PEDIATRIC ALLERGY, IMMUNOLOGY, AND PULMONOLOGY

Volume 25, Number 2, 2012

Mary Ann Liebert, Inc.
DOI: 10.1089/ped.2011.0133

Six-Minute Walk Test and Health-Related Quality of Life:

Objective Tools to Assess Improvement in Cystic Fibrosis
Patients Hospitalized for Pulmonary Exacerbation
Rajeev Bhatia, M.D., Daniel J. Lesser, M.D., Marlyn S. Woo, M.D., and Thomas G. Keens, M.D.

The 6 Minute Walk Test (6 MWT) has been shown to be a better test for submaximal exercise capacity than other
submaximal exercise tests. The cystic fibrosis (CF) Health-Related Quality of Life Cystic Fibrosis QuestionnaireRevised (CFQ-R) has been used in CF patients in order to assess the quality of life. There are a few studies that
examine measurements of multiple endpoints simultaneously [e.g., pulmonary function test (PFT), exercise
capacity, CFQ-R] with treatment in CF pulmonary exacerbation. We hypothesize that the 6MWT is safe to
perform during pulmonary exacerbation, and that 6 MWT, CFQ-R, and PFT improve with treatment in CF
pulmonary exacerbation. We further hypothesized that the improvements in 6MWT, CFQ-R, and PFT are
related. We performed 6 MWT, PFT, and CFQ-R in 21 CF subjects (age 720 years) admitted for pulmonary
exacerbation. 6 MWT, PFT, and CFQ-R were completed at admission, at the end of week 1, and at the end of
week 2. No complications were noted during the 6MWT.The 6MWT, PFT [forced expiratory volume in one
second (FEV1), FVC and forced expiratory flow25%75% (FEF25%75%)], and CFQ-R domains (Respiratory and
Physical) improved significantly at week 2. The physical domain change correlated with the 6MWT improvement, whereas the respiratory domain change correlated with the FEF 25%75% improvement at week 2. There
was no significant relationship observed between the 6MWT and PFT improvements. In conclusion, 6MWT is a
safe and well-tolerated test, and it can be utilized as an adjunct or alternative outcome measure to PFT in acute
CF pulmonary exacerbation. In addition, multiple outcome measures, including 6MWT and HRQOL, should be
utilized to assess the efficacy of treatment in CF pulmonary exacerbation.
used to measure aerobic fitness.11 Previous studies have also
documented that 6MWT is a reliable and valid test in children with CF.12,13 However, it has not been examined in CF
pulmonary exacerbations as an outcome measure of acute
improvement with treatment.
The CF Health-Related Quality of Life Ouestionnaire
(HRQOL) has been used in CF patients to assess the effect of
the disease on the quality of life.14,15 However, its use as an
objective outcome measure of treatment in acute pulmonary
exacerbation has not been tested as thoroughly.16 The U.S.
Food and Drug Administration has also encouraged the use
of patient reported outcomes in studies of patients with
chronic disease and, thus, the inclusion of these outcomes in
an exacerbation study provides critically needed information
about these measures. There are even fewer studies that have
examined the change in lung function, exercise capacity, and
HRQOL as outcome measures of treatment in pulmonary
exacerbation as a whole.17 Moreover, none of these studies
have used 6MWT, which is a better test for assessing submaximal exercise capacity, compared with other functional
tests.

Introduction

he occurrence of pulmonary exacerbation in cystic

fibrosis (CF) is considered one of the most important
clinical events in the course of this disease.1 There is a positive association between the annual rate of CF pulmonary
exacerbations and decline in pulmonary function, and a
negative association with the survival.2 Despite the known
significant impact of pulmonary exacerbations, there are no
objective measures of improvement with treatment except
the pulmonary function test (PFT).
The 6 Minute Walk Test (6 MWT) is a simple and inexpensive test that reflects overall fitness and the activities of
daily life.3,4 It is easier to administer, more reflective of activities of daily living, and better tolerated than the other
walk tests such as shuttle walk test and so on.3,5 It has been
widely used to evaluate submaximal exercise capacity in
adults with lung diseases,610 but it is used less commonly in
the pediatric population. A significant correlation has been
shown between 6MWT distance and peak oxygen uptake
(VO2 max) in children, suggesting that the 6MWT may be

Division of Pediatric Pulmonology, Department of Pediatrics, Childrens Hospital Los Angeles, Keck School of Medicine, University of
Southern California, Los Angeles, California.

