERS et al.
after respiratory syncytial virus infection promoted bronchial hyper-
reactivity, which is associated with decreased expression of pulmo-
55
nary regulatory T cells, Foxp3 mRNA, and TGF-­β1.
Taken together, these data indicate that the association between
early antibiotic use and the later development of allergic disease or
asthma might be partially explained by the induction of dysbiosis
and the consequent deviation of the immune response toward a pro-­
inflammatory profile.
Studies exploring early antibiotic exposure and the development
of allergic diseases are summarized in Table 1.
4.2  |  Antibiotic (over) prescriptions in
allergic conditions
There is a gap in knowledge concerning the increased antibiotic use
rate for allergic conditions such as allergic rhinitis, asthma, and atopic
eczema. Patients suffering from an allergic disease are thought to be
more vulnerable to developing bacterial infections because of changes
in mucosal immune system responses. Additionally, immune dysfunc-
tion caused by the allergic reaction is a predisposing factor for the
development of bacterial infection and, consequently, for antibiotic
consumption.56,57 The main factor contributing to the overprescription
of antibiotics in allergic conditions is that many of the common symp-
toms presenting in allergic conditions can mimic infectious ones.58
These characteristics could mislead the clinician and contribute to the
higher incidence of antibiotic consumption in an allergic patient.
4.2.1  |  Acute asthma exacerbations treatment
Antibiotics are prescribed in nearly 1:6 US pediatric ambulatory care
visits for asthma, leading to one million prescriptions annually when
13989995, 2021, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15046 by Cochrane Mexico, Wiley Online Library on [26/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
F I G U R E 2  Interface of microbiota and
several other factors and interventions
that ultimately influence the emergence of
atopic dermatitis. Legend: On the left side,
factors associated with the development
of atopic dermatitis are shown; whereas
on the right side possible treatment
options as mentioned in the text are
shown]
an antibiotic need is undocumented.59 Among adults, almost 50%
receive antibiotics for an acute asthma exacerbation.16,60
Patients with allergic asthma have an increased risk of filling at
least two antibiotic prescriptions per year compared with non-­allergic
asthma.61 For asthma, it is unsure when the antibiotic application re-
sults in a clinical benefit in acute asthma exacerbations or whether
they can do harm in the long term. A Cochrane systematic review,
including studies on 681 adult and childhood exacerbations, showed
inconsistent findings in very heterogeneous studies with varied meth-
odological quality. Number of symptom-­free days and pulmonary
function at 10  days after exacerbation were higher after macrolide
antibiotics in some studies. But authors concluded there was insuf-
ficient evidence for symptom improvement by antibiotics given for
an acute asthma attack.62 Additionally, a large retrospective cohort
study showed antibiotic prescriptions in 44% of patients admitted
with an acute asthma exacerbation. Antibiotic therapy was possibly
associated with a longer hospital length of stay, higher hospital cost,
but similar risk of treatment failure. The Azalea trial performed in the
United Kingdom revealed no clinical benefit of adding azithromycin
in adult asthma exacerbations. Of note, the recruitment process in
this trial was challenging since most of the patients showing up with
exacerbation had already been prescribed antibiotics by their GP
physician before presenting at the emergency room.63
Since asthma exacerbations are mainly of viral origin, antimicro-
bial treatment should be regarded as unnecessary in most cases and
particularly harmful due to the possibility of destabilization of the
respiratory microbiome and inducing resistance.
4.2.2  |  Chronic asthma and exacerbation prevention
Maintenance antimicrobial therapy, especially macrolide therapy, is
practiced in severe uncontrolled asthma to prevent exacerbations.
 TA B L E 1  The role of antibiotic exposure during pregnancy or early childhood on the development of asthma and allergic diseases (PubMed records 2015–­2020)

Age of participants
Study type, Antibiotic type and/or Exposure period/ at outcome (Adjusted) Odds/
Study ID country Sample size (n) Prescription frequency population measurement Outcome (disease) Hazard Ratio (95% CI)

Mitre et al. 201836 Retrospective 131708 Undefined 0–­6 months 4.6 years (median) Asthma 2.09 (2.05–­2.13)
Cohort, USA Allergic rhinitis 1.75 (1.72–­1.78)
Anaphylaxis 1.51 (1.38–­1.66)
TRAMPER-­S TRANDERS et al.

