BRONCHIAL HYPERRESPONSIVENESS BEFORE AND AFTER THE DIAGNOSIS

OF BRONCHIAL ASTHMA IN CHILDREN

Title:
Bronchial hyperresponsiveness before and after the diagnosis of bronchial asthma in
children. By: Mochizuki H, Shigeta M, Arakawa H, Kato M, Tokuyama K, Morikawa A,
Pediatrics, 00314005, December 1, 2000, Vol. 106, Issue 6
Database:
CINAHL with Full Text
ABSTRACT. Objective. To assess at what age bronchial hyperresponsiveness (BHR) is
acquired in children with asthma.

Background. A relationship between BHR and infantile wheezing diseases has been
reported. Infants with a genetic predisposition to atopy are more likely to wheeze with
respiratory viral infection or bronchiolitis, and it is suspected that the continued BHR after
the first attack of asthma may be induced or triggered by some viral infections. Also,
recent studies have reported the existence of atopic and BHR-related genes. However,
whether BHR is congenital or acquired after asthma attacks, and when BHR in children
with asthma is established or acquired remain unclear.

Methods. We performed methacholine inhalation challenge using a transcutaneous

oxygen pressure (tcPO2) monitoring system in 205 children without asthma from 6 months
to 6 years of age. During follow-up, 18 of these participants were diagnosed with asthma
(group N-A). This group and 15 age-matched children without asthma (group N-N) were
tested twice using methacholine inhalation challenge. For comparison, 39 age-matched
atopic-type asthmatic children (group A-A) were also given the inhalation challenge twice.
Methacholine inhalation challenge using a tcPO2 monitoring system was performed while
the participants were asleep in the supine position. Sequential doses of inhaled
methacholine delivered by oxygen mask were doubled until a 10% decrease in tcPO2 from
the baseline was reached. The cumulative dose of methacholine at the inflection point of
tcPO2 (minimal dose of methacholine [Dmin]-PO2) was considered to represent BHR.

Results. In groups N-N and A-A, there was no difference in Dmin-PO2 between the first and
second challenge. However, the Dmin-PO2 in group N-A significantly decreased from the
first challenge to the second challenge. There was no significant difference between the
Dmin-PO2 in group N-N and the first Dmin-PO 2 in group N-A; or between the Dmin-PO 2 in
group A-A and the second Dmin-PO[SUB 2] in group N-A.

Conclusions. These data suggest that BHR in many infants with asthma is acquired after
several asthma attacks. Pediatrics 2000;106:1442-1446; bronchial hyperresponsiveness,
childhood asthma, methacholine inhalation challenge, transcutaneous oxygen pressure.

ABBREVIATIONS. BHR, bronchial hyperresponsiveness; tcPO2, transcutaneous oxygen

pressure; Dmin, minimal dose of methacholine; Rrs, respiratory resistance.

Asthma is the most common chronic disease of children, and the association between
asthma and bronchial hyperresponsiveness (BHR) has been well-demonstrated. The
degree of BHR shows a good correlation with the severity of the asthmatic symptoms,(
n1, n2) but when and how BHR in children with asthma is established or acquired is still
unclear.

A relationship between BHR and infantile wheezy diseases has been reported. Infants with
a genetic predisposition to atopy are more likely to wheeze with respiratory viral infection
or bronchiolitis.( n3) Also, viral bronchiolitis might contribute to the development of
subsequent wheezing, or the illness diagnosed as bronchiolitis may be an early marker of
genetically determined asthma.( n4) Generally, viral infections exacerbate BHR,( n5) and
it is suspected that the continued BHR after the first attack of asthma may be induced or
triggered by some viral infections. Recent studies( n6, n7) have reported the existence of
atopic and BHR-related genes. However, whether BHR is congenital or acquired after
several asthma attacks is still unclear: a large prospective study is needed to solve this
problem.

