Download Interpreting spirometric results: The Z- Score

pulmonary function, but there is scatter
around the predicted value characterised
by the standard deviation (SD), creating a
reference range of “normal values”. An FEV1,
FVC or FEV1/FVC ratio can be considered
abnormally low, and hence compatible with
respiratory disease, if the measured value is
below that reference range. It is common
practice to use a 90% or 95% confidence
interval (CI) to delimit this reference range.
A 90% CI comprises 90% of all observations in
a healthy population (figure 1), i.e. the range
of predicted value ¬+1.64SD, so that 5% are
above (95th percentile, upper limit of normal,
ULN) and 5% below (5th percentile, lower
limit of normal, LLN= -1.64 z-scores) that
range. The 95% CI leaves 2½% of observations
in a healthy population below the LLN
(predicted value ¬+1.96SD or -1.96 z-scores)
and 2½% above the ULN. Depending on the
lower percentile adopted, the LLN therefore
leads to 5% or 2½% false-positive assessments,
respectively. The strength of this approach is
that it is valid for any index, such as test results
for lung function, biochemical variables,
height, etc. Also z-scores are unbiased by age,
height, sex and ethnic group
In respiratory care 80% predicted is
commonly regarded as the LLN. In 1979 Sobol
noted (Thorax 1979;34:1-3), “Nowhere else in
medicine is such a naive view taken of the limit
of normal.” The true LLN, when expressed
as % predicted, varies considerably with age.
Use of % predicted leads to considerable age,
height and sex related bias (table 1), and its use
should therefore be abandoned. The z-score,
a number that indicates how many standard
deviations a measured value differs from
the predicted value, should be used instead.
Regardless of age, height, sex, ethnic group
and the variable of interest, a z-score of -1.64
delineates the 5th percentile. Similarly a
diagnosis of COPD does not hinge on whether
the FEV1/FVC ratio is <0.70 (recommendation
of the GOLD group, a limit associated with
very significant age-related bias), but whether
it is below the LLN; in clinical practice using
Interpreting spirometric results:
The Z- Score
Prof. Philip H. Quanjer, Erasmus University, Netherland.
Introduction
Spirometry is indispensable in the diagnosis
and monitoring of airways obstruction, useful
to exclude a restrictive ventilatory syndrome
(i.e. on the basis of a normal FVC) and valuable
in assessing the effect of bronchodilator
drugs, pre-operative fitness assessment and
in monitoring normal or abnormal lung
development. Lung volumes and ventilatory
flows vary with age, stature, gender and
ethnic group. Therefore measurement results
need to be compared with a reference value.
The best predicted value for a patient is the
personal reference value, i.e. the
value obtained in a clinically
optimal period. Often
previous measurements
are not available, and
one needs to resort to
an external reference
value. It is essential
that such reference
values have been
derived from subjects
with no conditions that
could adversely affect the
respiratory system. They
should also be based on a
large, representative population
sample encompassing a wide age
range, and be specific for an ethnic group.
year 1970 differs from that of a 40 year old
person in the year 2010.
Predicted values for Indians and
Pakistani
Due to the paucity of prediction equations
for non-whites, predicted values are frequently
adjusted by a correction factor to fit different
ethnic groups. Thus it is commonly assumed
that the FEV1 and FVC in North Indians and
Pakistani is 90%, and in South Indians 87%
of that in whites. In 2012 the Global Lung
Function Initiative, using >74,000 records
from healthy non-smokers, published
predicted values for spirometry
for the 3-95 year age range
and for four ethnic
groups (EurRespir J
2012;40:1324–1343),
which sadly did not
cover India and
Pakistan. However,
it was estimated that
predicted values for
Indians and Pakistani
would be at least 15%
below those for whites.
Therefore an educated
guess, pending new studies,
is that predicted values for the
Indian subcontinent are 85% (or less) of
those for whites; this implies that provisionally
the GLI-2012 equations for African-Americans
can be used (see later). Free software is
available at http://www.lungfunction.org/
tools/85-equations-and-tools/equations/94gli-2012-desktop-software.html.
LLN
Limitations of predicted values
The above requirements are rarely
fully met. The great majority of studies
of normal pulmonary function relate to
subjects of European ancestry (“whites”),
and most of these are based on relatively
small population samples. They generally
cover limited age ranges (such as childhood,
adulthood, elderly), which leads to important
discontinuities at the transition from one
age group to the other. Some studies also
tend to get outdated due to secular trends:
improvements in socioeconomic conditions
and food availability during gestation and
in childhood affect body and lung growth.
One such effect is that leg length increases
proportionately more than the upper body
segment, altering the relationship between
lung volume and stature. Due to such secular
changes, which are especially pronounced in
developing countries, the pulmonary function
of, for example, a 40 year old person in the
What is the lower limit of normal, what
is the z-score?
People of the same height, age, gender
and ethnic group on average have the same
Table 1 – Percentage of patients who had low lung function as defined by FEV1 < 80% predicted and
FEV1 / FVC < 0.70 but were normal using LLN at cut-off. The percentage increased drastically in
older age groups.
Age group
(years)*
45
50
55
60
65
70
75
80
85
90
False positive
FEV1 (%)§
1.7
3.9
5.9
8.3
9.8
11.3
13.2
15.6
17.5
20.2
False positive
FEV1/FVC (%)‡
1.3
4.3
7.6
13.9
17.5
24.4
27.7
31.8
39.8
36.5
* 45 means 42.5-47.5 years; § based on LLN = 80% pred.;‡based on LLN = 0.70 (GOLD recommendation).
|Volume III, Issue IV, September 2013|RespiMirror 1
If measurements are well within
the normal or the pathological
range, such variability is of no
clinical consequence. However,
if a measurement result is just
above or just below the LLN,
there is great uncertainty how it
should be assessed. Clinical signs
and symptoms and prior evidence
of disease should then guide the
clinician.
ECSC/ERS reference values
My information is that most
clinicians in India use the ECSC/
ERS predicted values for whites,
applying a 0.90 adjustment. It is
known that these predicted values
are too low; they were derived 30
years ago by collating prediction
Figure 1 : Relationship between z-score (i.e. the number of standard
deviations the measured value differs from the predicted value) and the
equations rather than measured
percentage of data under the curve in the case of a normal distribution.
data and therefore leave much
In a healthy population 90% and 95% of observations occur between the
to be desired. In white males
+1.64 and +1.96 z-score ranges, respectively.
they are on average about 95%
the 0.70 fixed ratio as the LLN on average leads of the GLI-2012 predicted values for FEV1,
to over 20% misclassification of patients (Chest FVC and their LLN; corresponding findings
2011;139;52-59), but this misclassification rate in females are about 92% for FEV1, 87%
is quite age dependent (table 1).
for FVC, 86% for the LLN of FEV1 and 83%
of the LLN for FVC. Assuming that Indian
Selecting the lower limit of normal
clinicians have found the 0.9 correction
When interpreting multiple tests (FEV1, factor for ECSC/ERS predicted values to be
FVC, FEV1/FVC), applying the 5th centile LLN clinically valid, this implies that the GLIto each of them and accumulating the results, 2012 predicted values for African Americans,
leads to a high percentage of false positives. which are 15% lower than those for whites,
Using the 2.5th centile (z-score -1.96) reduces are likely to be appropriate for Indian males
this to about 5%. Therefore the 2.5th centile and females. One needs to keep in mind that
LLN (z-score -1.96) is recommended as the poor socioeconomic conditions are associated
decision limit for screening and case finding with poorer pulmonary function (Pediatr
purposes. However, in subjects with prior Pulmonol 2005; 39:528–536).
evidence of lung disease a borderline low value
of FEV1/FVC, FEV1 or FVC is more likely to Diagnosing airways obstruction
be associated with disease; taking into account
In the GLI-2012 study no clinically relevant
prior clinical evidence of respiratory disease differences were found between ethnic groups
as well as the cost and consequences of a false- in the FEV1/FVC ratio, the hallmark of airways
positive or false-negative test result, a LLN obstruction. The ECSC/ERS predicted values
at the 5th centile (z-score -1.64) is clinically are a bit too low, particularly after age 50 years,
acceptable (figure 1).
but the LLN differs little from that of the
It is important to keep in mind that the LLN GLI-2012 equations. In practice, therefore, a
is based on the between-person variability in transition to the GLI-2012 equations will lead
a population. However, there is also within- to nearly the same prevalence rate of airway
subject variability, often estimated at about obstruction.