Allergic conjunctivitis 1.42 (1.34–­1.50)

Hirsch et al. 201744 Longitudinal, 484 Penicillin, cephalosporins, <2 years <7 years Milk allergy 1.78 (1.28–­2.48)
USA 598 or macrolides, >three Non-­milk allergy 1.65 (1.27–­2.14)
3652 courses Other allergies 3.07 (2.72–­3.46)
Chen et al. 201839 Retrospective 4164 Undefined <2 years 2–­18 years Asthma 3.33 (2.67–­4.15)
Cohort, Macrolides +Bronchiolitis 2.87 (1.99-­.160
Taiwan Azithromycin 3.45 (1.62–­7.36)
Penicillins 1.77 (1.43–­2.20)
Cephalosporins 1.67 (1.32–­2.11)
Metzler et al. 201940 Birth cohort, 1080 Undefined Pregnancy <1 year Atopic dermatitis 1.66 (1.11–­2.48)
Switzerland Pregnancy <1year Food allergy 3.01 (1.22–­7.47)
& EU <1 year <4 years Atopic dermatitis 2.73 (1.66–­4.49)
<1 year 3–­6 years Asthma 1.65 (0.95–­2.86)
Loewen et al. 2018120 Cohort, Canada 213661 Undefined Pregnancy <1 year Asthma 1.23 (1.20–­1.27)
One course 1.15 (1.11–­1.18)
Two courses 1.26 (1.21–­1.32)
>Two courses 1.51 (1.44–­1.59)
Yamamoto-­Hanada et al. 2017121 Birth cohort, 1550 Undefined <2 years <5 years Asthma 1.72 (1.10–­2.70)
Japan Cephem Atopic dermatitis 1.40 (1.01–­1.94)
Cephem Allergic rhinitis 1.65 (1.05–­2.58)
Macrolide Asthma 1.97 (1.23–­3.16)
Allergic rhinitis 1.82 (1.12–­2.93)
Atopic dermatitis 1.58 (1.07–­2.33)
Ahmadizar et al. 201835 Review/Meta-­ 229080 Undefined <2 years Undefined Allergic rhinitis 1.23 (1.13–­1.34)
analysis, 394517 Atopic dermatitis 1.26 (1.15–­1.37)
Netherlands 23878 Food allergy 1.42 (1.08–­1.87)
Lapin et al. 2015122 Randomized, 301 Undefined Pregnancy <3 years Asthma 3.1 (1.4–­6.8)
USA
Yoshida et al. 2018 41 Retrospective 155556 Undefined Pregnancy <3 years Asthma 1.18 (1.08–­1.30)
cohort, Japan <1 year <3 years 2.43 (2.20–­2.69)
<1 year <6 years 1.23 (1.11–­1.36)
Fishman et al. 2019123 Retrospective 27403 1–­2 courses <2 years <4 years Asthma 1.34 (1.21–­1.49)
cohort, USA 22248 >2 courses 1.71 (1.54–­1.90)
|       3281

(Continues)

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 TA B L E 1  (Continued)
|

Age of participants
Study type, Antibiotic type and/or Exposure period/ at outcome (Adjusted) Odds/
3282     

Study ID country Sample size (n) Prescription frequency population measurement Outcome (disease) Hazard Ratio (95% CI)

