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* From the Program of Population Genetics (Drs. Xu, Niu, Chen, and Wang), Harvard School of Public Health, Boston, MA; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital (Dr. Weiss), Harvard Medical School, Boston, MA; Anhui Meizhong Institute for Biomedical Science and Environmental Health (Dr. Yang), Anqing, Anhui, China; and Anhui Medical University Center for Ecogenetics and Disease Control (Dr. Jin), Hefei, Anhui, China.
Correspondence to: Xiping Xu, MD, Associate Professor, Program for Population Genetics FXB-101, 665 Huntington Ave, Boston, MA 02115; e-mail: xxu{at}ppg.harvard.edu
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Abstract |
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Design: Two methods for calculating the provocative dose that decreases the airflow rate by 20% (PD20) were used as indexes for increased airway responsiveness: (1) a 20% drop in FEV1 calculated from baseline FEV1 (PD20b), and (2) a 20% drop in FEV1 from FEV1 measurements after inhalation of saline solution (PD20s). Both PD20b and PD20s were measured through induction by varying doses of methacholine.
Setting: Anqing, Anhui Province, China.
Participants: Study subjects were 8 to 74 years
of age and were classified into four groups: children (< 15 years
old), young adults (15 to 29 years old), adults (30 to 44 years old),
and older adults (
45 years old).
Interventions: The differences in estimated odds ratios of airway hyperresponsiveness with asthma and wheeze, sensitivity and specificity, and coefficients of variation were compared between PD20b and PD20s. The sample for analysis consisted of 10,284 subjects from 2,663 nuclear families with complete data on wheeze, asthma, and major potential confounding factors.
Measurements and results: The prevalence of asthma in this sample was lowest in subjects with no demonstrable PD20 and had a reverse dose-response relationship with PD20 across all age groups. Using the receiver operating characteristic, the sensitivity and specificity of the PD20s or PD20b were found to be almost identical. A similar trend was found for persistent wheeze, although the estimated odds ratios for persistent wheeze appeared slightly smaller than those for physician-diagnosed asthma.
Conclusions: This study demonstrates a dose-response relationship between increased airway responsiveness and asthma and wheeze in this Chinese population. PD20s or PD20b yielded virtually indistinguishable results, which indicated that either of the two tests could serve as an index of airway hyperresponsiveness.
Key Words: airway responsiveness • asthma • wheeze
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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Methodologic issues may also be of importance and influence the responsiveness-disease association in genetic linkage studies. One methodologic issue is the use of saline solution before the commencement of pharmacologic challenge with histamine or methacholine. Previous studies1 have often used saline solution response as the baseline to define the provocative dose that decreases the airflow rate by 20% (PD20), one of the usual clinical measures of increased airway responsiveness. The advantage of the saline solution application is safety; it allows investigators to screen out individuals with potentially large drops in FEV1 before the application of the first pharmacologic dose. The second theoretical advantage is a reduction in background variation. A potential disadvantage of the application of saline solution is that highly sensitive individuals will be excluded from further testing, thus limiting diagnostic validity. An additional issue is that saline solution may increase random variation at baseline and, hence, increase the variability of PD20.
A large, family-based epidemiologic study was conducted in Anqing, China to examine the contributions of environmental and genetic factors to asthma. Using data collected from 10,284 subjects, we observed significant associations between airway hyperresponsiveness and self-reported asthma/wheezing in a predominantly rural Chinese population, which has extended the generalizability of previous observations.1 2 3 In addition, we calculated the 20% drop in FEV1 from FEV1 measurements after inhalation of saline solution (PD20s) derived from these values. The sensitivity and specificity and the estimated association of these two sets of PD20s with asthma and wheeze were compared. All the analyses were conducted separately for children, young adults, adults, and older adults to explore the potential age-effect modification.
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Materials and Methods |
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Study Site
The study was conducted in collaboration with Anhui Medical
University and the Anqing Health Bureau in Anqing, China. Anqing
stretches for approximately 80 kilometers along the north bank of the
Yangtze River. The annual average temperature is 15.0°C. Anqing has
three urban areas and eight rural counties, with a total area of 15,000
square kilometers. The total population in 1990 was 5.8 million (urban,
9%; rural, 91%), with 29% < 15 years old, 63% between the ages of
15 years and 59 years, and 8% 60 years old. The birth and
mortality rates per thousand were 26.2 and 7.0, respectively, and
average life expectancy was 65 years.