86

6MWT AND HRQOL MEASURES IN CF PULMONARY EXACERBATION

Thus, in this pilot study, we aim at investigating (a)
whether 6MWT is a safe test to be performed during CF
pulmonary exacerbation; (b) how 6 MWT, HRQOL domains
score, and PFT change with treatment in CF patients hospitalized for pulmonary exacerbation. (c) Do the changes in
6MWT, HRQOL domains, and PFT correlate with each other? We hypothesize that the 6MWT is safe to be performed
during CF pulmonary exacerbation and that 6MWT, HRQOL
domains score [using Cystic Fibrosis Questionnaire-Revised
(CFQ-R)], and PFT improve with treatment in CF patients
hospitalized for pulmonary exacerbation. We further hypothesize that the improvements in 6MWT, CFQ-R domains,
and PFT correlate with each other.

Methods and Materials

Subjects
Twenty-two subjects with CF (ranging in age from 7 to 20
years) who were admitted between December 2008 and
August 2009 to the Childrens Hospital Los Angeles (CHLA)
with the diagnosis of pulmonary exacerbation were recruited. All patients were recruited consecutively. Twentythree patients were approached for this study based on age
criteria; however, 1 patient declined to participate in the
study. The CHLA institutional review board approved the
study (CCI-08-00210), and written informed consent was
obtained from the patients/parents and/or legal guardians.
Assent was also obtained from appropriate subjects. A respiratory culture was obtained from each subject on admission. Respiratory culture data were recorded based on the
culture results from 1 year earlier until this admission.
Pseudomonas aeruginosa was defined as being multi-drug
resistant if it was resistant to all agents in at least two of the
following groups of antibiotics: b-lactams, aminoglycosides,
and fluroquinolones. Patients were treated as per published
guidelines for the treatment of CF pulmonary exacerbation.18

6 minute walk test

The 6MWT was conducted as per the American Thoracic
Society guidelines.3 It was conducted within 3 days of admission, then at the end of week 1, and at the end of week 2.
All patients received the same orientation before each testing
session. The patients were instructed to walk as far as possible in 6 min on a standard indoor course, and the total
distance walked was measured at the end. Oxygen saturation (SpO2) and heart rate were recorded before and immediately after the 6MWT using a pulse oximeter (Nellcor,
Hayward, CA).

Cystic fibrosis questionnairerevised

The CFQ-R is a self-reported reliable and validated
HRQOL measure that is specifically designed for patients
with CF.19,20 It consists of 44 items on 12 generic and diseasespecific scales. The CFQR-child version (613 years old) and
the CFQ-R Teen/Adult Version (14 years and older) were
used in this study. The CFQ-R child version has eight domains: Physical, Emotional, Social, Body Image, Eating,
Treatment Burden, Respiratory, and Digestion. In addition to
these eight domains, the CFQ-R Teen/Adult version has the
following four domainsRole, Vitality, Health Perception,
and Weight. The scores in each domain range from 0 to 100.

87

The better HRQOL is represented by a higher score. The

CFQ-R was completed by the patients on the day of each
6MWT session.

Pulmonary function tests

PFT were measured within the first 3 days of admission
and at least weekly thereafter until discharge. Tests were
performed in the pulmonary function laboratory of the
Childrens Hospital Los Angeles, located near sea level. The
maximum expiratory flow rates (FEV1, FEF25%75%) and
forced vital capacity (FVC) were obtained using a computerized spirometer (Creative Biomedics International, San
Clemente, CA or Viasys Sensor medics VMAX system, Yorba
Linda, CA). The lung volumes were measured with a body
pressure plethysmograph (Sensor medics 2800Autobox,
Yorba Linda, CA). The values were collected as raw values
and as a percent of predicted values based on standard reference values.21,22

Statistical analysis
Data were described using mean, standard deviations,
and ranges. The change in variables from admission to the
end of week 2 was evaluated using a paired t-test. Data were
further divided on the basis of age to assess the effect of age
on improvements in PFT and 6MWT, and analyzed using a
two-sample t-test. Spearmans rank correlation was done to
examine the association among changes in 6MWT, CFQ-R
domains, and PFT at the end of week 2. Comparisons among
various distributions of 6MWT, FEV1, and CFQ-R domains
(Physical and Respiratory) from admission to week 1 and
week 2 were illustrated using box plot graphs. A P-value
of < 0.05 was considered statistically significant.