Ahmadizar et al. 2017124 Cohorts' meta-­ 8284 Undefined <3 years Undefined Asthma 2.18 (1.04–­4.60)
analysis, 1474 Asthma 0.93 (0.65–­1.32)
Netherlands exacerbations
& Scotland,
UK
Metsälä et al. 201537 Case-­control, 6690 Undefined Pregnancy 3–­10 years Asthma 1.31 (1.21–­1.42)
Finland Cephalosporins <1 year 1.46 (1.30–­1.64)
Undefined 1.60 (1.48–­1.73)
Cephalosporins 1.79 (1.59–­2.01)
Sulphonam-­trimethoprim 1.65 (1.34–­2.02)
Macrolides 1.61 (1.46–­1.78)
Amoxicillin 1.46 (1.35–­1.58)
Mulder et al. 2016125 Case-­control, 2456 Undefined Pregnancy <6 years Asthma 1.46 (1.34–­1.59)
Netherlands 3rd semester 1.40 (1.15–­1.47)
Sun et al. 2015126 Prospective 606 Macrolides <1 year <3 years Wheezing 1.09 (1.05–­1.13)
cohort, China
Xie et al. 2016127 Meta-­analysis, 772184 Undefined <1 year 2–­12 years Asthma 1.14 (1.10–­1.17)
China >4 courses + Familiar history 1.28 (1.19–­1.38)
Undefined 1.47 (1.20–­1.81)
Zhao et al. 201538 Meta-­analysis, 16610 Undefined Pregnancy Childhood Wheeze/Asthma 1.18 (1.11–­1.26)
China 193 1st semester 1–­5 years 1.09 (0.92–­1.29)
2nd semester 1.14 (1.01–­1.29)
3rd semester 1.33 (1.11–­1.60)
Popovic et al. 2016128 Birth cohort, 3530 Undefined Pregnancy: 1st Childhood Ever-­wheezing 1.02 (0.80–­1.30)
Italy 3985 semester Recurrent wheezing 0.99 (0.54–­1.82)
3rd semester Ever-­wheezing 1.12 (0.90–­1.39)
Recurrent wheezing 2.09 (1.32–­3.29)
Donovan et al. 2020 42 Birth cohort, 120973 Undefined, every Infancy, initially 4.5–­6 years Asthma 1.2 (1.19–­1.2)
USA additional during first year 1.10 (1.05–­1.19)
prescription
Broad-­spectrum vs.
narrow spectrum
TRAMPER-­S TRANDERS et al.

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 |

13989995, 2021, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15046 by Cochrane Mexico, Wiley Online Library on [26/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TRAMPER-­S TRANDERS et al.       3283

TA B L E 2  Summary on microbial strategies in allergic diseases, showing improvement (+), worsening/ no change (↔) or absent data (?) in
clinical outcomes

Probiotics/synbiotics Bacterial lysates

77,88,89
Asthma exacerbations
Asthma and wheezing prevention82,83
Allergic rhinitis treatment91,92,96,97
Atopic dermatitis treatment98,101
Atopic dermatitis prevention99,103,104
105-­108
Food allergy
+ Fewer asthma episodes + Shorter duration of asthma and/or wheezing
↔ Disease severity + Lower frequency of wheezing episodes and
↔ Asthmatic symptoms asthma exacerbations
↔ Number of symptom-­free days
↔ Forced expiratory volume
↔ Peak expiratory flow
↔ Overall risk of asthma ? Currently being studied
↔ Incidence of asthma and wheezing
+ Lower total nasal and ocular symptoms scores + Lower total nasal and ocular
+ Rhinitis Quality of Life (RQLQ) scores symptom scores
↔ Rhinitis Total Symptom Scores (RTSS)
↔ No improvement + Reduced number of new AD flares
+ Reduction in the cumulative incidence of AD ↔ Initially modest effect, later no change
? Limited data on prevention of IgE-­dependent ? No data
food allergy
? Limited data on treatment of cow's milk allergy

In 2015, a Cochrane review including 1513 patients concluded mac-
rolides not to be better than placebo on clinical outcomes including
hospital admissions and oral corticosteroid use for exacerbations,
although some studies suggested a steroid-­sparing effect. As with
many meta-­analyses, the evidence was of very low quality.64 Later
studies, including the AMAZES study, observed a decrease in ex-
acerbations after azithromycin prophylaxis in adults with persistent
65
uncontrolled asthma. A recent systematic review showed a reduc-
tion of asthma exacerbations after azithromycin maintenance ther-
apy (different regimens) for both eosinophilic and non-­eosinophilic
asthma.66 Although macrolides also reduce steroid requirements and
improve the quality of life, according to current evidence, their ac-
tion is via immunomodulation rather than bacterial load reduction.67
However, there is a growing body of evidence that macrolides alter
68
the airway microbiome profile. Notably, macrolides are strong
inducers of antimicrobial resistance because of their prolonged
half-­time and have led to high resistance rates in pneumococci and
staphylococci in areas with a high-­macrolide consumption.69
4.2.3  |  Atopic dermatitis—­treatment
resulted in no meaningful benefit from oral or topical antibiotics next
to topical steroids and emollients.73 Topical antiseptics, like chlorhex-
idine soap or sodium hypochlorite baths, are applied with different
clinical experiences, but no satisfactory evidence exists.
Therefore, many current studies aim to establish novel microbial
strategies to treat S.  aureus to replace the antimicrobials currently
used.74 This will be covered in the section on microbial-­derived
products.
In conclusion, the lack of data and knowledge on the effect of an-
tibiotic treatment for allergic disease exacerbations and the infection-­
mimicking symptoms are probable contributing factors to antibiotic
over-­ or misuse in allergic conditions. Tailored treatment based on
clinical or phenotypical characteristics might help reduce unnecessary
antibiotic therapy in allergic diseases. Additionally, microbial-­derived
products have been studied on a large scale in the treatment or pre-
vention of allergic diseases, covered in the next paragraph.
5  |  M I C RO B I A L S TR ATEG I E S TO PR E V E NT
A LLE RG I C D I S E A S E D E V E LO PM E NT O R
E X AC E R BATI O N S

