Effects of Reducing Indoor Air Pollution on the Adult Asthmatic Response
Phase: NA
Conditions: Asthma
Sponsor: Johns Hopkins University

 
 
Effects of Reducing Indoor Air Pollution on the Adult 
Asthmatic Response (INHALE 2) 
 
 
 
NCT02153359 
 
 
 
07/31/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol 
and 
Statistical 
Analytical 
Plan 
 
 
 
Title:  The Effect of Reducing Air Pollution on the Adult Asthmatic Response (INHALE2)  
  
Abstract  
Asthma is one of the most common chronic diseases in adults, and inner-city residents, who typically 
live in poorly maintained urban housing, suffer a disproportionate burden of asthma morbidity (1).  
Many factors contribute to this disparity, including the observation that the urban indoor environment 
has been shown to have higher concentrations of indoor air pollutants than suburban counterparts (2).  
An increasing amount of evidence has shown that air pollutants, which contain particulate matter, 
including coarse (PM2.5-10) and fine (PM2.5) particles, are associated with greater respiratory morbidity 
in asthmatics (3-9).   While the bulk of this data focuses on ambient air pollution, accumulating 
evidence suggests that indoor air pollution, which (unlike outdoor pollution is not EPA regulated) may 
be even more harmful (10). Moreover, exposure to these pollutants may be prolonged, as Americans 
spend most of their time indoors (11).  Fortunately, the indoor environment is more amenable to 
modifications by the individual, thus making it an attractive target for interventions aiming to improve 
asthma health.    
  
One such intervention is introduction of a HEPA air cleaner.  We have previously shown that 
introduction of a HEPA air cleaner results in sustained improvements in indoor pollution concentrations 
and respiratory symptoms (12,13).  Our prior work has investigated the effects of indoor particulate 
matter on biological and clinical markers of respiratory health in a cohort of inner city children in 
Baltimore. However, given the age of our participants and research procedure restrictions, we have 
been limited by the inability to collect bronchoscopic specimens, which could reveal important 
information regarding lung-specific immune responses within the lower airway.  The aim of this project 
is to extend these findings to a population of urban non-smoking adults with asthma, and characterize 
both local and systemic responses to the indoor environment.  In addition, we hypothesize that actively 
removing these pollutants through an air cleaner intervention will attenuate their impact on asthma 
morbidity.  This study, INHALE 2, extends evaluation of a subgroup of participants from a parent 
study, INHALE 1.  
  
In the parent study, 100 adult subjects will be studied longitudinally during a 1-week period at baseline 
and again at 3 months, during which environmental monitoring of indoor air quality, as well as health 
assessments (respiratory symptoms, lung function and serum markers) will be conducted.  As part of 
this initial study, we aim to further characterize the inflammatory and oxidative stress pathways that 
have been implicated in the airway’s response to PM in the published literature. To this end, markers 
in the blood, will be analyzed and linked to changes in indoor particulate matter.   Subsequently, a 
subset of 40 subjects from this cohort that meet safety criteria will then be randomized to having one 
of two interventions—HEPA air cleaners or sham air cleaners--placed in the home for 1 month’s 
duration. After this month, the true or sham air cleaner will be removed from the home, and no machines 
will be present in the home for at least another month (washout period).  In the final month of this 
study, the two intervention arms will be crossed over in a blinded fashion, and true/sham air cleaners 
will be placed in the home again for 1 month.  During the first and third months, homes will undergo 
continuous environmental monitoring and participants will undergo personal environmental 
monitoring, along with simultaneous health assessments that include questionnaires, diaries, lung 
function testing, and blood testing.  In addition, during the last week of each month with the 
intervention, participants will undergo bronchoscopy, during which we will obtain airway samples in 
order to compare lower airway response to the interventions.  

  
In summary, more evidence is needed to understand the local pulmonary and systemic mechanisms that 
contribute to the burden of asthma in susceptible populations such as urban dwellers exposed to high 
levels of indoor pollution. Furthermore, by examining the potential alleviating effect of actively 
reducing chronic exposure to air pollution in the indoor environment, we aim to strengthen the causal 
relationship between PM and worsening asthma. Such evidence has the promise to lay the groundwork 
for future clinical recommendations and public policies for environmental control practices.  
  