Previously, we described a technique of evaluating BHR, by monitoring transcutaneous

oxygen pressure (tcPO2), which can be used over a wide age range in childhood.( n8-n10)
In this study, to assess when BHR is acquired in children with asthma, we performed
methacholine inhalation challenge by using this technique in children without asthma and
measured BHR once again after they were diagnosed with asthma, and compared the
results. Age-matched disease controls without asthma and age-matched children with
asthma also participated in this study.

METHODS

Study Participants
We performed methacholine inhalation challenge on Japanese children without asthma.
We informed all of the outpatients at Gunma University Hospital, Department of
Pediatrics, Division of Allergy, Infection, Respiration and Cardiology of our study, and were
permitted to undertake the methacholine inhalation test by their doctors. We discussed
the procedures thoroughly with the parents of all children before the study, who gave
their informed consent, and performed the methacholine inhalation challenge on 205
children without asthma from June 1983 to November 1997. Of these, 133 (65%) have a
family history of allergies. During 1 or more years of follow-up, 18 of these participants
demonstrated 2 or more episodes of wheezing and dyspnea (Table 1). All 18 participants
had shown positive skin tests and/or radioallergosorbent tests, and were diagnosed as
having atopic-type asthma.

Informed parental consent to undertake a second methacholine inhalation challenge after

an interval of 1 year or more was obtained from the parents of the 18 participants
diagnosed with asthma after the first inhalation challenge (group N-A; Table 1). The
diagnoses at the first visit (patient numbers) were: chronic cough( n8); diagnosed as
having 8 weeks or more of continued cough without wheezing and respiratory infections;
siblings of children with asthma( n4); cough( n3); diagnosed as having <8 weeks of
continued cough without wheezing; atopic dermatitis( n2); and allergic conjunctivitis.( n1)
Fifteen age-matched controls without asthma (group N-N), and 39 age-matched atopic-
type asthmatic children (group A-A) were enrolled in this study (Table 2). None of these
children were receiving steroid therapy, and none had received any medication for at
least 12 hours before the inhalation challenge. They had been free of upper respiratory
tract infections for >4 weeks before the start of each study. Also, all of their parents were
directed to forbid smoking at home and to keep the home clean from air pollutants as
much as possible during follow-ups.

Methacholine Inhalation Challenge

Methacholine inhalation challenge was performed twice on all of the participants in the 3
groups. A previously described tcPO2 monitoring system was used to measure the
results.( n8, n11) The challenge was performed while the participants were sleeping in the
supine position after trichlorethyl phosphate monosodium syrup (70 mg/kg) was
administered.

Each methacholine inhalation challenge was performed using Takishima's procedure

described elsewhere.( n11) Briefly, the methacholine, (Daiichi Kagaku Yakuhin Co, Tokyo,
Japan), which was prepared on the day of the test, was serially diluted twofold with saline
(10 dose steps from 25 mg/mL to Is similar to 49 mu g/ml) and administered via an
Astograph used as the delivery system. The system consisted of 12 identical nebulizers
connected to a main tube and an air compressor that switched from one nebulizer to
another automatically at 1-minute intervals. Study participants inhaled methacholine mist
using an oxygen mask with a constant bias flow that was connected to the main tube of
an Astograph. Saline was used in the first nebulizer as a control. Salbutamol hemisulfate
was used in the final nebulizer to treat the induced bronchoconstriction (Fig 1).

tcPO2 was measured using a tcPO2 monitoring system (Cutaneous PO2 Monitor 820, Roche,
Switzerland). The sensor temperature was fixed at 45 Celsius and placed on the anterior
part of the forearm.