5% of the measured spirometric index.
Classifying the severity of airways
obstruction
The severity of respiratory impairment
correlates with the ability to work and function
in daily life, morbidity, respiratory complaints,
and prognosis, including a fatal outcome.
Whilst the FEV1 correlates with the severity of
symptoms and prognosis, one cannot use it to
accurately predict symptoms or prognosis for
individual patients. The European Respiratory
Society and American Thoracic Society
(EurRespir J 2005;26:948–968)recommend
the following classification:
Table 2 – Classification of severity of airways
obstruction :
Degree of severity
FEV1 % predicted
Mild
>70
Moderate
60-69
Moderately severe
50-59
Severe
Very severe
35-49
<35
Conclusion
It follows from the above that there is as
yet no scientifically validated set of reference
equations for Indians and Pakistanis. The
GLI-2012 all-age predicted values are to
be preferred over those of the ECSC/ERS.
Also the use of %predicted, and diagnosing
airways obstruction if FEV1/FVC <0.70, leads
to considerable bias and should therefore be
abandoned in favour of the use of z-scores.
But unless reliable predicted values for the
Indian population are generated, we cannot
use the LLN or the Z-Scores. It follows
that interpreting test results is an art rather
than science. Prior evidence of respiratory
disease, clinical signs and symptoms,
response to medication, if available previous
measurements, are indispensable in arriving
at a valid conclusion. When in doubt: (1) go
and see the patient; (2) treat the patient, not
the numbers.
(Prof. Quanjer is the retired professor
physiology, Leiden University, Netherland.
He was instrumental in deriving the reference
values for spirometry [ECCS equation 1983 and
GLI equation 2012]).
CRF’s Research Fellowship for Post Graduate Students in Respiratory Medicine
Grants up to
Rs. 50,000 can be
applied for Fellowship
Total of 4 Fellowships
in a Year
Selection will be made
by a Panel of experts
and will be competitive
Annoucement 1
Chest Research Foundation invites applications for “CRF Research Fellowship” for
1st & 2nd year post graduate students in Respiratory Medicine.
CRF has initiated
Research Fellowship
in order to
promote research
in Respiratory
Medicine amongst
postgraduate
students of
Respiratory Medicine.
Eligibility Criteria
• 1st & 2nd Year Post Graduate students in Respiratory Medicine.
• Research question should be : 1. Novel 2. Feasible 3. Applicable
• It should help change clinical practice either diagnosis or treatment.
• Should have appropriate study design viz. sampling strategy, sample size,
research tools, relevant end points, statistical analysis plan
• Should be supported by head of dept or institute
• Who is your Superior
• HOD supported
• Have a good mentor
For more details call 9822457258 or mail to [email protected]
2
RespiMirror|Volume III, Issue IV, September 2013|
Impulse
Oscillometry (IOS)
Dr. Bill Brashier, CRF
L
ets start with a statement “where
the spirometry fails to reach, Impulse
oscillometry (IOS) starts its journey”
in the lung investigations. Since long
spirometry has been emulated as an ECG
of respiratory system, and has been long
regarded as a standard tool to measure lung
functions. The lung disease status, particularly
absence or presence of airway obstruction
or probability of interstitial lung disease is
primarily based on changes in lung volumes
and its time dependent component, and
flow rates derived from spirometry. But,
spirometry has its distinct limitations. There
is a pertinent effort and skill required to
accurately perform spirometry, which often
precludes its utility in paediatric population
and in subjects with poor comprehension of
spirometric manoeuvres such as the elderly. In
such subjects the diagnosis of airway disease
is primarily based on clinical judgement,
which often can be wrong. Further, the
parents of potential asthmatic children remain
unconvinced of their child’s asthma till there is
an objective evidence to convince them. Also,
spirometry may fail to pick up early changes
in the airways.
So IOS is a great news for physicians. IOS
is almost independent of patient cooperation,
can test a larger patient range than spirometry
alone, from children to geriatric patients. This is
primarily because it measures airway function
under tidal breathing conditions. (Fig1) IOS
enables clinicians to detect subtle changes in
a patients airway function earlier than when
using conventional and more expensive
Impulse oscillometry is one type of FOT.
FOT uses only one frequency or change the
frequency “pseudo randomly, while IOS
delivers a packet of many frequencies at a
regular frequency of 5 times per second, from
which all other frequencies of interest are
derived. Smaller frequencies such as 5HZ
travel longer distance therefore are ideal to
measure lung mechanics of the whole lung,
while larger frequencies such as R20 HZ
travel shorter distance, therefore measure
lung mechanics of central or larger airways.
Therefore, IOS has the advantage of covering
a larger lung region during measurements
and emitting a continuous spectrum of
frequencies that may provide more detailed
characterization of respiratory function.
The IOS apparatus consists of a measuring
head, a resistor, a pneumotachograph and
pressure and flow transducers. The measuring
head, connected to one arm of an adapter,
contains a loudspeaker that generates pressure
oscillations. On the lower arm of the adapter,
a pneumotachograph is connected. The
transducer attached to the pneumotachograph
measures total pressure and flow, a summation
of the pressure and flow of the tidal breathing,
and that of the superimposed oscillatory
signals. As the patient breathes through a
pneumotachograph, a sound wave generated
by a loudspeaker is superimposed over their
breathing. The patients airflow and sound
wave response is transmitted to the apparatus
and used to calculate the various components
of resistance to breathing. (Figure-1)
IOS measures pulmonary impedance
(Zrs), which comprises pulmonary resistance
(energy required to propagate the pressure
wave through the airways) and reactance
(amount of recoil generated against that
pressure wave). Impulse oscillometry measures
Figure 2 - IOS clinical parameters to be
evaluated
oscillations, such as 20 Hz, transmit signals
more proximally and provide information
primarily concerning the central airways. Thus,
central airways obstruction will be reflected by
an increased R20. The difference between R5
Hz and R20 Hz then implies resistance in the
small airways, and increase in this difference
which also implies increase in small airway
resistance is also called frequency dependence.
(Figure: 2)
Impulse oscillometry may help distinguish
between asthma, chronic bronchitis, and
emphysema based on differences in pulmonary
resistance, frequency dependence of resistance,
Figure 3 - IOS Parameter & their application
Figure 1 - Principal of IOS
techniques, and allows differentiation of
central (proximal) airways resistance and
peripheral (distal) airways resistance.
