Download infection and atopic disease burden in african countries

INFECTION AND ATOPIC DISEASE BURDEN IN
AFRICAN COUNTRIES: KEY TO SOLVING THE
‘HYGIENE HYPOTHESIS’?
Charles C Obihara, MD, PhD
Department of Paediatrics, St Elisabeth Hospital,
Tilburg, The Netherlands
ABSTRACT
While most African countries are experiencing an
epidemic rise in chronic infectious diseases, such as
tuberculosis, malaria, HIV and parasites, industrialised, westernised countries are experiencing an
epidemic rise in atopic and auto-immune diseases.
One of the most popular explanations for this
increase is the so-called ‘hygiene hypothesis’, which
suggests that a decrease or altered exposure to
microbes in the environment, as a result of
improved sanitation and personal hygiene, smaller
family sizes, shorter duration of breastfeeding,
immunisations and lack of serious childhood infections, results in alteration of the immunoregulation.
It has been demonstrated in animal studies that
some infections may modulate the expression of
the immune system, resulting in the suppression of
allergic inflammation. This is achieved through the
priming of regulatory T-cell activity, and these cells
may be responsible for the protection of populations
with chronic infectious diseases against atopic disease. If the specific molecules involved in the
immunomodulatory and protective defence mechanisms of the host against these infectious agents
were to be defined or isolated, they could be manipulated in such a manner as to warrant application for
the development of both novel therapeutic and prophylactic strategies against atopic disease. African
countries, with both a high burden of chronic and
persistent infection and an increasing burden of
atopic diseases may form an ideal ‘nature’s own laboratory’ to investigate the hygiene hypothesis.
INTRODUCTION
During the last few decades, the prevalence of atopic
disease has increased globally, not only in industrialised
countries, but also in less industrialised countries,
especially in urban centres with a westernised
lifestyle.1-6 The hygiene hypothesis suggests that a relationship exists between improved hygiene and an
increase in atopic disease prevalence.7 It is clear that
this relationship may be more complex than initially
assumed. It may be under the influence of different factors, such as genetic variability, time of exposure,
amount and length of exposure, type of infection, and
the prevalence of environmental allergens.
An underlying mechanism for the hygiene hypothesis
is that lack of microbial stimulation leads to either an
inappropriate T-helper (Th) type immune response or
inappropriate Th-cell regulatory mechanisms.8 There is
evidence that the critical period for the establishment
Correspondence: Dr Charles C Obihara, Department of Paediatrics, St
Elisabeth Hospital, PO Box 90151, 5000 LC Tilburg, The Netherlands.
Tel +31-13-539-13-13, fax +31-13-535-94-33,
e-mail [email protected].
178
of the Th-cell balance is early childhood, when the Th2skewed human immune system gradually becomes
less Th2-skewed in non-atopic individuals, but not in
atopic individuals.9,10 Among the infectious agents
which have been inversely linked to atopic disease
prevalence are measles in Guinea-Bissau, hepatitis A in
Italian recruits and BCG-vaccination in schoolchildren
from Japan.11-13 However, most of these initial findings
have not been reproduced in other settings. Animal and
experimental studies have consistently identified
mycobacteria and parasitic infection as potential candidates in the hygiene hypothesis, by demonstrating that
infection with these organisms or exposure to their
products leads to regulatory mechanisms which
restored the immune homeostasis.8 In contrast, the
epidemiological relationship between infection and
atopic disease in humans is still unclear and controversial.13,15-22 Most of these studies have been conducted
in western populations with a low burden of infection.
It has been suggested that inhibition of atopic inflammation in the presence of chronic infections, such as
Mycobacterium tuberculosis and parasitic infection,
probably occurs through the stimulation of regulatory
and anti-inflammatory networks.8,22,23 In this paper we
review the published papers from the African region on
the relationship of mycobacterial and parasitic infection
and atopic disease. In addition, we discuss, based on
the most recent publications, the implication of these
findings for countries in Africa, where chronic infections with mycobacteria and parasites are highly prevalent.
