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Biomedical subjects

A Custovic

Publications and source records attributed to A Custovic.

At least 55 records · Page 3Linked to original sources

Lymphoproliferative responses in cord blood and at one year: no evidence for the effect of in utero exposure to dust mite allergens.

BACKGROUND: Maternal allergen exposure beyond the 22nd week of pregnancy may be important in foetal T cell priming. Allergen-specific cord blood mononuclear cell (CBMC) immunoproliferative responses without corresponding bacterial antigen responses (tetanus toxoid), have been suggested as evidence of in utero sensitization. OBJECTIVES: To investigate the relationship between lymphoproliferative responses at birth and at 1 year with maternal and 1-year infants house dust mite allergen exposure. METHODS: Home visits and dust sampling were performed by the 20th week of pregnancy, immediately after birth, and then at 1 years of age. Der p 1 was assayed using a two-site immunometric ELISA. CBMC immunoproliferative responses (AIM V serum-free medium; 1 x 105 cells/well) were measured for 225 neonates (171 had a high risk of atopy (HR)--both parents skin test positive; 59 had a low risk of atopy (LR) - both parents skin test negative, no history of atopy) by 3H-Thymidine (1microCi/well) incorporation after stimulation in primary culture with phytohaemagglutinin (PHA) (1 microg/mL), house dust mite [HDM] extract (30 microg/mL), immunopurified Der p 1 (30 microg/mL), Tetanus toxoid (TT) (aluma free, 30 Lf/mL) or vehicle. Blood was collected from 144 infants at the age of 1 years and stimulated proliferative responses were assessed using the same procedure. RESULTS: PHA-stimulated lymphoproliferative response was significantly lower in HR compared to LR neonates (mean difference 38%, 95% CI 15%-54%; P = 0.003); significantly lower proportion of positive CBMC responses to HDM occurred in LR than in HR neonates (30.4% vs. 46.6%; P = 0.034). There was no relationship between Der p 1 levels in maternal bed and CBMC immunoproliferative responses, despite the 21 000-fold range of maternal Der p 1 exposure. No significant differences in magnitude, or in proportion of positive responses to any stimulant were observed between the neonates at low, medium or high tertile of allergen exposure. Immunoproliferative responses at birth were not predictive of 1-year PBMC responses. There was no relationship between maternal allergen exposure in pregnancy and 1-year PBMC proliferative responses. However, the proportion of positive proliferative responses at 1 years significantly increased with increasing infant Der p 1 exposure at 1 years. CONCLUSION: These results indicate that the magnitude of immunoproliferative responses are unrelated to maternal mite allergen exposure and cannot be used as evidence for in utero sensitization to inhalant allergens. The immunoproliferative responses at 1 year seem to shift away from the genetically influenced responses at birth towards responses to specific stimulants which correlate with environmental exposure to those specific stimulants. These data support the concept of sensitization to inhalant allergens occurring in early life, but not in utero.

Allergens↗

Apoptosis signals in atopy and asthma measured with cDNA arrays.

A variety of studies have stressed the importance of the control of inflammatory cell longevity and the balance of pro-survival and pro-apoptotic signalling. Recently, asthma was found to be associated with reduced apoptosis of inflammatory cells in lung tissue. The aim of the study was to investigate the systemic activation of apoptosis pathways using cDNA array technology in atopy and asthma. Eighteen atopic asthmatics (AA), eight atopic non-asthmatic (AN) and 14 healthy control subjects (C) were included in the study. Peripheral blood mononuclear cells were separated with gradient centrifugation, mRNA purified and the reverse-transcribed probes hybridized to cDNA arrays. The signals were compared by standardizing to the 100 most expressed genes and group differences assessed with the Mann-Whitney U-test. We found a concerted up-regulation of several pro-survival cytokines and growth factors in AN and AA. FAS and FASL were not differentially expressed, but FAST kinase was over-expressed in AN and AA. The tumour necrosis factor pathway was activated in AN and AA with increased cytokine and receptor levels and increased TRAF2, an intracellular signalling product. There were indications of a down-regulated p53 system. In contrast, the Bcl-2 family of genes showed a net pro-apoptotic profile in AN and AA. The group of caspases showed a constant gene expression pattern in all groups. In conclusion, significant differences in the expression of apoptosis-related genes were found in peripheral blood of atopic individuals with and without asthma. cDNA array technology proved to be useful and may be complementary to DNA-based studies in order to analyse interactive and multidimensional pathways as shown here for apoptosis.