Objectives (include all primary and secondary objectives)  
  
Primary Objective:   
The aim of this project is to investigate the effects of an air cleaner intervention, compared to sham 
air cleaner, on the change in indoor air pollution, notably fine and coarse particulate matter (PM), in the 
home of adult asthmatics.  
  
Secondary Objectives:  
  
We will also investigate the effects of an air cleaner intervention, compared to sham air cleaner 
on clinical markers of asthma health, specifically day and nighttime symptoms, medication usage, and 
asthma-related quality of life using questionnaires. The effects on lung function using spirometry and 
alterations in airway and systemic biomarkers of inflammation will also be explored. Finally, the effects 
of the intervention compared to sham on the indoor air nicotine concentration will be assessed.   
  
Background  
The mechanisms by which indoor air pollution potentially worsens asthma morbidity are unclear.    
In epidemiologic studies, higher indoor PM levels have been associated with increased respiratory 
symptoms, decreased lung function, and more frequent rescue medication use. Potential mechanisms behind 
this observed relationship have been investigated in numerous studies, but these have largely been limited 
to animal models, in vitro systems, or human challenge models that high experimental loads of PM.  
Regardless, these studies have demonstrated that exposure to air pollutants triggers the release of specific 
cytokines (Il-6, Il-8) which play a central role in cell-to-cell communication, stimulating immune cells, and 
regulating inflammatory processes within lung tissue, and that this effect is potentiated in patients with 
asthma.  Such inflammatory effects have been demonstrated in bronchoalveolar lavage fluid and cultured 
bronchial epithelial cells, but also been shown to generate systemic inflammatory responses (as evident by 
elevated circulating levels of IL-6 and TNFα, as well as CRP), suggesting that inflammation is one of the 
main responses to PM. However, because this proposal investigates the effect of exposures in the native 
environment of human subjects, it will provide the opportunity to corroborate these findings in a real-world 
scenario.  Furthermore, this study is novel in that it will investigate the effects of pollution abatement and 
examine the effect on these asthmagenic processes when real-time PM exposure is actively reduced.  
A number of preliminary studies conducted by our group set the stage for this proposal(1). We have 
extensive experience performing environmental monitoring within Baltimore city and have found that the 
city has high levels of biologically active indoor PM.  In our prior cohort study of 150 asthmatic children, 
the mean (+SD) indoor PM concentration for PM2.5-10 (coarse) was 17.4 + 21.1 µg/m3 and for PM2.5 (fine) 
was 40.3 + 35.4 µg/m3, both of which were significantly higher than the average ambient measurements 
made over the same time period (10.3 ± 21.0 µg/m3 and 12.4 ± 6.2; p < 0.01 for both comparisons). Eighty-
five percent of homes had indoor levels of PM2.5 exceeding the EPA limit for ambient pollution (2, 14). In 
addition, we found that this indoor pollution is associated with increased asthma morbidity.  Specifically, 
each 10 µg/m3 increase in PM2.5-10 was associated with increases of 8% in the number of days of symptoms 

severe enough to slow activity, 8% in nocturnal symptoms, 11% in wheezing that limited speech, 6% in 
rescue medication use, and 6% in overall asthma symptoms (3). We have successfully reduced these in-
home PM levels in our prior experience with HEPA air cleaners.  In a randomized controlled trial of home 
environmental interventions in urban Baltimore children with asthma, concentrations of PM10 decreased 
30% compared to the control group after 6 months of air cleaner use (12). Asthma symptoms also 
significantly decreased over this time period.  A subsequent study of air cleaners in urban homes of children 
with asthma showed similar improvements in fine and coarse PM after 6 months, along with improvement 
in symptom-free days compared to a control group (13).  Therefore, we have demonstrated that HEPA air 
cleaners are able to reduce PM and improve asthma health in inner city children with asthma.  However, 
this has not yet been investigated in adults, and we also do not have an understanding of the biological 
mechanisms behind such an improvement in asthma symptoms (4). Lastly, our collaborators in the basic 
sciences have demonstrated that particulate matter has measurable effects on epithelial barrier function, 
showing that a single dose of PM (150 µg/ml) is associated with enhancement of barrier function and 
decreased permeability, but repeated exposures result in barrier disruption and increased permeability (15).  
This evidence supports the hypothesis that chronic pollution exposure can induce the natural airway 
epithelial barrier to become more leaky, allowing further entry of PM or allergens and triggering further 
inflammation.  
Currently, our research group is actively involved in gathering and analyzing environmental and 
health data from questionnaires, serum, urine, and exhaled breath samples in children with asthma in several 
Baltimore studies, and this study will draw upon this expertise, especially with regard to study protocols 
and operation of equipment.  Our field workers have many years of experience in recruiting both children 
and adult participants with asthma in inner city Baltimore.   Furthermore, colleagues in our division are 
currently engaged in research bronchoscopy in order to collect lower airway samples for their respective 
studies, and we will be modeling our protocols after these established studies.  
Study Procedures  
  