For atopic dermatitis, in 2003 alone, dermatologists prescribed 3–­4
million topical antibiotic courses.70 In hospitalized children with atopic
dermatitis, systemic antibiotics were prescribed in >80% of the pa-
tients.71 The broader knowledge of the alterations in AD skin microbi-
ota led to the hypothesis that stabilization of the disturbed microbiota
may have a therapeutic and/or prophylactic effect. However, systemic
antibiotics have no benefit on the skin condition unless skin lesions are
clinically superinfected, usually accompanied by S.  aureus superanti-
gens.72 Anti-­staphylococcal antibiotics will lead to decreased coloniza-
tion, but therapy with anti-­inflammatory skin regimens has also shown
reduced staphylococcal colonization. A randomized controlled trial
evaluating different treatment regimens in clinically infected eczema
Pre-­ and probiotics seem to help establish the normal gut flora and
modulate inflammatory mechanisms, showing promising benefits as
potential treatment and prevention strategies. Probiotics, defined
as “living organisms which when administered in adequate amounts
confer a health benefit on the host,” are mostly composed of bacte-
ria (eg, Lactobacillus and Bifidobacterium spp.) together with yeasts
(eg, Saccharomyces boulardii). In vitro studies show evidence of the
immune-­modulating effects of certain probiotics.75 On the other
hand, prebiotics are fermented food ingredients that allow specific
changes in composition/activity of the gastrointestinal microflora,
for example, fructooligosaccharides (FOS), galactooligosaccharides
(GOS), and trans-­galactooligosaccharides (TOS). Synbiotics are a
 |
3284      TRAMPER-­S TRANDERS et al.
synergic combination formula in which a prebiotic component se-
lectively favors a probiotic microorganism. Finally, postbiotics are
microbial fermentation components, including metabolites, short-­
chain fatty acids (SCFAs), microbial cell fractions, functional pro-
teins, extracellular polysaccharides (EPS), cell lysates, teichoic acid,
76
peptidoglycan-­derived muropeptides, and pili-­t ype structures.
Bacterial lysates could also be categorized as postbiotics.
Pre-­or probiotics are thought to be influential in developing sev-
eral allergic diseases, yet current evidence remains limited due to
studies with high heterogeneity in design and used probiotics and
variable outcome measures. Below, we describe evidence for bacte-
rial products in preventing allergic disease (exacerbations), summa-
rized in Table 2.
5.1  |  Asthma
5.1.1  |  Pre-­, pro-­, and postbiotics
Probiotics supplementation may be useful in asthma as a co-­
adjuvant treatment.77,78 In several studies, a more significant pro-
portion of children had fewer asthma exacerbation episodes when
taking probiotics. Assessing the number of asthma exacerbations,
two studies showed no significant difference. One contradictory
study reported that asthma exacerbations were more frequent in
the probiotic group. Moreover, laboratory data showed a significant
change in the inflammatory pathway (IL-­4, IFN-­γ, and IgE) in the
probiotic group versus controls, yet the methodological quality of
these studies is low. Most of these studies used Lactobacillus species
78-­81
as a probiotic. A meta-­analysis that included pooled data from
910 children with mild-­to-­moderate asthma demonstrated a higher
proportion of children with fewer asthma episodes following treat-
ment with probiotics as compared to controls (risk ratio [RR]: 1.3;
95% CI: 1.06, 1.59).77 In addition, the authors reported a probiotic-­
induced increase in IFN-­γ and a decrease in IL-­4 levels. However,
the above effects were not associated with significant changes in
disease severity as measured by childhood asthma control test, asth-
matic symptoms during the day or night, number of symptom-­free
days, forced expiratory volume (expressed as the percentage of pre-