Procedures
Details of the study design have been described
previously.8
Briefly, the survey was conducted between
1995 and 1998. The survey team was made up of locally hired
interviewers fluent in the dialect of the region, and faculty members
from Anhui Medical University. A letter explaining the study was sent
to each participant. Local officials and health centers arranged for
the interviews and measurements to take place at the central office at
times convenient to the participants. The diagnosis of asthma was made
by local physicians. Asthma-index families were collected in the eight
counties (Zongyang, Huaining, Qianshan, Tongcheng, Taihu, Wangjiang,
Susong, and Yuexi) as follows. First, core investigators from Anhui
Medical University and Anqing City Hospitals/Research Institutes held a
workshop in each township to train township and village doctors how to
identify qualified asthma-index families that met the study criteria.
Each township/village doctor was asked to go back to his or her own
clinic to prepare a list of all families who belong to that clinic that
have at least one proband with asthma or bronchitis. In the next couple
of days, the information from all index case families was collected
from the township/village doctors. Pulmonologists reviewed all index
case family lists with the township/village doctors to eliminate
ineligible families. After the workshop, the field-team members and
village doctors visited each index case family and used a short
questionnaire to confirm the information provided by the village
doctors. They also collected additional epidemiologic and clinical data
on (1) family size; (2) pedigree chart; and (3) health status,
respiratory symptoms, and medications of each family member. With this
information, index case families were considered eligible for
enrollment based on the following criteria: (1) the presence of an
index asthma patient who was at least 8 years old; (2) the existence of
one or more siblings at least 8 years old; (3) the availability of both
parents; and (4) no more than one parent with a history of asthma. If
the family was eligible for the study, informed consent was requested
from all members of the family. Further procedures were then carried
out (unless otherwise specified) in accordance with the National
Institutes of Health collaborative agreement on asthma genetics. The
study was approved by the institutional review boards of the Brigham
and Women’s Hospital and the Harvard School of Public Health.
Appropriate informed consent was obtained from all study participants.
From screening the residents in counties of Anqing (Zongyang, Huaining, Qianshan, Wangjiang, Taihu, Susong, Yuexi, and Tongcheng), we identified and recruited 2,756 asthma-index families (13,001 individuals). Among these subjects, 2,028 subjects from 1,314 nuclear families were excluded because their baseline FEV1 was < 60% of the predicted FEV1 level.
Questionnaire Data
Surveys of all subjects were conducted by trained interviewers
at central offices located in area hospitals. The type of detailed data
collected includes information on occupational exposures to dust,
fumes, chemicals, radiation, noise, and heat; body position during
work; rotating shift work; and potential confounding variables, such as
demographic characteristics, active and passive smoking, indoor coal
combustion, cooking oil fumes, alcohol consumption, diet, use of herbal
medicines, and physical activities outside the workplace. The
questionnaire is divided into two forms, one for adults (> 14 years
old), and one to be completed by parents (for children 
14 years
old). In each case, we have used personal interviews. Children 9
years old were privately asked about their cigarette smoking history,
while separated from their parents for pulmonary function testing.
Because no specific questionnaires have been validated for asthma genetic studies, we used a modified American Thoracic Society-Division of Lung Disease questionnaire to specifically address the issue of asthma genetics. This approach is currently being used by the US Asthma Genetics Collaborative Study.9
Pulmonary Function Tests
Standardized pulmonary function tests were conducted with
American Thoracic Society "Snowbird Guideline"-approved
equipment (Schiller; Boar, Switzerland), and the maneuvers were
performed in a standardized manner (subject seated with nose clip).
Each subject was encouraged to perform a minimum of five maneuvers and
a maximum of eight maneuvers to obtain three acceptable tracings. On
the basis of the Epidemiologic Standardization
Criteria,10
a minimum of 6-s duration, FVCs within
the lesser of 5% or 200 mL, and technician judgment of an adequate
maneuver constitute an acceptable test. The maximum of three
measurements was used for this analysis because it was believed to be
more reproducible than the mean and the "best test" was the
simplest and most practical result to record.10
Airway Challenge Test
If baseline FEV1 was > 60% of predicted
value, the airway challenge test was performed. A standard protocol for
methacholine challenge was used with a modified Chai
protocol,11
which is generalizable and fully comparable to
that used in the US Asthma Genetics Collaborative Study9
and other investigations. Briefly, there were up to five steps to
accomplish the methacholine challenge test with the following
respective breath/dose schedules: saline solution, 5 mg/mL (one
breath), 5 mg/mL (four breaths), 25 mg/mL (one breath), and 25 mg/mL
(four breaths). At each dose, two additional satisfactory
spirometry maneuvers were obtained. The methacholine challenge test
continued until the dose with a 20% drop in FEV1
or the final dose, and was followed by a bronchodilator
test.11
Two methods for calculating the
PD20 were used as indexes for increased airway
responsiveness: (1) a 20% drop in FEV1
calculated from baseline FEV1
(PD20b), and (2) PD20s.