Adult↗

Pet allergen levels in homes in Ghana and the United Kingdom.

The frequency of cat and/or dog ownership in Ghana is comparable to that in the United Kingdom (approximately 50%). However, in Ghanaian communities pets are predominantly kept outdoors. Levels of pet allergens (Fel d 1 and Can f 1) in 100 Ghanaian homes (49 without pets) were compared with levels in 410 homes in the United Kingdom (258 without pets). Homes with pets in the United Kingdom contained much higher allergen levels than homes with pets in Ghana (for Fel d 1: mean difference, 275-fold; 95% CI, 129-fold to 594-fold; P <.0001; for Can f 1: mean difference, 75-fold; 95% CI, 33-fold to 169-fold; P <.0001). Homes without cats in the United Kingdom contained significantly higher levels of Fel d 1 than homes with cats in Ghana (mean difference, 3.7-fold; 95% CI, 2.0-fold to 7.2-fold; P <.0001). In the United Kingdom, homes with dogs contained 75-fold (95% CI, 47-fold to 139-fold) more Can f 1 than homes without dogs, whereas in Ghana, homes with dogs contained 3.1-fold (95% CI, 1.5-fold to 6.1-fold; P =.003) more Can f 1 than homes without dogs. In the United Kingdom, homes with cats contained 77-fold more Fel d 1 (95% CI, 46-fold to 129-fold; P <.0001) than homes without cats; there was no difference in cat allergen levels between homes with cats and homes without cats in Ghana. In conclusion, levels of pet allergens in Ghanaian homes with pets were (1) between 75-fold (dog) and 275-fold (cat) lower than levels in homes with pets in the United Kingdom and (2) lower than or comparable to levels in homes without pets in the United Kingdom.

Allergens↗

Risk factors for asthma in urban Ghana.

BACKGROUND: Asthma is increasing in prevalence and severity in Africa. Previous studies have suggested that the prevalence of atopy in West Africa was low. OBJECTIVE: We sought to investigate the risk factors for asthma in Ghanaian school children. METHODS: Fifty children (age range, 9-16 years) with a physician diagnosis of asthma and asthma symptoms within the previous 12 months and 50 age- and sex-matched healthy control subjects were randomly selected and evaluated by means of questionnaire, skin testing, total and specific IgE measurements, and allergen level measurements from bed dust samples (mite, cat, dog, and cockroach). RESULTS: Asthmatic children were exposed to higher levels of mite allergens than were control children (geometric mean, 19 microg/g [95% CI, 13.6-26.5] vs. 11.2 microg/g [7.4-15.7]; P <.05). Cat and dog allergen levels were low. There was a marked dissociation between skin test responses and the presence of specific IgE to cat and dog (CAP method). However, 84% of subjects with positive cat dander-specific IgE levels in cat CAP tests and negative skin test responses did not have Fel d 1-specific IgE (chimeric ELISA). In the univariate analysis significant associations with the patient group were found for sensitization to mite (odds ratio [OR], 9.3; 95% CI, 3.7-23.4) and cockroach (OR, 3.9; 95% CI, 1.3-11.6), inner-city residence (OR, 3.5; 95% CI, 1.4-8.9), asthma in family member (OR, 3.5; 95% CI, 1.4-9.0), low (<5) position in sibship (OR, 3.6; 95% CI, 1.2-11), presence of smoker in home (OR, 3.7; 95% CI, 1.2-11.9), small household size (OR, 0.57; 95% CI, 0.35-0.93), and use of electricity as domestic fuel (OR, 0.34; 95% CI, 0.12-0.97). In the multivariate analysis sensitization to mites remained the strongest risk factor associated with the asthmatic group (OR, 10.4; 95% CI, 3.5-30.9). The other significant associations were inner-city residence (OR, 4.8; 95% CI, 1.5-5.2), sensitization to cockroach (OR, 4.9; 95% CI, 1.3-18.6), and position in sibship of less than 5 (OR, 6.3; 95% CI, 1.3-29.4). CONCLUSION: Sensitization to dust mite and cockroach allergens, inner-city residence, and low position in sibship were independent risk factors for asthma in Ghanaian children.