INFECTION AND ALLERGIC DISEASE IN
AFRICA
Recent insight into the hygiene hypothesis of atopic
disease suggests that the protective effect of chronic
infections, such as that caused by M. tuberculosis and
parasites, on atopic disease would logically be more
evident in populations with a high burden of these
infections (such as in many non-affluent, mainly rural
areas in African countries, where exposure to these
chronic infections is more likely to be intense and persistent) than in populations with a low infectious burden (as in most industrialised countries and in some
affluent urban areas in Africa with a westernised
lifestyle, where exposure is more likely to be sporadic
and intermittent). Although the epidemiological relationship between atopic disease and mycobacterial
and parasitic infection has been reviewed recently, this
relationship has not been evaluated in African countries, which carry the highest global burden of both
mycobacterial and parasitic infection.22,24 Table I summarises the characteristics and findings of studies on
the relationship between mycobacterial and parasitic
exposure and atopic disease in different populations in
Africa.18-20, 25-30
Mycobacterial infection and atopic disease
In children from Guinea-Bissau, Aaby et al.25 found less
positive skin-prick test (SPT) to aeroallergens among
the BCG-immunised group of children compared with
the non-immunised group (odds ratio (OR) 0.19, 95%
Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4
Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4
179
The Gambia
S. Africa
S. Africa
Ota et al.20
Obihara et al.26
Obihara et al.27
MTB/BCG
MTB
MTB
Ethiopia
The Gambia
Ethiopia
Gabon
S. Africa
Scrivener et al.18
Nyan et al.19
Dagoye et al.30
Van den Biggelaar et al.15
Obihara et al.32
T. trichiura/hookworm
Any intestinal parasite
T. trichiura/A. lumbricoides/
hookworm
T. trichiura/A. lumbricoides
A. lumbricoides
2006
2004
2003
2001
2001
2000
2006
2005
2003
2000
Year of
publication
†
Unclear the number of persons included in the analysis.
* 132 children out of 520 included in the nested control trial.
BCG – bacille Calmette- Guérin; MTB – Mycobacterium tuberculosis; RCT – randomised controlled trial; S. Africa – South Africa.
Gabon
Van den Biggelaar
et al.31
Parasitic infection
Schistosoma haematobium
Guinea-Bissau
Country
Aaby et al.25
Reference
Mycobacteria
BCG
Type of infectious
agent studied
Cross-sectional
RCT
Cross-sectional
Cross-sectional
Nested case-control
Cross-sectional/
nested case-control
Cross-sectional
Cross-sectional
Cross-sectional
Cross-sectional
Study
type
359
341
563-856†
429
572
520/132*
841
337
507
271 (400)
Sample
size
6-14
5-13
1-4
Yes
Yes
No
Yes
Yes
≥16
15-34
Yes
Yes
Yes
No
Yes
Inverse
relationship?
5-14
6-14
6-14
8-12
3-14
Age
(yr)
Table I. Characteristics and findings of studies on the relationship between mycobacterial and parasitic exposure or infection and atopic disease in different populations in
Africa
confidence interval (CI) 0.06-0.59). This study’s results
were however limited because BCG exposure was
defined as positive history of neonatal BCG immunisation or the presence of BCG-scar only.25 There was no
tuberculin skin test (TST) performed to exclude the
influence of other mycobacteria in the environment. In
children from a TB endemic urban suburb of Cape
Town, South Africa, a significant inverse relation
between M. tuberculosis infection and both questionnaire-reported atopic disease symptoms (OR adj 0.43;
95% CI 0.24-0.79) and objectively confirmed atopic
rhinitis (ORadj 0.06; 95% CI 0.007-0.5) was
observed.26,27 Not only was there strongly positive TST
reactivity observed in more than 50% of the children
(median TST size ≥ 18 mm), there was no influence of
other environmental mycobacteria on the results.
