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208
a
b
c
d
–1
Volume (L)
zs
V. Koucký and N. Cobanoglu
10
8
6
4
)
2
0
–2
Flow (L·s
–4
–6
–8
–10
Volume (L)
e
4
2
10 4
8
6
4
2
6
0
–2
–4
–6
–8
–10
f
3
2
1
0
4
2
–1
–2
–3
–4
Volume (L)
g
12
2
h
Fig. 16.3 Typical shapes of the ow-volume loops. (a) Normal ow volume loop; (b) peripheral airway obstruction; (c) one-sided main bronchus obstruction; (d) large (central) airway instability (tracheomalacia); (e) xed upper airway obstruction (mild); (f) xed upper airway obstruction (severe); (g) variable extrathoracic upper airway obstruction; (h) variable intrathoracic upper air­way obstruction
percentage of the norm (% n), and 80% was traditionally considered as a level of normality (values >80% n were ‘healthy’, and those <80% were ‘diseased’). This approach has several limitations and is no longer recommended [9]. The main rea­son for that is the fact that the reference data distribution of the respective outcomes is not uniform and the standard deviations differ for the respective outcomes. Thus, 80% may be still within the norm for one outcome but not for the other. Moreover, the classication of the impairment severity is not uniform for all the parameters (see example in Table16.2, which is based on Zapletal’s reference values) [8].
Currently, use of z-score is preferred. Z-score may be calculated as follows:
−=
standard deviation
measured value reference value
core
16 Spirometry andUpper Respiratory Tract
209
Table 16.1 Forced spirometry outcome parameters
Abbreviation
Parameter
(unit)
Denition
Forced vital capacity FVC (L) Maximal forcefully exhaled volume from
maximal volume level (TLC) to minimal volume level (RV)
Forced volume exhaled in the rst t-seconds
FEVt (L) Maximal forcefully exhaled volume during
the rst t-seconds (usually 0.5, 1 and 6s) Peak expiratory ow PEF (L/s) Maximal ow during exhalation Maximal expiratory ow at
25%, 50% and 75% levels
a
of FVC
MEF25, MEF50, MEF75 (L/s)
Maximal expiratory ow when 25, 50, or
75% of FVC remains to be exhaled
Area under the curve Aex (L*L/s) Area under the expiratory part of the FV
loop Maximum inspiratory ow MIF (L/s) Maximal ow during inspiration Maximum inspiratory ow
at 50% level of FVC
a
Alternatively (typically in US), FEFxx may be used. XX denotes how much of the FVC has
MIF50 (L/s) Maximal inspiratory ow when 50% of
FVC has been inhaled
already been exhaled. Thus, MEF75=FEF25, MEF50=FEF50, and MEF25=FEF75. We use MEFxx in the text, which is preferred in Europe. TLC = total lu ng capacity
Table 16.2 Zapletal’s classication of airway obstruction based on MEF25, MEF50 and PEF for preschool children
Peripheral airway Central airway
Degree Description
MEF % n
25
MEF
50
PEF
1 Mild 70–60 75–66 80–72 2 Moderate 59–50 65–58 71–64 3 Severe < 49 < 57 < 63
and when comparing to norm, it reects also the variability of the reference population (standard deviation). Thus, there is just one level of normality for all the outcomes, which is usually set to 1.65SD (Fig.16.4). Moreover, the clas­sication of the impairment severity is uniform for all outcomes (Table16.3). Additionally, for the rst-line evaluation of the results, lower and upper limits of norm (LLN and ULN) may be used. Limits of the norm are borderline values of the parameter, which are just in the norm. Everything, that is under (LLN) or above (ULN), is already pathologic. Limits of the norm may be used to simplify the interpretation of lung function results.
