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Airborne Endotoxin
by Robert Dales, David Miller, Ken Ruest, Mireille Guay, and Stan Judek
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Children's Health
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Airborne
Endotoxin Is Associated with Respiratory Illness in the First 2 Years of
Life
Robert Dales,1
David Miller,1 Ken Ruest,2 Mireille Guay,1
and Stan Judek1
1Air Health Effects Division, Health
Canada, Ottawa, Ontario, Canada; 2Research Division, Canada
Mortgage and Housing Corporation, Ottawa, Ontario, Canada
Abstract
To determine the influence of endotoxin on the incidence of acute
respiratory illness during the first 2 years of life, we carried out a
longitudinal follow-up study, beginning at birth, of 332 children born in
Prince Edward Island, Canada. We measured 5-day averaged air endotoxin in
the homes of children, whose parents provided information by daily
symptom diaries and twice-monthly telephone contact for up to 2 years.
Endotoxin concentration was 0.49 ± 3.49 EU/m3 (geometric mean
± geometric SD), and number of annualized illness episodes was 6.83 ±
2.80 (mean ± SD). A doubling of the air endotoxin concentration was
associated with an increase of 0.32 illness episodes per year (p =
0.0003), adjusted for age, year of study, breast-feeding, environmental
tobacco smoke, child care attendance, indoor temperature, and income.
Indoor mold surface area and fungal ergosterol were not significantly
associated with endotoxin. Airborne endotoxin appears to be a risk factor
for clinically symptomatic respiratory illnesses during the first 2 years
of life independent of indoor fungus. Key words: bacteria,
children, endotoxin, housing, respiratory illness.
Address correspondence to R.
Dales, Ottawa Hospital (General Campus), 501 Smyth Rd., Box 211, Ottawa,
Ontario K1H 8L6, Canada. Telephone: (613) 737-8198. Fax: (613) 739-6266.
E-mail: rdales@ottawahospital.on.ca
This work is supported by Health Canada, Canada
Mortgage and Housing Corporation, Prince Edward Island Reproductive Care
Program, Prince Edward Island Medical Society, Carleton University, and
Prince Edward Island Department of Health and Social Services.
The authors declare they have no competing financial
interests.
Received 23 March 2005; accepted 3 November 2005.
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Introduction
Endotoxins are lipopolysaccharide components of the
outer membranes of gram-negative bacteria. Endotoxin has been implicated in
bysinnosis, organic dust toxic syndrome, and illness in swine confined
animal feeding operations workers (Douwes et al. 2002). Endotoxin in
settled dust in residential environments has been associated with an
increase in asthma symptoms, asthma medications, and reductions in lung
function in those with atopy or asthma (Douwes et al. 2000; Gehring et al.
2001a; Michel et al. 1991, 1996; Park et al. 2001a; Rizzo et al. 1997).
Despite these adverse effects, early exposure may reduce future allergies
and asthma (Lapa e Silva et al. 2000; Litonjua et al. 2002; Reed and Milton
2001; Von Ehrenstion et al. 2000; Von Mutius et al. 2000). Most studies
were of adults or school-age children, with two focusing on infants. In the
present study we examined the association between airborne endotoxin and
the incidence of respiratory illnesses in children during the first 2 years
of life. We accounted for exposure to a potential confounder, indoor
fungus, which has been associated with respiratory symptoms and may be
associated with the presence of indoor endotoxin (Gehring et al. 2001b;
Verhoeff and Burge 2004).
Materials
and Methods
Study design. Data for the present study were abstracted from an
ongoing study of the influence of indoor environmental factors on
respiratory illness during the first 2 years of life. The study began in
1997 in the province of Prince Edward Island, Canada, which has a
population of approximately 150,000. The study was approved by the ethics
review boards of the Ottawa Hospital and the Health Protection Branch of
the Canadian government. Recruitment occurred during the late autumn and
winter (cold season) of each year when the ground was frozen. Because of
resource constraints, we recruited approximately 60 consecutive newborns
each year. All physicians who practice obstetrics in the province
participated in recruitment. Women in the third trimester of pregnancy
received letters from the physicians’ offices describing the study and
requesting participation. Interested women were contacted by telephone to obtain
informed consent. Excluded from the study were babies born > 4 weeks
premature, those with neonatal respiratory difficulties requiring prolonged
hospitalization at birth, and those whose families expected to change
residence within 2 years of birth. Only one child per household was
studied. Baseline information was obtained on sociodemographics and family
history. The participating parents maintained a daily symptom diary from
birth until 2 years or until the study ended, on large multipurpose calendars.