Results
Data from 21 CF subjects (10 males, age range 720 years,
15 Hispanics, 5 Caucasians, and 1 African American) were
analyzed (Table 1). One subject was excluded from data
analysis because of incomplete data points. The mean FEV1
at admission was 56.2% 19.7% predicted with a range of
26%103% predicted, indicating the wide range of severity of
illness in our subject population. Thirteen patients showed
colonization with pseudomonas aeruginosa, and seven of
these patients had multi-drug-resistant pseudomonas. Five
subjects were colonized with Achromobacter xylosoxidans,
whereas only one subject was colonized with methicillinresistant staphylococcus aureus.
No complications were noted during the 6MWT. All
subjects were able to complete the test at admission, at week
1, and at week 2. Subjects tolerated the procedure well with
no significant dyspnea or fatigue. There were no significant
episodes of hypoxemia or tachycardia noted immediately
after the test. The mean SpO2 at the beginning of 6MWT
done at admission was 95.9 2.9, which was not significantly
different from that at the end of the test (95.9 2.8; P = 0.92)
.The mean heart rate increased from 103.9/min to 107.4/min
(P = 0.042) at the end of the test, which, although statistically
significant, is unlikely to have clinical importance.
Figure 1 shows the serial plot of 6MWT for each subject.
There was an individual variation at the end of week 1, but
all subjects (except one) showed improvement at week 2 as
compared with on admission. Mean 6MWT continued to

88

BHATIA ET AL.
Table 1.

Demographic Characteristics and Pulmonary Function Test Parameters at Admission

Variable
Age at baseline (years)
Height (cm)
Weight (kg)
BMI (kg/m2)
FVC (% predicted)
FEV1 (% predicted)
FEF 25%75% (% predicted)
RV (% predicted)

All subjects (n = 21)

Mean SD(Range)

Males (n = 10)
Mean SD(Range)

Females (n = 11)
Mean SD(Range)

13.1 3.8 (720)

148.1 17.2 (117179)
40.4 16.5 (20.791.3)
17.6 3.2 (13.528.5)
66.3 17.8 (3999)
56.2 19.7 (26103)
43.1 29.2 (8127)
237.7 81.4 (109372)

14.8 3.3 (1020)

157 14.3 (126179)
48.3 17.8 (23.691.3)
18.9 3.7 (14.928.5)
62 21.4 (3999)
54 26 (26103)
43.1 38.6 (9127)
269.5 91.2 (109372)

11.6 3.7 (720)

140.1 16.1 (117168)
33.2 11.8 (20.760)
16.4 2.1 (13.521.3)
70.3 13.5 (4289)
58.3 12.4 (3376)
43.2 19.1 (869)
208.7 61.7 (126303)

BMI, body mass index; FVC, Forced vital capacity; FEV1, forced expiratory volume in one second; FEF
flow 2575%; RV, residual volume.

improve from admission to the end of week 2 (Table 2 and

Fig. 2). As expected, FEV1, FVC, and FEF25%75% also improved from admission to the end of week 2 of IV antibiotics
(Table 2 and Fig. 2). In addition, the physical and respiratory
domains of CFQ-R improved significantly from admission to
the end of week 2. (Table 2 and Fig. 2).
In order to assess the potential effect of age on the observed changes in 6MWT, the subjects were divided into two
groups of < 12 years or 12 years. Both groups had comparable FEV1 (% predicted) at admission. In < 12 years age
group, two out of seven patients had pseudomonas aeruginosa, and both these subjects had multi-drug-resistant
pseudomonas. In older children, 11 out of 14 were psuedomonas aeruginosa positive. Five of these 11 patients had
multi-drug-resistant psuedomonas. Children younger than
12 years showed substantial improvement in FEV1 with
treatment but did not show as substantial improvement in
6MWT when compared with older subjects. In contrast,
while older children ( 12 years) showed substantial improvement in 6MWT, they did not display the degree of improvement in FEV1 seen in the younger age group (Table 3).
To assess the relationship among changes in 6MWT, PFT,
and CFQ-R at the end of week 2, Spearman Correlation was
performed. Although both 6MWT and PFT parameters improved significantly compared with at admission, there was
no significant correlation found between the change in

FIG. 1. Serial 6MWT plot of each

subject from admission to the end of
week 1 and week 2. 6MWT, 6 Minute
Walk Test.

