Discussion
We have tested the hypothesis that early life exposures to geohelminths
- through an infected mother during pregnancy or early childhood, or
both - protect against wheeze/asthma and atopy at school-age. To do
this, we did a birth cohort study to measure the effects of maternal and
early childhood geohelminths on the development of atopy (measured as
SPT), wheeze/asthma, and airways reactivity and inflammation at 8 years.
Our findings indicate that maternal geohelminths have persistent effects
on childhood SPT but that this effect was strongest among children of
infected mothers who also acquired infections during early childhood. A
maternal effect on increased wheeze and airways inflammation was seen
among non-atopic children, the dominant phenotype in non-affluent
societies.21,22 The maternal effect on SPT was not
associated with a specific parasite species, while that on wheeze
appeared to be mediated by T. trichiura infection. In contrast,
early childhood T. trichiura protected against wheeze
irrespective of atopy.
There are few previous longitudinal analyses of the effects of early
geohelminth infections on development of allergy, and none of these have
adequately addressed effects of maternal or childhood geohelminths on
asthma or atopy: 1) a birth cohort in Ethiopia that did not measure
maternal gehelminths and in which the prevalence of geohelminths
(<4%) in early childhood was too low to explore effects on
allergy at 5 years;23 and 2) a longitudinal study in
Brazil, with no data on maternal geohelminths, showed that T.
trichiura infections in early childhood, particularly at higher
parasite burdens were associate with a reduced risk of SPT in later
childhood.24 To our knowledge, the only other study to
show effects of maternal geohelminths on allergy-related outcomes was an
observational analysis in Uganda showing maternal hookworm to be
associated with a reduced risk of eczema in children to 5
years.25
Previous cross-sectional studies have provided evidence that childhood
geohelminths might protect against wheeze/asthma: 1) a study in Ethiopia
in 1-4 year olds showed a negative association between A.
lumbricoides infection and wheeze;26 2) a study among
schoolchildren in a rural region in Ecuador showed an inverse
association between heavy infections with T. trichiura and atopic
wheeze27 - most previous cross-sectional studies,
however, showed no effects of T. trichiura on asthma
symptoms;8,21,28,29 and 3) three separate studies in
Ethiopia showed an inverse relationship between hookworm infection and
asthma symptoms.8 With respect to A.
lumbricoides infections in school-age children, several studies have
shown a positive association between A. lumbricoides infection or
allergic sensitization to Ascaris antigens and asthma
symptoms8,28,30,31 and airways
reactivity,29,31,32 an effect that was strongest in
non-atopics.28 Our data showed positive associations
between greater parasite burdens with A. lumbricoides in mothers
and risk of asthma and markers of airways inflammation in non-atopic
children, while A. lumbricoides in children was associated with
elevated FeNO.
Our observation that maternal infections protect against atopy are
consistent with observations of inverse associations between
geohelminths and SPT from cross-sectional studies of
schoolchildren.21,24,33 A protective effect of
maternal geohelminth (against mite) was present from 3 years of
age.15,16 Childhood infections appeared to protect
against SPT to perennial allergens from 5 years,16 but
the observation that the effect was only seen among children with
infected mothers irrespective of childhood infection status, indicate
the maternal effect is key. Maternal geohelminths were strongly
associated with childhood infections to 5 years of age – reflecting a
shared risk of infection in the household environment – a child growing
up in a household where one or more family members are infected, is at
greater risk of infection.34 The previous observation
from Brazil showing a protective effect of early life T.
trichiura infections against SPT at school age24could have been mediated by maternal infections which were not measured
but with which early childhood infections are likely to be strongly
associated. A maternally-mediated effect on SPT could explain two
previous observations from Ecuador: 1) bimonthly anthelmintic treatments
in schoolchildren showed no treatment effect on allergen
SPT;10 and 2) community mass drug administrations with
the broad-spectrum anthelmintic, ivermectin, over 15 years for the
elimination of onchocerciasis, was associated with an increase in SPT
prevalence in schoolchildren. Long-term ivermectin started before most
children were born, likely resulted in reduced geohelminth infections in
mothers.35
We have shown previously in this population that newborns of mothers
infected with A. lumbricoides have evidence of sensitization of
CD4+ T cells to Ascaris antigens.36 The same is
likely to be true for T. trichiura that, although purely enteric,
has an intimate relationship with the mucosal immune
system.7 Certainly, geohelminth antigens are present
in the blood37 of infected mothers and can cross the
placenta to sensitize the foetus. Immunological sensitization of the
foetus could increase or decrease immune responsiveness. Decreased
responsiveness could be associated with tolerization to parasite
allergens including those that are cross-reactive with aeroallergens.
Extensive cross-reactivity has been demonstrated between helminth
parasites and aeroallergens such mite allergens,38 and
such cross-reactivity can mediate cross-sensitization in immediate
hypersensitivity skin reactions in murine models.39The suppressive effect of maternal geohelminths on SPT, particularly to
mite allergens, in children could occur through tolerization to
cross-reactive allergens.
The effect of maternal T. trichiura on childhood wheeze likely
occurs through a distinct non-allergic mechanism, perhaps through the
interconnected mucosal immune system.40 The
evolutionary significance of such an effect resulting in increased
mucosal responsiveness could, for example, increase chemical signals
leading to airways reactivity and wheeze symptoms (as observed here) but
the same signals in the gut might enhance peristalsis and expulsion of
parasites. The type of immune response generated in the foetus likely
will be affected by a number of factors such as host genetics, the
‘intensity’ of exposure, and geohelminth parasite species and could be
parasite antigen-specific. The maternal effect of T. trichiurawas evident only among children of infected mothers who did not acquireT. trichiura infections during the first 5 years of life. The
acquisition of childhood T. trichiura abrogated the maternal
effect indicating that in utero effects could be modified by
exposure during childhood, presumably by modulation of the same
mechanisms.
Asthma is a highly heterogeneous disease for which several phenotypes
and endotypes have been described.41 Numerous traits
have been described for asthma (e.g. airflow limitation and airway
inflammation) caused by distinct causal mechanisms.42Similarly, geohelminths are a diverse group of parasites with distinct
life cycles and niches within (and outside) the intestine in humans. The
human host has developed a wide variety of inflammatory mechanisms,
primarily mediated by Th2 cytokines, with which to kill and expel
geohelminths.7 Balanced parasitism requires an
accommodation between host and parasite to allow parasites to survive
without severely debilitating their host. Such an accommodation includes
the modulation of host anti-parasite Th2 responses.7Our observations of parasite species-specific effects on different
‘traits’ (e.g. wheeze symptoms, airways reactivity and elevated FeNO)
likely reflects this complex interaction.
Strengths of the study include prospective design with follow-up from
birth, stool data on maternal geohelminths during pregnancy, and
collection of large number of sociodemographic and lifestyle variables
allowing us to control for potential confounders. Potential biases were
reduced by using objective measures of geohelminth infections,
performing all evaluations blind to the child’s exposure status, and
high retention in the cohort to 8 years (~80%).
Repeated exposure measures for childhood geohelminths during the first 5
years of life provided more precise estimates of infection rates but
children with positive stools were treated thus reducing prevalence and
parasite burdens.