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52 Textbook of Diagnostic and Therapeutic Procedures in Allergy
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Inhalation of methacholine at increasing concentrations/doses causes airway narrowing
measured on spirometry as a decrease in FEV1 values. If the FEV1dropsby≥20%ataconcentration
below, which healthy subjects do not show this effect (16 mg/mL methacholine), it is called positive
MCT. The smaller the concentration/dose of methacholine required to cause the 20% drop in FEV1,
the greater the degree of airway hyperresponsiveness.
Contraindications
Conditions That May Compromise the Quality of the Test
Patients unable to perform good quality spirometry tests despite repeated attempts and poorly
trained technicians/medical personnel to perform this test are general contraindications for this test.
A minimum of 20 supervised tests are required for a person to become proficient in methacholine
challenge testing.
Conditions That Will Compromise Safety and Cause Discomfort
FEV1 < 60% predicted or absolute FEV1 < 1.5 liters, history of uncontrolled hypertension (systolic
> 200 mmHg, diastolic > 100 mmHg), a recent history of eye surgery, myocardial infarction, stroke
or ventilation-perfusion mismatch causing arterial hypoxemia are contraindications for performing
this test.
Precautions
Sudden bronchospasm to methacholine while performing the test can occur, therefore it is
important to ensure that there is a medical doctor performing the test who can manage an acute
asthma exacerbation. Drugs such as adrenaline, intravenous corticosteroids, anti-histamine
injections, oxygen and a salbutamol inhaler with a spacer/nebulizer should be kept in the MCT
room. A stethoscope, sphygmomanometer and pulse oximeter must also be kept handy. In case
of acute bronchospasm, nebulized salbutamol or salbutamol via MDI plus spacer should be given
immediately. After the MCT test is performed, subjects are often given inhaled salbutamol and made
to wait for 30–45 minutes before they can be sent home.
The MCT must be avoided in pregnant and nursing women. Also, patients receiving
anti-cholinesterase medications for myasthenia gravis should not undergo MCT.
Method
The MCT must be performed by a well-trained person with all precautions as mentioned above.
Provocholine, manufactured in Canada, is the only methacholine agent that is approved by the US
FDA. Industrial sources of methacholine are not recommended as they are not approved by the
US FDA. Purity, quality and consistency are mandatory as it is a bronchospastic chemical that is
inhaled. The methacholine vial is available in a dose of 100 mg and needs to be prepared freshly
for the test.
Drugs that need to be discontinued prior to the MCT are salbutamol, salmeterol, formoterol,
theophylline and anticholinergic drugs. Smoking and alcohol need to be avoided at least for a
day. No discontinuation is required for ICS, antihistamines, cromones, antileukotrienes and oral
contraceptive pills (Coates et al. 2017).
Preparation of the methacholine solution should be done according to strict safety standards.
Clean and sterile test tubes and pipettes must be used to make the solution. The starting solution
should be 6.25 mL of 16 mg/mL made from the stock powder. The 3 mL of this solution should then
be mixed with 3 mL diluent (0.9% NaCl) to get a concentration of 8 mg/mL. From this 3 mL should
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be removed and put into another 3 mL diluent solution to give a concentration of 4 mg/mL. These
steps need to be continued until we have the following dilutions in each test tube, i.e., 2 mg/mL,
1 mg/mL, 0.5 mg/mL, 0.25 mg/mL, 0.125 mg/mL, 0.0625 mg/mL and 0.03125 mg/mL. The last
tube should have only 0.9% normal saline (Malmberg et al. 2018).
After explaining the test to the patient and obtaining written informed consent, the first step is
to perform baseline spirometry on a calibration-checked spirometer. The next step is to administer
the plain diluent solution (0.9% normal saline). Tidal breaths are recommended. Deep breathing
or reaching TLC is not recommended because deep breathing causes bronchodilation, at least in
healthy subjects. FEV1 values are measured 1 minute and 3 minutes after the end of inhaling the
saline (a timer is required for this). The lowest of the two highest FEV1 values (highest at 1 minute
and highest at 3 minutes) is used for calculation. If the drop in FEV1 is more than 10%, the test is
stopped as it indicates hyperresponsiveness to saline.