More than 50 years ago, Dubois et al.
conceptualized forced oscillation technique
(FOT), and showed that imposition of pressure
waves generated by sound waves on air flow
induce pressure fluctuations on the airway
which could evaluate airway mechanics.
impedance over a range of frequencies (5–20
Hz). Resistance (R) and reactance (X) when
measured at 5 Hz, are designated as R5 and
X5, respectively. Lower-frequency oscillations,
such as 5 Hz, generally travel farther to the lung
periphery and provide indices of the entire
pulmonary system. Therefore, when either
proximal or distal airway obstruction occurs,
R5 and X5 may be increased. Higher-frequency
and pulmonary reactance. It also has been used
to determine lung function in individuals
with stable asthma and during provocation
by methacholine. (Figure 3)
In the emergency room setting, IOS
may be used to evaluate lung function and
assess response to treatment of acutely ill
children with asthma, who may be unable
to perform forced expiratory maneuvers. In
obstructive sleep apnea syndrome, IOS has
been used to evaluate the degree of upper
airway obstruction and determine the optimal
continuous positive airway pressure required
to treat the obstruction.
|Volume III, Issue IV, September 2013|RespiMirror 3
T
he airways of asthmatics narrow
almost immediately after exposure to
cold or dry air and inhaling chemical
substances such as histamine, methacholine,
adenosine monophosphate or prostaglandins
at concentrations that do not cause any effect
or only little effect in healthy subjects. This
phenomenon is called ‘bronchial hyper
responsiveness’ or BHR and is the hallmark
of asthma. BHR is best described by watching
the leaves of Mimosa Pudica or Touch-me-not,
shrivel after touching even a single leaflet [Fig
1]. BHR in asthma can also be described as a
personality disorder of the airways, where the
smooth muscles undergo a ‘panic’ constriction
in response to innocuous stimuli.
Figure 1: Mimosa Pudica
The exact underlying molecular
mechanisms of BHR has still remained
elusive despite many years of research, but
it is known that BHR is independent of
airways inflammation, but does worsen with
mucosal inflammation and reduces as airways
inflammation subsides. BHR can be assessed
using “direct” stimuli that act on the airway
smooth muscle (eg, histamine, methacholine,
PGD2) or “indirect” stimuli that require the
presence of inflammatory cells such as mast
cell is mediated by exercise, osmotic challenge
or Adenosine Monophosphate. Indirect stimuli
trigger the release of histamine or other
bronchoconstrictor agents from these cells,
which in turn lead to bronchospasm.
Choice of Agent:
Nearly all the published studies on asthma
and COPD have utilised histamine and
methacholine
provocation
tests
for
measurement of BHR. Histamine has been
widely studied and used in clinical practice
for diagnosis of asthma but is associated with
more systemic side effects, including headache,
flushing, and hoarseness.
5’AMP is a better marker for measuring
BHR associated with underlying mucosal
inflammation and reduction in BHR indicates
reduction in mucosal inflammation. More
recent studies tend to use 5’AMP to measure
BHR, but because it is expensive and not easily
available in India, it’s use is limited only to
research studies.
Methacholine is a synthetic derivative of the
4
RespiMirror|Volume III, Issue IV, September 2013|
BRONCHIAL
CHALLENGE TEST
Dr. Sneha Limaye, CRF
neurotransmitter acetylcholine; a substance
that occurs naturally in the body and its effects
can be easily reversed by salbutamol or anticholinergic agents. Therefore, methacholine
remains the agent of choice for bronchial
challenge test and will be discussed as a
prototype further in this article.
Measuring BHR has several applications
in clinical practice, including:
1.Confirming a diagnosis of Asthma–
especially in patients who have symptoms
suggestive of asthma but have normal
spirometry, cough variant asthma and as
a gold standard confirmatory diagnosis
of asthma in potential military recruits.
2. Diagnosis of occupational asthma
3. Marker of severity assessment –Severe BHR
is associated with greater symptoms,
recurrent exacerbations and poor outcomes
as compared to those with mild BHR.
4.Evaluation of drug efficacy in clinical
trials: bronchoprotective efficacy of drugs
can only be established by studying the
change in BHR. It is one of the most
widely used parameters to measure the
anti-inflammatory effects of novel asthma
medications.
manufactured by Methpharma, Canada) and
is the agent of choice for bronchoprovocation
challenge testing. Sterile normal saline (0.9%
sodium chloride) is used as a diluent. Solutions
should be prepared fresh before the test. The
solutions should be prepared in a clean and
sterile environment and the test tubes should
be kept pre-labeled before preparing the
solution to avoid errors in mixing solutions
[Fig 2]. Preparation of methacholine solution
should be in a closed but well ventilated room
with the technician wearing gloves and apron
[Fig 3].
Fig 2: Preparation of solution
Fig 3: Precautions while preparing solution
Contraindications:
Absolute
• Severe airflow limitation (FEV, < 50%
predicted or < 1L)
• Heart attack or stroke during the previous
3 months
• Uncontrolled hypertension, systolic BP >
200, or diastolic BP > 100
• Known aortic aneurysm
Relative
• Moderate airflow limitation (FEV, < 60%
predicted or < 1.5 L)
• Inability to perform acceptable quality
spirometry
• Pregnancy or Nursing mothers
• Current use of cholinesterase enzyme
inhibitor medication
Procedure:
MCT is a specialized test and requires a
proficient technician to ensure good quality
result and patient safety. It is estimated that
about 4 days of hands-on training and at
least 20 supervised tests are required for
a new technician to become proficient in
methacholine challenge testing.
Preparation of Methacholine solutionMethacholine
(acetyl-P-methylcholine
chloride), is available as a dry crystalline
powder(100mg per vial as Provocholine
Prepare solutions in doubling dilutions
as per Table 1 and keep the solutions and
emergency management drugs near the
patient dosing area. It is recommended to
use a dosimeter for MCT to ensure accurate
dose delivery. The dosimeter is an electrically
valved system that administers aerosol for 0.6 s
during inhalation from the nebulizer.
The dose may be triggered manually by
pressing a button or by an automatic system
that delivers a single dose soon after the onset
of a deep breath. Many clinics use nebulizers
for delivering the doses during MCT but we do
not recommend this because of the inaccuracy
of methacholine dose delivery. As per
American Thoracic Society recommendation,
it is acceptable to perform this technique with
brands of nebulizer, which deliver an aerosol
with a particle mass median diameter (MMD)
between 1.0 and 3.6 microns.
Saline challenge as control – the first
procedure is always done with 3ml of diluent
used for preparing the solution (normal saline)
to rule out any hypersensitivity associated to
the diluent. If the FEV1 falls by 10% or more
with saline, MCT should not be conducted.
Five-breath dosimeter protocol – 2ml of
solution from each dilution prepared is put
in the dosimeter/nebulizer and the patient
is instructed to breath from the dosimeter.
Ask the patient to hold the nebulizer upright
with the mouth- piece in his/her mouth. Watch
the patient during the breathing maneuvers to
ensure that the inhalation and breath-hold are
correct and that the nebulizer is not tipped.
The patient should wear a noseclip while
inhaling from the nebulizer. Encourage the
patient to continue inhaling slowly (about
5 s to complete the inhalation) and to hold
the breath (at total lung capacity, TLC) for
another 5 s.
Measure the FEV, at 30 and 90 s after the
fifth inhalation from the nebulizer. Obtain an
acceptable quality FEV1, at each time point.