210
–4
Probability that a healthy individual has abnormal results
V. Koucký and N. Cobanoglu
95% of population
–3 –2 –1
–1,645 SD
LLN
0.01
0.11510203050
1:10 000 1:1000 1:1001:201:10
01234
z-score
70 80 90 95 99
Percentile
1,645 SD
ULN
Fig. 16.4 Z-score, percentiles and impairment probability for normally-distributed. SD standard deviation; LLN lower limit of norm; ULN upper limit of norm
Table 16.3 Classication of impairment severity based on z-score for whatever parameter proposed by ERS 2022 [9]
Degree
Description
1 Mild 2 Moderate 3 Severe
SD standard deviation
a
For whatever outcome parameter
a
z-score
1.65 to 2.5 SD
2.5 to 4 SD < 4 SD
16.3 Forced Spirometry andUpper Airway Pathology
Spirometry is not primarily intended to evaluate upper airway pathology. Other lung function methods such as rhinomanometry, body plethysmography (airway resis­tance measurement), etc., may be more helpful. The value of spirometry in assess­ing upper airway obstruction is based on the fact, that it is widely available and may raise suspicion about upper airway obstruction during the rst-line lung function testing. The most common clinical scenarios, when upper airway obstruction may be present include laryngomalacia and tracheomalacia (airway instability—variable obstruction), xed obstruction in laryngeal stenosis, (bilateral) vocal cord palsy, laryngeal oedema, tracheal stenosis—extraluminal (compression by great vessels, goitre), intraluminal (mucus stagnation, granulation tissue, foreign body, tumours) or intramural (complete cartilaginous rings). It is important to note, that both the
16 Spirometry andUpper Respiratory Tract
211
specicity and sensitivity of spirometry for upper airway pathology are not very high. Other methods such as computed tomography or exible endoscopy are nec­essary to conrm the suspicion.
The value of forced spirometry and FV loop for diagnosing upper airway obstruc­tion has been evaluated previously and different criteria have been proposed. Upper airway obstruction may be suspected based on the shape of the FV loop (so-called visual criteria). Variable extrathoracic upper airway obstruction (e.g. laryngomala­cia) is characterised by ow limitation during the inspiration, while the expiratory part of the FV loop is without alteration (Fig.16.3g). In the case of variable intra­thoracic upper airway obstruction, ow limitation is present during expiration, while the inspiratory part of the FV loop is without alteration (Fig.16.3h). In xed upper airway stenosis (e.g. laryngeal stenosis, subglottic stenosis, etc.), both inspi­ratory and expiratory ows at higher levels of FVC (more than 50%) are limited. Thus, PEF, MEF75 and MIF50 are reduced, while those at lower volume levels (MEF50 and MEF25) may be normal. The typical FV loop shapes are shown in Fig.16.3e, f. In upper airway obstruction, the lung volumes (FVC and others) are usually not affected. Typical shapes of FV curves in upper airway obstruction men­tioned above have been described by different authors [1013] and are usually called sawtooth (or knee) shape (Fig.16.3d), FV loop with plateau, oscillations, etc.
Quantitative criteria to detect upper airway obstruction have been developed [10,
1418]. The most frequently used criteria include:
1. Ratio of FEV1 (in ml) to peak expiratory ow (PEF, in l/min)>10ml/(l/min)1
(based on the criteria of Empey [14]).
2. Difference between PEF z-score and FEV1 z-score≤−2 (based on the criteria of
Zapletal [18]).
3. Ratio of MEF
(MIF
); an abnormal MEF
50%
to the ow at the mid-point of the forced inspiratory manoeuvre
50%
50%
/MIF
is dened as <0.30 or >1 (based on the
50%
criteria of [15]).
4. Ratio of FEV1 to forced expiratory volume in the rst 0.5s (FEV
) >1.5 (based
0.5
on the criteria of Rotman etal. [17]).
5. MIF
<100L/min (based on the criteria of Rotman etal. [17]).