Subsequent doses were doubled, until a 10% decrease in tcPO[SUB 2] from the baseline
was reached. The cumulative dose of methacholine administered at the inflection point
where tcPO[SUB 2] decreased linearly (minimal dose of methacholine [Dmin]-PO 2) was
taken as the reactivity of tcPO2 to methacholine, which was significantly related to the
change of respiratory resistance (Rrs) (Dmin-Rrs) obtained from the oscillation method in
children.( n8) One Dmin unit was considered to be equal to 1 minute of inhaling an
aerosolized methacholine solution (1.0 mg/ml) during tidal breathing.

In the present study, the Dmin-PO2 of participants who could successively inhale the
maximum dose of methacholine without a significant decrease in tcPO2 was calculated to
be 49.952 units, which was the maximum cumulative dose of methacholine.

Data Analysis
The nonparametric analysis of variance (Kruskal-Wallis method) was used to determine
the significant variance among the 3 groups. A Mann-Whitney U test was performed to
assess the significant difference between paired groups. For convenience, data are
expressed as means +/-SD. P values <.05 were considered to be significant.

RESULTS
There was no difference in the mean age among the children in the 3 groups either at the
first trial or at the second trial (Kruskal-Wallis method). In group N-N, there was no
difference in Dmin-PO2 between the first and second challenge (16.6 units and 20.5 units,
respectively, Mann-Whitney U test). Also, in group A-A, there was no difference in Dmin-
PO2 between the first and second challenge (5.2 units and 5.3 units, respectively).
However, Dmin-PO2 in group N-A was decreased significantly from the first challenge
(19.4 units) to the second challenge (2.8 units, P < .001) (Fig 2). There was no significant
difference between Dmin-PO2 in group N-N and the first Dmin-PO2 in group N-A; or also
between Dmin-PO]2 in group A-A and the second Dmin-PO2 in group N-A (Kruskal-Wallis
method).

In group N-A, there was no difference between Dmin-PO2 in the first challenge in the male
and that in the female group, and between Dmin-PO2 in the second challenge in the male
and that in the female group. Also, in group N-A, the change in Dmin-PO2 in the male
group (n = 14, from 14.8 to 2.6 units) was not significantly different from that in the
female group (n = 4, from 27.7 to 4.0 units), (Mann-Whitney U test).

DISCUSSION
It has been hypothesized that nonspecific BHR is a risk factor in accelerated pulmonary
function decline during aging and in the development of chronic airflow obstruction.( n12,
n13) Also, large prospective studies have suggested that the degree of BHR is one of the
significant variables that predicts persistent symptoms. A strong association has been
found between the presence and degree of BHR and the need for medication in
adulthood.( n14, n15) In other words, BHR indicates the asthma prognosis. These results
suggest the possibility that BHR has an effect on asthmatic symptoms in childhood.
However, the basic problems of when and how BHR in children with asthma is acquired,
and whether BHR universally precedes the onset of asthma or not, is still under
discussion.

It has been reported that BHR is already present in very young children, and that
asymptomatic infants demonstrating BHR will subsequently develop asthma.( n16) These
findings are consistent with the theory that infants are either born with BHR or develop it
soon after birth. Also, previous investigations have suggested that participants with
asymptomatic BHR had a greater frequency of developing asthma symptoms than did
normal responsive participants.( n15-n21) A longitudinal population study showed an
increase in the prevalence of asthma with asymptomatic BHR, and that BHR is a more
important risk factor for the development of asthma than other atopic symptoms.( n22)
However, the number of participants in these reports, in which BHR was measured by
using V`max functional reserve capacity( n16,n21) was small. Also, in longitudinal
population studies, study participants were young adults or children >6 years old.( n15,
n17-n20) We believe that it is important to measure BHR in children <6 years old,
because previous reports have shown that the first attack of asthma frequently occurs
within the first few years of life, and that 80% of children develop symptoms before the
age of 5.( n23)