If the drop is less than 10%, methacholine solutions are administered starting with the lowest
concentration and increased step-by-step. FEV1 values are measured at 1 minute and 3 minutes post
and evaluated for any drop. If the drop is more than 20%, the test is stopped. If the drop is less than
20%, it is continued with the next dose and the same steps are applied until the FEV1 drops by at
least 20% or the highest concentration of methacholine (16 mg/mL) is reached.
The method of administering the methacholine should be either a nebulizer (each concentration
for 1 minute or more as planned) or a dosimeter which is also a nebulizer that delivers a fixed dose
of the methacholine with each breath. The number of breaths need to be standardized and is most
often 5 breaths.
Provocative Concentration to Cause a 20% Drop in FEV1 (PC20) or
Provocative Dose to Cause a 20% Drop in FEV
Earlier, PC20 was used as the main endpoint readout. However, more recently, PD20 is accepted
universally and is the endpoint that should be used. In PC20, we were measuring only the
concentration of the methacholine that caused a 20% drop in FEV1, while in PD20 we measure the
actual dose of methacholine that caused the 20% drop. Table 3 compares the PC20 values versus the
PD20 values when methacholine was administered by the English Wright nebulizer for two mins.
If the subject shows a 20% drop in FEV1, before the final concentration of methacholine is
reached (16 mg/mL), it is termed the presence of airway hyperresponsiveness (AHR) to methacholine.
The lower the concentration at which the 20% drop occurs, the greater the degree of AHR.
The bronchial challenge test requires a fair amount of patient cooperation and patience, as it can
take a long period as well as many forceful exhalation blows. The test can be conducted in children
as young as 6–7 years of age who are cooperative and the technician is well-versed and experienced
in doing the test on these children.
(PD20)?
1
Table 3. Comparing PC20 values versus PD20 values when methacholine was administered by the english wright nebulizer
for two minutes (Ref: Coates A.L., et al ERJ 2017; 49: 1601526).
Concentration mg/mL Dose µg
0.0625 1.425
0.125 2.969
0.25 5.938
0.5 11.875
1 23.75
2 47.5
4 95
8 190
16 380
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THE ROLE OF LUNG OSCILLOMETRY IN ASTHMA DIAGNOSIS
Introduction
“Sound” is the major medium through which we all communicate with each other in our
day-to-day activities; not only that but there is also a wide range of applications of sound when
it comes to diagnosing some of the most important diseases in medical practice. Diagnostic tests
such as the heart doppler test, carotid doppler, fetal ultrasound and ultrasound of the abdomen and
thorax, all use sound waves as their basic principle for diagnosis. Procedures such as lithotripsy and
phacoemulsification use sound for therapeutic purposes.
Sound is also used in lung oscillometry testing for the detection of airway obstruction. The
lung oscillometry tests include the forced oscillation technique (FOT) discovered by DuBois in
1956 (Dubois et al. 1956), and the impulse oscillometry system (IOS) developed by Michaelson in
1975 (Michaelson et al. 1975). Oscillometry techniques were developed in the 1950s but have only
recently started to gain clinical and diagnostic importance. They measure the mechanical properties
of the lungs which act as important determinants to identify several lung diseases. Oscillometry
techniques are non-invasive and easy to perform, even in preschool children and relatively more
sensitive than spirometry to diagnose obstruction in the airways.
The sound generated through a loudspeaker or any other source (oscillating piston or vibrating
mesh) is used to generate pressure waves of different frequencies ranging from 5 Hz to 30 Hz and
are then pushed into the lung through a mouthpiece. The FOT emits sound waves as sine waves of
a single frequency at a time, whereas IOS emits square-shaped multiple-frequency waves. Sound
waves of smaller frequencies, i.e., 5 Hz travel deeper into the lungs while those of higher frequencies
suchas≥20Hztravel only uptothelargerairways.Apneumotach flow sensor attachedtothe
mouthpiece measures the drop in pressure and thereby flows while transmitting the pressure waves.
Pressure divided by flow gives us airway/lung resistance (Brashier et al. 2015).
