J Bras Pneumol jbpneu Jornal Brasileiro de Pneumologia J. bras. pneumol. 1806-3713 1806-3756 Sociedade Brasileira de Pneumologia e Tisiologia BCWh8cskVLTPTtd3pzpGBkd S1806-37132020000200152 10.36416/1806-3756/e20200046 00152 CONTINUING EDUCATION Identifying small airway dysfunction in asthma in clinical practice 0000-0001-7718-2576 Jackson Natalie 1 0000-0001-7735-0461 Rafique Jethin 1 * 2 0000-0001-8918-7075 Singh Dave 1 2 . Medicines Evaluation Unit, Wythenshawe, Manchester, United Kingdom. Medicines Evaluation Unit Manchester United Kingdom . University of Manchester, Manchester, United Kingdom. The University of Manchester University of Manchester Manchester United Kingdom

DS and JR designed the research. JR and NJ organised data collection. DS and NJ wrote the manuscript. JR reviewed and approved the manuscript.

 22 04 2020 2020 46 02 e20200046 This is an open-access article distributed under the terms of the Creative Commons Attribution License BACKGROUND

Small airways are defined as those with a diameter ≤ 2 mm.1 There is a current focus on small airway dysfunction (SAD) in asthma and the techniques used in order to measure this.1-3 Postma et al. reported that SAD is present across all severities of asthma and can be measured using different techniques, including lung volumes and oscillometry.1,3 The case histories described here illustrate how these methods can be applied in a clinical setting to identify SAD in asthma.

CASE HISTORIES

Table 1 shows data from two patients with moderate to severe asthma (Global Initiative for Asthma classification system = 4) who attended our research centre for lung function assessment. Both were non-smoking females of a similar age with uncontrolled asthma; both had Asthma Control Questionnaire scores = 2.3. There were similar levels of fractional exhaled nitric oxide (21 and 12 ppb), FEV1 (68% and 72% of the predicted value), and FEV1/FVC ratio (0.61 and 0.70). Patient 1 demonstrated greater reversibility than patient 2 (420 mL and 22% and 240 mL and 12%, respectively).

Demographic and clinical data.
Variable Patient 1 Patient 2
Gender Female Female
Age, years 45 41
Smoking status Never smoker Never smoker
BMI, kg/m2 31 26
GINA 4 4
ACQ-7 2.3 2.3
FeNO, ppb 21 12
FEV1, L 1.87 2.03
FEV1, % predicted 68 72
FEV1/FVC ratio 0.61 0.70
Reversibility, mL 420 240
Reversibility, % 22 12
RV, % 153 100
R5 − R20, kPa/L/s 0.23 0.01

BMI: Body mass index; GINA: Global Initiative for Asthma; ACQ-7: Asthma Control Questionnaire 7; FeNO: fractional exhaled nitric oxide; RV: residual volume; R5: resistance at 5 Hz; and R20: resistance at 20 Hz.

Body plethysmography was used to assess lung volumes (Autobox 6200 DL; Sensormedics Corporation, CA, USA). Residual volume (RV) was increased (153% of predicted) in patient 1, indicating gas trapping due to SAD. There was no evidence of gas trapping in patient 2. Impulse oscillometry was used in order to measure airway resistance (Masterscreen IOS; Erich Jaeger, Hoechenberg, Germany), with peripheral airway resistance measured by resistance at 5 Hz minus resistance at 20 Hz (R5 − R20).3 Patient 1 demonstrated a value of 0.23 kPa/L/s, whereas patient 2 had a much lower value of 0.01 kPa/L/s, indicating minimal peripheral airway resistance. These differences in R5 − R20 can be due to small airway inflammation, remodelling or bronchoconstriction.

 CLINICAL MESSAGE

The evidence that SAD is present from mild to severe asthma3 raises the practical issue of how to diagnose and monitor SAD in clinical practice. SAD was previously thought to be difficult to measure due to the inaccessible nature of the lung periphery.1 However, these case studies show the potential value of RV and oscillometry measurements in clinical practice; the two cases presented here had very similar clinical characteristics based on spirometry and asthma control, but only one had evidence of significant SAD.