To solve the problem of BHR onset in children with asthma, a large longitudinal study and
a simple, safe, and reliable technique for measuring infantile BHR is required. The
assessment of BHR in infants has not been uniformly successful, and measurements of
BHR over the childhood period are associated with a number of problems. Some previous
reports have recommended the use of provocation tests using tcPO 2 or oxygen
saturation.(n21, n24-n29) Previously, we studied a technique of evaluating the BHR in
infants with asthma by monitoring tcPO2.( n8) During an acute attack of asthma, tcPO2
correlates lineally to the severity of the attack. Methacholine-induced airway obstruction
results in hypoxia because the narrowing of the airways changes the local
ventilation/perfusion ratio and results in decreased arterial PO2. Although this tcPO2
change only reflects the indirect caliber change, we have demonstrated that this method
is simple, painless, and effort independent with high reproducibility, which means that it
is suitable for use with infants.( n9) Van Broekhoven and Wilts also reported measurement
of BHR using the tcPO2 method in younger children, and suggested its convenience and
safety.( n24, n25)

Using this technique, we demonstrated that BHR in most children who will develop
asthma is not detectable before asthma attacks, but it is observable after at least the
second attack in children with asthma. Our results differed from some previous reports,
which indicate a relationship between silent BHR and the development of asthma.
However, in our results, patients 6, 7, and 8 previously exhibited BHR at the first
inhalation challenge. Therefore, it is thought that in most children who go on to develop
asthma, BHR is not detected before asthma attacks, and that some of these children
demonstrate silent BHR. However, in this study, we were not able to distinguish between
these 2 groups by family history, past history, skin tests, or radioallergosorbent tests.
Another possible explanation for the difference between our results and the results of
others may be resulting from our choices, which were a large sample number, younger
participants and a suitable method for measuring infantile BHR.

In this report, all infants diagnosed with asthma had the atopic type. One can speculate
that atopic-type infants have a congenital predisposition to acquire BHR. It seems to occur
more frequently in the presence of atopy, and many patients with allergic rhinitis and
other atopic diseases have increased BHR.( n30) Duiverman et al( n31) demonstrated that
children without asthma, but with borderline BHR, had a family history of asthma, and
that asthmatic children with a relatively low degree of BHR had no family history of
asthma. Heredity as a factor in BHR is also suggested in the studies of twins( n32) and
familial aggregation of BHR.( n33) There is clearly an hereditary component in BHR
because a family history of atopy is the most important risk factor for atopy in children,
and childhood asthma is linked to a family history of atopy.( n34) Allergy and BHR may be
related by genetically-linked traits, chronic inflammatory processes, or both.

Our results suggest that infants who develop asthma may not have shown clinical BHR at
birth, but that BHR is clearly present after asthma has been diagnosed. Considering these
results, we hypothesize that BHR is not a necessary precursor to the first attack of
childhood asthma, although BHR is a factor in the exacerbation of childhood asthma.
According to previous reports, factors such as atopy, gender, and respiratory infections in
early life are closely associated with the onset of childhood asthma and play important
roles in the acquirement of BHR.( n35, n36) We believe that some of these factors may
turn on the BHR switch in the children who are predisposed to having asthma, and the
activated BHR exacerbates childhood asthma for the long-term. However, persistent BHR
depends not only on individual predisposition, but also on the cause. In this report, we
cannot define the precise mechanisms by which BHR in children with asthma persists for
long periods: further investigation is needed.

A ROSE-TINTED VIEW OF CHILDHOOD

How was your childhood? Did you like school? Was your little brother your mother's
favorite? Were your parents too strict? Did you prefer books to sports? Here's a surprise.
No matter what you think you remember feeling as a child, there is a good chance that
you are wrong. In fact, a stranger taking a wild guess would be just as likely to be right.

Such is the finding of Daniel Offer, a psychiatry professor at Northwestern University

Medical School in Chicago. Dr Offer tracked down 67 men he had interviewed in 1962,
when they were all 14-year-old boys, as part of a study of "typical" American teens.
Thirty-four years later he asked the study subjects, now 48 years old, to think back to
their teen years and answer the same questions. So many had changed their answers
that, statistically, anybody taking a guess in the survey would have scored just as well. Dr
Offer concludes that, as people get older, their view of the past changes. His findings are
published in the June 2000 issue of the Journal of Child and Adolescent Psychiatry.

