Download A Comparison of a Single-Step Cold-Dry Air

A Comparison of a Single-Step Cold-Dry
Air Challenge and a Routine Histamine
Provocation for the Assessment of
Bronchial Responsiveness in Children
and Adolescents*
Bernhard Steinbrugger, MD; Ernst Eber, MD; Manfred Modi, MD;
Elisabeth Weinhandl; and Maximilian S. Zach, MD
Background: It has remained unclear whether bron¬
chial responsiveness as measured by a single-step
cold-dry air challenge (CACh) correlates closely to the
responsiveness that is assessed by a routine pharma¬
cologic challenge.
Methods: On 2 consecutive days, we performed a
CACh and a histamine challenge in 128 symptom- and
medication-free pediatric and adolescent asthma pa¬
tients. The CACh consisted of 4 min of isocapnic
hyperventilation of -10°C, absolutely dry air; respon¬
siveness was expressed by the induced change in FEVi
(AFEVi). The histamine challenge consisted of se¬
quential inhalations of incremental increases in con¬
centrations of histamine; responsiveness was expressed
by the concentration which caused a 20% fall of FEVi
(PC20).
Results: Five children did not bronchoconstrict suffi¬
ciently in the histamine challenge for measuring a
PC20 and were excluded from analysis. In the remain¬
ing 123, AFEVi (CACh) ranged from +5 to -73%, PC20
(histamine) from 0.05 to 7.2 mg/mL. There was a sta¬
tistically significant correlation between AFEVi and
measured by
routinelysubstances
like
active
inhaling pharmacologically
histamine or methacholine; alternatively, it can be as¬
sessed by challenges that apply physical stimuli like the
hyperventilation of cold and dry air (cold-dry air
challenge=CACh).
The CACh can be done in two ways. Some authors
have advocated a multiple-step approach with increas¬
ing levels of cold-dry air hyperventilation; in analogy to
challenges, a dose-response curve is
pharmacologic
constructed and bronchial responsiveness is expressed
as that dimension of hyperventilation that causes a
change of lung function.12 Others have
predetermined
used a single-step approach; after applying one single
dose of cold-dry air hyperventilation, bronchial respon-
TJronchial responsiveness is
-¦"*
Respiratory and
Allergic Disease Division, Pediatric
of Graz, Austria.
University
Department,received
November 8, 1994; revision accepted Febru¬
Manuscript
ary 24, 1995.
Pediatric Dept, University of
Reprint requests: Dr. Steinbrugger,
A-8036 Graz, Austria
*From the
Graz, Auenbruggerplatz 30,
PC20 (r=0.54, p<0.001), but also a considerable scatter
of individual data points around the regression line.
Fifty-two subjects were hyperresponsive by CACh and
114 by histamine criteria.
Conclusions: There is a relatively weak correlation
between the results of these two challenges; thus, one
cannot be substituted one for the other. Histamine
appears as more sensitive in detecting airway hyper¬
responsiveness than CACh. The poor correlation be¬
tween the responses to these two challenges can be
explained by differences between the challenge pro¬
tocols, or, alternatively, by differences between ap¬
plied stimuli and activated mechanisms.
(CHEST 1995; 108:741-45)
CACh=cold-dry air challenge; FEVi=forced expiratory
volume in 1 s; PC20=provocation concentration of hista¬
mine causing a 20% fall in FEVi
Key words: bronchial responsiveness; cold-dry
lenge; histamine provocation; pediatric asthma
air chal¬
quantified in terms of the effected change
The relationship of the responses to a conventional
challenge on one side and CACh on the
pharmacologic
other has been studied repeatedly, but results have so
far remained contradictory. Several studies that com¬
the responses to a multiple-step CACh with
pared
those to a histamine or methacholine challenge dem¬
onstrated a very close correlation.8"12 When comparing
a histamine or methacholine provocation to a singlestep CACh, however, some authors found close cor¬
relations,13 while others observed only weak correla¬
tions with a relatively low correlation coefficient and a
substantial scatter around the regression line.14,15 One
study, done in a small number of pediatric subjects,
failed altogether to find a correlation between hista¬
mine and CACh responses.5
When compared with conventional pharmacologic
a single-step CACh has several practical
challenges,
and theoretical advantages for measuring bronchial
responsiveness.5"7 Before substituting a single-step
siveness is
in lung function.3"7
CHEST /108 / 3 / SEPTEMBER, 1995
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741
challenge, however, the
pharmacologic
the responses to these two
relationship between
different types of challenges requires further evalua¬
tion. We therefore compared the responses to a
single-step CACh and to a conventional histamine
challenge in a large group of pediatric subjects with a
CACh for
a
wide range of bronchial responsiveness.