Each study family was phoned twice monthly to document information from the
diary. If parents had omitted recording symptoms on a daily basis, they
provided information for the previous 2 weeks based on recall. Parental
reporting of child care attendance was also recorded every 2 weeks.
Definition of respiratory illness. We adapted the method of Samet et
al. (1992) to define a respiratory illness episode, the purpose being to
identify discrete acute illnesses as opposed to persistent ongoing
symptoms, such as a chronically runny nose. We defined the beginning of an
illness episode as 2 consecutive days with any one of the four following
symptoms: stuffy nose, cough, wheeze, and shortness of breath. The illness
episode starts on the first of these 2 consecutive days and ends when there
are 2 consecutive days with none of these symptoms, the last day of the
illness episode being the last day with a symptom.
The
primary outcome of interest was the number of illness episodes prorated on
an annual basis (number multiplied by 365/days of observation). A secondary
outcome measure, illness days, was defined as the sum of all days occurring
within illness episodes, also prorated on an annual basis. For example, if
a child had two illness episodes each lasting 3 days, six illness days
would be assigned. If a child had two illness episodes each lasting 5 days,
10 illness days would be assigned.
Air sampling for endotoxin and ergosterol. Sampling was done within the first
year of birth, and for 81%, within the first 4 months. Air from the child’s
bedroom was sampled for both endotoxin and ergosterol through a three-piece
cartridge equipped with a polycarbonate filter for approximately 5-7 days
with a Buck model SS sampling pump (AP Buck, Orlando, FL, USA) calibrated at
2 L/min at the beginning and end of the sampling. Forty-eight hours after
the pump was installed, the flow rate was checked to ensure it was within
5% of the initial reading. Very high dust concentrations can clog the
filter and reduce the pump flow. If this happened, the pump was stopped and
air endotoxin concentration was calculated based on the reduced sampling
time. The total volume of air sampled ranged from 6.0 to 23.9 m3,
limited by the need to maintain an acceptable flow rate. Once collected,
the cartridges and filters were sealed in new plastic bags and stored at
room temperature under dry conditions.
For
endotoxin analysis, the filters were extracted with depyrogenated water
(LRW, Associates of Cape Cod Ltd., East Falmouth, MA, USA) assisted by
sonication. Samples taken before April 2001 were analyzed by the Limulus
amoebocyte lysate (LAL) assay gel clot method from Associates of Cape Cod.
The detection limit was 0.25 EU/filter. All subsequent analyses were done
by the LAL chromogenic method, also from Associates of Cape Cod. The
detection limit was 0.1 EU/filter. All analyses were performed by the same
analyst in the same laboratory according to the manufacturer’s
instructions. Apart from differences in the lower limit of detection, the
two methods gave similar results.
We
analyzed ergosterol, an indicator of fungal biomass, by gas chromatography
and mass spectroscopy as described by Foto et al. (2005). The volume of air
sampled ranged from 10.7 to 25.4 m3. Ergosterol was determined
using an Agilent model 5973 quadrupole mass spectrometer (Agilent
Technologies, Inc., Palo Alto, CA, USA) operating in the electron
ionization mode at 70 eV. Compounds were separated on an Agilent 6890
series gas chromatograph equipped with a 30 m  0.25
mm inner diameter  0.25
µm ZB-5 capillary column. The concentration of ergosterol was determined
against an authentic external standard in the selective ion mode using m/z
363 and 396. The detection limit in selective ion mode was 4.5 ± 0.6 ng/mL.
Ergosterol standard (Sigma Chemical Company, St. Louis, MO, USA) was
recrystalized, freeze-dried, and stored at 4°C.
Definition of covariates other than ergosterol. During the postnatal interviews,
several characteristics were recorded every 2 weeks for a period of 2
years: the presence of furry or feathered pets in the house, the presence
of smokers inside the house, whether the baby was breast-fed, and the
number of hours per week the child was cared for outside the home. Based on
this information, we created a summary variable for each of the
characteristics. For the first three characteristics, we calculated the
percentage of postnatal interviews where the characteristic was declared.