Although normal ranges for oscillometry measurements have yet to be firmly established,4 the R5 − R20 value for patient 1 is beyond the threshold for SAD used in previous publications.4,5 Establishing normal ranges for oscillometry is an important future consideration for this technique in clinical practice.

The clinical management of SAD can include the use of inhaled treatments with smaller particle sizes that target the small airways. The diagnosis of SAD may therefore lead to different clinical management. The cases presented here show that the use of RV and R5 − R20 measurements can facilitate the diagnosis of SAD. We believe that diagnosing SAD in asthma should not be overlooked as the opportunity for targeted treatment may be missed.

 ACKNOWLEDGMENTS

Dave Singh is supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC).

 REFERENCES 1. van der Wiel E, ten Hacken NH, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review. J Allergy Clin Immunol. 2013;131(3):646-657. https://doi.org/10.1016/j.jaci.2012.12.1567 van der Wiel E ten Hacken NH Postma DS van den Berge M Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma a systematic review J Allergy Clin Immunol 2013 131 3 646 657 https://doi.org/10.1016/j.jaci.2012.12.1567 2. Postma DS, Brighling C, Fabbri L, van der Molen T, Nicolini G, Papi A, et al. Unmet needs for the assessment of small airways dysfunction in asthma: introduction to the ATLANTIS study. Eur Respir J. 2015;45(6):1534-1538. https://doi.org/10.1183/09031936.00214314 Postma DS Brighling C Fabbri L van der Molen T Nicolini G Papi A Unmet needs for the assessment of small airways dysfunction in asthma introduction to the ATLANTIS study Eur Respir J 2015 45 6 1534 1538 https://doi.org/10.1183/09031936.00214314 3. Postma DS, Brighling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A, et al. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study [published correction appears in Lancet Respir Med. 2019 Sep;7(9):e28]. Lancet Respir Med. 2019;7(5):402-416. https://doi.org/10.1016/S2213-2600(19)30049-9 Postma DS Brighling C Baldi S Van den Berge M Fabbri LM Gagnatelli A Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS) baseline data from a prospective cohort study [published correction appears in Lancet Respir Med 2019 7 9 e28 https://doi.org/10.1016/S2213-2600(19)30049-9 4. Galant SP, Komarow HD, Shin HW, Siddiqui S, Lipworth BJ. The case for impulse oscillometry in the management of asthma in children and adults. Ann Allergy Asthma Immunol. 2017;118(6):664-671. https://doi.org/10.1016/j.anai.2017.04.009 Galant SP Komarow HD Shin HW Siddiqui S Lipworth BJ The case for impulse oscillometry in the management of asthma in children and adults Ann Allergy Asthma Immunol 2017 118 6 664 671 https://doi.org/10.1016/j.anai.2017.04.009 5. Usmani OS, Singh D, Spinola M, Bizzi A, Barnes PJ. The prevalence of small airways disease in adult asthma: A systematic literature review. Respir Med. 2016;116:19-27. https://doi.org/10.1016/j.rmed.2016.05.006 Usmani OS Singh D Spinola M Bizzi A Barnes PJ The prevalence of small airways disease in adult asthma A systematic literature review Respir Med 2016 116 19 27 https://doi.org/10.1016/j.rmed.2016.05.006

At the time of the study

 EDUCAÇÃO CONTINUADA Identificando a disfunção de pequenas vias aéreas em asma na prática clínica 0000-0001-7718-2576 Jackson Natalie 1 0000-0001-7735-0461 Rafique Jethin 1 * 2 0000-0001-8918-7075 Singh Dave 1 2 . Medicines Evaluation Unit, Wythenshawe, Manchester, United Kingdom. . University of Manchester, Manchester, United Kingdom.

DS e JR projetaram a pesquisa. JR e NJ organizaram a coleta de dados. DS e NJ escreveram o manuscrito. JR revisou e aprovou o manuscrito.

 CONTEXTO

As pequenas vias aéreas são definidas como aquelas com diâmetro ≤ 2 mm.1 Atualmente, há um enfoque na disfunção das pequenas vias aéreas (DPVA) na asma e nas técnicas utilizadas para medi-la.1-3 Postma et al. relataram que a DPVA está presente em todos os níveis de gravidade da asma e pode ser medida usando diferentes técnicas, incluindo volumes pulmonares e oscilometria.1,3 Os casos clínicos descritos aqui ilustram como esses métodos podem ser aplicados em um ambiente clínico para identificar DPVA na asma.