Asthma and Wheeze
The outcomes of interest included physician-diagnosed asthma and
persistent wheeze. Asthma was defined as a history of
physician-diagnosed asthma at any time in the past. Persistent wheeze
was defined as ever wheezing or whistling from the chest apart from
that because of the common cold.
Weight and height were also measured by standard methods. The subjects removed their shoes and outerwear before measurement. Height was measured to the nearest 0.1 cm on a portable stadiometer. Weight was measured to the nearest 0.1 kg with the subject standing motionless on the scale.
Statistical Methods
The outcome variables were physician-diagnosed asthma and
persistent wheeze. Subjects were classified into four groups according
to age: (1) children (< 15 years old), (2) young adults (15 to 29
years old), (3) adults (30 to 44 years old), and (4) older adults
( 45 years old). The coefficient of variation was calculated as
follows: standard deviation/mean x 100%. Multiple logistic
regression was used to assess the association of hyperresponsiveness
with increased asthma and wheeze. Separate logistic models were used
for each age group. Sex, age, age squared, and smoking were adjusted
for in all the regression models. In these models, age was treated as a
continuous variable, and the other variables including sex, airway
responsiveness, and smoking were treated as categorical variables.
Specifically, cigarette smoking was treated in our analyses by using
two dummy variables: one dummy variable was used to denote whether or
not the subject was a current smoker (yes = 1, no = 0), and another
dummy variable was used to denote whether or not the subject was a
former smoker (yes = 1, no = 0). Airway hyperresponsiveness was
defined as the methacholine dose at PD20. Two
PD20 values, derived from
FEV1 values at baseline
(PD20b) and after saline solution inhalation
(PD20s), were used to relate
PD20 to physician-diagnosed asthma and persistent
wheeze. In order to compare the sensitivity and specificity of the
methacholine challenge tests defined by PD20b and
PD20s, the receiver operating characteristic
curves were constructed for asthma and wheeze separately for each
respective age group using appropriate software (SAS/STAT version 6.12;
SAS Institute; Cary, NC).
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Discussion |
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A variety of population-based studies have documented an association of airway responsiveness with either methacholine or histamine to physician-diagnosed asthma in children12 13 14 15 16 and adults.17 18 19 20 The strength of this relationship clearly depends on the degree of airway responsiveness. Prior studies21 in clinical populations have suggested that a PD20 of < 8 mg/mL had virtually 100% sensitivity and specificity for a doctor’s diagnosis of asthma. Our data support the high specificity associated with low-dose responsiveness to methacholine but do not support high sensitivity. The lack of sensitivity can clearly be explained by selection factors in clinical studies and the variability in airway responsiveness seen among asthmatic subjects as a result of variation in environmental exposures influencing responsiveness status.
The question on self-reported doctor-diagnosed asthma is appropriate to ask in rural China, and in the current study we found that self-reported doctor-diagnosed asthma was significantly associated with both wheeze and airway hyperresponsiveness. The previous literature comments that in the general population, the prevalence of self-reported asthma is usually smaller than the prevalence of wheezing.22 23 It should be noted that the prevalence cited herein is not a true population prevalence given the inclusion and exclusion criteria and should be referred to only as the proportion of the study sample. In our study, the prevalence of asthma (19.0%) turned out to be larger than the prevalence of wheezing (10.8%) in the overall population and in each of the four age groups (Table 1) . There are two reasons accounting for our observations: (1) there are potential misclassification biases if physician-diagnosed asthma was self-reported (the majority of the self-reported doctor-diagnosed asthma was diagnosed by local clinic physicians, which might have included a small proportion of individuals with bronchitis); and (2) wheezing in our study was defined as "wheezing or whistling from chest apart from that because of the common cold"; therefore, those with wheezing symptoms only during common colds were not considered to have wheeze in this study.
The ascertainment of the physician diagnosis of asthma is based on patient’s self-report. The sensitivity and specificity of the methacholine challenge would then only relate to the probability of patients reporting an asthma diagnosis (accurate or otherwise), and not to an actual clinically confirmed asthma diagnosis. Self-reported questionnaire information can be distorted for numerous reasons. The subjects may misunderstand the diagnosis, or they may be unwilling to report it. For determination of the validity of such study results, the consistency between subjective self-reported diseases and available medical sources of respective disease information should be compared.