These findings contrast with a recent Gambian study in
which no inverse relation was found between positive
TST and atopy in children.20
Parasitic infection and atopic disease
In Gabonese children, a lower frequency of positive
SPT for house-dust mite (HDM) was observed in the
group with urinary schistosomiasis (a tissue parasite)
than in the group without (OR 0.32; 95% CI 0.160.63).15 In this study, a significant inverse relationship
was also observed between the level of schistosomaspecific interleukin (IL) 10, an anti-inflammatory
cytokine, and SPT to HDM. In Ethiopia, Scrivener et
al.18 observed a reduced risk of wheeze in persons with
hookworm infection (OR 0.48; 95% CI 0.24-0.93). In
The Gambia, an inverse relationship was observed
between atopy and intestinal parasite infection (OR adj
0.37, 95% CI 0.15-0.92).19 In another study from
Ethiopia, Dagoye et al.28 reported a lower prevalence of
recent wheezing (< 12 months) in children infected
with Ascaris lumbricoides compared with those without (OR adj 0.5; 95% CI 0.3-0.9). This effect was doserelated. The same was not found in the group of children with hookworm or Trichuris trichiura infection. The
strongest evidence so far for a causal relationship
between intestinal parasite infection and atopy in an
African setting is derived from the intervention study
conducted in Gabonese children.29 Van den Biggelaar
et al.29 observed that repeated anthelminthic treatment
of children infected with A. lumbricoides resulted in a
significant increase in the rate of SPT for HDM compared with the control group (hazard ratio 2.51; 95% CI
1.85-3.41). In urban South African children, we
observed, in contrast to previous studies, a higher frequency of atopic disease symptoms, positive SPT for
HDM and bronchial hyper-responsiveness (BHR) in children with elevated A. lumbricoides specific-IgE than in
those without.30 The difference in finding was attributed to the intermittent parasite infectious burden (low
median number of A. lumbricoides eggs) due to periodic anthelminthic prophylaxis given to schoolchildren
from the area. Surprisingly it was observed that
M. tuberculosis co-infection modified the expression of
atopy in the children.30 In children without M. tuberculosis co-infection, elevated Ascaris specific-IgE was
associated with significantly increased risk of atopic
symptoms (ORadj 6.5; 1.9-22.4), while in those with
M. tuberculosis co-infection this association was not
observed (ORadj 0.96; 0.4-2.8). That this effect disappeared in the group of children with M. tuberculosis
infection, seems to suggest that mycobacterial coinfection might influence the relationship between
intestinal parasite infection and atopy. There was no
association observed between T. trichiura infection and
atopy.30
180
HOW CHRONIC INFECTION MAY PROTECT AGAINST ATOPIC DISEASE
The hygiene hypothesis of atopy has been supported
by different epidemiological studies, especially from
industrialised countries. Recent evidence stresses the
importance of reduced immune suppression rather
than of erratic immune deviation to explain the rising
global incidence of atopy.14 According to this view,
lower microbial burden does not act by directly inducing a lower production of Th1-cytokines but by decreasing the activity of regulatory T cells (Tregs).8,14 The
mechanism of suppression by Treg is mediated
through the production of inhibitory or anti-inflammatory cytokines, such as IL-10 and transforming growth
factor beta (TGFβ).8,23,31 Tregs selectively express several toll-like receptors (TLRs), a family of proteins with
a critical role in the detection of and response to
pathogens, and can suppress both Th1 and Th2
responses.22,31 Treg signalling is an essential link
between innate immune system (mainly antigen-presenting cells, (APC) and adaptive immune system
(mainly T cells or natural killer (NK) cells). There are indications that anergy, peripheral tolerance and active
immune suppression are related to different stages of
Treg cell-mediated immune deviation. Tregs normally
inhibit Th2 cytokine expression and proliferation of
peripheral blood mononuclear cells (PBMC) from nonatopic individuals in response to allergen exposure.31, 32
There are indications that exposure to bacterial endotoxin or lipopolysaccharide (LPS) enhances the suppressive function of Treg.33 The higher level of endotoxin, increased blood level of CD14 (another LPS
receptor) and TLR2 in European children from a farming environment than in those from a non-farming environment was associated with a lower prevalence of
atopic diseases.34 Experimental administration of TLR2
or TLR4 agonists leads to reduced atopic reaction after
sensitisation with an allergen.35 Missing immune deviation is assumed to be the result of reduced stimulation of TLRs in westernised society.36
WHAT ARE THE IMPLICATIONS OF THIS
IMMUNOLOGICAL MODEL OF THE
HYGIENE HYPOTHESIS FOR THE EPIDEMIOLOGY OF ATOPY IN AFRICA?