Title:
Non-steroidal anti-inflammatory therapy for bronchial asthma. By: Banner AS, Lancet,
00995355, January 3, 1998, Vol. 351, Issue 9095
Database:
CINAHL with Full Text
NON-STEROIDAL ANTI-INFLAMMATORY THERAPY FOR BRONCHIAL ASTHMA
Section: Commentary
Bronchial asthma is no longer thought to be solely an abnormality of airway smooth
muscle and its neural control, but is regarded as an inflammatory disorder, involving a
variety of cell types and mediators.[1] Corticosteroids have assumed a dominant role in
asthma therapy, with bronchodilators relegated to a subsidiary status in all but very mild
disease. The development of inhaled corticosteroids has made such treatment attractive,
since this mode of delivery is not accompanied by the toxicity associated with oral
administration.

Systemically administered corticosteroids are reserved for acute exacerbations or for

chronic maintenance therapy in more severely affected individuals. In the latter group of
patients, there seems to be a spectrum of steroid effectiveness; some individuals remain
symptom-free on small corticosteroid doses whereas others require relatively high doses
for even modest symptom control. A small subset of patients gain little benefit from
corticosteroids while remaining responsive to b-adrenergic agonists--that is, they are
steroid resistant.

The precise mechanisms underlying steroid resistance are unknown but are thought to
relate to the manner in which steroids exert their effects at the cellular level.[2]
Corticosteroids are transported into the nucleus bound to receptors and there they attach
to DNA sites that code for cytokine production. Corticosteroid resistance has been related
to defects in DNA binding, a decrease in the number of corticosteroid receptors, and
decreased ligand-receptor affinity.[3] The last condition is common in steroid-resistant
asthmatic patients and is thought to result from airway inflammation.[4] In this
circumstance, corticosteroid resistance is confined solely to T cells, with other tissues
remaining susceptible to steroid toxicity, so patients treated with corticosteroids may
appear cushingoid, yet gain no anti-inflammatory benefit. A small number of patients
have a decreased number of steroid receptors, and here steroid resistance is manifested
by all cells. Such patients gain no benefit from corticosteroids, but neither are they prone
to steroid toxicity.

Corticosteroid resistance and the toxicity associated with systemic corticosteroid

administration has prompted the evaluation of other anti-inflammatory agents for the
treatment of asthma.[5] Many of these drugs have an accepted value in the treatment of
inflammatory and immune conditions such as rheumatoid arthritis, systemic lupus
erythematosus, psoriasis, gout, and allograft rejection. The results of trials of some of
these agents in asthmatic patients are summarised in the accompanying panel. On the
basis of non-randomised, open trials, most of these drugs are thought to be able to
reduce the patient's need for steroids. In the few placebo-controlled studies that have
been done, such steroid-sparing effects have been inconsistent. Whether certain subsets
of patients respond better than others has yet to be demonstrated. Nearly all the
alternative agents are associated with serious toxicity.

Cyclosporin has been shown, in vitro, to inhibit lymphocyte transformation and to block
transcriptional activation of a variety of cytokine genes. It has had steroid-sparing effects
in asthmatic patients in open studies, but not in one placebo-controlled trial.[6] Side-
effects were observed in most patients.

The mechanism of the anti-inflammatory effects of methotrexate is not well understood

but is thought to relate to neutrophil migration and adherence. For asthma, randomised,
placebo-controlled trials have yielded inconsistent findings. Serious side-effects have
been noted in up to 40% of patients. When used in conjunction with corticosteroids there
is a predisposition for Pneumocystis carinii infection.