For example, if 20 of 50 postnatal interviews mentioned the presence of
pets inside the house for a particular child, the value of the pet variable
would be 0.4. The last characteristic, the number of hours per week that
the baby was cared for outside the home, was averaged over the entire
2-year period to create the child-care variable. For presentation, we then
categorized some summary variables. The pet variable was categorized into
“never declared pets,” “sometimes declared pets,” and “always declared
pets,” which divided responses almost equally into thirds. The
exposure-to-smoke variable was categorized into terciles. The
breast-feeding and the child-care variables were kept as continuous data.
The age variable was defined as the age of the child in the middle of the
span of the follow-up period. “Mold surface area” refers to the total
surface area of the home with mold visible to trained home inspectors.
Statistical analysis. We tested the association between
the number of illness episodes per year and airborne bedroom endotoxin
concentration using multiple linear regression analysis. Valid endotoxin
results were obtained for 351 houses. A total of 19 homes were excluded
from the analysis--15 because of missing temperature data and four because
of missing income data--leaving 332 homes for analysis. Eleven babies of
332 (3.3%) exited the study before turning 2 years of age (mean age, 1.1
years), and 56 babies had not reached 2 years of age (mean 1.7 years) by
the last day of data collection used for this analysis. This is an ongoing
study with children entering and exiting at different times. The illness
episodes and covariates were annualized and thus adjusted for duration of
follow-up. To test the effect of the 11 babies who exited early, we
repeated the analysis with and without them, and no differences were found
in the illness-endotoxin association.
Mold
surface area was expressed as ranks from highest to lowest. Endotoxin
values followed a log-normal distribution, so they were log-transformed. A
multiple linear regression model with the number of respiratory illness
episodes per year as the dependent variable and the natural logarithm of
endotoxin concentration as the primary independent variable of interest was
built with the stepwise method. A categorical variable--the year of sample
collection--was added to the model to account for any seasonal variations
in illness from year to year and also the change in the lower limit of
detection of the endotoxin analytic technique after 2001. Endotoxin and
year of home sampling were held in the model along with any variables with p-values
< 0.10, resulting in the final model, with variables endotoxin, year of
home sampling, temperature, age, mean hour per week that the baby was cared
for more than 1 day a week outside the home, percentage of postnatal
interviews in which the baby was breast-fed, income, and categorized
percentage of postnatal interviews where smokers were declared in home.
A
potential confounder was defined as a variable (Tables 1 and 2) that, if
added to the model, would change the parameter (β) of the natural
logarithm of endotoxin by > 10%. No confounders were found for the
illness episodes model. The residuals from the regression equation were
normally distributed (Shapiro-Wilk statistic = 0.9932, p = 0.1362).
We also examined the homogeneity of variance assumption, and the chart of
residuals against predicted values showed no particular pattern.
Interactions biologically plausible were also tested, and none were found
to be statistically significant at the 5% level. We found no evidence of
interaction between allergies or asthma in parents and endotoxin. Careful
examination of each of the partial residual plots (i.e., the
component-plus-residual plot) did not reveal any sign of nonlinearity in
the relationship between illnesses and air endotoxin. Further, adding a
square term for endotoxin did not improve significantly the R2
of the model.
The
endotoxin measurement was made only at the beginning of the 2-year
follow-up. To determine the robustness of the endotoxin-illness
association, we measured it at several time points between the initial
endotoxin measurement and symptom assessment. We would assume that a true
causal association would remain stable or weaken over time. If the association
increased or fluctuated randomly with time of follow-up, this would reduce
the probability of a causal association. We measured the results from 90-,
180-, 270-, 360-, 450-, 540-, 630-, and 720-day windows around the time of
endotoxin sampling. The regression model obtained previously for a 2-year
period was applied to each of these windows. The β-coefficient for the
effect of the natural logarithm of endotoxin on illness episodes and total
illness days along with its 95% confidence interval were graphed against
the size of the window.
Results
Table 1
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Table 2
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Table 3
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Table 4
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Table 5
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Figure 1. The effect size over time between illness and bedroom
endotoxin measured at birth. (A) Annualized illness episodes. (B)
Annualized illness days. Effect size is represented as the
β-coefficient for the effect of the natural logarithm of endotoxin
on illness along with its 95% confidence interval.
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The characteristics of the 332 children, overall and
stratified by bedroom airborne endotoxin level, are presented in Tables 1
and 2. Of the categorical variables (Table 1), only year of testing was
significantly associated with endotoxin, with no secular trends (p
< 0.0001). The pets variable was not associated with endotoxin concentrations.