Principle
An oscillating pressure wave generated through sound waves or other sources is forced into the
lung at different frequencies (usually from 4–25 Hz) and the resulting Impedance comprising of
resistive and reactive forces is derived by measuring the change in pressure and change in flow that
gives us the mechanical properties of the lung. Resistance is directly proportional to the change in
pressure and inversely proportional to the change in flow, which means if the resistance increases,
pressure will increase and flow will decrease. Our lungs are divided into larger airways and distal
airways, which further divide into bronchioles and alveoli, just like the branching pattern of trees.
Sound waves of smaller frequencies (4 Hz to 5 Hz) travel up to the small airways, whereas sound
waves of higher frequencies travel only up to the larger airways. Any obstruction in the larger
airways is detected by a change in resistance at 20 Hz also known as R20. Resistance at 5 Hz or R5
represents total airways/lung resistance, and subtracting R20 from R5 (R5–R20), gives us resistance
in the smaller airways. Respiratory resistance also denoted as “Rrs” and is found to be generally
constant between 5 Hz to 20 Hz, i.e., independent of frequency in healthy adult airways. In children,
resistance is dependent on frequency and in case of obstruction, the values obtained will be higher
than in adults. The unit used for measuring resistance denoted as “R” is measured in cmH2O.L−1 .s−1
or kPa.L−1 .s
−1
Parameters Measured
Along with respiratory resistance (Rrs), respiratory reactance denoted by “Xrs” is also measured,
which when added together with Rrs is known as Impedance (I). Respiratory reactance (Xrs) is
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defined as a combination of Inertance (I) and Capacitance (C). Inertance is the force applied by the
air present in the airway column and capacitance represents the elastic property of the small airways
or compliance of the lung periphery.
Impedance (Z) = Resistance (Rrs) + Reactance (Xrs)
Impedance (Z) = Resistance (Rrs) + Inertance (I) + Capacitance (C)
In addition to Impedance, resonant frequency also called “Fres” is the frequency at which
Inertance and capacitance are equal. The normal range for Fres varies between 8 Hz to 12 Hz and is
generally higher in children and decreases with age, but increases with both obstructive and RLD.
Another parameter that adds to the importance of lung oscillometry tests is the Area of reactance
(Ax) also known as the “Goldman’s Triangle,” which is the integrated area between a low frequency
of 5 Hz and Fres, which is measured in cmH2O.L–1 or kPa.L−1 (Figure 5). The normal AX is usually
DISTAL AIRWAYS PROXIMAL AIRWAYS
Rrs (Line of Respiratory Resistance)
(kPa/(l/s))
Resistance
Ax (Area of Reactance/ Goldman’s tr iangle)
Xrs (Line of Respiratory Re actance)
Fres (Resonant Frequency)
(kPa/(l/s))
Reactance
CAPACITANCE INERTANCE
Frequency of Oscillation (Hz)
Figure 5. Lung oscillometry parameters.
< 0.33 kPa.L–1 and is a good indicator to measure small airway patency along with any changes in
terms of obstruction in the peripheral airways, which can be closely related to R5–R20.
How to Perform Lung Oscillometry Test (Figure 6)
1. Explain the procedure to the patients
2. The sitting position is preferred with uncrossed legs to reduce extrathoracic pressure
3. A nose clip should be worn
4. The mouthpiece of the FOT/IOS device should be at a comfortable height
5. Ensure that there is a tight seal between the mouthpiece and lips to prevent air leaks
6. The tongue position should not interfere with the free airflow through the mouthpiece
7. Cheeks to be held firmly
8. Tidal breathing for at least 30–40 sec (120–150 sound impulses are pushed)
9. A minimum of three such readings should be performed (pre- and post-BD each)
56 Textbook of Diagnostic and Therapeutic Procedures in Allergy
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Figure 6. Subject performing lung oscillometry test.
Clinical Applications of Lung Oscillometry
FOT/IOS is useful for the diagnosis of asthma and COPD (in adults and children) (Ahmed et al.