Perform no more than three or four maneuvers
after each dose. It should take no more than
3 min to perform these maneuvers with each
concentration. To keep the cumulative effect
of methacholine relatively constant, the time
interval between the commencements of two
subsequent concentrations should be kept to 5
min. At each dose report the highest FEV1 from
acceptable maneuvers. The test may last for
upto an hour in many patients and therefore
requires patience and committed time. Make
sure the technician performing this test is free
from any other responsibilities for the duration
of test.
If the FEV, falls more than 20% from
baseline (or the highest concentration has
been given), give no further methacholine,
note signs and symptoms, administer inhaled
salbutamol, wait for 15 min, and repeat the
spirometry for safety assessment.
Reading results:
The results are usually expressed as
the provocation concentration (PC20) or
dose (PD20) producing a 20% fall in forced
expiratory volume in one second (FEV1).Please
refer table 2 for interpreting the results of BHR.
DILUTION SCHEMES FOR THE TWO ATS RECOMMENDED
METHACHOLINE DOSING SCHEDULES
Strength
Take
Add NaCl(0.9%)
Obtain Dilution
A. Dilution schedule* using 100 mg vial of methacholine chloride & the 2 min
tidal breathing protocol
100 mg
100 mg
6.25
A: 16 mg/ml
3 ml of dilution A
3 ml
B: 8 mg/ml
3 ml of dilution B
3 ml
C: 4 mg/ml
3 ml of dilution C
3 ml
D: 2 mg/ml
3 ml of dilution D
3 ml
E: 1 mg/ml
3 ml of dilution E
3 ml
F: 0.5 mg/ml
3 ml of dilution F
3 ml
G: 0.25 mg/ml
3 ml of dilution G
3 ml
H: 0.125 mg/ml
3 ml of dilution H
3 ml
I: 0.0625 mg/ml
3 ml of dilution I
3 ml
J: 0.031 mg/ml
B. Optional Dilution schedule using 100 mg vial of methacholine
chloride & five breath dosimeter protocol
100 mg
100 mg
6.25
A: 16 mg/ml
3 ml of dilution A
9 ml
B: 4 mg/ml
3 ml of dilution B
9ml
C: 1 mg/ml
3 ml of dilution C
9ml
D: 0.25 mg/ml
3 ml of dilution D
9ml
E: 0.0625 mg/ml
Classification of Bronchial Responsiveness based on PC20 values
Sr.No.
PC20 (mg/ml)
Interpretation
1
>16
Normal Bronchial Responsiveness
2
4.0-16
Border BHR
3
1.0-4.0
Mild BHR(positive test)
4
<1.0
Moderate to severe BHR
Before applying this interpretation scheme, the following must be true i) baseline airway
obstruction is absent ii) Spirometry quality is good iii) there is a substantial post challenge
FEV1 recovery
Pulmonary Hypertension | 3rd August 2013
1st Winner
Dr. Niranjan Babu
SCB medical college and hospitals,
Cuttack, Odisha.
2nd Winner
Dr. Omkar Thopte
Sri Satya Sai Institute of
Higher Medical Sciences,
Prashanthigram, Andhra Pradesh.
|Volume III, Issue IV, September 2013|RespiMirror 5
Understanding the value of the
SIX MINUTE WALK DISTANCE
Author: Paul Enright, MD from Tucson, Arizona, USA supervised the pulmonary
function testing of thousands of adults in epidemiological studies and then wrote drafts
of the American Thoracic Society standards for the six-minute walk test (6MWT) more
than a decade ago and is currently a member of the committee updating the guidelines.
I
t is easy and safe to measure the distance
that a patient can walk in six minutes. They
walk at their own pace and can stop at any
time during the six minutes. No instruments
are needed, only a kitchen timer and two traffic
cones. A pulse oximeter can be used before and
after the exercise to measure desaturation, but
is not needed for safety. The distance walked
(6MWD) does not help with the differential
diagnosis of dyspnea, but is associated with
impairment, the quality of life (QoL), and is an
independent predictor of mortality in patients
with moderate to severe COPD, interstitial lung
disease, pulmonary hypertension, and heart
failure. As a rule of thumb, a 6MWD of less
than 350 meters predicts a poor prognosis.
The 6MWD is also an excellent measure of
treatment response in these diseases and
others.
The cardiopulmonary system has large
functional reserves in healthy people. Both
heart and lung diseases reduce these reserves
and the ability for maximal exercise. Patients
may not notice the gradual loss of one-third to
one-half of their resting lung function (an FEV1
or DLCO of 50% predicted) unless they try to
exercise. They may not respond positively to
questions about dyspnea during exercise using
standardized questionnaires such as the old
Medical Research Council (MRC) scale of 0 to
5 dyspnea. However, either the gold standard
(expensive) cardiopulmonary exercise test
(CPX) which measures peak oxygen uptake
and helps to differentiate heart versus lung
causes for exercise-induced dyspnea, or the
non-specific but inexpensive six-minute walk
test can often detect and quantitate clinically
important exercise limitation.
t2
e
uc
o
nn
A
n
me
CRF
Invites
abstracts!
Investigators in India and elsewhere
have performed studies using the 6MWT to
measure improved outcomes during treatment
for patients with various cardiopulmonary
diseases. For example, while a pulmonary
rehabilitation program for patients with severe
to very severe COPD may not improve FEV1
or DLCO, improvements in the 6MWD are
measured. For adult patients, the minimum
clinically important difference (MCID) for the
6MWT is about 30 meters. Since there is a
learning effect, when a change in the 6MWD is
to be measured, two tests should be done prior
to treatment and at the end of the treatment
period. The highest 6MWD from the two
tests should be recorded at each visit.
When a 6MWT
is done only once to
estimate the presence
or degree of exercise
impairment (and not
change over time), a
reference equation is
necessary because in
healthy people, men
can walk farther than
women, older people
cannot walk as far
as young people,
and taller people
can walk farther than short people. Several
studies measured the 6MWD in populationbased samples of healthy children, adults, and
elderly people and then published reference
equations; however, professional standards
com-mittees have not recommended any
one reference equation, stating only that
a published equation from a local group
TYPE OF AWARD: THOSE SELECTED FOR AWARD WILL RECEIVE
6
Box with a clinical vignette:
Vladimir Padmakumar was a 60 year-old
automobile salesman, former smoker, with
very severe COPD whose chief complaint was
shortness of breath climbing stairs from the
street to his home. His FEV1 was only 0.7 liters
(pre- and post-bronchodilator) and his oxygen
saturation at rest was 92%. He had been
taking tiotropium every morning for three
months with no noticible improvement in his
dyspnea on exertion. His doctor measured
his 6MWD as 150 meters during two visits to
her office. On the second visit, she then gave
him 2 liters per minute of oxygen by nasal
prongs from a small tank with wheels and
measured his 6MWD again, while he pulled
the tank of oxygen behind him. His 6MWD
improved to 200 meters and he was less short
of breath at the end of the six minute walk. She
then prescribed oxygen for him using a new
portable oxygen concentrator (which he could
easily afford since he drives a new Mercedes).
Post graduate students of Respiratory Medicine who have presented their research at local, national or
international conferences are encouraged / invited to submit their abstracts to CRF for evaluation to receive
the young Respiratory researcher award.
The award is intended to recognize good quality research conducted by post graduate students of Respiratory
Medicine from all over India. Selection will be made by a panel of judges based on quality of research study.
CRF’s Young Respiratory Researcher Award
ii
ii
ii
ii
of healthy people with the same age range
and race/ethnicity is preferred. An excellent
6MWD reference study of healthy school-aged
children was recently published by D’Silva and
colleagues from Kasturba Medical College,
and a small study of 60 healthy Indian women
and men, ages 50-65, who performed a 6MWT
was published by Sivaranjini and colleagues.