Methods
Subjects
Subjects were the first 150 participants of an ongoing epidemi¬
ologic study that evaluates all asthma patients of this pediatric res¬
piratory center 1.5 years after having become symptom-free and 1
year after having become medication-free. This epidemiologic study
aims at evaluating the prognostic value of lung function, bronchial
responsiveness, and allergy skin test reactivity by doing these mea¬
surements and then following up the patients clinically and with
repeated measurements. This group of subjects was believed to be
ideally suited for the present comparison of two bronchial provo¬
cation methods for several reasons: (1) a previous pilot study had
shown this group as having a wide range of bronchial responsive¬
ness,16 and (2) the absence of any antiasthmatic medication that
could influence both challenge mechanisms differently.
Twenty-two of these 150 subjects were excluded from being
challenged. Six patients had marked airwayin obstruction without
significant bronchodilator responsiveness their baseline lung
functions. Ten further patients remained unable to cooperate with
lung function testing and/or hyperventilate sufficiently in the CACh.
Another six refused to do more than one bronchial challenge pro¬
cedure.
The remaining 128 patients, 48 girls and 80 boys, had a mean age
of 13.1 years (SD=2.7; range, 7.8 to 19.4), a mean body weight of
51.4 kg (SD=16.2; range, 23 to 94), and a mean body length of 158
cm (SD=14.3; range, 126 to 187). All were well trained to cooper¬
ate with lung function testing and bronchial provocation proce¬
dures. All were long-term patients of this pediatric asthma center
who, previously, before becoming symptom free, had met the clin¬
ical definition of bronchial asthma,17 and had been treated with
various antiasthmatic medications (disodium cromoglycate, topical
steroids, theophylline, bronchodilators) for a minimum of 3 years
before becoming medication free.
Single-Step CACh
Single-step CACh was done according to an established proto¬
col.5' Cold and dry air was produced by a commercially available
heat exchanger (RHES; Jaeger; Wuerzburg, Germany). After the
measurement of prechallenge FEVi, subjects hyperventilated ab¬
solutely dry, 10°C air at 75% of their maximum voluntary venti¬
lation for 4 min. The correct level of hyperventilation was main¬
tained by having the subjects compete with a target balloon. A CO2
analyzer continuously monitored the CO2 concentration in the ex¬
pired air, and CO2 was added to the inspired air to keep the sub¬
ject eucapnic. Three minutes after termination of the CACh, FEVi
was measured again. The change of FEVi (AFEVi) from the preCACh to the post-CACh measurement was expressed in percent
baseline FEVi.
For this method, a 9% fall of FEVi or more defines airway hy¬
perreactivity.5,1819
Histamine Challenge
Histamine challenge was done according to the present Austrian
standardization,20 which is based on the method of Cockcroft et al.21
As a tidal breathing method, this approach is identical with a later
European standardization,2 with the exception of using a nebulizer
a higher output.
Briefly, each step ofthis multiple-step protocol consists of a 2-min
inhalation by quiet tidal breathing through a mouthpiece using a
nose clip. The first aerosol inhaled after the baseline measurement
of FEVi is the diluent, and this is followed at 5-min intervals by
doubling concentrations of histamine from 0.03 to 8.0 mg/mL. The
FEVi is measured before, at 30 and 60 s, and at 2.5 min after each
inhalation. The test is stopped when the FEVi has fallen by 20% or
more from baseline or when having gone through all concentrations
of histamine. A dose-response curve is constructed by plotting the
percent fall in FEVi against the concentration of histamine on a log
scale. The result is expressed as the concentration of histamine
with
causing a 20% fall in FEVi (PC20).