For dogs, the geometric mean and geometric standard deviation (GSD) were
0.46 ± 3.82 if dogs were never reported present in the home and 0.54 ± 3.15
if ever reported to be in the home (p = 0.22). There was also no
significant difference in endotoxin values between homes where dogs were
reported in < 50% of interviews compared with at least 50% of interviews
(p = 0.12). Similarly, there was no significant association between
cats and endotoxin. Of the continuous variables (Table 2), only indoor
relative humidity was positively related to endotoxin (p = 0.01).
Illness
episodes correlated best with the individual symptoms of cough and stuffy
nose; Pearson correlation coefficients were 0.69 and 0.76, respectively,
both at p < 0.01. For illness days, respective values were 0.83
and 0.95. Wheeze was also significant for both illness episodes and illness
days at 0.37 and 0.41, respectively (p < 0.01). The annualized
number of respiratory illness episodes and total days of illness episodes
were positively related to endotoxin at p = 0.13 and p =
0.07, respectively (Table 3). All of the individual respiratory symptoms
were greater in the higher compared with the lower endotoxin group, but
only the incidence of wheeze reached statistical significance, being a relative
248% greater in the higher compared with the lower endotoxin group (p
= 0.01).
The
unadjusted Pearson correlation coefficients between log-transformed
endotoxin and illness episodes and illness days were 0.105 (p =
0.056) and 0.106 (p = 0.053), respectively. The association for
number of days with wheeze was 0.271 (p < 0.0001), but other
individual variables were not significant at p = 0.05. The adjusted
associations for illness episodes and total illness days were highly
significant (Tables 4 and 5). The multiple linear regression model for
illness episodes resulted in a β-coefficient of 0.46 (SE 0.13) for the
natural logarithm of endotoxin (p = 0.0003), which means that each
1.0 unit increase in the natural logarithm of airborne endotoxin concentration
was associated with 0.46 more illness episodes per year. An alternative
expression of the relation would be that a doubling of air endotoxin
concentration was associated with an increase of 0.32 illness episodes per
year (p = 0.0003), adjusted for age, year of study, breast-feeding,
environmental tobacco smoke, child care attendance, indoor temperature, and
income. Also, starting from the geometric mean (0.49) and increasing
endotoxin by its geometric mean resulted in 4.7% excess illnesses per year.
Similarly, doubling air endotoxin was associated with an increase of 3.25
illness days per year (p = 0.005), adjusted for age, year of study,
breast-feeding, child care attendance, indoor temperature, and sex.
Starting from the geometric mean (0.49) and increasing endotoxin by its
geometric mean resulted in 5.5% excess illness days per year.
Significant
covariates in the regression of illness episodes were year of testing,
indoor temperature, age, child care, environmental tobacco smoke, and
income (all p < 0.05). Similar results were found with illness
days with a β-coefficient of 4.68 (SE 1.66, p = 0.005).
In
Figure 1, the β-coefficient for the effect of the natural logarithm of
endotoxin on illness episodes and total illness days is graphed against the
size of the window. The magnitude of the association between illness
episodes and endotoxin levels was almost linearly decreasing with the use
of longer observation periods extending further from the original sampling.
Because the effect of endotoxin levels on illness episodes was highly
significant for a 2-year period, it would be even more significant for
shorter observation periods.
Discussion
Air
endotoxin was positively associated with an increase in episodes of
respiratory illness among children during their first 2 years of life
despite adjustment for many host and environmental factors, including
indicators of fungal exposure. The method of endotoxin collection is unique
compared with previous studies of indoor air, most of which sampled floor
dust rather than airborne dust, which may be better correlated with
inhalation exposure. Air sampling, done infrequently in previous studies,
usually consisted of a grab sample (up to 30 min), whereas our 5-day
collection period would be expected to provide a more stable average
estimate of exposure. Another unique feature of exposure is that endotoxin
sampling was done during the cold season when the ground is frozen and
usually snow covered. This makes it less likely that the measured endotoxin
in air is simply a reflection of what was present outdoors at the time of
the sampling. Rylander (2002) suggested that fungal products, and
specifically (1-3)-β-d-glucan, may coexist with endotoxins and thus
may confound the association. In the present study, ergosterol, a marker of
fungal growth in Prince Edward Island homes, did not influence the
illness-endotoxin association.
