Asthma Attila Somfay Dept Pulmonology University of Szeged

Asthma Attila Somfay Dept. Pulmonology, University of Szeged, Deszk, Hungary

Medical history of D. B. • 30 -year-old woman, school teacher • Complaints for 20 years: periods of S. O. B. , particularly in the August-October period, but also during exercise (tennis), cold air exposure (skie) or under stress (exams). • Severity changes considerably time to time, with frequent attacks of wheezing, between attacks no complaints • Never smoked • Mother also had asthma

Acute admission • Severe attack which responded poorly to BD drugs and inhaled CS. • Exhausted, dehydrated, very anxious • On examination: dyspneic, orthopneic, accessory muscles of respiration were active • Lungs hyperinflated, musical rhonchi in all areas • HR: 110/min with pulsus paradoxus • Sputum scant and viscous

Definition of asthma - inflammatory disorder of the airways, characterized by periodic attacks of wheezing, shortness of breath, chest tightness, and coughing, tipically during the night and early morning. - a condition characterized by recurrent attacks of bronchoconstriction and excessive mucus production, in response to a variety of factors. - the attacks releave spontaneously or by bronchodilators - chronic inflammation results in bronchial hyperreactivity

DEFINITION OF ASTHMA Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation. NEW! Wenzel, Lancet 2006

Asthma and COPD mortality Mathers, PLos Med 2006

Prevalence of astma (A) and asthmatic symptoms (B) between 1965 and 2005 in children and young adults

Asthma morbidity in Hungary Prevalence 290 201 290 422 Incidence 15 836 14 629 OKTPI, 2016

Asthma – variable nature allergenes, viruses cold weather, exercise increases Use os releaver, symptom time Asthma control decreases Exacerbation

Prevalence 3 -5% of adults and 7 -10% of children. *Half of the people with asthma develop it before age 10 and most develop it before age 30. Asthma symptoms can decrease over time, especially in children. Concomittant diseases Many people with bronchial asthma have an individual and/or family history of allergies such as hay fever (allergic rhinitis) or eczema. Others have no history of allergies or evidence of allergic problems.

Asthma phenotypes Wenzel, Nature Med 2012

Symptom – inflammation relationship Haldar, AJRCCM 2008

Inflammatory cells Mast cell eosinophil Th 2 basophil neutrophil platelet Structural cells Epithel Smooth muscle Endothel Fibroblast Nerves Mediators Histamin Leukotrienes Prostanoids PAF Kinins Adenosin Endothelins NO Cytokines Chemokines Growth factors Effects Brochospasm Plasma exsudation Mucus secretion AHR Structural changes

Etiology * In sensitive individuals, asthma symptoms can be triggered by inhaled allergens (allergy triggers) such as pet dander, dust mites, cockroach allergens, pollens. * Asthma symptoms can also be triggered by respiratory infections (virus!), exercise, cold air, tobacco smoke and other pollutants, stress, food or drug allergies. * Aspirin and other non-steroidal anti-inflammatory medications (NSAID) provoke asthma in some patients.

House dust mite (Dermatophagoides pteronyssimus)

„The September epidemic” (Ontario, Canada, 2001 -2004) Johnston & Sears, Thorax 2006

MODERN VIEW OF ASTHMA Allergen Macrophage Mast cell Th 2 cell Mucus plug Neutrophil Eosinophil Epithelial shedding Nerve activation Subepithelial fibrosis Plasma leak Oedema Mucus Vasodilatation hypersecretion New vessels hyperplasia Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy/hyperplasia

Inflammatory and immune cells involved in asthma

Infect theory Th 1 – Th 2 imbalance

Typical pathologic features: epithel shedding + basement membrane thickening After ICS Before ICS

Effect of inhaled steroid in asthma Laitinen LA, et al. J Allergy Clin Immunol 1992; 90(1): 32 -42

Asztma and COPD 1.