In my opinion, the best 6MWT reference
equations for Caucasian 40-80 year-old adults
is from Ciro Casanova and colleagues (from 7
countries). However, a larger study of a wider
age range of adults from multiple locations in
India is urgently needed since the best 6MWD
reference studies from Caucasians in Europe
and the United States probably do not apply
well to adults in India.
In summary, if you are not yet using the
6MWT for patients, read the ATS guidelines
and see how easy the test is for your staff
and patients and how useful it can be for
making clinical decisions regarding exercise
impairment and objective determinations of
the clinical severity of chronic heart and lung
diseases.
A certificate
An invitation to CRF with travel & stay to present their
research work live to peers during PURVIEW webcast
Webcast will be archived on our website for years
A coupon for complimentary hands on training on
PFT / Advance PFT at CRF
RespiMirror|Volume III, Issue IV, September 2013|
1. Title
-- Details Needed --
2. Name and year of
conference submitted at.
3. Type of presentation accepted for :
(Oral/ Thematic Poster/ lectronic Poster etc)
4. Awards/Sponserships Won
(PLEASE ATTACH A COPY OF THE ABSTRACT)
SEND TO: [email protected]
EXHALED BREATH CONDENSATE: An easy tool for noninvasive assessment of pulmonary diseases
Subhabrata Moitra, CRF
W
e can see our breath in cold
weather because of the condensed
particles and water vapor,
collectively called aerosol. When we breathe
out, along with carbon di-oxide and water
vapor, many micro-particles are also exhaled.
These micro-particles are composed of some
volatile substances present in the inner
lining of the alveoli and the bronchioles. As
these substances come out directly from the
inner core of the lungs, they carry significant
signatures of the underlying health of the lungs.
These substances can be collected by passing
the exhaled air through a cooling apparatus
(sometimes called condensing apparatus),
which ultimately result in the accumulation
of fluid in a container. This fluid is referred to
as exhaled breath condensate (EBC). The idea
of EBC as biomarker of respiratory diseases
was first conceptualized by the scientists of
the former Soviet Union during the early
90’s, but it was ignored by the Western world
for a long time. EBC is a non-invasive and
probably the easiest way to collect the volatile
compounds and components present in the
airway lining fluid. It is cheap and does not
require any specialized person for handling
the instrument. It is portable and beside
a conventional diagnostic setup, it can be
performed in any outdoor area also. However,
analysis of the breath condensates may be
expensive.
The physics and physiology of EBC
Air turbulence provides energy to the
airway wall to aerosolize particles of airway
lining fluid (ALF). The formation of this
aerosolized ALF increases in accordance to
the energy provided to the airway wall such
as increased ventilation during exercise.
During quiet tidal breathing, the formation
of aerosol is thought to occur predominantly
at the first several generations of carina, along
the bronchial and tracheal walls where the
cartilaginous rings alter airflow, and at other
sites of airflow direction change, including the
glottis and pharynx. Aerosols can be formed
during both inspiration and expiration,
providing a mechanism of transfer of fluid,
and conceivably bioactivity, between different
levels of the airway.
Collection of EBC
Collection of aerosolized EBC is a
noninvasive process that is both simple and
safe. As exhaled air cools below the dew point
by transfer of heat to a chilled condenser
surface, condensation occurs on available
aerosolized ALF particles and is collected in
the condenser. By this method, it is possible
to collect 1ml of EBC over 5 to 15 minutes
of breathing in the condenser, although this
is largely dependent upon total expired air
volume, condenser material, temperature,
and turbulence characteristics.
The least expensive and simplest technique
involves exhaling through a tube that is
suspended through a bucket of ice. However,
most researchers use custom devices,
fashioned in individual laboratories, consisting
of jacketed cooling pipes, tubes in buckets of
ice, or glass chambers in ice with inhalation
and exhalation ports. Following is a schematic
diagram of an EBC collection device. It is
very much possible that the collected fluid
may be contaminated with oral micro flora
and salivary fluid. To avoid this, some form
of saliva trap or filter may be used.
Identifiable compounds in EBC
A huge number of biomolecules are present
in the airway lining fluid. Some of them are
volatile and cannot be found in conventional
Figure legend: Schematic diagram of a device
for collecting EBC. (a) A portable collection
device and (b) An EBC device with power
pack to cool the collection panel
Table 1: Characteristics of the available compounds found in the EBC
Compounds
Features
Hydrogen peroxide
(H2O2)
It is a common metabolite produced during oxidation reaction in the body. It is an oxidant, which can readily attack unsaturated fatty acid
molecules present in the cell membrane leading to cellular stiffness and death. It is the principal factor behind oxidative stress. It can also
modulate the activity of various enzymes present in the DNA and cause damage.
Isoprostanes
These are a group of 64-compounds originally generated from arachidonic acid and are currently known as one of the most reliable marker of
oxidative stress and inflammation.
Leukotriens (LT)
These belong to the eicosanoid family of inflammatory mediators. These are synthesized from arachidonic acid through the lipoxygenase
pathway. They are mainly produced by the leukocytes and are major indicators of inflammation.
Prostanoids
A part of eicosanoid family, prostanoids are synthesized through the cyclooxygenase pathway. These consist of prostaglandins, thromboxanes
and prostacyclins all of which are the indicators of inflammation and vasoconstriction.
Nitrogen reactive
species
These are mainly the oxides of nitrogen produced from nitric oxide. It is a good marker of oxidative stress due to ongoing cell damage
EBC proteins
EBC proteins like interleukins (IL-1β, 2, 6, 8, 12, 17), interferons (IFN-γ), tumor necrosis factor (TNF-α) present in the airway lining fluid (ALF)
play crucial role in determining airway diseases. Regulatory cytokines like tissue growth factor (TGF-β) are also indicators of immune tolerance
in patients with compromised immune response due to airway disorders.
|Volume III, Issue IV, September 2013|RespiMirror 7
diagnostic measures like induced sputum or
bronchoalveolar lavagae (BAL). Below are the
identifiable compounds, which are found in
an exhaled breath condensate.
Table 2: Inflammatory mediators in the EBC in different respiratory diseases
Respiratory
disturbances
Common identifiable
mediators
Other mediators
Asthma
H2O2, 8-isoprostane
Nitrotyrosine, thiobarbituric
acid reactive substances,
leukotrienes (Cys-LT and LTB4),
nitrogen reactive species
COPD
H2O2, 8-isoprostane
Cytokines (IL-2, tumor necrosis
factor-α), LTB4, PGE2
Cystic fibrosis
H2O2, 8-isoprostane
Nitrotyrosine, IL-8
Bronchiectasis
H2O2
ARDS
H2O2
Prostaglandin-E2
Smoking
H2O2, 8-isoprostane
Nitrotyrosine, keratin (in
some instances)
Compounds Features
Hydrogen peroxide (H2O2) It is a common
metabolite produced during oxidation reaction
in the body. It is an oxidant, which can readily
attack unsaturated fatty acid molecules present
in the cell membrane leading to cellular
stiffness and death. It is the principal factor
behind oxidative stress. It can also modulate
the activity of various enzymes present in the
DNA and cause damage.
Isoprostanes:
These are a group of
64-compounds originally generated from
arachidonic acid and are currently known as
one of the most reliable marker of oxidative
stress and inflammation.