How gold salts exert their effects is poorly understood. Parenterally administered gold has
been used extensively in Japan for asthma, but toxicity has been a problem. Orally
administered gold produced modest corticosteroid-sparing effects in both open and
controlled studies, but it causes eczema and gastrointestinal effects in a substantial
percentage of patients

There have been a few studies, none placebo-controlled, of intravenous immune globulin
in asthma. One showed some steroid-sparing effects in a group of severely steroid-
dependent asthmatic children.[7] Toxic effects are unusual but include anaphylaxis and a
potential for viral transmission. The main limitations are high cost and lengthy treatment.

Recently colchicine has been evaluated in a group of patients with steroid-dependent

asthma. It was no better than the placebo in reducing corticosteroid dose.[8]

Because of the paucity of data, and the inadequate design of many studies, meaningful
conclusions cannot be drawn on the value of any of the alternative therapies. None can
be recommended even for severe asthma. In decisions to use these drugs the
questionable benefits must be weighed against the known risks. Before considering use of
these agents for their steroid-sparing effects, attempts should be made to lower steroid
doses by intensive asthma management. In a placebo-controlled study of methotrexate,
corticosteroid doses could be devreased in 40% of the placebo group.[9] The investigators
attributed this result to frequent evaluation and intensive monitoring.

The value of non-steroidal anti-inflammatory agents for steroid-resistant asthma is

unknown, since no study has specifically evaluated these drugs in this population. The
care of these difficult patients is best left to physicians who are experienced in these
matters. Such patients require a careful assessment before a diagnosis of corticosteroid
resistance is made.[3] Disorders such as chronic obstructive pulmonary disease,
bronchiectasis, and vocal-cord dysfunction must be excluded, as must abnormal steroid
pharmacokinetics such as poor absorption or rapid turnover.[10] Exacerbating conditions
such as sinusitis and gastroesophageal reflux should be treated. Environmental control
must be sought and compliance issues need to be addressed. When a diagnosis of steroid
resistance is established, unproved therapies can be tried, most appropriately within a
controlled clinical trial. The National Institutes of Health are supporting cooperative trials
of alternative asthma therapies. Perhaps then the value of non-steroidal anti-
inflammatory agents will be clarified.

1. Barnes PJ. Anti-inflammatory therapy for asthma. Annu Rev Med 1993; 44: 229-42.
2. Spahn JD, Leung DYM. The role of glucocorticoids in the management of asthma. Allergy
Asthma Proc 1996; 17: 341-50.
3. Spahn JD, Leung DYM, Szefler SJ. New insights into the pathogenesis and management of
steroid-resistant asthma. J Asthma 1997; 34: 177-94.
4. Spahn JD, Leung YM, Surs W, et al. Reduced glucorticoid binding affinity in asthma is related
to ongoing allergic inflammation. Am J Respir Crit Care Med 1995; 151: 1709-14.
5. Kane GC, Peters SP, Fish JE. Alternative anti-inflammatory drugs in the treatment of
bronchial asthma. Clin Pulm Med 1994; 1: 69-77.
6. Alexander AG, Barnes NC, Kay AB. Trial of cyclosporin in corticosteroid-dependent chronic
severe asthma. Lancet 1992; 339: 324-28.
7. Mazer B, Gelfand EW. An open-label study of high dose intravenous immunoglobulin in
severe childhood asthma. J Allergy Clin Immunol 1991; 87: 976-83.
8. Fish JE, Peters SP, Chambers CV, et al. An evaluation of colchicine as an alternative to
inhaled corticosteroids in moderate asthma. Am J Respir Care Med 1997; 156: 11651/471.
9. Erzurum C, Leff JA, Cochran JE, et al. Lack of benefit of methotrexate in severe steroid
dependent asthma. Ann Intern Med 1991; 114: 353-60.
10. Hill MR, Szefler SJ, Ball BD, et al. Monitoring glucocorticoid therapy: a pharmacokinetic
approach. Clin Pharmacol 1990; 48: 390-