Differences in airway obstruction COPD Asthma

Asztma and COPD 2

Clinical characteristics of asthma

Symptoms 1. *Most people with asthma have periodic wheezing attacks separated by symptom-free periods. *Some asthmatics have chronic shortness of breath with episodes of increased shortness of breath. *Asthma attacks can last minutes to days, and can become dangerous if the airflow becomes severely restricted

Symptoms 2. Cough, Wheezing, Dyspnoe - usually begins suddenly - episodic - may be worse at night or in early morning - aggravated by exposure to cold air, by exercise, by reflux - resolves spontaneously or by bronchodilators - cough with or without sputum (dyscrinia) - breathing that requires increased work - intercostal retractions - abnormal breathing pattern: exhalation (breathing out) more than twice as long as inspiration (breathing in)

Dyscrinia (because sputum scant and viscous)

Symptoms 3. Emergency symptoms *extremely difficult breathing *bluish color to the lips and face *severe anxiety *rapid pulse (pulsus paradoxus) *sweating *decreased level of consciousness (severe drowsiness or confusion) during an asthma attack

Signs and tests Listening to the chest (auscultation) during an episode reveals wheezing. Lung sounds are usually normal between episodes. Tests may include: *pulmonary function tests *chest X-ray *allergy testing by skin testing or serum tests (Ig. E) *arterial blood gas *eosinophil count

Diagnostics -Lung function 1. - Between the attacks: may be normal - During the attacks: obstruction (PEF, FEV 1 decreased) - Patients with - normal lung function: provocation tes - obstruction: pharmacodynamic test

Metacholin provocation test bronchial hyperreactivity

Pharmacodynamic test reversible obstruction

Lung function 2. Provocation test *Specific provocation-allergen challenge (rarely done, neber in routine, can be dangeorus – anaphylaxis, suffocation) inhalation causes prompt and sign. bronchoconstriction *rapid decline in FEV 1: lasts: 15 min. - 1 hour *=early asthmatic reaction (EAR)=early phase response *After this phase resolves (spontaneously or with -agonist), the FEV 1 reaches a level to the pre-chall. baseline. *6 -24 hours after exposure to the allergen bronchoconstriction can be developed=late asthmatic response (LAR). The decline in FEV 1 may be less severe. *Aspecific provocation (histamin, metacholin): *Exercise test – 6 -8 min run, pre/post spirometry Pharmacodynamic test: baseline obstr. lung function, resolved in 15 min due to inh. bronchodilator (salbutamol)

Differencial diagnostics I. Respiratory • COPD • Large airway obstruction – Foreign body – Tumor – VCD • Pulmonary embolism • Eosinophil pneumonia • Chronic cough – – Bronchitis simplex Sinusitis Tracheitis Dyskinesis Non-respiratory • CHF • Gastroesophageal reflux (GERD) • Chronic cough – Drug-induced (ACE inhibitor, -blocker)

Differencial diagnostics II. • • • X-ray (chest, sinuses) Oesophageal p. H monitoring Bronchoscopy, Laryngoscopy Echocardiography CT angiography, V/Q scan

Vocal cord dysfunction

Asthma diff. dg. 1. /A COPD 61 years old man Farmacodynamic test: prae post FVC: 2, 00 (47%)- 1, 89 (44%) FEV 1: 0, 93 (28%)- 0, 88 (26%) FRC: 5, 29 (150%)- 5, 09 (144%) RV: 4, 65 (201%)- 4, 57 (198%) Raw: 6, 01 -6, 19 (<2, 24) Irreversible obstructive pulmonary disease

Asthma diff. dg. 1. /B COPD/Emphysema Lung function 68 years old man FVC: 3, 05 86% FEV 1: 1, 03 37% VC: 3, 56 96% FRC: 5, 93 171% RV: 4, 27 173% RV/TLC%: 55% DLCO: 1, 6 20% Blood gas analysis p. H: 7, 42 p. O 2: 66, 6 Hgmm p. CO 2: 37, 2 Hgmm Sat: 93%