Leukotriens (LT): These belong to the
eicosanoid family of inflammatory mediators.
These are synthesized from arachidonic acid
through the lipoxygenase pathway. They are
mainly produced by the leukocytes and are
major indicators of inflammation.
Prostanoids: A part of eicosanoid family,
prostanoids are synthesized through the
cyclooxygenase pathway. These consist
of prostaglandins, thromboxanes and
prostacyclins all of which are the indicators
of inflammation and vasoconstriction.
Nitrogen reactive species: These are mainly
the oxides of nitrogen produced from nitric
oxide. It is a good marker of oxidative stress
due to ongoing cell damage
EBC proteins: EBC proteins like interleukins
(IL-1β, 2, 6, 8, 12, 17), interferons (IFN-γ),
tumor necrosis factor (TNF-α) present in the
airway lining fluid (ALF) play crucial role
in determining airway diseases. Regulatory
cytokines like tissue growth factor (TGF-β) are
also indicators of immune tolerance in patients
with compromised immune response due to
airway disorders.
Compounds present in EBC in different
respiratory disorders
Asthma
The most commonly found substance in
EBC of the asthmatics is hydrogen peroxide
(H2O2). It was also observed that thiobarbituric
acid reactive substances (TBARS) remain
present in significant amounts in the EBC
of the asthmatic patients. The appearance of
nitrotyrosine, an end-product of peroxynitrite,
was predominant in the EBC of the asthmatics
in contrast to non-smoking healthy adults
although the concentration of nitrotyrosine
was found highest among the mild asthmatics
but not among moderate or severe asthmatics
8
RespiMirror|Volume III, Issue IV, September 2013|
who were under corticosteroid therapy.
It has also been observed that in different
severities of asthma and depending upon
the concentration of steroids used for treating
them, different types of substances appear in
EBC. Isoprostanes, compounds produced in
non-enzymatic degradation of membrane
phospoholipids during oxidative stress is
predominant in asthmatics. Its concentration
is maximal among the severe asthmatics and
even in the mild ones its concentration is as
much as twice as a healthy adult. Leukotrienes
are also high among the asthmatics.
Chronic obstructive pulmonary
disorder (COPD)
H2O2 is also predominant in COPD as
a result of excess oxidative stress. Patients
with COPD have higher EBC concentration
of 8-isoprostane, nitrite and nitrosothiols
compared to a non-smoker healthy adult.
COPD patients also used to have a higher
concentration of chemo-attractant substances
like leukotrienes (such as LT-B4).
Cystic fibrosis
Patients with cystic fibrosis have an
increased concentration of nitrites in the
EBC. However, no significant change of
H2O2 concentration was observed among
the patients when compared with the normal
healthy adults. Exhaled 8-isoprostane level was
high in the EBC of the cystic fibrosis patients
according to previously published reports. In
some reports, presence of interleukin-8 (IL-8)
was also shown.
Bronchiectasis
Bronchiectasis is a lung disease featured by
significantly increase of oxidative stress in the
lungs. This enhanced oxidative stress releases
significant amount of hydrogen peroxide into
the EBC. It has also been observed that patients
with bronchiectasis undergoing corticosteroid
therapy did not have much deviation of
H2O2 in the EBC compared to those who
were not receiving corticosteroid therapy. It
underscored an ineffective responsiveness of
corticosteroids on the neutrophil-induced
excess production of H2O2.
Smoking
Smoking is attributed to a higher degree
of respiratory symptoms with an advanced
oxidative stress in the lungs. This leads to
an elevation of peroxides (H2O2) in the
breath condensate. Nearly 5-fold increased
concentration of H2O2 was observed in the
EBC of the smokers than a non-smoker. Apart
from H2O2, significant amount of TBARS
remain present in the EBC of the persons
having a regular exposure to tobacco smoke.
Future promise
EBC is a very promising instrument in
the field of medical diagnostics for its simple,
noninvasive technique to sample the lining
fluid of the lower respiratory tract for various
biomarkers. The most accepted advantage of
this instrument is its noninvasive nature and
ease of use. The wide array of biologically
relevant compounds in the fluid and their
predictable alterations during pathologic
processes raise the possibility of significant
new findings resulting from the expanded
use of EBC assays for investigation into the
mechanisms of lung disease, particularly when
it comes to assessing acute exacerbations of
illnesses such as asthma and COPD, where
an invasive technique can be fatal. And
moreover, as the necessity of understanding
the molecular biology of disease-specific
biomarkers has increased tremendously, EBC
can readily supply needed data.
Infection control in the Pulmonary Function Test laboratory
T
here has been a sharp increase in
the number of pulmonary function
tests (PFTs) undertaken each day in
India. Typically, patients perform normal
tidal breathing, forced inspiratory and forced
expiratory manoeuvres while undergoing
pulmonary function tests. This may lead to
formation of sputum droplets which may
be a source of infection for other patients
using the instruments. This raises concerns
of transmission of airborne infections
from patient to patient through the PFT
instruments. It is therefore imperative to
ensure that we, the respiratory healthcare
fraternity, are not responsible for adding to the
burden of infectious diseases in our patients.
Simple methods such as regular hand washing,
maintenance of general hygiene and sanitation
in the pulmonary function test laboratory will
help to curb this rising risk of transmission of
infection through the PFT lab.
Infection control and hygiene is useful in
maintaining a safe working area as well as
providing a safe testing area for patients. Studies
have shown that bacterial contamination can
be as high as 92% on mouth pieces and 50%
on proximal tubing of the PFT instruments.
Sources of infection:
A large number of air-borne and fluidborne infections can be spread through the
PFT laboratory. These include various viruses
(RSV, HIV, Hepatitis A, B, C, D and E viruses,
Rhinovirus), bacteria (M. tuberculosis, B.
cepacia [Pseudomonas], Methicilin-resistant
Staphylococcus aureas [MRSA], H. influenza,
B. catarrhalis, S. Pneumonia, Legionella)
and, on rare occasions, fungi (Aspergillus
fumigatus). Spread of infection in a pulmonary
function test lab can be through various
sources.
Direct contamination
There have been concerns regarding
transmission of air-borne infections
(respiratory, enteric and blood borne) through
direct contact in the PFT lab. This may be
due to use of a common mouthpiece for a
large number of patients. Use of common
mouthpieces can also lead to transmission
of blood-borne infections like HIV, HBV,
HCV, HDV, etc if patients have open mouth
sores. These viruses, however, are not known
to survive in the saliva if exposed to the
environment, thus reducing the chances of
cross contamination. Yet these cannot be
overruled.
Indirect contamination
Fomites are carriers of infections through
aerosols of the infection in sputum particles,
exhaled breath and dust molecules. The
possible sources of infection through fomites
are mouthpieces, the instrument in use, the
tables on which the instruments are placed,
the chairs used by the patients, etc. Droplets
containing the active bacteria or viruses can
easily be transmitted in this manner. This
is a very common route of transmission of
infection not only through infected patients
but also through PFT technicians.
Restriction spread of infections in the
PFT laboratory
General hygiene:
Maintenance of general sanitation in the
PFT laboratory can help restrict a majority
of infections. Simple procedures like hand
washing between two patients can reduce the
bacterial load by 77% while hand washing with
soap and water can reduce the bacterial load
by 92%.
Hand Washing
Use of a 70-90% alcohol rub/ sanitizer as
a hand rub is another very effective method
of infection control. Regular wet dusting of
all countertops and wet mopping of the PFT
room can also help in reducing the spread of
infections.