Title:
Adverse effect of previous bronchial asthma on disability in chronic airflow obstruction. By:
Laszlo G, Nicholson EM, Denison J, Goddard PR, Lancet, 00995355, August 26, 2000, Vol.
356, Issue 9231
Database:
CINAHL with Full Text
ADVERSE EFFECT OF PREVIOUS BRONCHIAL ASTHMA ON DISABILITY IN
CHRONIC AIRFLOW OBSTRUCTION
Section: RESEARCH LETTERS
The average distance covered when attempting to hurry on the level for 12 min (12 min
walking distance) is linearly correlated to forced expiratory volume in 1 s in healthy
middle-aged individuals and patients with chronic airflow obstruction. Patients with
current or past asthma, with or without chronic bronchitis and emphysema, walk more
slowly than those with chronic obstructive pulmonary disease for a similar degree of
airflow obstruction. A previous history of asthma may be a factor in the limitation of effort
caused by chronic respiratory disease.

The measurement of forced expiratory volume in 1 s (FEV1) is an essential part of the

assessment of the severity of chronic airflow obstruction in chronic obstructive pulmonary
disease (COPD). FEV1 is a marker of life expectancy and to some extent correlates with
maximum exercise ventilation and with disease-specific quality of life. However, its
relation to disability is not well defined. Most investigators have concluded that
ventilatory function accounts for a small proportion of the impairment of below-maximum
performance in patients with chronic lung diseases, and ascribe the remainder to
differences in the perception of respiratory discomfort, reduced habitual activity, or
psychological factors.
McGavin and colleagues[1,2] used a 12 min walking test to assess sustained exercise
performance in patients with a wide range of disability. Patients were asked to walk as far
as as they could, resting if necessary. The correlations between hurrying speed and both
relaxed expired vital capacity and FEV1 were weak. There was a linear, although loose,
relation between hurrying speed and declared disability on the 5-point Medical Research
Council (MRC) scale. We have confirmed these findings in healthy middle-aged individuals
and patients with heart disease and COPD.[3] Further analysis of our findings has
suggested that individuals with a known history of asthma are more disabled by COPD
than those with chronic bronchitis and emphysema alone.

We studied 56 individuals (24 patients with COPD, 14 with asthma, and 18 healthy
middle-aged controls) who gave informed consent to take part in an ethically approved
study of the value of computed tomography in the diagnosis of emphysema. Our aim was
to recruit individuals with airflow obstruction with a wide range of disability. Participants
had to be older than 35 years and be able to hold their breath for 20 s while lying flat in a
computed tomography scanner (EMI 5005, EMI Medical, Wembley, UK). We measured 12-
min walking speed (hurrying),[1] FEV1/vital capacity ratio, single-breath carbon-monoxide
transfer factor and transfer coefficient, MRC dyspnoea grade, and emphysema scores
(table).[4]All tests were completed within a day. Bronchodilators were used if already
prescribed. For the COPD group we recruited individuals with an FEV 1/vital capacity ratio
of less than 70% or with emphysema diganosed by standard chest radiographic criteria,
or expectoration of sputum for 3 months in every year for 2 years. Asthma was strictly
defined as the presence of intermittent wheezing or dyspnoea (unconnected with lower
respiratory infections) starting at less than 40 years of age, or a documented response of
FEV1 to salbutamol of more than 0.4 L and more than 20% when not acutely ill.