Based on the output (0.46 mL/min) of the nebulizer used
(Inhalierboy; Pari; Starnberg, Germany), a PC20 under 4 mg/mL
defines airway hyperreactivity.20
Study Protocol
The two different challenges were done in random order, at 10
days. Before the first challenge, a brief history
clinical examination was performed; patients
presenting with a recent history and/or the symptoms of an acute
respiratory tract infection or an allergen exposure were not accepted
for testing, but received a second, later (minimum interval, 6 weeks)
appointment. Before each challenge, subjects rested for 1 h in a
controlled climate (20°C, 40% relative humidity).
Lung function testing was done on a water-filled spirometer
(Spiro-Junior; Jaeger; Wuerzburg, Germany) in accordance with
standardized guidelines.22 FEVi was expressed in absolute terms
and in percent predicted as based on established reference
standards.23 After each challenge, recovery of lung function was
observed for 20 min; if by then the FEVi had not returned to
baseline, the patient was treated with nebulized salbutamol. Such
treatment was also administered immediately after the challenge
when the patient subjectively felt any shortness of breath.
Informed consent to the study was obtained from patients and
am on 2 consecutive
was obtained and a
parents.
The least squares correlation analysis was used for the statistical
comparison of the responses to CACh and histamine. Logarithmic
transformation of the PC20 values was performed for this regres¬
sion analysis. Prechallenge lung functions were compared by one¬
way analysis of variance. A p value of 0.05 and below was taken as
indicating statistical significance.
Results
In five subjects, a 20% fall of FEVi could not be
effected in the entire histamine challenge, and a PC20
could thus not be determined. These subjects were
excluded from further analysis.
In the remaining 123 subjects, the baseline FEVi
measurements before CACh (100.7± 11.2% predicted;
range, 62 to 126) did not differ significantly from those
before the histamine challenge (98.4± 11.1% pre¬
dicted; range, 66 to 126).
The induced change in FEVi (CACh) was
-11.4±13.8% baseline (range, +5 to -73%). The PC20
(histamine) was 1.87±1.96 mg/mL (range, 0.05 to 7.2).
The correlation of AFEVi (CACh) to PC20 (histamine)
is shown in Figure 1. This correlation was statistically
However, as illustrated by a rel¬
significant
(p<0.001).
low
correlation
coefficient (r=0.54) and a con¬
atively
siderable scatter of individual data points, this corre¬
lation remained a relatively weak one.
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Clinical Investigations
n = l23
r = o.5a
p< 0.001
1I
2
Sg30±
0,06 0,125
Figure 1. Correlation of AFEVj (CACh) to
PC20 (histamine). Dashed lines indicate the
0,25
Histamine challenge
PC 20 (mg/ml)
52 subjects were found to be hyperAlthoughtoonly
the
CACh, 114 were hyperresponsive to
responsive
the histamine challenge. Fifty subjects met the defi¬
nition of bronchial hyperresponsiveness in both tests;
conversely, seven were normoresponsive in both prov¬
ocations. Sixty-four were hyperresponsive by histamine
but normoresponsive by CACh criteria. Only two
subjects with a normal histamine response met the
definition of bronchial hyperresponsiveness by CACh
criteria; their AFEVi (CACh) was -10% and -11%,
to the CACh
respectively. Thus, a positive response
histamine
criteria
predicted hyperresponsiveness by
with a probability of 96.2%, while a negative CACh
response predicted normoresponsiveness by histamine
criteria with a probability of only 15.8%.
Discussion
demonstrates a statistically significant
studybetween
the airway response to a single
relationship
dose of cold-dry air hyperventilation on one side, and
bronchial responsiveness, as measured by a routine
histamine challenge, on the other. As indicated by a
around the
This
wide
scatter of the individual data points
regression line, however, this correlation remained a
weak one. For practical purposes, this indi¬
relatively
that the result of a single-step CACh can hardly
substitute for measuring bronchial responsiveness by a
routine histamine challenge, and vice versa. Such a
weakness in the observed correlation could be ex¬
plained
by one or several of the following factors: (1)
technical inconsistencies in performing the challenges;
(2) conceptual differences between the challenge
and (3) basic differences between applied
procedures;
stimuli and activated mechanisms.