Adolescent↗

Decreased prevalence of sensitization to cats with high exposure to cat allergen.

We investigated the relationship between current exposure to cat allergen and sensitization to cats. A questionnaire was administered and skin prick testing and home visits for collection of dust samples (Fel d 1; ELISA) were performed in 2502 adults (mean age, 31.8 years; age range, 18-58 years; 1251 women). The results for Fel d 1 in relation to sensitization to cats were analyzed for 10 deciles of cat allergen exposure (cut points [microg/g]: 0.05, 0.34, 0.48, 0.72, 1.13, 1.92, 7.2, 44, 151). The prevalence of sensitization to cat was significantly decreased in the lowest and the highest exposure groups. In the multivariate regression analysis (age, sex, socioeconomic status, and current smoking being adjusted for), the risk of sensitization to cats was significantly increased with medium exposure to Fel d 1 (3rd centile, OR 2.3, 95% CI 1.2-4.4, P =.01; 4th centile, OR 2.1, 95% CI 1.1-4.0, P =.03; 5th centile, OR 2.2, 95% CI 1.2-4.3, P =.04, 6th centile, OR 2.5, 95% CI 1.3-4.9, P =.005). These results indicate that the prevalence of sensitization to cat is decreased in the lowest and highest cat allergen exposure groups.

Adolescent↗

Exposure and sensitization in infants and children.

The complex relationship between allergen exposure, atopic sensitization and asthma in individuals and in populations has recently been a subject of controversy. A number of studies have demonstrated that allergen exposure in sensitized asthmatic individuals increases the severity of disease. A simple dose-response relationship between mite allergen exposure and specific sensitization in infants and children has been confirmed. However, the concept that there is a direct relationship between allergen exposure and the initiation of asthma has been challenged. The relationship between allergen exposure and subsequent disease development is complex, and is confounded by a number of important factors. Populations and individuals are exposed to a mixture of several allergens, irritants and pollutants, and we know very little about the impact of these mixtures and their possible synergistic effect. The dose-response relationship between allergen exposure and allergic disease may not be linear, and may be different for different allergens. For example, a protective effect of cat ownership on sensitization and allergic disease has been reported, raising the question of whether the dose-response relationship between exposure and sensitization may be different for cat compared with mite allergen. It has been suggested that many children who are exposed to a high level of cat allergen make a modified T helper type 2 response, characterized by the presence of IgG4 antibody to cat proteins without becoming allergic (i.e. no IgE response), which could be regarded as a form of tolerance. This could explain a decreased risk of asthma in children living in homes with cats, without invoking a concept of a shift in the balance of T helper types 1 and 2 responses. Cat allergen is ubiquitous, and passive exposure (e.g. home without cats and public places) may induce specific IgE responses in non-cat owners, whereas those exposed to very high levels of cat allergen may initially mount an IgE response, which may be replaced by a modified T helper type 2 response (tolerance). It is likely that the population susceptibility to allergic sensitization and also end-organ responsiveness has altered, and allergen exposure may still be important in initiating disease in an increasingly susceptible population, although the pattern may differ for different allergens.

Adolescent↗

The role of indoor allergen exposure in the development of sensitization and asthma.