Identification of possibly infected
technicians and patients can also aid in
reduction of the risk of transmission of
infection.
Patients who could be a possible
source of infection, which includes
patients with active tuberculosis or infective
exacerbations of asthma or COPD should
preferably be placed in an isolated room
which can then be sterilized at the end of
the testing day. Alternatively, they should
be reserved for PFT testing towards the
end of the day and if possible, a separate
instrument for testing these patients should
be used.
Technicians with active infection must
refrain from the use of the PFT laboratories
as far as possible. Use of a face mask can be of
use in cases where this is not possible.
Patients susceptible to the risk of
developing infections, which include
patients with cystic fibrosis, bronchiectasis,
very severe COPD patients and
immunocompromised should be subjected
to PFT testing at the beginning of the day
prior to the rush of the OPD.
Ms. Shweta Rasam, Dr. Komalkirti Apte, CRF
Maintenance of instruments:
All instruments used in the PFT laboratory
should be cleaned, maintained, sterilized
or disinfected as per the manufacturer’s
instructions.
Mouthpieces, nose clips, valves and
nebulizers used for PFT testing should be
sterilized after each use (details mentioned
in table 1).
Use of disposable mouth pieces for
spirometry is strongly recommended as the
best measure of infection control. These
should be discarded after a single use.
If non disposable mouthpieces are used,
ensure appropriate disinfection by dipping
the used mouthpieces in disinfectant
solutions containing glutaraldehyde (2%)
eg: Korsolex, Cidex, etc. as per the
recommendations.
Some mouthpieces are fitted with a one
way valve. This is beneficial in preventing
inhalation of infectious particles. These valved
mouthpieces, although easier on the expense,
cannot measure inspiratory flow. They can
however be used in peak flow meters.
However, their use reduces lung function
(2-4% decrease in FEV1& FVC and
approximately 6% in PEF). To eliminate
this decrease in measures of lung function,
laboratory personnel should use the filters
during their daily calibration as well as take
this decrease in to account when calculating
the lung volumes and flows.
Spirometry Test
Tubing, petri-dishes, funnels, cryo-vial,
eppendorf tubes, polypropylene centrifuge
tubes used in induced sputum testing should
be autoclaved.
Spirometers:
Ideally, when a patient performs spirometry,
he should first perform the forced expiratory
|Volume III, Issue IV, September 2013|RespiMirror 9
Breathing filters (disposable pad with
reusable filter housing) may be used for
reusable mouthpieces. It has been shown
that filters help trapping up to 99.9% of
pathogenic organisms.
manoeuvre followed by a deep inhalation. This
will serve the purpose of filtering the system
with the patient’s own breath, thus reducing
the risk of transmission of infection through
a spirometer.
Flow sensor based spirometer:
For open circuit systems, only that portion
of the circuit through which air is inhaled needs
to be decontaminated between two patients.
Disinfection of mouthpieces is easiest way of
preventing cross contamination in such open
circuit systems. A 5 min gap in between tests
helps to remove microorganisms. Modern
spirometers provide a fan which speed up
this procedure. Some instruments offer
pneumotachometers which can be changed
between two patient tests. This is advantageous
when a possibly infected patient has to be
tested in the peak laboratory testing interval.
Volume displacement spirometer:
Mouthpieces, tubing use in volume
displacement spirometer should be sterilized in
between patients. Air flushing of the spirometer
with at least 5 litres of air after every patient
test is a recommended method for infection
control.
Rolling seal spirometer:
Peak flow meter:
Soda lime absorber, used in dry rolling
spirometers, kills microorganism and reduces
infection effectively.
Infections via peak flow meters can
be prevented by using a one-way valve
mouthpiece which avoids inspiration from
the peak flow meter. Appropriate counselling
of patients to only exhale forcefully into the
peak flow meter can also help eliminate the
transmission of infection through the peak
flow meter.
All PFT facilities must implement the
above mentioned standardized procedures to
ensure the best and most effective manner of
infection control in the PFT laboratory.
Body Plethysmograph:
The body plethysmograph has an in-built
and detachable heated pnemotachograph
which provides a dry environment which is
hostile to microorganisms. This also reduces
the viability of microorganisms. Wet mopping
of inner surfaces of the body plethysmograph
is extremely useful in infection control.
Table 1: Disinfection/ sterilization of techniques in the PFT laboratory.
Equipment
- Invitation PFT Registry
Method
Eliminates
infection of
• Rinse in running tap water.
Then dip in solution (1:19
dilution) for 40 minutes and
finally rinse in sterile water.
• Keep in solution for 3 hours
with the same remaining steps
• Vegetative bacteria
including TB, viruses
including HIV and
Hepatitis viruses.
• Bacterial spores
Mouthpieces, valves,
tubing, spacers used
for reversibility testing,
Chemical
disinfection
(2% activated
gluteraldehyde)
Tubing, petri-dishes,
funnels, cryo-vial,
eppendorf tubes,
polypropylene centrifuge
tubes(autoclavable).
Steam under
pressure
(Autoclave)
Autoclave at 121°C at
15 psi for 15 minutes
Vegetative bacteria
including TB, viruses
including HIV and
Hepatitis viruses and
bacterial spores
Mopping of floor and
work surfaces
Phenols
As per instructions
Disinfection
Infected/ isolation rooms
Fumigation
(150gm KMnO4
+ Formalin 500
ml for a 1000
sq.ft room)
Mix the solution and leave it
in a well sealed and packed
room for 24 hours. Ensure
adequate ventilation before
the next patient testing.
Vegetative bacteria
including TB, viruses
including HIV and
Hepatitis viruses and
bacterial spores
Ultrasonic spirometer:
Use of an ultrasonic spirometer minimizes
the chances of infection. Changing the spirettes
used for testing after every patient test ensures
adequate infection control.
Type of
disinfection/
sterilization
Pulmonary Function Laboratory Registry
Pulmonary Function Testing is a rapidly growing area providing plenty of business and career opportunities. In last few years PFT labs in India have grown
exponentially. However, this humongous growth has brought forth challenges in business viability of PFT labs, inadequate educational support, lack of trained
manpower, affordability, dearth of awareness amongst clinicians about the clinical value of PFTs, issues related to quality of PFTs, etc. Most of these problems
cannot be solved at individual levels and need undertaking collective measures. As an initial step towards fortifying growth of PFT labs, Chest Research Foundation
has undertaken an initiative to form a registry of Pulmonary Function Laboratories across India.
We request you to register your Pulmonary Function Laboratory by just writing to [email protected] or [email protected] or sending sms on
+91 99 2141 2644 along with your contact details.
Who can register?
Is there a registration fee?
a. All those who have a Spirometer with or without other Pulmonary Function Tools
b. All those who have either of the facilities like Impulse Oscillometry, Diffusion Lung
Capacity, Body Box Plethysmography, Sputum Induction, Bronchial Challenge Test
c. Those who refer patients for PFT
No. There will be no registration fee if
you register before 31 November 2013.
Benefits of PFT registration
Benefits to PFT Labs
10
•
More people will know about the lab
•
Access to professional information and knowledge
•
Medium to communicate with other PFT labs and referring physicians
•
Benefits of sharing problems and solutions
RespiMirror|Volume III, Issue IV, September 2013|
Benefits to Practicing Physicians
•
•
•
•
Awareness about nearest PFT lab and PFTs accessible for referring patients
Access to information related to clinical applications of PFTs
Guidance for establishing PFT lab
Medium to communicate with PFT labs and other physicians
Mr. Nitin Vanjare, CRF
A
sthma cannot be cured but can be
controlled well enough to allow the
patient to lead a normal life. Inhaled
corticosteroids are the first drugs of choice in
the management of asthma and are important
to achieve complete control of asthma. GINA
guidelines recommend titrating the dose of
ICS based on asthma control (uncontrolled,
partially controlled and well controlled).