Study design:  
  

Figure 1. Study design 
  
 Eligible participants for this protocol will be recruited from the community and health care facilities.  All 
study procedures will be performed as part of this research proposal, with none of the investigations part of 
routine care.  However, clinically significant study results will be shared with participants as needed.  
 Over the course of 3-5 years, 40 participants that meet criteria will be recruited from the parent study 
(INHALE 1) which occurs over a 3 month period, and enrolled for an additional months of investigations 
(i.e. this study will pick up immediately after the parent study leaves off). Informed consent will be obtained 
at the beginning of the parent study, and hereafter, the participant will be enrolled in both INHALE 1 and 
INHALE 2 studies, though study procedures for Inhale 2 will not commence until the study period of 
INHALE 1 is completed.  
 The study period is broken up into 1st, 2nd, and 3rd assessment periods.  During the first month, assessments 
of each participant’s indoor air quality will be accomplished by environmental monitoring of air pollution 
(PM, nicotine) inside the home. During this month, either true or sham air cleaners will be placed for the 
entire duration of the month (see figure 1).  To measure the air cleaner use compliance, air cleaners will be 
outfitted with a HOBO data logger, Onset Corporation (Bourne, MA) that has been exempted by Clinical 
Engineering. Participants will be blindly randomized into receiving one or the other during this time.  
During the last week of the month, health assessments will be conducted, which include in-home health 
questionnaires, symptom-, and activity- diaries/recalls, blood, and handheld spirometry.   Participants will 
also be asked to wear a light backpack with air monitoring devices during the course of the day during the 
last week in order to measure their exposures to pollutants. Finally, at the end of the month, participants 
will be asked to report to the Johns Hopkins outpatient endoscopy suite for bronchoscopy, during which 
airway sampling will occur under conscious sedation.    
Bronchoscopy: Women of childbearing age will have a repeat pregnancy test (one is  
already performed in the parent study) during the first month of the study to ensure eligibility as pregnant 
subjects would be excluded from the study). All bronchoscopies will be performed at the Johns Hopkins 
Hospital Endoscopy Suite, and will be consented again for the bronchoscopy on the appropriate Johns 
Hopkins Endoscopy Procedure consent form.  Participants who meet safety criteria (including FEV1>60% 
predicted) will fast at least 8 hours prior to the procedure and conscious sedation will be administered in 
accordance to Conscious Sedation Guidelines using intravenous anxiolytics.  All participants will have 

peripheral blood drawn and nasal rinse prior to bronchoscopy.  Subjects will undergo a research fiberoptic 
bronchoscopy procedure with BAL fluid collected following instillation of room temperature saline in the 
lung. BAL and blood will be processed for the measurement of cell count and inflammatory mediators.  
Weekly telephone calls and home visits will occur throughout the study as needed to trouble-shoot and 
perform quality checks for the study.    
  
 At the completion of the first month, the subjects will enter a wash out period of at least 1 month, during 
which there are no interventions or assessments made.  After the wash out period, the subjects will then 
cross over with regard to the air cleaner-sham cleaner intervention and receive the opposite intervention.   
During the last month of the study period, all study procedures from the 1st month are repeated.  The study 
is concluded after the completion of the repeat bronchoscopy.    
  