Data points in the figure indicate that the studied
population was somewhat skewed toward subjects with
increased airway responsiveness, and the
only mildlyarises
whether the correlation would
cates
question
have
borders between normal and increased bron¬
chial responsiveness for both challenges.
been better if subjects had been more evenly distrib¬
uted. As the scatter of data points increases with
increasing airway responsiveness, however, a substan¬
tial gain in the quality ofthe correlation by a more even
distribution seems highly unlikely.
Noise from some inaccuracies in the application of
the challenge is an unlikely explanation for the major
part of the observed scatter. A previous study of
CAChs, done with the same
repeated single-step
and
challenge protocol, has demonstrated
technique
excellent short-term reproducibility.5 Furthermore,
care was taken in the present study to avoid technical
and to exclude subjects who did not hyperven¬
pitfalls
tilate sufficiently. One previous study that compared
the response to a single-step CACh with the outcome
of a pharmacologic challenge found a close correla¬
tion,13 while another such investigation failed to do so5;
both studies were done in only a small number of
subjects. Two other similar investigations demon¬
strated statistically significant, but relatively weak cor¬
relations.1415 Of these two, the investigation by Filuk
et al15 has many similarities to the present study. These
authors also found a substantial scatter of individual
data points around the regression line and suggested
that this finding could be explained by frequently ob¬
served technical difficulties, especially a noncompliance of many of their subjects with the hyperventila¬
tion protocol. Based on the above-mentioned care that
was taken to avoid such technical inaccuracies in the
present study, it seems that this hypothesis can now be
rejected, and that other explanations for the apparent
weakness of this correlation must be looked for.
As an alternative explanation, the observed differ¬
ence in the responses to a single-step CACh and a
routine histamine challenge might stem from basic
differences between the protocols of the two chal¬
the case of the histamine challenge, a doselenges. Incurve
was constructed and bronchial responresponse
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743
by
siveness was characterized that bronchoconstrictor
concentration that effected a certain
predetermined
lung function. In the case of the single-step
change ofa size-corrected
CACh,
predetermined bronchocon¬
strictor dose was administered, and bronchial respon¬
siveness was quantified in terms of effected lung
function changes. These two approaches differ sub¬
and one might speculate that this difference
stantially, for
the observed weakness of correlation.
accounts
Such a speculation might find some support from the
relevant literature. It seems that those who applied
CACh by a multiple-step protocol and thereby imi¬
tated the protocol of routine pharmacologic challenges
found closer correlations to histamine and methacho¬
line provocations than those using a single-step
CACh.8"15 On the other side, this hypothesis implies
that single-step and multiple-step CACh protocols,
using the same stimulus and recruiting the
despite
same reaction mechanisms, would produce two types
of bronchial response measurements that are only
Paradoxically, such directly com¬
weakly correlated.
parative studies of single-step and multiple-step CACh
have as yet not been done (to our knowledge).
The third hypothesis, offering an explanation for the
in the correlation of
observedweakness
AFEVi (CACh)
and PC20 (histamine), relates to the obvious differ¬
ences between applied stimuli and activated mecha¬
nisms. Unlike aerosols of histamine and metha¬
choline, nonpharmacologic challenges do not act di¬
rectly on bronchial smooth muscle, but rather invoke
intermediate events like the release of mediators from
cells in the airway lumen and submucosa.24 A bron¬
choalveolar lavage study in mildly asthmatic subjects
demonstrated that isocapnic hyperventilation effects
increases in a spectrum of bronchoactive mediators
and inflammatory cells.25 Clearly, when different chal¬
stimuli and activate different
lenges apply different
should
be measuring different types
mechanisms, they
of airway responsiveness. To take this concept further,
there might be no such entity as "nonspecific" bron¬
chial responsiveness, and the responses to any type of
provocation might, at least in part, remain specific for
the applied stimulus.
Coming back to the relatively weak correlation be¬
tween AFEVi (CACh) and PC20 (histamine) that was
observed in the present study, it seems that technical
inconsistencies can be excluded from the list of possi¬
ble reasons; thus, one is left with the question of dif¬
ferent protocols vs different stimuli. Design and results
of the present study do not allow us to decide between
these two alternatives; thus, further relevant studies are
needed.
urgently
When using the respective established cutoff points
between normal and increased bronchial responsive¬
ness, the histamine provocation defined many more
subjects as hyperreactive than the CACh. While only
CACh-positive subjects, both with marginally el¬
evated AFEVi (CACh), remained histamine-negative,
no less than 64 presented with the combination of
normal CACh and increased histamine responsiveness.