The role of indoor allergen exposure in the development of sensitization and asthma remains a subject of controversy. From a number of cross-sectional and longitudinal studies we can conclude that there is a very close association between allergen exposure and the sensitization of an individual. The dose-response relationships seem to differ between allergens; house dust mite and cockroach allergens appear to have a positive linear relationship, whereas cat allergens appear to act quite differently, with maximum sensitization developing at moderate exposure levels. Very low levels of cat allergen exposure are likely to induce no response and very high levels are likely to develop a form of tolerance, with a modified T helper cell type 2 response and the production of IgG4 antibodies and but not IgE. The relationship between indoor allergen exposure and asthma is, however, less clear. The proposed mechanism for the development of disease is that allergen exposure causes sensitization, and continued exposure leads to airway responsiveness and inflammation. As yet, the evidence for allergen exposure being a primary cause of asthma remains weak, and the results of ongoing prospective, randomized allergen avoidance trials are awaited to clarify this issue.

Air Pollution, Indoor↗

B-cell isotype control in atopy and asthma assessed with cDNA array technology.

B-cell isotype switching and the production of IgE is regulated by a variety of gene products through different mechanisms. A better understanding of these processes has the potential to identify markers of disease and new therapeutic targets. The aim of the study was to investigate human B-cell isotype control and IgE production in atopy and asthma with cDNA array technology. Eighteen atopic asthmatic, eight atopic nonasthmatic, and fourteen healthy control subjects were included. Peripheral blood mononuclear cells were separated by gradient centrifugation, mRNA was purified, and the reverse-transcribed probes were hybridized to cDNA membranes. Group differences were assessed with the Mann-Whitney U-test. Twenty-three of seventy-eight tested IgE-related genes had significantly altered expression in atopy and asthma compared with that in the healthy subjects. The differentially expressed genes include surface molecules involved in T- and B-cell interaction and activation, cytokines, intracellular signaling products, and transcription factors. In conclusion, both atopic nonasthmatic and atopic asthmatic individuals had activated proinflammatory pathways, a minimal requirement for B-cell isotype switching, and a clear net pro-IgE cytokine climate.

Adolescent↗

Allergen avoidance.

Allergen exposure is a risk factor for sensitisation, prevalence and severity of allergic disease. Effective allergen avoidance strategies have been devised. The cost-benefit in public health terms should be established by prospective controlled studies that are under way around the world.

Air Pollutants↗

Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study.

BACKGROUND: Inhaled corticosteroids are currently the cornerstone of asthma treatment. Some studies of high-dose fluticasone propionate in patients with no or mild asthma have, however, suggested substantial systemic absorption. We investigated the pharmacokinetics of fluticasone propionate in patients with asthma receiving appropriate doses for severity. METHODS: We did a double-blind, randomised, crossover study in 11 patients with asthma and 13 matched healthy controls (age 20-65 years; asthma patients forced expiratory volume in 1 s <75% and stable on high-dose inhaled corticosteroids). Patients received one 1000 microg intravenous dose or 1000 microg daily for 7 days inhaled (via spacer device) fluticasone propionate. In the 12 h after dosing, we monitored plasma fluticasone propionate and cortisol concentrations by mass spectrometry and competitive immunoassay with use of direct chemiluminescence. Analysis was by intention to treat. FINDINGS: After inhalation, geometric mean values were significantly lower in the asthma group than in controls for fluticasone propionate plasma area under curve (1082 [95% CI 850-1451] vs 2815 pg mL(-1) h(-1) [2262-3949], -62% difference [45-72]; p<0.001), maximum concentrations (117 [91-159] vs 383 pg/mL [302-546], -68% [-50 to -81]; p<0.001), and systemic bioavailability (10.1 [7.9-14.0] vs 21.4% [15.4-32.2], -54% [-27 to -70]; p=0.001). Intravenous-dose clearance, volume of distribution at steady state, plasma half-life, and mean residence time, were similar in the two groups. Less suppression of plasma cortisol concentrations was seen in the asthma group than in controls 4-12 h after inhaled fluticasone propionate. INTERPRETATION: Systemic availability of fluticasone propionate is substantially less in patients with moderate to severe asthma than in healthy controls. Inhaled corticosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for disease severity, and not in normal volunteers.

Administration, Inhalation↗

Manchester Asthma and Allergy Study: low-allergen environment can be achieved and maintained during pregnancy and in early life.