2018). Lung oscillometry parameters are found to be more sensitive when compared to spirometry
values (Table 4). Resistance and reactance parameters can also be used as alternatives to spirometry
parameters (Nikkhah et al. 2011) (4). Respiratory resistance at 5 Hz is shown to be significantly
associated with FEV1 in COPD patients, whereas respiratory resistance (Rrs) at 20 Hz and respiratory
reactance (Xrs) at 5 Hz are found to be significantly associated with FEV1 in the asthmatic group.
Unlike other pulmonary function tests, lung oscillometry parameters are more sensitive to evaluate
the functional assessment of peripheral airways. In addition, R20 values can help differentiate
between COPD in which case the peripheral airways resistance is increased and asthma in which
Table 4. Showing differences between spirometry and lung oscillometry values (Adapted from Brashier, B. and Salvi, S.
2015. Measuring lung function using sound waves: role of the FOT and IOS. Breathe (Sheff) 11(1): 57–65).
Parameter Spirometry FOT/IOS
Principle Flow sensor/volume displacement helps
measureowratesandlungvolumes
Parameters measured FEV
Patient cooperation +++ +
Type of breathing
maneuvers
Variability (intrasubject)
Sensitivity to Airways Location
Central + +++
Peripheral ++ +++
Cut-ofor
bronchodilator
response
Cut-ofor
bronchoconstrictor
response
Standardized
methodology
Availability of robust
reference values
, FVC, PEFR, FEF
1
Forced exhalation Tidal breathing
3–5% 5–15%
12–15% for FEV1 40% for R5 or X5
20% for FEV1 50% for R5
+++ ++
+++ +
25%–75%
Sound waves of multiple frequencies are
pushed into the lungs as pressure waves to
measure the Impedance
Zrs, Rrs, Xrs, Fres, Ax
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the proximal airways resistance is increased. Therefore, in the case of COPD R5 value will increase
and the R20 value will be closer to normal, whereas, in asthma, both R5 and R20 may increase.
Bronchodilator reversibility in COPD patients is poor when measured by spirometry, whereas lung
oscillometry parameters show significant improvements at follow-up with a decrease in AX by 37%
and R5 by 20%. This suggests that lung oscillometry parameters are highly sensitive when it comes
to monitoring therapeutic responses in patients with COPD. Lung oscillometry parameters are also
useful to evaluate post-lung transplantation surgeries (Cho et al. 2020). A very recent study showed
that oscillometry values such as R5, R5–R19, X5 and area of reactance identified graft rejection
after 6–9 weeks of lung transplantation, whereas FEV1 and FVC values remained normal even after
three months in the same patients.
Small airways dysfunction (SAD) asthma phenotype is unique, and it predominantly affects
small airways (like COPD). This phenotype of asthma is difficult to treat, has recurrent exacerbations,
predominant night-time symptoms and is associated with obesity-induced asthma. Diagnosing them
accurately will help in prescribing drugs that have ultrafine particles. R5–R20, AX and X5 are
sensitive parameters to detect SAD asthma.