Firstly, the model of reduced immune suppression of
the hygiene hypothesis refutes the previous assumption of immune deviation that the interaction between
infection and allergens is limited to the ‘window of
opportunity’ in early life after which it no longer took
place.14 This model suggests that reduced immune
suppression retains some flexibility well into later
childhood and adulthood. This may, for example, logically explain why previously asymptomatic adult
African migrants who move to westernised, industrialised countries develop atopic disease symptoms, if
they are genetically predisposed.14 It is not yet clear,
though, if this phenomenon could explain the urbanrural differences in the incidences of atopic disease in
Africa. More prospective cohort or randomised controlled trials are needed to answer this question.
Secondly, the importance of infection pressure on the
relationship between infections and atopy in a specific
population is highlighted. As earlier indicated, the
mechanism of suppression by Treg is mediated
through the production of inhibitory or anti-inflammatory cytokines (mainly IL-10 and TGFβ).23,31 Pathogens
that cause chronic infections might have evolved
strategies to subvert the host immune responses,
through the stimulation of increased production of
Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4
these anti-inflammatory mediators, which normally
function to contain excessive immune effector reponses of the host.31 These regulatory mechanisms might
be beneficial to the host by maintaining a balance
between effector and memory responses, but with
low inflammatory response that causes minimal damage to the host.37 One practical positive ‘spin-off’ of
this effect would be the suppression of allergic inflammation in populations exposed to a very high chronic
infectious burden. This suggests that the protective
effect of infections on atopic disease would logically be
more evident in populations with a high and persistent
burden of these infections (such as those living in rural
and non-affluent urban areas of Africa, where exposure
to these chronic infections is more likely to be intense
and persistent) than in populations with a low burden
(as in most industrialised countries and westernised,
affluent, mainly urban areas in Africa, where exposure
is more likely to be sporadic and intermittent).
FACTORS POSSIBLY INFLUENCING HETEROGENEITY IN STUDY RESULTS IN AFRICAN
POPULATIONS
Among the important factors which may explain the
heterogeneity in study results on this topic from the
African region, next to differences in the study population, design and methodology (Table I), are differences
in type, definition, amount and persistence of exposure
to infection in the populations studied, and the lack of
uniformity in the definition of atopy.22 One of the reasons for studying the relationship between infections
and atopic disease is not only to understand the mechanism involved, but also to utilise it for future prevention and/or treatment of atopic disease. It is logical to
assume that to solve the riddle of the hygiene hypothesis, studies need to be carried out in populations with
both a high burden of chronic infections and a high
prevalence of environmental allergens, as in some
African regions. These studies would have to be multicentre, prospective cohort and interventional in design,
in order to study effectively the urban-rural, genetic and
interregional differences.
Type of infectious agent. The species of microbe or
parasite may be very important in determining the
degree of immune activation strong enough to induce
suppression of atopic inflammation. For instance, there
are suggestions that BCG immunisation evokes a
weaker and shorter immune stimulation and memory,
and is therefore not able to mimic the persistent
immune stimulation provided by frequent exposure to
wild-type M. tuberculosis.14 To support this are studies
showing that M. bovis BCG is a poorer inducer of IL-12
than natural M. tuberculosis infection.38 Moreover,
M. tuberculosis infection is associated with a larger
TST size than M. bovis BCG or environmental
mycobacteria.39 Although in African children neonatal
BCG immunisation caused a transient TST reactivity,
this became weak or even non-reactive at 5 years of
age.40 Moreover, while some of the studies on the relationship between A. lumbricoides and atopic disease
observed an inverse relationship, none of the studies in
Africa which studied the relationship between
T. trichiura infection and atopic disease observed a relationship. This seems to suggest either a weaker
immune modulatory effect or a different mechanism of
immune activity.
Amount of infection. There are indications that triggering the innate immune system through endotoxin
exposure and the derived effect (increased or
decreased atopic inflammation) may not only depend
on the exposure but also on the amount of endotoxin.22
This has been shown in children from farming environ-
ments in Europe.33,34 In line with this observation it has
been proposed that the difference in the amount and
persistence of infections which trigger the innate
immune system may be important in explaining the
lower prevalence of atopic disease in the developing
world.14 The same mechanism might be applicable in
explaining the differences in atopic disease prevalence
between rural and urban Africa.