BACKGROUND: Early exposure to dust mite allergens may be critical for primary sensitization. Reducing exposure may offer a realistic chance for primary prevention of sensitization and asthma, but it is essential to implement measures that can achieve and maintain the low-allergen environment. OBJECTIVE: Our purpose was to assess the effectiveness of mite allergen avoidance measures in achieving and maintaining a low-allergen environment during pregnancy and in the first year of life. METHODS: The Manchester Asthma and Allergy Study is a prospective, prenatally randomized study that follows the development of asthma and atopy in a cohort of infants at high risk (both parents atopic) who are randomly allocated to full mite allergen avoidance or to a normal regimen. Avoidance measures comprise (1) mite-proof covers (mattress, pillow, and quilt) for parental bed, (2) high-filtration vacuum cleaner, (3) vinyl flooring in infant's bedroom, (4) new crib and portable crib mattresses encased in mite-proof material, (5) benzyl benzoate (Acarosan) applied on carpets and soft furniture, (6) bed linens washed in hot water weekly, and (7) washable soft toys. Dust samples from the parental bed, bedroom floor, living room floor, infant's mattress, and nursery floor were collected between the 10th and 14th weeks of pregnancy, immediately after birth, and then at age 6 months and 1 year, and Der p 1 levels were determined by mAb-based ELISA. RESULTS: Recovered Der p 1 from maternal mattress was reduced by 97. 25% (95% confidence interval [CI] 95.25%-98.41%) during the second and third trimesters of pregnancy, with the effect persisting for 6 months (98% reduction, 95% CI 97.25%-99.1%) and 12 months (97.6% reduction, 95% CI 95.7%-98.6%) after the birth (active vs control, P <.000001). Total Der p 1 from bedroom floor in the active group was reduced by 53.7% (95% CI 25.7%-71.2%) in samples collected within 4 weeks of the child's birth, with the percentage reduction being 62. 8% (95% CI 39.3%-77.2%) at 6 months and 26.5% (95% CI -24% to 57.1%) at 1 year (active compared vs control, P <.007). Der p 1 levels in crib mattress and nursery floor in the active group were extremely low (crib mattresses geometric mean [95% CI] 2.3 ng [1.6-3.4] at birth, 6.8 ng [4.5-10] at age 6 months, and 15.6 ng [9.8-24.8] at age 1 year [active vs control, P =.001]; nursery 1 ng [0.9-1.1] at birth, 1.7 ng [1.2-2.5] at age 6 months, and 2 ng [1.3-3.5] at age 1 year [active vs control, P <.00001]). The total amount of allergen recovered at age 1 year was 29-fold (95% CI 15.1- to 56.7-fold) higher in the control group than in the active group. CONCLUSIONS: The avoidance measures used in this study achieved and maintained a low mite allergen environment during pregnancy and in the first year of life in homes of infants at risk of atopy.

Allergens↗

Synthetic pillows contain higher levels of cat and dog allergen than feather pillows.

The use of non-feather pillows has increased over the last few decades. Recently, we found significantly higher levels of dust mite allergens in synthetic pillows than in feather ones. This study investigated the levels of pet allergens in feather and synthetic pillows. Dust samples were collected from 14 pairs of pillows (consisting of one synthetic fibre-filled and one feather-filled). Each pair of pillows had been on the same bed for at least 2 years. The pillows were vacuumed for 1 min on each side through a 355-microm diameter mesh onto a 5-microm vinyl filter, producing a sample of fine dust. Samples were extracted, and cat (Fel d 1) and dog (Can f 1) allergens determined using monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA). Results were expressed both as total amount of allergen recovered and concentration of allergen per unit weight (ng/g). Total levels of pet allergens were significantly higher in the synthetic pillows (Fel d 1: 6.7-fold difference [95% CI 1.5-29.7], p=0.01; Can f 1: 8-fold difference [95% CI 1.6-39.5], p=0.01). Similarly, when the results were expressed as ng/g, synthetic pillows contained significantly more allergens than feather pillows (Fel d 1: 3.7-fold difference [95% CI 1.3-10.1], p=0.01); Can f 1: 4.4-fold difference [95% CI 1.5-13.2], p=0.01). We have therefore demonstrated that synthetic pillows contain significantly more pet allergens than feather pillows, supporting the view that tightly woven encasements surrounding feather pillows act as a barrier for allergens.