A routine histamine provocation will thus define a
higher proportion of a given population as having
bronchial hyperresponsiveness than a single-step
CACh. It follows that a single-step CACh has a high
positive predictive value for a positive histamine chal¬
but a low negative predictive value for a nega¬
lenge,
tive histamine result. This finding is in agreement with
the work of Galdes-Sebaldt et al,26 who compared
and pharmacologic challenges for
nonpharmacologic
bronchial
asthma in a pediatric population;
identifying
was less sensitive but more
found
that
a
CACh
they for
asthma
than a conventional meth¬
specific defining
acholine challenge. Such findings could be understood
as one range of bronchial responsiveness being divided
two
by two differently placed borderlines; alternatively,
however, these results might again indicate that one is
at two somehow related but nevertheless dif¬
looking
ferent
of bronchial
types
responsiveness.
extent, the observed poor correlation be¬
tween CACh and histamine responses could be a spe¬
cial feature of the studied population. Pediatric asthma
To
some
in or nearing remission could be characterized by a
tendency toward positive responses to direct pharma¬In
ones to indirect stimuli.
cologic stimuli, and negative
contrast, currently active asthma could be character¬
ized by positive responses to both direct and indirect
stimuli. If this was true, pediatric asthma could be
staged by comparing the responses to pharmacologic
and nonpharmacologic challenges. Results of the
present study, however, do not allow us to draw such
conclusions, and further studies, comparing the CACh
and histamine responses of patients with clinically ac¬
in
tive asthma to
those with asthma remission, are
needed.
When compared with pharmacologic provocations,
nonpharmacologic challenges might have several the¬
oretical and practical advantages.24 By applying natu¬
rally occurring stimuli and by activating intermediate
events like mediator releases from cells in the airways,
challenges might be a more mean¬
nonpharmacologicmodel
of hyperreactive airway disease
ingful
laboratory
than the inhalation of bronchoconstrictor substances.
Furthermore, such provocations are ethically more
acceptableairin epidemiologic work.10 In the case of
there is the additional
cold-dry ofhyperventilation,
a
stimulus
that
is more easily stan¬
advantage
using
dardized than a bronchoconstrictor aerosol. Such
aerosol application of the stimulus is complicated by
numerous factors like different nebulizer output, losses
in tubing and valves, interindividual differences in
breathing pattern and aerosol deposition, etc.2 From a
pediatric viewpoint, there are the additional unre-
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Clinical
Investigations
solved problems relating to a size correction of air en¬
trapment and aerosol deposition; in fact, these prob¬
lems invalidate any comparison of such response
measurements between children of different age and
size 27
Such methodologic drawbacks must result in inac¬
and thus illustrate the need to
search for alternatives. Of those presently available,
single-step CACh is probably the most attractive one.
It is brief and thus can be applied accurately to pedi¬
atric patients with limited compliance.3-7 Its relative
maximum reaction pla¬
safetyinstems fromwithreaching a and
teau patients
asthma7 from the lack of any
late asthmatic reaction.28 There is some indication that
CACh might help identify patients with life-threaten¬
ing asthma.29 The present study adds to this body of
that a single-step CACh cannot
by showing
knowledge
for
a
conventional pharmacologic
simply substitute
rather
measures
a specific type of
but
challenge,
bronchial responsiveness. Like any other measure¬
ment of bronchial responsiveness, however, the result
of a CACh should be interpreted in relation to the
patient's clinical history.
11 Heaton RW, Henderson AF, Costello JF. Cold air as a bronchial
provocation technique: reproducibility and comparison with his¬
tamine and methacholine inhalation. Chest 1984; 86:810-14
12 Tessier P, Ghezzo H, L'Archeveque J, et al. Shape of the doseresponse curve to cold air inhalation in normal and asthmatic
subjects. Am Rev Respir Dis 1987; 136:1418-23
13 Aquilina AT. Comparison of airway reactivity induced by hista¬
curate measurements
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