25%75%,

forced expiratory

6MWT and the change in any PFT parameter. The improvement in 6MWT was significantly correlated with the
physical domain of CFQ-R at the end of week 2. (r = 0.48,
P = 0.029). There was a significant correlation found between
improvements in FEF25%75% and the respiratory domain of
CFQ-R after 2 weeks of IV antibiotics (r = 0.45, P = 0.038;
spearman correlation). At the end of week 2, the relationship
between changes in FEV1 and the CFQ-R respiratory domain
was moderate but did not reach statistical significance
(r = 0.38, P = 0.08).

Discussion
Our study showed that the 6MWT is a safe and welltolerated test in CF patients hospitalized for pulmonary exacerbation. The 6MWT, PFT parameters (FEV1, FVC, and
FEF25%75%), and CFQ-R domains (respiratory and physical
domains) improved significantly with treatment. After 2
weeks of IV antibiotics, the change in the CFQ-R physical
domain correlated with the 6MWT improvement, whereas
the change in the respiratory domain correlated with an
improvement in FEF25%75%. However, there was no significant relationship seen between 6MWT and PFT improvements.
There are limited studies in the literature evaluating the
utility and safety of the 6MWT in CF patients, especially in

6MWT AND HRQOL MEASURES IN CF PULMONARY EXACERBATION

Table 2.
Variable
6MWT distance (m)
FVC (% predicted)
FEV1 (% predicted)
FEV1/FVC (%)
FEF25%-75% (% predicted)
RV (% predicted)
CFQ-R Domains
Physical symptoms
Emotional Functioning
Social functioning
Body image
Eating
Treatment burden
Respiratory symptoms
Digestive symptoms

89

Trend of Variables from the Admission to the End of Week 2

Admission(Mean SD)

Week 1(Mean SD)

Week 2(Mean SD)

P-valuea

423 63.4
66.3 17.8
56.2 19.7
73.7 12.8
43.1 29.2
237.7 81.4
51.6 23
71.9 20.3
64.1 17.1
75.7 22.4
71.5 27.8
63.6 19.5
39.7 21.7
83.1 19.7

443.9 65.3
73.5 20.5
62.5 20.9
75.1 12.7
46.6 31.5
220.9 77.8
61.3 22.8
77 16.2
66.4 16.5
72.3 23.6
85.2 19.1
61.8 18.9
57.7 26.3
84.1 25.6

472.3 74.6
79.4 20.5
70.5 20.4
77.6 9.7
55.6 28.3
226.2 87.6
61.2 23.9
81 14.8
64.8 15.5
83.2 19.4
81.5 21.1
64.7 19.8
72 21
87.4 14.5

(0.0000)b
(0.0002)b
(0.0005)b
(0.0658)
(0.0255)b
(0.1635)
(0.0312)b
(0.0518)
(0.8850)
(0.0889)
(0.0596)
(0.7985)
(0.0000)b
(0.2929)

Week 2 variables compared with admission (Paired t-test).

Significant P-value < 0.05.
6MWT, 6 Minute Walk Test; CFQ-R, cystic fibrosis questionnairerevised.
b

the pediatric population. In adults, Chetta et al. concluded

that cystic fibrosis patients with mild to moderate lung disease experienced a significant fall in oxygen saturation and
an increased breathlessness perception during 6MWT.23
With regard to children, Rubinowicz et al. performed 6MWT
in CF patients for four consecutive years along with spirometry and clinical parameters. They concluded that CF
patients had significant desaturation during the test.24
However, none of the studies just mentioned were performed during an acute pulmonary exacerbation, which is an
important component of CF disease. To our knowledge, our
study is the first study that objectively assesses the usefulness of 6MWT as a clinical outcome in CF pulmonary exacerbation. Despite the fact that our subjects were acutely ill,
the 6MWT was well tolerated, and no complication was
noted, including hypoxemia.