Also, the asthma diagnosis for children may be a "parent proxy," rather than a self-report. The issue with regard to the recall bias and selection bias associated with parent proxy vs self-reporting is an interesting topic. To date and to our knowledge, only one study24 has addressed this problem, and future research should address the following questions: (1) How accurate is parent proxy information on the asthma diagnosis for children? (2) What factors are related to inconsistencies between parent proxy and self-report? (3) What is the impact of these biases on the overall estimate of asthma prevalence in a population?
In our study, there appeared to be very few individuals who demonstrated airway responsiveness with no prior asthma diagnosis. These would be false-positives, and this is the complement of specificity. Also, there are patients who have asthma but are not classified as such by methacholine testing. This is the complement of sensitivity. False-negative results derive from deficiencies in sampling, screening, and interpretation. For example, both selection factors and airway responsiveness variability may affect the detection of false-negatives. There is no agreement as to which of these causes is the most significant. Both sampling and screening deficiencies are a significant source of false-negatives, and errors of interpretation constitute a less common source of false-negatives.
Our studies have several advantages. First, in rural China, the use of asthma medication is virtually nonexistent and, in particular, there is no use of inhaled corticosteroid medications. Thus, active anti-inflammatory treatment is not likely to confound the relationship in the current investigation. Second, one unique aspect of our analysis is the comparison of PD20 determined from a post-saline solution baseline (PD20s) with PD20 determined from baseline FEV1 (PD20b). The universal feature of methacholine and histamine challenge protocols is the inclusion of a saline solution step before the application of a pharmacoconstrictor agonist. Our data suggest that there are negligible differences in the relationship of PD20 to physician-diagnosed asthma and to wheeze, as well as negligible differences in sensitivity and specificity of the PD20 as a result of using the baseline FEV1 rather than the saline solution FEV1. If anything, there is slightly better performance in saline solution PD20 for adults and slightly better performance in baseline PD20 for children, but the differences are negligible and investigators can be encouraged that calculation of PD20 by either method is acceptable, probably because the differences in positive testing results in changes only in the highest categories of methacholine dose. Thus, sensitivity and specificity are largely uninfluenced at the lower doses.
It is important to recognize that there are a substantial number of doctor-diagnosed asthmatic patients who fail to respond to methacholine at any dose. The reason for this nonresponse is unknown and may reflect physician misdiagnosis, changes in airway geometry, or true disease resolution. In any case, what appears striking in our data is that, for children < 15 years old, the proportion of physician-diagnosed, asthma PD20-negative subjects (ie, false-negatives) is substantially greater, representing 29.6% or 48.9%, depending on whether one uses baseline or saline solution PD20. In this study, we used wheeze as a source for ascertaining concurrent validity of the odds ratio assessed for past asthma diagnosis. The use of wheeze in epidemiologic research has important implications, where a clinical diagnosis may not be available.
The present study has several limitations. First, self-reported doctor-diagnosed asthma refers to a medical history of asthma that may have occurred in the patient’s early lifetime but was not present in this particular subject at the time when the study was conducted. The tests for PD20b and PD20s were performed only during this study interval, and therefore the cross-sectional study design could result in a decrease in sensitivity for testing, whether or not the subject has ever had asthma before. Second, a variety of environmental exposures, such as allergen levels, respiratory illnesses, and particulate air pollution, were not measured in this study and, thus, may limit our ability to link responsiveness to current, active symptoms. Third, by virtue of any direct or indirect measures of inflammation, we cannot assess the extent to that the relationships observed are enhanced or attenuated by our lack of knowledge of those inflammatory markers that are thought to link responsiveness with asthma. Fourth, individuals with low levels of pulmonary function (FEV1 < 60% of predicted) were excluded from challenge testing. This censoring presents a particular difficulty for genetic epidemiologic studies, in that it creates missing data in families, which reduces our sample size. An additional limitation of the cross-sectional design is imposed by the comparison of responsiveness at a single point in time with cumulative lifetime prevalence of asthma. Despite this limitation, virtually identical results are obtained when current persistent wheezing is substituted for a physician’s diagnosis of asthma.
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Acknowledgements |
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Footnotes |
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Supported in part by grant HL56371 from the National Heart, Lung, and Blood Institute.
Received for publication July 27, 1999. Accepted for publication October 5, 2000.
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This article has been cited by other articles:
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  N. Scichilone, M. Messina, S. Battaglia, F. Catalano, and V. Bellia Airway hyperresponsiveness in the elderly: prevalence and clinical implications Eur. Respir. J., February 1, 2005; 25(2): 364 - 375. [Abstract] [Full Text] [PDF]
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