Glossary of Abbreviations
AHR – Airway hyperresponsiveness
AMP – Adenosine Monophosphate
Ax – Area of Reactance
BDR – Bronchodilator Reversibility
BEV – Back Extrapolated Volume
C – Capacitance
cmH2O/L/S – Centimeters of Water Per Liter Per Second
COPD – Chronic Obstructive Pulmonary Disease
EOFE – End of Forced Expiration
FEF
– Forced Expiratory Flow After 0.75 Seconds
0.75
FEF
FeNO – Fractional Exhaled Nitric Oxide
FET – Forced Expiratory Time
FEV1 – Forced Expiratory Volume in the First One Second
FEV2 – Forced Expiratory Volume in 2 Seconds
FOT – Forced Oscillation Technique
Fres – Resonant Frequency
FVC – Forced Vital Capacity
GINA – Global Initiative for Asthma
Hz – Hertz
I – Inertance
ICS – Inhaled Corticosteroids
IL – Interleukin
IOS – Impulse Oscillometry
kPa/L/S – Kilopascal Units Per Liter Per Second
L/min – Liters Per Minute
LABA – Long-Acting Beta-Adrenergic Agonist
LAMA – Long-Acting Muscarinic Antagonist
Mcg – Micrograms
MCT – Methacholine Challenge Test
Mg – Milligrams
mmHg – Millimeters of Mercury
– Forced Expiratory Flow Between 25% of Forced Vital Capacity to 75% of Forced Vital
25–75%
Capacity
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NO – Nitric Oxide
OAD – Obstructive Airways Disease
PC20 – Provocative Concentration to Cause a 20% Drop in FEV1
PD20 – Provocative Dose to Cause a 20% Drop in FEV1
PEF – Peak Expiratory Flow
PEFR – Peak Expiratory Flow Rate
PFM – Peak Flow Meter
Ppb – Parts Per Billion
R20 – Resistance at 20 Hertz
R5 – Resistance at 5 Hertz
R5–R20 – Resistance at 5 Hertz Minus Resistance at 20 Hertz
RLD – Restrictive Lung Disease
Rrs – Respiratory Resistance
SABA – Short-Acting Beta-Adrenergic Agonist
SAMA – Short-Acting Muscarinic Antagonist
Sec – Second
TLC – Total Lung Capacity
Type 2 – T-Helper Cellular Type 2
US FDA – United States Food and Drug Agency
VC – Vital Capacity
Xrs – Respiratory Reactance
Zrs – Respiratory Impedance
Z-Score – Lower 5th Percentile Value
References
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6(2): 5–7.
Ahmed, M. M., Kader, M. A. A. and Mohammed, E. M. 2018. Impulse oscillometry to differentiate between chronic
obstructive pulmonary disease and bronchial asthma. Egypt J. Bronchol. (12): 373–378.
Brashier, B. and Salvi, S. 2015. Measuring lung function using sound waves: role of the forced oscillation technique
and impulse oscillometry system. Breathe (Sheff) 11(1): 57–65.
Busse, W. W., Wenzel, S. E., Casale, T. B. et al. 2021. Baseline FeNO as a prognostic biomarker for subsequent
severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the
LIBERTY ASTHMA QUEST study: a post-hoc analysis. Lancet Respir Med. 9(10): 1165–1173.
Buzoianu, E., Moiceanu, M. and Plesca, D. A. 2014. Asthma control assessment in children: Correlation between
asthma control test and peak expiratory flow. Maedica. 9(4): 338.
Chan, M., Sitaraman, S. and Dosanjh, A. 2009. Asthma control test and peak expiratory flow rate: independent
pediatric asthma management tools. Journal of Asthma 46(10): 1042–1044.
Cho, E., Wu, J. K. Y., Birriel, D. C., Matelski, J., Nadj, R., DeHaas, E., Huang, Q., Yang, K., Xu, T., Cheung, A. B.,
Woo, L. N., Day, L., Cypel, M., Tikkanen, J., Ryan, C. and Chow, C. W. 2020. Airway oscillometry detects
spirometric-silent episodes of acute cellular rejection. Am. J. Respir Crit. Care Med. 201(12): 1536–1544.
Coates, A. L., Wanger, J., Cockcroft, D. W., Culver, B. H., Bronchoprovocation Testing Task Force: Kai-Håkon
Carlsen, Diamant, Z., Gauvreau, G., Hall, G. L., Hallstrand, T. S., Horvath, I., de Jongh, F. H. C., Joos, G.,
Kaminsky, D. A., Laube, B. L., Leuppi, J. D. and Sterk, P. J. 2017. ERS technical standard on bronchial challenge
testing: general considerations and performance of methacholine challenge tests. Eur. Respir J. 49(5): 1601526.
Dobra, R. and Equi, A. 2018. How to use peak expiratory flow rate. Archives of Disease in Childhood-Education and
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Dubois, A. B., Brody, A. W., Lewis, D. H. et al. 1956. Oscillation mechanics of lungs and chest in man. J. Appl.
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Dweik, R. A., Boggs, P. B., Erzurum, S. C., Irvin, C. G., Leigh, M. W., Lundberg, J. O., Olin, A. C., Plummer, A. L.
and Taylor, D. R. 2011. American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels
(FENO) for Clinical Applications. An official ATS clinical practice guideline: interpretation of exhaled nitric
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Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (GINA). May, 2021. https://
ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2- WMS.pdf (accessed Dec 30, 2021).