dicted), or peak expiratory flow (Table 2).77
In a large recent meta-­analysis comprising data from 5.157 infants
<1-­year-­old exhibiting asthma or wheezing, probiotic therapy (in most
of the studies with Lactobacillus species) was not found to reduce the
82
overall risk of asthma or wheeze. Probiotics administration was as-
sociated with a reduction in the incidence of wheeze among 225 in-
82
fants with atopic disease. Finally, in a meta-­analysis comprising 4.755
children at high risk of atopy, there was no difference in the incidence
of asthma and wheezing between infants who received probiotics
(gestational or at <3 months old) compared with those who did not.83
Overall, these results suggest that probiotics lack consistent ef-
ficacy in asthma prevention; however, their use may be associated
with a reduction in the incidence of wheeze in atopic infants, al-
though larger trials are necessary.
13989995, 2021, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15046 by Cochrane Mexico, Wiley Online Library on [26/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
A recent study has highlighted the potential role of short-­chain
fatty acids (such as butyrate), one of the most promising postbiotics
in preventing allergy and asthma.84 In contrast, bacterial secretion of
histamine in the gut is associated with a more severe asthma pheno-
type, although murine models suggest potential protective effects
also on lung inflammatory responses.85,86 Intranasal administration
of Bidifobacterium might prevent exaggerated viral replication and
viral-­induced inflammation, as shown in a murine model.87 Whether
this leads to a decrease in asthmatic disease, exacerbations should
be further studied.
5.1.2  |  Bacterial lysates
Bacterial lysates have been prescribed for the prevention of pre-­
school wheezing and asthma exacerbations in infants and children.
A meta-­analysis (N = 4851) on the efficacy and safety of the bacte-
rial lysate OM-­85 in pediatric recurrent respiratory tract infections
included 8 Chinese studies (702 children) that assessed wheezing
episodes. Bacterial lysate OM-­85 therapy resulted in a substantial
reduction in the duration of wheezing.88
Our recent systematic review with meta-­analysis has shown
that although studies are scarce and heterogeneous, there was a
moderate beneficial effect of oral application of bacterial lysates on
pre-­school wheezing episodes and allergic asthma exacerbations in
children.89 The frequency of wheezing episodes and asthma exacer-
bations was reduced in patients who received bacterial lysates: OM-­
85, Ismigen, or MV130 compared with placebo. Whether they act by
decreasing the number of viral respiratory tract infections and sub-
sequent asthma exacerbations and/or dampening the Th2 response
with parallel increased regulatory responses should be studied fur-
ther. Murine models show a direct effect on airway immune cells,
Th2 inflammation, and airway hyperreactivity.90
5.2  |  Allergic rhinitis
5.2.1  |  Pre-­, pro-­, and postbiotics
For allergic rhinitis, probiotics showed reduced symptoms and
improved quality of life in patients with allergic rhinitis in a meta-­
analysis using studies with mainly Lactobacillus or Bifidobacterium
species as probiotics.91 Contrastingly, no effects on symptom scores,
IgE, or regulatory T cells were seen. The postbiotic Lactobacillus pa-
racasei 33 has shown an improvement in the quality of life measured
by a modified pediatric rhino-­conjunctivitis quality of life question-
naire (PRQLQ).92
Meta-­analysis data have demonstrated an effect of probiotics
on the type 1/2 inflammation balance, but no apparent effect on IgE
levels.91,93,94 In a meta-­analysis comprising 2.242 children and adults
with AR, probiotic therapy resulted in a significant reduction in total
nasal and total ocular symptoms scores.93 Conversely, in a meta-­
analysis of 1.919 patients, the positive effect of probiotics on Rhinitis