50%
Although they are primarily intended for use in adults, some of them may be used even in children. Their sensitivity and specicity have been studied previously. Modrykamien et al. [19] examined spirometry in 475 adults, who had accepted­standard tests for upper airway obstruction available (bronchoscopy, laryngoscopy, neck CT and chest CT). The prevalence of upper airway obstruction was low (7.5%) in a population of patients referred for spirometry to a tertiary centre. The authors concluded that the diagnostic performance of the individual quantitative criteria for detecting upper airway obstruction from the ow-volume loop was poor. The sensitivity ranged from 5.5 to 47.2% and the specicity from 60.5 to 96.8%. There
1
In children, the cut off value >8mL/L/min was proposed by some authors to increase the sensitiv-
ity [22].
212
V. Koucký and N. Cobanoglu
was a signicant risk of undetecting upper airway obstruction when relying on spi­rometry alone. When aggregated, the diagnostic performance could be slightly improved: the sensitivity of the aggregated criteria ( 1 quantitative criterion) was
69.4% and specicity 30.2%; area under the receiver-operator characteristic curve for the aggregate criteria exceeded 0.6, while for the individual criteria, it ranged from 0.4 to 0.5.
Spirometry indices in children with tracheomalacia were studied by Boonjindasup etal. [20]. The ‘knee’ shape of the FV loop was common in children with tracheo­malacia and PEF was signicantly reduced in children with tracheomalacia. However, the Empey index was normal (8.21± 1.59, mean ±standard deviation) and could not be used to characterise tracheomalacia. In children with subglottic stenosis, the role of spirometry has been investigated by Abdullah etal. [21]. The Empey index ranged from 7.34 to 21.40mL/L/min and signicantly improved after dilation. It did not correlate with the severity of the stenosis. The authors concluded that spirometry might be a useful marker in following up patients with subglottic stenosis and a good indicator to determine intervention outcomes. Olbers etal. [22] studied spirometry results in children after surgical repair of oesophageal atresia with tracheoesophageal stula. They found elevated Empey index (FEV1/ PEF>8mL/(L/min)) in 58% of cases. Recurrent pneumonias were more frequent in children with elevated Empey index (73% vs. 27%). About 87% of children with increased Empey index had respiratory symptoms of any kind.
Especially in children, special attention must be paid to the quality and reproduc­ibility of the FV loop as improper technique may result in falsely pathological results. For instance, muscle weakness, collapsibility of the soft tissues in the upper airway, mouthpiece obstruction via tongue or improper position of mouthpiece may all result in ndings mimicking upper airway pathology. For these reasons, repeated manoeuvres are helpful in distinguishing artefacts from true pathology. Development of the ndings during follow-up may also be helpful.
In conclusion, different visual and quantitative criteria to detect upper airway obstruction from forced spirometry have been proposed. Their diagnostic value was studied in different clinical situations and seems to be limited. Despite this fact, they should not be neglected when spirometry is available as it may raise suspicion of upper airway pathology. Conrmation using other standard diagnostic tests (endos­copy, computed tomography) is required.

References

1. Lum S, Hülskamp G, Merkus P, Baraldi E, Hofhuis W, Stocks J.Lung function tests in neo­nates and infants with chronic lung disease: forced expiratory maneuvers. Pediatr Pulmonol. 2006;41:199–214.
2. Graham BL, Steenbruggen I, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand TS, etal. Standardization of spirometry 2019 update an ofcial American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med. 2019;200(8):E70–88.
3. Beydon N, Davis SD, Lombardi E, Allen JL, Arets HGM, Aurora P, etal. An ofcial American Thoracic Society/European Respiratory Society statement: pulmonary function testing in pre­school children. Am J Respir Crit Care Med. 2007;175(12):1304–45.
16 Spirometry andUpper Respiratory Tract
4. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, etal. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.
5. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, etal. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43.
6. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC.Lung volumes and forced ventilatory ows. Eur Respir J. 1993;6(Suppl 16):5–40.
7. Zapletal A, Paul T, Samánek M.Signicance of contemporary methods of lung function test­ing for the detection of airway obstruction in children and adolescents (author’s transl). Z Erkr Atmungsorgane. 1977;149(3):343–71.