Asthma control can be assessed based on
patient’s symptoms and more reliably by
the Asthma Control Questionnaire (ACQ)/
Asthma Control test. However ACQ is
a subjective tool that depends on proper
history taking and patient’s memory about
symptoms and involves physician’s time.
These are the drawbacks of ACQ. Mucosal
airway inflammation is centrally important in
asthma. Lung function tests like Spirometry,
PEFR etc are used to monitor disease activity,
however studies have shown that changes in
lung function tests are not closely related to
the degree of inflammation and intensive
inflammation processes may well precede
changes in lung function. Direct assessment
of airway inflammation can be done by
investigations like bronchoscopy and sputum
induction but these investigations are invasive,
difficult to perform, time consuming and
require trained personnel.
Exhaled NO (FeNO) has emerged as a
non- invasive technique used for monitoring,
differential diagnosis and assess response to
treatment. It can also be used in children, its
non invasive, instantaneous, repeatable and
safe.
Nitric oxide (NO) is well known as a
pollutant which is present in vehicle exhaust
emission and in cigarette smoke. Apart from
being an atmospheric pollutant, NO is also
produced by the human lung and is present
almost in all mammalian organ systems. It is
present in exhaled breath of all humans and
it has been recently found that exhaled NO
(FeNO) acts as a biological mediator. It is a
marker of eosinophilic airway inflammation.
The levels of exhaled NO are found to
be elevated during eosinophilic airway
inflammation.
In humans, nitric oxide is produced from
L-Arginine by three enzymes (isoforms)
called nitric oxide synthases (NOS): inducible
(iNOS), endothelial (eNOS), and neuronal
(nNOS). Endothelial and neuronal NOS
are constantly active in endothelial cells and
neurons respectively, whereas iNOS’ action
can be induced in states like inflammation (for
example, by cytokines) and infection stimuli.
In inflammation, several cells including
eosinophils use iNOS to produce NO. The
increase in NO in exhaled breath in asthma
is presumed to originate from increased iNOS
expression in the respiratory tract, although
eNOS and nNOS isoforms may also contribute.
Increased iNOS expression is found in the
airway epithelial cells of patients with asthma
and is reduced by inhaled corticosteroids
(ICS).
It is often claimed that FeNO is a diagnostic
test for asthma, but many cases of asthma may
not be due to airway eosinophilia (neutrophilic
airway inflammation), when FeNO may be
low. Also eosinophilic inflammation may
occur in several non-asthma disease states.
FeNO helps to identify the eosinophilic
asthma phenotype. In patients presenting
with variable cough, wheeze, shortness of
breath, an increased FeNO provides supportive
rather than conclusive evidence for an asthma
diagnosis.
FeNO and corticosteroid responsiveness
Studies have shown that FeNO predicts
the likelihood of steroid responsiveness
more consistently than peak flow variation,
Spirometry, bronchodilator response, or
FeNO value
(ppb) in subjects
≥12 years
AHR to methacholine. In asthma, response
to treatment is heterogeneous, not all patients
respond to corticosteroids. FeNO helps to
decide the treatment i.e. who might benefit
from steroid treatment, and who should
try other medications and in whom steroid
treatment may be safely withdrawn. In patients
who have already been treated with inhaled
steroids, the test may be falsely negative.
Thus the utility of FeNO is to identify steroid
responsiveness, rather than the exact clinical
diagnosis.
Reference values
Reference values have limited application
in practice. Rather, evidence based cut points
that are shown to have diagnostic significance
appear to be more relevant. When monitoring
individual patients with asthma and assessing
their treatment requirements, achieving
personal best rather than normal values is
more helpful. In many patients, changes in
FeNO in relation to a baseline when clinically
stable may be more relevant.
Procedure/ Technique
NO analyzers system
The fraction of eNO in an exhaled
breath (FeNO) can be measured with a
chemoluminescent/electrochemical analyzer.
FeNO is usually reported in parts per billion
(ppb). FeNO can be measured either online or
offline. Online measurements sample exhaled
gas continuously at the mouth while offline
measurements analyze the collected exhaled
air later on.
Procedure
The first step begins with inspiration
through an NO scrubber (NO free gas)
followed by exhalation to residual volume
(RV). The subject is then instructed to inhale
from RV to total lung capacity (TLC), without
breath holding the patient is then asked to
exhale slowly and evenly while exhaled gas
is sampled continuously. The patient exhales
against an expiratory resistance (+5cm H2O),
which helps to maintain a positive pressure at
the mouth. Positive pressure causes the velum
in the posterior pharynx to close, preventing
the contamination of the lower airway
Low
Intermediate
‹25
25-50
High
› 50
If › 40% increase from previously stable levels, interpret as high FeNO
Consider as
significant increase
in FeNO
Increase › 10ppb from last measurement
Increase › 20ppb from
last measurement
Consider as
response to ICS
Decrease › 10ppb from last measurement
Decrease ≥20ppb from last
measurement
|Volume III, Issue IV, September 2013|RespiMirror 11
sample with the nasal NO. The fractional
concentration of NO in the exhaled gas varies
inversely with the flow. To standardize online
measurements, an exhaled flow of 50ml/sec
±10% is recommended. This flow allows dead
space gas to be exhaled and a plateau in NO
to be observed in about 10 seconds. There
should be a plateau in the NO signal and FeNO
should be measured from a 3 second window
in which NO does not vary more than 10% .It
is advised not to use a nose clip as with the use
of a nose clip there is a possibility that nasal
NO will accumulate and contaminate the lower
airway sample.
Repeatability criteria
Three tests that agree within 10% or two
within 5% should be performed with 30
seconds interval and mean NO should be
recorded.
Prerequisites:
Patient should refrain from smoking,
drinking or eating at least 1 hour before
testing. Any recent infections, as well as
the current medication regimen should be
recorded. ICS should be stopped a day prior
of the measurement. The FeNO measurement
should be performed before other tests such
as Spirometry, bronchial challenge or exercise
testing.
Cost and Expenses
The hand held/portable NO equipment
costs roughly around 5.5 lakh Rs.while the
stationery NO (chemiluminesense analyzer)
is much more costlier. Consumables required
are filters and the sensor. The sensor has a
certain shelf life and has to be replaced after
that or after given number of measurements
are done. Cost of a single test is approximately
1300 Rs.
4th Advanced Pulmonary Function Testing Workshop
Chest Research
Foundation, Pune
3 rd August 2013
Those intereseted,
may contact :
9822457258 or
9970537116
International Primary Care Respiratory Group, World Conference
7th World Conference
Athens, Greece | 21st – 24th May 2014
Registration and Abstract Submission: 10TH September 2013
Abstract Deadline: 10th January 2014
For details visit: www.ipcrg2014.org
For ‘9 good reasons to submit an abstract to the IPCRG conference’:
Click here: http://www.ipcrg2014.org/abstract-submission
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Phone: +91 20 27035361/66208053
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12
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Edited by : Mrs. Monika Chopda Published by : Chest Research Foundation, Pune n Printed by : Saniya Communications, Pune
RespiMirror|Volume III, Issue IV, September 2013|