Simultaneous exposure to infection and allergen. There
are suggestions that the simultaneous exposure to
both environmental allergens and infectious agents
may be the key factor to the suppression of atopy.41,42
This may partly explain the differences in findings in the
studies carried out in areas with comparable prevalences of infectious disease, but difference in the
prevalence of allergen exposure. For instance, Janssen
et al.41 argued that it might not be the Th1-inducing
properties of mycobacteria, but simultaneous exposure
to both mycobacteria and allergen, which induced an
allergen-specific Th1 response strong enough to prevent induction of atopy. Recombinant mycobacteria
mice challenged with a peptide of Der p I, underwent a
switch from Th2 to Th1 profile, which was specific only
for vaccines expressing allergen peptide. This means
that priming of allergen-specific Th1 responses may be
crucial in establishing a memory response capable of
long-term protection against allergen-specific Th2
response.41 In support of this, Sano et al.42 demonstrated in an experimental mouse model that simultaneous M. tuberculosis infection and allergen challenge
might stimulate an immune response strong enough to
suppress Th2 activity. They also observed that stimulation of T cells with ovalbumin only induced Th2 dominant responses, whereas concomitant stimulation with
both ovalbumin and M. tuberculosis caused induction
of antigen-specific Th1 responses, with secretion of
interferon-gamma (IFN-γ), mediated by IL-12.42 If this
phenomenon, where both M. tuberculosis and allergens are simultaneously presented by APC to the Tcell, also applies to humans, then it is most likely to
occur where M. tuberculosis infection and allergen
exposure are both highly prevalent. In such a setting,
exposures to environmental allergens and M. tuberculosis would be more likely to occur simultaneously than
in a low prevalence setting.
Low positive predictive value of allergy testing. A
recent analysis highlighted the discrepancy between
environmental allergen exposure, clinical allergy and
laboratory or clinical measurements of atopy in African
populations.43 In Africa, allergen-specific serum IgE and
allergen-specific SPT seem to be poorer predictors of
clinical allergy than in populations in western Europe
and the USA. It was hypothesised that this may be
related to the influence of (as yet) unidentified local
allergens, such as mites, grass and tree allergens in
Africa. The authors stressed the need for developing
assays to identify important local environmental allergens.43 Although genetic factors may also play an
important role in this discrepancy, there are indications
that other environmental factors, such as co-infections,
may partly influence the sensitivity of blood and skin
tests for allergy in African populations. For instance,
recent findings in South Africa suggest that M. tuberculosis infection might modify the expression of atopy
in populations with a high burden of disease (Fig. 1).27
It was observed that in a group of children with a negative TST (N = 158), more than 70% of those with
atopic symptoms versus only 13% of those without
symptoms had positive allergy SPT (p < 0.001). In contrast, in a group of genetically comparable children with
positive TST (N = 179) from the same area, only 7% of
those with atopic symptoms and 18% of those without
symptoms had a positive allergy SPT (p = 0.7).27
Current Allergy & Clinical Immunology, November 2007 Vol 20, No. 4
181
4.
Faniran AO, Peat JK, Woolcock AJ.
Prevalence of atopy, asthma symptoms and diagnosis, and the management of asthma: comparison of an
affluent and non-affluent country.
Thorax 1999; 54: 606-610.
5.
Yemaneberhan H, Bekele Z, Venn A,
Lewis S, Parry E, Britton J.
Prevalence of wheeze and asthma
and relation to atopy in urban and
rural Ethiopia. Lancet 1997; 350: 8590.
6.
Calvert J, Burney P. Effect of body
mass on exercise-induced bronchospasm and atopy in African children. J Allergy Clin Immunol 2005;
116: 773-779.
■ Recent allergic symptom
■ No allergic symptom
7. Strachan D. Hay fever, hygiene and
household size. BMJ 1989; 289:
1259-1260.
TST negative children (N = 158)
TST positive children (N = 179)
Fig. 1. Percentage of skin-prick test (SPT) positivity in symptomatic and asymptomatic children with negative or positive tuberculin skin test (TST).
Prospective intervention studies are needed to confirm
these findings.
Discrepancy in the definition of atopy. Lack of uniformity in the definition of atopy makes it difficult to compare results of studies carried out in African countries.
This may also account for some of the heterogeneity of
study results from the continent. While some studies
defined atopy as questionnaire-reported symptoms or
positive SPT or elevated serum specific IgE to common
environmental allergens, others used both definitions.