Subjects and study staff will be blinded to whether a true or sham air cleaner is randomly assigned to each 
home.  This blinding is to reduce bias on the part of researchers and participants.  Due to the crossover 
design, each participant serves as his/her own control.  Since all participants receive the true air cleaner for 
one month of the study, they are not deprived of any potential benefits of the air cleaner.   
  
  
1. Inclusion/Exclusion Criteria  
  
  
Inclusion Criteria:  
1. Age 18-50 years of age  
2. Non-smoker (<100 cigarettes in lifetime)  
3. Physician diagnosis of asthma  
4. Symptoms of asthma and/or reliever medication use in the past 6 months  
5. Living in the current residence >= 6 months within Baltimore   
  
  
Exclusion Criteria:  
1. Current diagnosis of another major pulmonary disease, other significant morbidity  
2. Pregnancy (as defined by a positive urine pregnancy test at screening of all women of 
child-bearing potential)  
3. Planning to relocate residence or activity that necessitates travel away from home for 
prolonged period of time during the study period   
4. Current use of an air cleaner in the home   
2. Study Statistics  
  
A.  Primary outcome variable  
The change in concentration of fine and coarse particulate matter (PM2.5 and PM2.5-10) with the 
intervention of an air cleaner, compared to sham air cleaner.   
  
B.  Secondary outcome variables  
1. 
Asthma control will be compared between the intervention and sham groups. This will 
include evaluation of changes in respiratory symptoms from self-reported diaries, asthma morbidity 
and asthma-related quality of life from questionnaires.  

2. 
In addition, we will assess the effects of the intervention compared to the sham on other 
markers of asthma health. This includes lung function as measured by spirometry, and biomarkers 
of inflammation as measured in the blood and the lower airways via bronchoscopy.  
3. 
Finally, we will assess the effects of the intervention compared to the sham on the indoor 
air nicotine concentration.   
  
C.  Statistical plan including sample size justification and interim data analysis.   
  
  
  
  
We aimed to enroll 40 participants in this crossover design in order to detect with 80% power 
(and an alpha of 0.05) a 40% difference in PM concentrations between groups, accounting for an 
ultimate drop out/loss to follow up rate of approximately 10-15%. The estimate in sample size 
was based on a prior study from Butz et al. (18), which showed that a sample size of 77 
participants was adequate to detect a 44% difference in PM concentrations between the 
intervention and control groups. [Note that over the course of the study, the planned sample size 
of 40 was not attained due to difficulties with recruitment. Only patients in the parent  
observational study willing to undergo bronchoscopies were recruited, resulting in a total of only 
23 patients followed, with 2 lost to follow-up by the end of the study.]  
  
A descriptive analysis will be performed with calculation of means, standard deviations, and 
medians for continuous variables and proportions for categorical variables. Bivariate analyses to 
assess differences before and after the intervention in each group will be conducted using t-tests or 
the Wilcoxon rank-sum test for continuous variables and χ2 or Fisher’s exact test for categorical 
variables.  
  
  
  
 
  
Citations:  
1. Matsui EC, Hansel NN, McCormack MC, Rusher R, Breysse PN, Diette GB. Asthma in the inner 
city and the indoor environment. Immunol Allergy Clin North Am. 2008 Aug; 28(3): 665-86,  
2. Breysse P, Farr N, Galke W, Lanphear B, Morley R, Bergofsky L. The relationship between 
housing and health: Children at risk. Environ Health Perspect. 2004 Nov; 112(15): 1583-1588. 
PMCID: PMC1247625.  
3. Delfino RJ, Zeiger RS, Seltzer JM, Street DH. Symptoms in pediatric asthmatics and air 
pollution:  Differences in effects by symptom severity, anti-inflammatory medication use and 
particulate averaging time.  
4. Environ Health Perspect. 1998 Nov; 106(11): 751-761. PMCID: PMC1533499.  
5. Dockery DW, Speizer FE, Stram DO, Ware JH, Spengler JD, Ferris BG,Jr. Effects of inhalable 
particles on respiratory health of children. Am Rev Respir Dis. 1989 Mar; 139(3): 587-594.  
6. McConnell R, Berhane K, Gilliland F, London SJ, Vora H, Avol E, Gauderman WJ, Margolis 
HG, Lurmann F,Thomas DC, Peters JM. Air pollution and bronchitic symptoms in southern 
california children with asthma. Environ Health Perspect. 1999 Sep; 107(9): 757-760. PMCID: 
PMC1566453.  
7. McConnell R, Berhane K, Gilliland F, Molitor J, Thomas D, Lurmann F, Avol E, Gauderman WJ, 
Peters JM.  Prospective study of air pollution and bronchitic symptoms in children with asthma. 
Am J Respir Crit Care Med. 2003 Oct 1; 168(7): 790-797.  
8. Mortimer KM, Neas LM, Dockery DW, Redline S, Tager IB. The effect of air pollution on 
innercity children with asthma. Eur Respir J. 2002 Apr; 19(4): 699-705.  