Michel
et al. (1991) measured endotoxin concentrations in the house dust of 28
adult subjects with chronic stable asthma. Exposure to higher levels (>
5.6 ng lipopolysaccharide/mL) was associated with poorer asthma control
measured by symptoms, medication use, and lung function. In a subsequent
study, Michel et al. (1996) refined their previous findings in a group of
69 adults with asthma who were sensitized to house dust mites. Asthma
control was related to house dust endotoxin, averaging 2 ng/mg dust in
those exposed to Der p 1 levels > 10 µg/g dust, but not in those exposed
to lower levels of the major dust mite antigen. Rizzo et al. (1997) and Douwes
et al. (2000) reported adverse effects of settled dust endotoxin in
school-age children with asthma, atopy, or asthma symptoms but not in those
without an atopic history. Park et al. (2001a) and Gehring et al. (2001a)
reported increased wheezing in infants living in homes with increased
levels of settled dust endotoxin, consistent with the findings of the
present study in which airborne endotoxin was measured and fungal burden
was accounted for using airborne ergosterol. Indoor fungus therefore is not
likely to have confounded the observed relation, although fungus has been
associated with respiratory symptoms and may be associated with indoor
endotoxin (Gehring et al. 2001b; Verhoeff and Burge 2004). Compared with
occupational settings, the indoor air endotoxin concentrations in our study
were low (on average, < 2 EU/m3), yet associations with
adverse health effects were observed. The relatively large sample size with
daily symptom monitoring over 2 years in each subject appeared to give us
the power to detect these effects. Further support from health effects at
low levels comes from Park et al. (2000), who reported airborne endotoxin
in Boston homes during the warm season to be generally < 1 EU/m3,
and corresponding floor dust was < 100 EU/mg (estimated values taken
from a log-scaled graph). Before our study, Park et al. (2001a) also found
associations between settled dust endotoxin and wheeze.
Endotoxins
are also postulated to confer health benefits. Lipopolysaccharide, the main
component of endotoxin, may shift the cytokine response toward a Th1
response and away from a Th2 response, thereby reducing the
chance of developing atopy (Lapa e Silva et al. 2000). Consistent with this
theory is the observation that children growing up on farms, where endotoxin
exposure is higher than in urban areas, have less atopy (Von Ehrenstion et
al. 2000; Von Mutius et al. 2000). Evidence thus far suggests that early
childhood exposure to endotoxin may protect against future asthma, but
later in life endotoxin appears to exacerbate asthma (Reed and Milton
2001). The present study indicates that very early exposure is not benign
but associated with increased illness episodes. Litonjua et al. (2002)
reported on 226 children between the ages of 1 and 5 years with a parental
history of atopy who were followed for 4 years. House dust endotoxin was
associated with reported wheezing that decreased with increasing duration
of follow-up. This observation suggests that early exposure offers future
protection, or that the initial endotoxin measure became less
representative of ongoing endotoxin exposure over time. The present study
was somewhat different: beginning at birth, including all children
irrespective of parental history of atopy, using airborne rather than dust
endotoxin, including indicators of respiratory illness in addition to
wheeze, and considering confounding by indoor mold exposure. Nevertheless,
even with children not selected based on atopic parents, we also found that
wheeze was the symptom with the strongest association with endotoxin, and
the effect size became smaller with increased duration of follow-up.
Sources of endotoxins. Gram-negative bacteria are found in
water, soil, and outdoor air. Reported indoor sources of gram-negative
include contaminated humidifiers, pets, storage of food waste, and
increased amounts of settled dust (Park et al. 2001b). The need for water
availability is consistent with our finding that relative humidity was
positively associated with air endotoxin, not previously described. Gehring
et al. (2001a) found that dust concentrations were higher with cats and
dogs present. These studies found that endotoxin was higher in old
buildings, with longer duration of occupancy, low ventilation rate, and
poor housekeeping. Indoor pets were not associated with air endotoxin in
the present study, which was carried out during the cold season with frozen
ground and often snow cover. Perhaps pets would be less likely to go
outside and subsequently bring in soil on their paws.
In
summary, the present study supports a positive association between airborne
endotoxins and the incidence of acute respiratory illnesses during the
first 2 years of life, independent of allergic history and exposure to
indoor mold that may coexist with contamination by bacterial endotoxin.
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Environmental
Health Perspectives Volume 114, Number 4, April 2006
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