Previous investigators have assessed changes in submaximal exercise capacity in CF children hospitalized for
pulmonary exacerbation. Cox et al. showed that the multiple
shuttle test performance improved in CF hospitalized children, which is similar to our results.25 They also observed an
improvement in FEV1 but did not find any significant correlation between the change in multiple shuttle test performance and FEV1. Similarly, Pike et al. demonstrated an
improvement in exercise tolerance (using the 3 min step test)
as well as lung function (FEV1, FVC, and FEF25%75%) in
pediatric patients with CF admitted for pulmonary exacerbation.26 For our study, we chose 6MWT, because it has
shown to be superior to other functional tests in assessing
sub-maximal exercise capacity.3,5
We also measured HRQOL (using CFQ-R) in these patients to assess the impact of treatment on the quality of life.

FIG. 2. Comparison among

various distributions of (A)
6MWT, (B) FEV1(% predicted),
and CFQ-R domains ([C]
physical and [D] respiratory)
from admission to the end of
week 1 and week 2. CFQ-R,
cystic fibrosis questionnairerevised; FEV1, forced expiratory
volume in one second.

90

BHATIA ET AL.
Table 3. Comparison of 6 Minute Walk Test and Forced Expiratory Volume in One Second
(% predicted) Change at the End of Week 1 and Week 2 in Patients < 12 Years
(n = 7; 6 Females) and 12 Years (n = 14; 5 Females) of Age

Variable
6MWT distance (m)
FEV1 (% predicted)

Age
< 12
12
< 12
12

years
years
years
years

Admission
(Mean SD)

Week 1
(Mean SD)

Week 2
(Mean SD)

Changea
(% change)

404.6 60.4
432.2 65
55.9 11.7
56.4 23.1

421.6 52.5
456.9 70.6
75.7 14.2
55.4 20.9

433.3 66.7
491.8 72.7
79 15.6
66.2 21.7

28.7 m(7.1%)
59.6 m(13.7%)
23.1(41.3%)
9.8(17.3%)

Pvalueb
c

0.0022
c

0.0008

Change (% change) from admission to week 2.

Comparison between the 6MWT change and the FEV1 change between groups.
Significant P-value < 0.05.

b
c

Although CFQ-R is frequently used in the outpatient setting

as a HRQOL measure, it has not been utilized thoroughly in
acute settings of pulmonary exacerbation.14,15 In a previous
study done during CF pulmonary exacerbation, Modi et al.
showed that the respiratory domain score improved significantly after IV antibiotic treatment, which is consistent with
our results of improvement in physical and respiratory domains.16 We also observed in our subjects that the change in
the CFQ-R physical domain correlated with the 6MWT improvement, whereas the change in the respiratory domain
correlated with the improvement in FEF25%75%. This may be
due to the fact that 6MWT assesses the overall fitness,
whereas the PFT measures the ventilatory function only.
Quittner et al. in a study done on CF patients with pulmonary exacerbation reached a similar conclusion that CFQ-R
measures different aspects of clinical efficacy as compared
with those measured by physiologic variables.27 Thus, using
one test as an outcome measure for the treatment of pulmonary exacerbation may not be adequate.
We did not observe any significant correlation between
the improvement in PFT parameters and the 6MWT distance.
Interestingly, we demonstrated that the pattern of improvement in 6MWT and FEV1 differed in children younger than 12
years and 12 years and older, even if they had similar baseline
FEV1, which suggests that there may be an interaction between 6MWT and age. In addition, this difference could be
due to the fact that PFT is an assessment of ventilatory function only, whereas 6MWT assesses functional capacity, which
is influenced by not only ventilatory function but also cardiovascular, muscular, inflammatory, and metabolic factors.
There is evidence that intolerance to exercise in patients with
CF is multifactorial, and that pulmonary function, nutritional
state, and bronchial colonization agents play a role in that
regard.17,26,28 This highlights the fact that simply relying on
one test as an outcome measure may provide incomplete information. Multiple outcome measures can provide a better
and more complete picture that provides further direction in
clinical decision making. Particularly, we have observed that
an important subset of patients with severe CF disease may
display minimal change in PFT parameters with the treatment
of acute exacerbation. In these individuals, the 6MWT and
CFQ-R can be used to assess the response to treatment along
with PFT. Hence, 6MWT and CFQ-R can be a useful adjunct
to PFT in assessing overall clinical improvement in CF patients hospitalized for pulmonary exacerbation.
There are very few studies in the literature examining the
measurement of multiple measures simultaneously (e.g.,
change in PFT, exercise capacity, and HRQOL) with IV

treatment in CF pulmonary exacerbation. Bradley et al.