8. Zapletal A, Chalupová J.Forced expiratory parameters in healthy preschool children (3-6 years of age). Pediatr Pulmonol. 2003;35(3):200–7.
9. Stanojevic S, Kaminsky DA, Miller MR, Thompson B, Aliverti A, Barjaktarevic I, etal. ERS/ ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J. 2022;60(1):2101499.
10. Miller RD, Hyatt RE.Obstructing lesions of the larynx and trachea: clinical and physiologic characteristics. Mayo Clin Proc. 1969;44(3):145–61.
11. Anzueto A, Levine SM, Tillis WP, Calhoon JH, Bryan CL.Use of the ow-volume loop in the diagnosis of bronchial stenosis after single lung transplantation. Chest. 1994;105(3):934–6.
12. Sanders MH, Martin RJ, Pennock BE, Rogers RM.The detection of sleep apnea in the awake patient. The “saw-tooth” sign. JAMA. 1981;245(23):2414–8.
13. Vincken W, Cosio MG.Flow oscillations on the ow-volume loop: a nonspecic indicator of upper airway dysfunction. Bull Eur Physiopathol Respir. 1985;21(6):559–67.
14. Empey DW.Assessment of upper airways obstruction. BMJ. 1972;3(5825):503–5.
15. Miller RD, Hyatt RE. Evaluation of obstructing lesions of the trachea and larynx by ow­volume loops. Am Rev Respir Dis. 1973;108(3):475–81.
16. Yernault JC, Englert M, Sergysels R, De Coster A.Upper airway stenosis: a physiologic study. Am Rev Respir Dis. 1973;108(4):996–1000.
17. Rotman HH, Liss HP, Weg JG.Diagnosis of upper airway obstruction by pulmonary function testing. Chest. 1975;68(6):796–9.
18. Alois Z, Milan Š, Tomáš P.Lung function in children and adolescents: methods, reference values, vol. 22. Basel; NewYork: Karger; 1987.
19. Modrykamien AM, Gudavalli R, McCarthy K, Liu X, Stoller JK.Detection of upper airway obstruction with spirometry results and the ow-volume loop: a comparison of quantitative and visual inspection criteria. Respir Care. 2009;54(4):474–9.
20. Boonjindasup W, Marchant JM, McElrea MS, Yerkovich ST, Thomas RJ, Masters IB, etal. Pulmonary function of children with tracheomalacia and associated clinical factors. Pediatr Pulmonol. 2022;57(10):2437–44.
21. Abdullah A, Alrabiah A, Habib SS, Aljathlany Y, Aljasser A, Bukhari M, etal. The value of spirometry in subglottic stenosis. Ear Nose Throat J. 2019;98(2):98–101.
22. Olbers J, Gatzinsky V, Jönsson L, Friberg LG, Abrahamsson K, Sillén U, etal. Physiological studies at 7 years of age in children born with esophageal atresia. Eur J Pediatr Surg. 2015;25(5):397–404.