Asthma diff. dg 2. Tumor in large airways

Asthma diff. dg 3. Heart failure

Asthma severity Sympotms Day Night IV. Chronic severe Folyamatos, naponta többször folyamatos gyakori Exercise capacity Folyamatosan korlátozott Lung function (FEV 1 or PEF) FEV 1 60% PEF variability 30% III. Chronic moderate FEV 1 60 -80 % Panaszok idején napi tünetek fizikai terhelhetőség PEF variability 30% agonista 1 hét II. Chronic mild Hetente többször, Nagyobb fizikai de nem minden nap terhelés köhögést és FEV 1 80% bronchospazmust PEF variability 30% 1/hét, de 1/nap 2/hó provokál I. Intermittent, epizodic Havonta többször, de Hosszabb futás nem minden héten Minden nap minden nap 1 hét, a rohamok között 2/hó tünetmentesség PEF normál köhögést és bronchospazmust provokál FEV 1 80% PEF variability 20%

What to treat…

Treatment 1. Controllers (Anti-inflammatory) - ICS, inhaled corticosteroid: (budenosid, fluticasone, beclomethason, ciclesonide) - leukotriene inhibitors (montelukast, zafirlukast, pranlukast) - LABA(long acting beta-2 agonists) – salmeterol, formoterol – only with ICS - xantin derivates (teophyllin) - Biological therapy: omalizumab (anti Ig. E) mepolizumab (anti IL-5)

Treatment 2. Releavers (bronchodilators ) - beta-2 agonist: short(fast)-acting (SABA): inhaled (salbutamol, terbutalin, formoterol) - aminophylline or theophylline (I. v) - anticholinergics inhaled (ipratropium)

GINA 2017

Severity of asthma exacerbations I. Mild Moderate Severe Walking Can lie down sentences Talking Prefers sitting phrases At rest Hunched forward words alertness Usually agitated Usually agiteted Respiratory Increased rate Increased >30/min dyspnea Talks in Resp. arrest Drowsy or confused

Severity of asthma exacerbations II. Mild Moderate Severe Resp. arre st Paradox thoracoabdominal movement Abscence of wheeze Accesory not muscles usually wheeze moderate loud Usually loud Pulse rate <100 100 -120 >120 Pulsus Absent 10 -25 >25 mm. Hg Abscence bradycardi a

Severity of asthma exacerbations III. Mild PEF Moderate Severe >80% 60 -80% <60% Pa. O 2 >60 mm. Hg <60 mm. Hg Pa. CO 2 <45 mm. Hg >45 mm. Hg Sa. O 2 >95% 91 -95% <90% Resp. arre st

Treatment of asthma exacerbation SABA DPI, MDI: 4 -10 puff (400 -1000 g salbutamol ) 20 min, repeat max. 3 times Improves No improvement Mild exacrebation Severe exacerbation Some impovement Moderate exacerbation

Further treatment Mild exacerbáció Moderate exacerb. Severe excerbation Roham oldódik, PEF! iv. or per os 40 mg O 2, iv. 40 -80 mg 100 -200 g methylprednisolon, SABA continue for 5 -7 days (iv. xantin), 4 -6 h for 2 -3 days +SABA/SAMA inh. steroid dose: 2 x transfer to ED for 2 -4 weeks

Hospital treatment (above the previous ones, if needed)

DEFINITION OF SEVERE ASTHMA • When the diagnosis of asthma is confirmed and comorbidities addressed, • severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy. F. Chung et al, ERJ 2014.

HETEROGENEITY OF EOSINOPHILIC ASTHMA - Brusselle G. et al, Nature Medicine 2013.

DEFINITION OF UNCONTROLLED ASTHMA • At least one of the following: 1. Poor symptom control: ACQ consistently > 1. 5, ACT < 20 2. Frequent severe exacerbations: two or more bursts of systemic CS in the previous year 3. Serious exacerbations: at least one hospitalisation or ICU stay in the previous year 4. Airflow limitation: after appropriate bronchodilator withold FEV 1 < 80% predicted F. Chung et al, ERJ 2014.

Difficult to treat vs. severe, refracter asthma Not (under) treated Nem (alul) kezelt Diff. to Nehezen kezelhető treat Severe refrakter, terápia rezisztens asztma (~50%) Refrakter Difficult to treat: • Not asthma • Poor compliance • Comorbidities, environmental factors, triggers Dolan CM et al. Ann Allergy Asthma Immunol 2004; 92: 32 -9. Moore WC et al. J Allergy Clin Immunol 2007; 119: 405 -13.

F. Chung et al, ERJ 2014.