TRAMPER-­S TRANDERS et al.
Quality of Life (RQLQ) scores was significant though there was no ef-
91
fect on Rhinitis Total Symptom Scores (RTSS). In their 2015 system-
94
atic review (N = 1.527), Peng et al reported a significant combined
improvement of the quality of life scores and nasal symptom scores
of patients with AR. There was a high risk of bias in the majority of the
studies, highlighting the need for better quality trials.
5.2.2  |  Bacterial lysates
Bacterial lysates have been shown to inhibit the inflammatory cy-
tokines, infiltration of pro-­inflammatory cells, and increased serum
IgG1 and IgE, indicative of a type 2 immune response, in a mouse
95
model of AR, and some clinical benefit was shown in a small
(N  =  60) randomized trial from China with respiratory pathogen
lysates (reduced medication use, nasal symptoms, and improved
type 1/2 cytokine balance).96
A recently published trial including 70 children with seasonal
allergic rhinitis showed significant efficacy of respiratory bacterial
lysate therapy on allergic nasal and ocular symptoms.97
5.3  |  Atopic dermatitis
5.3.1  |  Pre-­, pro-­, and postbiotics
By now, the data published on the efficacy of oral probiotics (bac-
teria of the Lactobacillus and Bifidobacteria species, which were
taken alone or combined with other probiotics, and were given with
or without prebiotics) in established AD has shown no or negligi-
ble improvement.98 Perinatal probiotics supplementation reduced
the cumulative incidence of AD, having a modulator effect, espe-
cially on non-­IgE associated phenotype.99 Prebiotics that have been
studied by far were assessed in different groups of AD patients.
Nevertheless, results are inconclusive in most of the cases. Limited
evidence supports the use of synbiotics and postbiotics for the
treatment of AD, particularly in children.100
Another potential management strategy is a skin application of
live probiotics or bacteria-­derived preparations topically. Seven dif-
ferent bacterial strains have been used to date in preliminary stud-
ies, including Roseomonas mucosa and commensal staphylococci.101
These topical interventions have suggested beneficial effects and a
good safety profile. Nevertheless, this exciting concept requires fur-
ther investigation to assess its clinical benefits fully. There are also
early trials underway to develop an anti-­S. aureus vaccine, which, if
successful, could start a new era in AD management.102
5.3.2  |  Bacterial lysates
Bacterial lysates (Enterococcus faecalis and Escherichia coli lysates),
given between 2 and 7 months of life, have been studied in the pre-
vention of atopic dermatitis in infancy. A modest effect was shown
|
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      3285
in the first year in infants with paternal atopy, but after 4 years the
prevalence of AD was identical between the study groups.103,104
5.4  |  Food allergy
Patients with cow's milk allergy may benefit from pro-­ and prebi-
otics. Children treated with Lactobacillus GG might have earlier oral
tolerance to cow's milk105 and, in some cases, earlier recovery of
hematochezia.106 Human milk oligosaccharides (HMOs) have been
identified as a useful preventive tool in cow's milk allergy only for
infants.107 Few studies have investigated synbiotics in children. A
mixture of probiotic bacteria and fructo-­oligosaccharide (FOS) re-
vealed an improvement of thriving in these patients.108
Despite many studies, clear evidence in humans for the role of
pre-­and probiotics in allergy prevention and treatment is still lack-
ing. Heterogeneity in strains, doses, and timing and study population
largely vary. Further studies are needed to understand the mecha-
nism behind their immune-­modulating effect and guide treatment in
a personalized fashion.
6  |  M I C RO B I A L S TR ATEG I E S TO PR E V E NT
S I D E E FFEC T S O F A NTI M I C RO B I A L
TH E R A PY
Probiotics are widely prescribed for prevention of antibiotics-­
associated dysbiosis and related adverse effects. Two sys-
tematic reviews described a reduction in antibiotic-­associated
diarrhea (relative risk of 0.58 [95% CI, 0.50–­0.68]) and specifically
Clostridium difficile-­associated diarrhea (relative risk 0.40 [95% CI
0.30–­0.52]). Significant heterogeneity was observed and need for
additional studies identifying the best probiotic strain/group and de-
fine patient groups.109,110
Long-­term data on probiotics restoring the microbiome after an-
tibiotic therapy are scarce. Especially with respect to the associa-
tion of early-­life antibiotics with allergy development, high-­quality
studies are absent. Multi-­strain probiotic therapy induced a delayed
and persistently incomplete indigenous stool/mucosal microbiome
reconstitution compared to spontaneous post-­antibiotic recovery in
mice and healthy adult volunteers.111 Thus, the presumed probiotic-­
induced protection from antibiotic-­associated adverse effects may
not be risk free.
Although probiotics might overcome some of the short-­term side
effects of antimicrobial therapy, it is to be preferred to practice anti-