 RELATOS DOS CASOS

A Tabela 1 mostra dados de duas pacientes com asma moderada a grave (sistema de classificação da Global Initiative for Asthma = 4) que compareceram ao nosso centro de pesquisa para avaliação da função pulmonar. Ambas eram não fumantes, com idades semelhantes e asma não controlada; ambas apresentaram um escore no Questionário de Controle da Asma = 2,3. Houve níveis semelhantes de fração de óxido nítrico exalado (21 e 12 ppb), VEF1 (68% e 72% do valor previsto) e relação VEF1/CVF (0,61 e 0,70). A paciente 1 demonstrou maior reversibilidade que a paciente 2 (420 mL e 22% vs. 240 mL e 12%).

Dados demográficos e clínicos.
Variável Paciente 1 Paciente 2
Sexo Feminino Feminino
Idade, anos 45 41
Status tabágico Não fumante Não fumante
IMC, kg/m2 31 26
GINA 4 4
ACQ-7 2.3 2.3
FeNO, ppb 21 12
VEF1, L 1.87 2.03
VEF1, % previsto 68 72
VEF1/CVF 0.61 0.70
Reversibilidade, mL 420 240
Reversibilidade, % 22 12
VR, % 153 100
R5 − R20, kPa/L/s 0.23 0.01

IMC: índice de massa corpórea; GINA: Global Initiative for Asthma; ACQ-7: Asthma Control Questionnaire 7; FeNO: fração de óxido nítrico exalado; VR: volume residual; R5: resistência a 5 Hz; e R20: resistência a 20 Hz.

A pletismografia corporal foi utilizada para avaliar os volumes pulmonares (Autobox 6200 DL; Sensormedics Corporation, CA, EUA). O volume residual (VR) estava alto (153% do previsto) na paciente 1, indicando aprisionamento aéreo devido à DPVA. Não houve evidências de aprisionamento aéreo na paciente 2. A oscilometria de impulso foi utilizada para medir a resistência das vias aéreas (Masterscreen IOS; Erich Jaeger, Hoechenberg, Alemanha), com a resistência das vias aéreas periféricas medida pela resistência a 5 Hz menos a resistência a 20 Hz (R5 − R20).3 A paciente 1 demonstrou um valor de 0,23 kPa/L/s, enquanto a paciente 2 apresentou um valor muito menor de 0,01 kPa/L/s, indicando resistência mínima das vias aéreas periféricas. Essas diferenças em R5 − R20 podem ser causadas por inflamação das pequenas vias aéreas, remodelação ou broncoconstrição.

 MENSAGEM CLÍNICA

A evidência de que a DPVA está presente na asma leve a grave3 levanta a questão prática de como diagnosticá-la e monitorá-la na prática clínica. Antes, pensava-se que a DPVA era difícil de ser medida devido à natureza inacessível da periferia pulmonar.1 No entanto, esses estudos de caso mostram o valor potencial das medidas de VR e oscilometria na prática clínica; os dois casos aqui apresentados apresentavam características clínicas muito semelhantes com base na espirometria e no controle da asma, mas apenas um apresentava evidências significativas de DPVA.

Embora os intervalos normais para medições de oscilometria ainda não tenham sido firmemente estabelecidos,4 o valor R5 − R20 da paciente 1 está além do limiar para DPVA usado em publicações anteriores.4,5) O estabelecimento de intervalos normais para oscilometria é uma importante consideração futura para essa técnica na prática clínica.

O manejo clínico da DPVA pode incluir o uso de tratamentos inalatórios com partículas de menor tamanho direcionadas às pequenas vias aéreas. O diagnóstico de DPVA pode, portanto, levar a um manejo clínico diferente. Os casos aqui apresentados mostram que o uso de medidas de VR e R5 − R20 pode facilitar o diagnóstico de DPVA. Acreditamos que o diagnóstico de DPVA na asma não deve ser esquecido, pois a oportunidade para o tratamento direcionado pode ser perdida.

 AGRADECIMENTOS

Dave Singh recebe suporte financeiro do National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC).

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