213

Allergen Testing: Purpose, Procedure, Interpretation

CansuÖzdemiral andÜmitMuratŞahiner
Abbreviations
AECs Allergen Exposure Chambers BAT Basophil activation test CAMP Childhood Asthma Management Program CRD Component resolved diagnosis CCD Cross-reactive carbohydrate determinants EAACI European Academy of Allergology and Clinical Immunology EMA European Medicines Agency ECP Eosinophilic cationic protein FDA Food and Drug Administration FEV1 Forced expiratory ow in 1s GA2LEN Global Allergy and Asthma European Network ICDRG International Contact Dermatitis Research Group NAC Nasal allergen challenge nsLTP Non-specic lipid transfer proteins PNIF Peak nasal inspiratory ow RAST Phadebas radioallergosorbent test PAF Platelet activating factor PFAS Pollen Food Allergy Syndrome sAT Serum acute tryptase sBT Serum baseline tryptase SPT Skin prick test sIgE Specic IgE
17
C. Özdemiral · Ü. M. Şahiner (*) Department of Pediatric Allergy and Asthma, Hacettepe University Faculty of Medicine, Ankara, Türkiye e-mail: cansuozdemiral@hacettepe.edu.tr; umit.sahiner@hacettepe.edu.tr
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 H. Yüksel et al. (eds.), Pediatric Airway Diseases, Comprehensive ENT,
https://doi.org/10.1007/978-3-031-74853-0_17
215
216
TNSS Total Nasal Symptom Score VAS Visual analog scale
C. Özdemiral and Ü. M. Şahiner

17.1 Introduction

Allergic diseases exert a signicant global burden, impact individuals across all age groups. Allergies to food, aeroallergens, drugs, and venom complicate patients’ lives and, at sometimes pose life-threatening risks. Type 1 immediate hypersensitivity and Type 4 delayed hypersensitivity constitute major underlying mechanisms in allergic diseases. Clinical history takes a light for the allergist to make a diagnosis and fre­quently diagnosis is completed with the basic tests. Skin prick/puncture tests, intrader­mal tests, and patch tests are skin tests that have been utilized to diagnose allergic diseases. The SPT is the most frequently used method that is safe and reliable. SPT typically induces a wheal and are reaction, indicative of Type 1 hypersensitivity. Positive SPT results are dened by wheal diameters 3mm, taking into account the results of both positive and negative controls. In intradermal skin testing, allergen extracts are administered into the dermis at a concentration that is 100–1000 times less than that used in SPT.Patch tests are typically used for patients experiencing delayed­type hypersensitivity reactions. Nevertheless, conducting skin tests and accurately interpreting the results need adequate training and also involve the possibility of unex­pected systemic responses. Total serum IgE measurement has limited utility in allergic diseases. Serum-specic IgE (sIgE) measurement, as a complementary or alternative diagnostic tool, is widespread. Component-resolved diagnosis might be benecial in cases where polysensitization complicates the diagnosis, or when negative skin prick test (SPT) ndings are obtained despite a potential history of allergy. The allergen provocation test could be used as a gold standard method in particular patients.

17.2 Tests

17.2.1 Skin Tests
Skin tests involve introducing an allergen through a break in the skin, which are could be utilized for detecting allergies to inhalants, food, insect venom, or drugs. When sensitivity to the relevant allergen exists, specic IgE molecules bound to mast cell surface receptors become cross-linked, triggering mast cells to degranu­late and release histamine along with other mediators. Skin tests result in the forma­tion of a wheal and are response, which is indicative of Type 1 hypersensitivity [1]. In 1865, Charles H.Blackley, a physician suffering from allergic rhinitis, conducted the rst skin test on himself. Using a lancet, he scratched a quarter-inch area of his skin and applied grass pollen grains placed on wet gauze to the scarred area, cover­ing it with an occlusive bandage. This experimental procedure resulted in signicant itching and a large cutaneous response [2]. Due to the increased pain, reduced
17 Allergen Testing: Purpose, Procedure, Interpretation
217
repeatability, and possibility of maintaining several linear depigmented patches fol­lowing scratch testing, as well as the higher risk of causing a systemic allergic response, it is no longer recommended to use scratch tests. Instead, skin prick/punc­ture tests, intradermal tests, and patch tests have been widely utilized in diagnosing allergic diseases [3].