microbial stewardship to avoid overexposure to antibiotics.
7  |  A NTI B I OTI C S TE WA R DS H I P I N
A LLE RG I C D I S E A S E S
Antimicrobial stewardship refers to coordinated interven-
tions designed to improve and measure the appropriate use
 |
3286      TRAMPER-­S TRANDERS et al.
of antimicrobials by promoting the optimal antimicrobial drug
regimen, dose, duration of therapy, and administration route.
Antimicrobial stewards aim to achieve optimal clinical out-
comes related to antimicrobial use, minimize toxicity and other
adverse events, reduce healthcare costs for infections, and
112
limit the selection for antimicrobial-­r esistant strains. It also
involves transparent monitoring of prescription data and the
use of available expertise and resources.113 These elements
could be accomplished by education, implementation of clinical
practice guidelines, antimicrobial order forms, and dose opti-
mization.114 Many studies have shown antimicrobial steward-
ship programs (ASP) to effectively reduce antibiotic prescribing
without negatively affecting the quality of care and patient
115,116
mortality.
Concerning allergic diseases, antibiotic stewardship starts with
awareness and following guidelines. Although many national guide-
lines state routine antibiotic prescriptions are not indicated for an
acute asthma exacerbation, current practice is the opposite, as
shown above.
Antibiotic stewardship policies with biomarker-­guided therapy
(eg, serum pro-­calcitonin) have shown that antibiotic use for asthma
117,118
exacerbations can safely be reduced by about 50%. Adoption
in the clinic, however, is not yet common practice in many places.
Also, rapid viral PCR testing reduced antibiotic duration in asthma
exacerbations.119
8  |   S Y N O P S I S/FU T U R E D I R EC TI O N S
In this review, we have highlighted the relation between microbiota,
antimicrobial therapy, and allergic diseases.
Overuse of antibiotics in childhood and during pregnancy
is associated with the risk of disturbing colonization of the
13989995, 2021, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15046 by Cochrane Mexico, Wiley Online Library on [26/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
F I G U R E 3  Synopsis, recommendations,
and knowledge gaps with respect to
antibiotic use and allergic diseases.
Legend: This figure shows the relation
of antimicrobial therapy with the
development of allergic diseases (left) and
the (over)treatment of allergic diseases
and provides recommendations for the
clinical practice and future research
directions
intestinal and respiratory microbiome, which leads to dysbiosis
and an increased risk of acquiring allergic diseases. At the same
time, whether there is a role for specific bacteria in the pathogen-
esis of certain allergic diseases and/or their exacerbations still re-
mains uncertain. In fact, there are no conclusive studies that could
suggest such a relationship. The only exceptions regard (1) skin
colonization with S. aureus and its role in exacerbations of AD, and
(2) the presence of M.  pneumoniae and overrepresentation with
Proteobacteria in severe asthma and patients with exacerbations
of neutrophilic asthma.
Contrarily to guidelines, antibiotic therapy is often described for
(exacerbations of) allergic disease conditions while there is no evi-
dence for efficacy, except scarce data for the prevention of exacer-
bations in severe asthma. Pre-­, pro-­, or postbiotics might modify the
allergic disease course but clear evidence is lacking, also because of
heterogeneity in strains, doses, and timing.
We are urging that the future EAACI Recommendations on
Antibiotic Stewardship should recommend limiting antibiotic ther-
apy in pregnancy and early childhood as a method contributing to
the reduction of the allergy epidemic in children. Recommendation
should also focus on restricting antibiotic therapy in exacerbations
and chronic treatment of allergic diseases, mainly concerning asthma
and atopic dermatitis. Antimicrobial treatment should be prescribed
cautiously and following current recommendations with the use of
the narrowest possible spectrum of antibiotics. Figure 3 summarizes
the knowledge provided in this paper, provides recommendations
and knowledge gaps.
Future research should be aimed at antibiotic stewardship im-
plementation strategies and biomarker-­guided therapy, discerning
those patients that might benefit from antibiotic therapy.
AC K N OW L E D G E M E N T S
We want to thank Zuzana Lukasik for the creative work.

TRAMPER-­S TRANDERS et al.
C O N FL I C T O F I N T E R E S T
All authors declare no conflicts of interest with respect to this work.
ORCID
Gerdien Tramper-­Stranders  https://orcid.
org/0000-0002-0228-5375
Marina Atanaskovic-­Markovic  https://orcid.
org/0000-0003-1354-6072
Cristina Boccabella  https://orcid.org/0000-0003-1942-8886
Ervin Mingomataj  https://orcid.org/0000-0002-6541-1914
Milena Sokolowska  https://orcid.org/0000-0001-9710-6685
Eva Untersmayr  https://orcid.org/0000-0002-1963-499X
Wojciech Feleszko  https://orcid.org/0000-0001-6613-2012
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