Graham, B. L., Steenbruggen, I., Miller, M. R., Barjaktarevic, I. Z., Cooper, B. G., Hall, G. L., Hallstrand, T. S.,
Kaminsky, D. A., McCarthy, K., McCormack, M. C., Oropez, C. E., Rosenfeld, M., Stanojevic, S., Swanney,
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Chapter 3C
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Sinus Imaging for Patients with
Allergy and Asthma
Mary Beth Cunnane
Introduction
Modern imaging allows safe, rapid assessment of the sinuses in patients with allergy and asthma.
Computed tomography is the workhorse of sinus imaging, but MRI is useful for problem solving,
particularly if there is concern for neoplasm. This chapter presents an introduction to radiographic
anatomy of the sinuses and illustrates several classic findings in patients with sinusitis.
Computed Tomography
In modern multi-detector scanners, Computed Tomography (CT) of the sinuses can be performed in
less than a minute. The rapidity of scanning, along with dose reduction techniques, has made sinus
CT a fast, low-risk procedure for the evaluation of paranasal sinus disease. In many centers, CT has
replaced plain films in the initial evaluation of a patient with sinus disease.
Sinus CTs are typically performed without intravenous contrast and images are acquired in the
axial plane. Modern scanners allow slice thicknesses of less than 1 mm which results in smooth
multiplanar reformations in the coronal and sagittal planes. Images acquired for diagnostic purposes
may also be used for intraoperative guidance, should surgery be indicated.
Sinonasal Anatomy and Variants
The nasal cavity typically contains three pairs of turbinates: the inferior, middle and superior
(Figure 1). Lateral and inferior to the turbinates are air spaces which are the corresponding superior,
middle and inferior meati. The superior meatus drains the ipsilateral posterior ethmoid air cell
and the sphenoid sinus (Figure 2). The middle meatus drains the ipsilateral anterior ethmoids,
the maxillary sinus via the infundibulum, and the frontal sinus via the fronto-ethmoidal recess
(Figure 3). The inferior meati drain the nasolacrimal duct bilaterally.
Knowledge of the drainage pathways allows one to deduce a site of obstruction. For example,
opacification of the frontal, anterior ethmoid and maxillary sinuses implies obstruction at the level
of the middle meatus into which all of these sinuses ultimately drain. This is an anterior pathway
pattern of obstruction. Isolated opacification of the posterior ethmoid and ipsilateral sphenoid sinus
implies obstruction at the level of the superior meatus or a posterior pathway pattern of obstruction.
Department of Radiology, Massachusetts Eye and Ear, 243 Charles St. Boston, MA 02114.
Email: MaryBeth_Cunnane@meei.harvard.edu
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Figure 1. Coronal CT in bone windows demonstrates the superior turbinate (star), the middle turbinate (hatched arrow) and
the inferior turbinate (solid arrow). The air spaces lateral and inferior to the turbinates are the corresponding meati.
(A) (B)
(C)
Figure 2. Posterior drainage pathway. (A) The superior meatus is the air space lateral and inferior to the superior
turbinate, indicated by white arrows. (B) The posterior ethmoid drainage (arrow) into the superior meatus. (C) The bilateral
sphenoethmoidal recesses, along the anterior aspect of the sphenoid sinuses (arrows), drain into the superior meatus.
There are a number of normal anatomic variants in the paranasal sinuses and nasal cavities.
Haller cells are ethmoidal air cells that lie within the maxillary sinus, bordering the orbital floor
(Figure 4A). Onodi cells are posterior ethmoid cells that extend superior to the sphenoid sinus and
border the optic canal (Figure 4B). A concha bullosa is a pneumatized middle turbinate (Figure 4C).
Septal deviation is the most common normal variant, seen in over 50% of patients (Figure 4D). Most
anatomic variants do not contribute to rhinosinusitis. The exception is a large nasal septal spur that
contacts the lateral nasal wall. This may result in headaches. The remaining variants are important
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