Allergens↗

The -403 G-->A promoter polymorphism in the RANTES gene is associated with atopy and asthma.

Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (-403 G-->A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV1) and methacholine challenge (PC20). The -403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, non-atopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the -403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV1 < or = 80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction.

Adenine↗

Allergen avoidance: does it work?

The first recorded example of allergen avoidance in the treatment of allergic disorders dates from the 16th century. The Italian physician Gerolamo Cardano (1501-1576) was invited to Scotland by John Hamilton, Archbishop of St Andrews (and brother of the Regent), to give advice on the treatment of his asthma. Cardano recommended that the Archbishop should get rid of his feather bedding, which was followed by a 'miraculous' remission of otherwise troublesome symptoms. The first controlled attempts to treat asthma by environmental manipulation date to the beginning of 20th century. In 1925, the Leopold brothers treated patients with asthma and other allergic disorders by moving them into a dust free room. Storm van Leeuwen created a 'climate' chamber in The Netherlands in 1927 and demonstrated that asthmatic patients improved when moved from their homes into the chamber. One year later, Dekker observed that measures aimed at reducing the amount of dust in bedrooms had a beneficial effect on asthma symptoms in patients allergic to house dust. Van Leeuwen wrote: 'In our endeavours to find the cause of the attack ... we utilised the known fact that the environment of the asthmatic patient is, as a rule, of primary importance in determining the intensity and frequency of his attacks'. Nowadays, more than ever, it is essential to address the environmental influences on the increasing prevalence of asthma and allergic disorders.

Air Conditioning↗

Washing the dog reduces dog allergen levels, but the dog needs to be washed twice a week.

BACKGROUND: Many asthmatic patients allergic to dogs refuse to part with their dog, and it is essential to develop techniques for lowering exposure with a dog in the home. OBJECTIVE: This study investigated the effect of dog washing on the subsequent recovery of Can f 1 from dog hair clippings and on the airborne allergen over a 7-day period. METHODS: Dogs, which had not been washed for at least the previous 3 weeks, were washed with a hand-held shower and proprietary shampoo. Hair clippings and dander samples from 25 dogs were collected before and immediately after washing. After these initial studies, 16 dogs had a small tuft of hair clipped from the collar or spinal area before washing and then daily for the next 7 days. Air sampling was performed in 5 homes, and the air samples were collected (airflow rate, 9 L/min) over an 8-hour period per day on 10 consecutive days (3 days of baseline sampling before washing and then 7 consecutive days after washing). Can f 1 level was measured by using 2-site ELISA. RESULTS: Washing significantly reduced recoverable Can f 1 from clippings (84% reduction: from 73 microg/g to 12 microg/g [geometric mean]; P <.0001) and from dander samples (86% reduction: from 347 microg/g to 50 microg/g [geometric mean]; P <.0001). There was a significant reduction in Can f 1 levels in dog hair over the observed 8-day period (F = 18.4, P <. 0001). By using a multiple comparison test, this observed significance was found to be due to the difference between the baseline levels and those on days 1 and 2 after washing, with no difference in the baseline Can f 1 compared with days 3 to 7. Airborne Can f 1 levels showed a downward trend, which reached statistical significance when the data were grouped into 3 sampling periods as follows: baseline (ie, mean of 3 days before sampling) was compared with days 1 to 4 after washing (41% reduction, 95% CI 13%-60%) and days 5 to 7 after washing (61% reduction, 95% CI 2%-84%; P =.014). CONCLUSIONS: Washing the dog reduces recoverable allergen from dog hair and dander. The dog needs to be washed at least twice a week to maintain the reduction in recoverable Can f 1 from its hair. Washing the dog achieves a modest reduction in the level of airborne Can f 1 in homes with a dog.

Air Pollution, Indoor↗