performed pulmonary function testing, modified shuttle
testing, and an HRQOL questionnaire in adult CF patients
hospitalized for pulmonary exacerbation to assess the effect
of IV treatment with multiple outcome measures.17 There
was significant improvement in lung function, exercise capacity, and quality of life after treatment, which is similar to
what was observed in our study. However, this study was
done in older patients (mean age 23 years) in contrast to our
study, where we had a younger population (mean age 13.1
years). This study along with our study provides evidence
that exercise capacity and HRQOL should be included along
with PFT in the overall assessment of CF pulmonary exacerbation treatment. So far, the most commonly used objective
measure of the end point of treatment is PFT only, which
may provide a limited index of the outcome.
A significant number of subjects in our study were
Hispanics (71%). This is the strength of the study given the
relative paucity of data on patients with CF who are
non-Caucasians. The training effect of 6MWT can be a potential limiting factor of our study. There is literature on adults
that describes the possible effect of training on 6MWT performance.29,30 However, in these studies, the 6MWT was done
on consecutive days. We believe that in our subjects, the
training effect may not have such a significant impact, because
the tests were conducted a week apart. Moreover, in our
study, the orientation was provided before each test, which
we expect to have also minimized the training effect to a
certain extent. A potential limitation of our study relates to
assessment of the 6MWT change based on published normative pediatric values of 6MWT.31 All male and female subjects
(except one) in our study were below the 3rd percentile on the
reference percentile curves for normal children. Thus, it was
not practical to assess the change based on normative values.
However, we do not believe that the inability to normalize the
data significantly impacts the validity of our results. In this
study, each subject functioned as his or her own control, and
correlations were executed across the tests carried out for each
subject. A final limitation relates to our sample size, which
was not sufficient to assess the effect of age, gender, and
ethnicity on the relationship among changes in 6MWT, CFQ-R
domains, and PFT with treatment.
In conclusion, the 6MWT is a safe and well-tolerated test,
and it can be utilized as an adjunct or alternative outcome
measure to pulmonary function testing in CF patients hospitalized for pulmonary exacerbation. In addition, multiple
outcome measures, including 6MWT and HRQOL assessment along with PFT, should be utilized to assess the efficacy

6MWT AND HRQOL MEASURES IN CF PULMONARY EXACERBATION

of treatment in CF pulmonary exacerbation and to guide
clinical decision making. We speculate that the use of multiple
outcome measures as end points in clinical trials will afford a
more complete picture of the impact of new therapeutics in
patients functional capacities and quality of life.

Acknowledgments
This study was partly supported by a grant from the
Webb foundation. The authors would also like to acknowledge Frederick Dorey, PhD, for aid in statistical analysis and
the patients and their families for participating in this study.

Authors Contributions
Rajeev Bhatia: Performed the tests, interpreted and analyzed the data, and wrote the article. Daniel J. Lesser: Performed some tests, and reviewed the article. Marlyn S. Woo:
Helped formulating the design of the study, and reviewed
the article. Thomas G. Keens: Supervised the study, interpreted and analyzed the data, and reviewed the article.

Author Disclosure Statement

None of the authors have any conflict of interest to declare that is related to this article.

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Address correspondence to:

Rajeev Bhatia, M.D.
Division of Pediatric Pulmonology
Department of Pediatrics
Childrens Hospital Los Angeles
Keck School of Medicine
University of Southern California
4650, Sunset Boulevard
Mail Stop # 83
Los Angeles, CA 90027
E-mail: rbhatia0211@gmail.com
Received for publication November 28, 2011; accepted after
revision March 4, 2012.