9. Norris G, YoungPong SN, Koenig JQ, Larson TV, Sheppard L, Stout JW. An association between 
fine particles and asthma emergency department visits for children in seattle. Environ Health 
Perspect. 1999 Jun;107(6): 489-493. PMCID: PMC1566574.  
10. O'Connor GT, Neas L, Vaughn B, Kattan M, Mitchell H, Crain EF, Evans R,3rd, Gruchalla R, 
Morgan W,Stout J, Adams GK, Lippmann M. Acute respiratory health effects of air pollution on 
children with asthma in US inner cities. J Allergy Clin Immunol. 2008 May; 121(5): 
11331139.e1.  
11. Koenig JQ, Mar TF, Allen RW, Jansen K, Lumley T, Sullivan JH, Trenga CA, Larson T, Liu LJ. 
Pulmonary effects of indoor- and outdoor-generated particles in children with asthma. Environ 
Health Perspect. 2005 Apr; 113(4): 499-503. PMCID: PMC1278493.  
12. Klepeis NE, Nelson WC, Ott WR, Robinson JP, Tsang AM, Switzer P, Behar JV, Hern SC, 
Engelmann WH. The national human activity pattern survey (NHAPS): A resource for assessing 
exposure to environmental pollutants. J Expo Anal Environ Epidemiol. 2001 May-Jun; 11(3): 
231-252.  
13. Klepeis NE, Nelson WC, Ott WR, Robinson JP, Tsang AM, Switzer P, Behar JV, Hern SC, 
Engelmann WH. The national human activity pattern survey (NHAPS): A resource for assessing 
exposure to environmental pollutants. J Expo Anal Environ Epidemiol. 2001 May-Jun; 11(3): 
231-252.  
14. McCormack MC, Breysse PN, Matsui EC, Hansel NN, Williams D, Curtin-Brosnan J, Eggleston 
P, Diette GB, Center for Childhood Asthma in the Urban Environment. In-home particle 
concentrations and childhood asthma morbidity. Environ Health Perspect. 2009 Feb; 117(2): 
294298. PMCID: PMC2649234.  
15. Sidhaye VK, Chau E, Breysse PN, King LS. Septin-2 mediates airway epithelial barrier function 
in physiologic and pathologic conditions. Am J Respir Cell Mol Biol. 2011 Jul; 45(1): 120-126.  
16. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay 
RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ. Guidelines for methacholine and 
exercise challenge testing-1999. this official statement of the american thoracic society was 
adopted by the ATS board of directors, july 1999. Am J Respir Crit Care Med. 2000 Jan; 161(1): 
309-329.  
17. American Society of Anesthesiologists Task Force on Sedation and Analgesia by 
NonAnesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. 
Anesthesiology. 2002 Apr; 96(4):1004-1017.  
18. Butz AM, Matsui EC, Breysse P, Curtin-Brosnan J, Eggleston P, Diette G, Williams D, Yuan J, 
Bernert JT, Rand C. A Randomized Trial of Air Cleaners and a Health Coach to Improve Indoor 
Air Quality for Inner-City Children with Asthma and Secondhand Smoke Exposure. Arch Pediatr 
Adolesc Med. 2011;165(8):741-748.