Skin prick test (SPT): In 1959, H.Ebruster reported the identication of Type 1 hypersensitivity reactions through the use of the SPT [4]. Pepys modied the SPT at 1970, and it is still frequently utilized for allergy diagnosis today [5]. Both the EAACI (European Academy of Allergology and Clinical Immunology) and the US Council of Allergy Asthma and Immunology recommended the initial use of skin prick/puncture tests for individuals whose clinical histories suggest Type 1 hyper­sensitivity reactions to inhalant allergens [1, 6]. SPTs are minimally invasive, quick, inexpensive, reproducible, and reliable, exhibiting a strong correlation with symp­toms [7]. The implementation of standardized procedures became imperative owing to variances in performing SPT, selecting allergens, and interpreting the results. The Global Allergy and Asthma European Network (GA2LEN) conducted a study across 17 centers in 14 countries, leading to the development of a standardized SPT protocol [8]. Standardized protocol, includes using Histamine dihydrochloride
0.1% as positive control, NaCl 0.9% as negative control, and an allergen panel
Table 17.1 Standard skin prick test panel [7]
Positive control Histamindihydrochloride 0.1% Negative control NaCl 0.9%
Alder Alnus incana Birch Betula alba Cypress Cupressus sempervirens
Grass mix Smooth meadow grass/Poa pratensis, cock’s foot grass/Dactilis
glomerata, perennial rye grass/Lolium prenne, timothy grass/Pheleum pratense, meadow fescue/Festuca pratensis, meadow oat grass/ Helictotrichon pretense
Hazel Corylus avellana Mugwort Artemisia vulgaris Olive Olea europaea
Parietaria Parietaria
Plane Platanus vulgaris Ragweed Ambrosia artemisiifolia
Dermatophagoides farinae
Dermatophagoides pteronyssinus
Blatella Blatella germanica Alternaria Alternaria alternata (tenuis) Aspergillus Aspergillus fumigatus Cladosporium Cladosporium herbarum
Cat Dog
218
lancet
tip lancet
C. Özdemiral and Ü. M. Şahiner
involving common allergens, as detailed in Table17.1 [7]. A minimal amount of an allergen extract containing particular components, both genuine and cross-reacting, is required for the test [9]. The allergen panel selection can be determined according to patients’ age, clinic, and geographic area, typically encompassing 8–12 allergens, which is usually adequate [10, 11]. The allergen extracts must possess high potency and stability, while also considering their shelf life. The pricking device should be sterile and only be used once for each allergen. They are available in a variety of sizes (single or multiple puncture devices), shapes (lancet, needle, bifurcated lancet, with or without guard), materials (plastic or metal), and preparations (precoated with the allergen extract, or not) [9]. The examples of pricking devices are depicted in Fig.17.1. No SPT device has been established as the gold standard in the litera­ture [9]. SPT is conducted on the anterior arm or back and is limited to healthy skin [12]. To prevent cross-contamination, a minimum of 2cm spacing between prick tests is recommended. The most commonly used SPT method involves applying a drop of the allergen extract to a marked area of the skin and then inserting the device through the drop at a 45–60° angle, ensuring it does not penetrate beyond the epi­dermis. If the device is inserted at a 90° angle, it is referred to as a skin puncture test, skin test methods are illustrated in Fig.17.2 [12]. A different SPT technique was used, in which submerge the device into the allergen, then drop to the test area, and apply vertical pressure. Comparable results were found with less effort and expense [13]. It’s important to note that performing the SPT should not cause bleeding [12]. The best outcomes can be anticipated by selecting a single prick/puncture tool and effectively training skin technicians in its use. Skin test prociency protocols should be used to establish consistency in skin test performance among technicians in order to achieve quality assurance. Post-histamine control applications have been advised to adhere to proposed standards, such as a coefcient variation of less than 20% (as per EAACI) and less than 30% (as per Childhood Asthma Management Program— CAMP) [14, 15]. The peak reactivity of prick/puncture tests occurs between 15 and 20min, then the diameters of the erythema and wheal should be measured in mil­limeters (mm) and compared with positive and negative controls. An example of the SPT is exhibited in Fig.17.3. The wheal diameter is determinative while interpret­ing the test result. In clinical studies, wheal diameters 3mm are considered posi­tive in SPTs whereas less than 3mm may be accepted positive in epidemiologic studies [16]. Although the severity of clinical symptoms is not always predicted by wheal size, larger wheal sizes may indicate a favorable positive response to nasal provocation. The correlation between wheal size and clinical symptoms may be
Fig. 17.1 The examples of skin prick test devices
ALK SPT lancets
Stallerpoint
ALK Duo
ALK multitest