The use of the recently accepted World Allergy
Organization (WAO) definition of atopy, as clinical allergic symptoms in combination with a positive SPT
and/or an elevated serum IgE antibody level, makes it
possible for future studies to define atopy more uniformly.44
CONCLUSION
The results of epidemiological studies in African populations on the relationship between chronic infection
such as that caused by mycobacteria and parasites are
as inconclusive as those in other parts of the world.
Part of this inconclusiveness may be attributed to differences in study design, population and methodology.
However, it is not unthinkable that other environmental
factors such as the type, amount and persistence of
infection, prevalence of environmental allergens and
sensitivity of allergy tests in the African populations
may equally be of influence. Last but not least is the
lack of uniformity in the definition of atopy used in the
different studies. Despite the above-mentioned shortcomings of the present epidemiological studies on the
relation of infection and atopic disease, the high prevalence of chronic infections and the rising incidence of
atopic disorders due to westernisation in some communities in the African region, indicate that these communities form an ideal epidemiological platform to
investigate the possible protective effect of infection
on the development of atopy.
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Allergy and Asthma: Practical Diagnosis and Management
Massoud Mahmoudi
September 2007, ISBN 9780071471732, paperback, 400 pp, McGraw-Hill, R395
Clear, authoritative guidance for your day-to-day allergy and asthma practice
Allergy and Asthma: Practical Diagnosis and Management is a concise guide that puts the most salient
insights in allergy medicine right at your fingertips. Written by a leading allergy clinician, along with 30
nationally recognized expert contributors, this resource is perfect for front-line general practitioners, especially primary care physicians and allied health care providers. Inside, you’ll find the most clinically relevant
information on the pathophysiology, diagnosis, treatment, and prevention of all major allergic disorders.
Features
Need-to-know coverage that spans the entire scope of adult allergy and asthma-geared for real world
medical practice
A timely look at occupational allergies and allergies linked to unhealthy environments
Organization by specific organ, which guides you to diagnostic and therapeutic solutions quickly and
easily
Essential chapters on the principles of diagnosis and on medications used in the management of
simple and complex allergy
Coverage of new complementary and alternative medicine techniques in the management of allergic
disorders
Over 100 outstanding illustrations
Key concepts, management protocols, and recent references that deliver a highly accessible over
view of today’s allergy practice
Contents
1: Introduction to Immune System. 2:The History and physical examination of the allergic patient. 3: Prevalence
and changes of allergic diseases in childhood, adults and elderly. 4: Allergic diseases of the eye. 5: Prevalence
of pollens in the United States and the other continents. 6: Allergic rhinitis. 7: The Effect of rhinitis on sleep,
quality of life, daytime somnolence and fatigue. 8: Sinusitis. 9: Allergic Diseases of the Ear. 10: Cough and
allergic diseases. 11: Urticaria and Angioedema. 12: Atopic dermatitis. 13: Allergic contact dermatitis. 14: Pediatric Asthma. 15: Adult asthma. 16: Exercise induced asthma. 17: Occupational Asthma. 18: Asthma and
pregnancy. 19: Pseudo- asthma: when cough, wheezing, and dyspnea are not asthma. 20: Hypersensitivity
pneumonitis. 21: Allergic bronchopulmonary aspergillosis. 22: Serum sickness. 23: Complement systems and
allergic diseases. 24: Food allergy. 25: Insect allergy. 26: Latex allergy. 27: Drug Allergy. 28: Smoke, pollution
and allergies. 29: Sick building syndrome. 30: Allergy in Elderly. 31: Diagnostic testing in allergic diseases.
32: Immunodeficiency. 33: HIV infection. 34: Complementary and alternative therapy in treatment of allergic
diseases. 35: Nutrition, diet, and allergic diseases. 36: Prevention and control measures in management of allergic diseases. 37: Antihistamines and mast cell stabilizers. 38: Bronchodilators. 39: Glucocorticoids. 40: Anti IgE
antibody. 41: Allergy Immunotherapy. 42: Anaphylaxis and its management
ORDERS: Medical Book Seller, PO Box 3784, Tygervalley 7536. Tel 083 303 8500.
Fax (021) 975 1970. E-mail: [email protected]
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