Lung function and computed tomography data

Healthy Patients
Controls Asthma Asthma COPD
and COPD

Demography
Number of individuals 18 10 4 24
Mean age (years) 50.0(5.9) 52.0(9.1) 60.8(6.4) 57.3(7.8)
Sex (male/female) 14/4 6/4 1/3 20/4

Clinical data*
FEV1(L) 4.2(0.87) 2.5(0.90) 1.2(0.60) 1.6(0.74)
Vital capacity(L) 5.4(1.1) 4.0(1.6) 2.6(1.0) 3.3(1.0)
FEV1/vital
capacity ratio (%) 81(53) 63(15.7) 47(7.0) 47(14.1)
CO transfer factor
(diffusing capacity) 9.6(2.0) 7.7(1.5) 5.1(1.6) 5.7(2.0)
CO transfer
Coefficient 1.49(0.2) 1.52(0.3) 1.23(0.5) 1.17(0.4)
Emphysema score
(out of 64) 0 0 22(14-32) 28(6-57)
Dyspnoea grade 1(1-2) 3(1-4) 3(3-4) 3(1-5)

*Data are mean (SD) or median (range). CO=carbon monoxide.

All patients classified with COPD were smokers with airflow obstruction (FEV1/vital
capacity <70%), except one who had widespread emphysema on computed tomography.
Four patients with asthma had COPD.

70% of the variation in walking speed could be accounted for by FEV1 and a previous
history of bronchial asthma (figure). The prediction is 12 min walking distance in
metres(m)=588+142 FEV1-164 if asthmatic, with an SD of the estimate of 152 m
(p<0.01). Age, sex, and height made no significant contribution to the regression,
because the use of the actual measurement of FEV1 (in preference to its proportion of a
reference value), allowed for these factors.[1] A greater proportion of the patients with
asthma were women, but the negative correction coefficient for walking distance in the
presence of asthma was the same when only men were included (-148; p=0.062; n=41).

Relation between 12 min

walking distance and FEV 1: 12 min walking distance (m)=526+151 FEV 1. r [2]
(adjusted)=62.7%; SD of the estimate=77; p<0.0001.

MRC dyspnoea grade was inversely correlated in a linear fashion with FEV1. Patients with
asthma perceived their disability in the same way as those with pure COPD, allowing for
FEV1. Our patients attended a long experimental session on a single day and performed
only one walk, so the distances achieved within each MRC category were systematically
lower than described previously by about 105 m.[2] Visual emphysema score[4] did not
influence the walking distance. Single-breath carbon-monoxide transfer factor and
FEV1/vital capacity ratio, which were closely correlated with FEV1, had no additional
predictive value.

Patients with airflow obstruction who have or have had asthma walk more slowly for the
same resting FEV1 than patients with pure chronic bronchitis and emphysema by about
0.22 m/s (0.8 km/h). Morgan and colleagues[5] showed that self assessment was
"delicate" and accounted for more of the variation in walking speed than simple indices of
lung function. Our patients were all born before 1940 and were children when it was
customary not to give young people a diagnosis of asthma. Exercise avoidance was the
only way of coping with exercise-induced asthma. At this time "delicate" was used to
describe children who were not robust, which implied poor attendance at school or
inability to take part in play or sport for reasons of health or physique. Such children had
to allow for their condition by adopting a steady pace. If this became an established habit,
then patients developing COPD who had a long experience of exercise-induced asthma
might adapt by walking more slowly than individuals previously accustomed to walking
briskly.

We are indebted to Denise Smith for technical assistance.

Correspondence to: Dr Gabriel Laszlo (e-mail: GLaszlo11@aol.com)

 1. McGavin CR, Gupta SP, McHardy GJR. Twelve minute walking test for assessing disability in
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~~~~~~~~

By Gabriel Laszlo, FRCP, Department of Respiratory Medicine, Bristol Royal Infirmary,

Bristol BS2 8HW, UK; Elizabeth M Nicholson, MD, Department of Respiratory Medicine,
Bristol Royal Infirmary, Bristol BS2 8HW, UK; Jeanette Dennison, MSc, Department of
Respiratory Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK and Paul R Goddard,
FRCR, Department of Radiodiagnosis, Bristol Royal Infirmary, Bristol BS2 8HW, UK

Adapted by FRCP , MD , MSc and FRCR

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