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GENERAL PAPERS

ASTHMA IN CYSTIC

Marcela Daniela Ionescu, Ioana-Alina Anca, Mihaela Balgradean „Carol Davila“ University of Medicine and Pharmacy, Bucharest

ABSTRACT Cystic fi brosis (CF) is the most common autosomal recessive disease in Caucasians. disease is charac- terized by impaired mucocilliary clearance with and chronic pulmonary infection and infl am- mation. Wheeze is a common symptom in CF, but in some cases the wheeze is due to the presence of con- comitant . There is no consensus on how to defi ne CF asthma, but the diagnosis is predominantly based on the patient’s strong family and personal history of atopy.

Keywords: cystic fi brosis, wheeze, asthma, atopy

Cystic fi brosis (CF) is a complex multysistem obstruction by abnormal viscid secretions, airway disease, caused by defects in a single . It is the smooth muscle contraction due to stimulation by a most common autosomal recessive disease in Cau- host of infl ammatory mediators. (5) casians associated with early death. Pulmonary Asthma is a common condition but the diagno- manifestations are responsible for most of the mor- sis of asthma can be diffi cult especially in preschool bidity and mortality. (1) CF lung disease begins children. International Paediatric Asthma Consensus early in life and is characterized by impaired muco- Group defi ned asthma as: episodic wheeze and/or cilliary clearance with airway obstruction, and in a clinical setting where asthma was likely chronic pulmonary infection and infl ammation. and other rarer conditions have been excluded. This Chronic bacterial endobronchial infection is asso- defi nition is particularly unhelpful in patients with ciated with an intense neutrophilic infl ammatory CF. (6,7) Various defi nitions are used, and common response that damages the airway, impairs local to them all are reversible airway obstruction and host – defence mechanism, and facilitates further chronic airway infl ammation. Classical symptoms infection. This vicious cycle of infl ammation and of asthma are wheeze, cough, dyspnea and chest infection with airway damage, result in progressive tightness. For diagnosing asthma are important: , gas trapping, impaired gas ex- history taking, objective documentation of revers- change and ultimately leads to ible bronchial obstruction, allergy, bronchial hyper- (2,3). esponssiveness (BHR) testing, assessing airway Wheeze is a common symptom in CF and, whilst infl ammation whenever possible. (7) in many patients this is due to their underlying lung It is even harder to defi ne CF asthma but an at- disease, in some cases the wheeze is due to the tempt has been made by the US and Canadian Epi- presence of concomitant asthma. It is diffi cult to demiologic Study of Cystic Fibrosis (ESCF). The determine which patients have a combination of patient is reported as having concomitant asthma if, asthma and which have asthma like symptoms in the treating physician’s opinion, asthma contrib- caused by infl ammation of the CF lung. (3,4) utes signifi cantly to the patient’s lung disease. The The pathogenesis of airway obstruction and diagnosis of asthma is suggested by the following: wheezing in CF involves several overlapping episodes of acute airway obstruction reversed by mechanisms: airway mucosal oedema secondary to bronchodilators (especially if seasonal); a strong chronic infection and infl ammation, mechanical family history of asthma and/or evidence of atopy

Corresponding author: Marcela Daniela Ionescu, „Carol Davila“ University of Medicine and Pharmacy, 37 Dionisie Lupu St., Bucharest E-mail: [email protected]

118 ROMANIAN JOURNAL OF PEDIATRICS – VOL. LXIV, No. 2, YEAR 2015 ROMANIAN JOURNAL OF PEDIATRICS – VOL. LXIV, NO. 2, YEAR 2015 119

(such as eczema or hay fever); laboratory evidence um in patients with CF who do not have asthma, of allergy such as eosinophillia or elevated IgE. whereas ipratropium does not effi ciently reverse This defi nition is accepted although the use of se- histamine – induced bronchospasm in those with rum IgE and eosinophilia is only of value if allergic concomitant symptoms of asthma. These suggest bronchopulmonary aspergilosis (ABPA) has been that the increased airway reactivity in patients with excluded. (4,6-8) CF is vagally mediated and results from the airway damage caused by the lung disease. (10) HOW MAY CF ASTHMA BE DIAGNOSED? The response to indirect stimuli such as hyper- tonic or exercise is different in CF, because Some symptoms are of less relevance to CF pa- the patients usually bronchodilate after such chal- tients. For example, a history of wheezing is impor- lenges. (10) tant but non-specifi c and most patients with CF Exercise testing has a important role in evaluat- have recurrent whether or not they have ing both CF and asthma. The differences between asthma. Probably the most appropriate indicators the response to exercise in the two conditions are are a family history of atopy (including asthma) important. In asthma, after the normal transient and a personal history of eczema and allergic rhini- bronchodilatation, progressive bronchoconstriction tis. Physical examination is unhelpful, hyperinfl a- occurs, and its maximum 5-10 minutes after stop- tion is common in both CF and asthma. (3,5,6) ping exercise. Simptoms are usually gone within Early physical fi ndings include increased antero- 15-30 minutes and lung function is back to normal posterior diameter of the chest, generalized hyper- within 30-60 minutes. In CF there is a marked in- resonance, scattered or localized coarse crackles crease in peak expiratory fl ows during exercise and digital clubbing. Cyanosis is a late sign. which is most exaggerated in those worst lung dis- ease. After exercise, the decrease in peak fl ow is LUNG FUNCTION seen to a much lesser extent than in asthma. It is probable that the main cause of these results is the Standard clinic may indicate the instability of the CF airway. (1,4,6,10,11) presence of airway obstruction. It does not differ- All patients with CF should be tested to see if entiate obstruction due to concomitant asthma that their spirometry improves after the use of a bron- due to typical CF lung disease. Measurements of chodilator (ex. , terbutaline or ipratropi- small airway function, such as maximal expiratory um bromide) given by aerosol or . (11) fl ow at 25% vital capacity will not help because Bronchodilator responsiveness is recommended they tend to be reduced in most CF patients and are for the diagnosis of asthma, but its usefulness in CF quite variable. asthma diagnosis is less obvious. The reason for Measuring peak expiratory fl ow rate are often this is that due to the degree of variability in lung useful, except in CF where the obstruction mainly function measures (which can vary by as much as involves medium and small airways. Reduction in 15-20% spontaneously, including same day test- peakfl ow is only a late sign. (2-6) Body plethys- ing). CF patients often show a degree of bronchodi- mography can give further information including lator responsiveness whether or not they have CF the degree of hyperinfl ation and airway resistance, asthma and most studies show no relationship with but it is not specifi c to CF asthma. (4,6) atopy. (4,6) Hypersensitivity of the airways in CF has long BRONCHIAL HYPERREACTIVITY (BHR) been recognized and many patients with CF wheeze. This may be due to bronchospasm, muco- BHR is common in CF patients of all ages. BHR sal edema or retained secretions in the airways. tests are not routinely performed in pediatrics. BHR Once allergic bronchopulmonary and to histamine or methacholine is found in at least gastroesofageal refl ux have been excluded we can 40% of patients with CF. (4,9) If bronchial reactiv- use medication for this. (4,6,11) ity is measured in CF using challenge testing, many Patient with CF have concomitant asthma are patients exhibit periods of enhanced bronchial re- manifested by recurrent acute symptoms of dys- activity, particularly during and immediately after pnea that is impressively responsive to an inhaled infective exacerbations. (1,6,9) β2-agonist and/or systemic (8). The airway hyperresponsiveness of CF also dif- However, many others have a degree of bronchodi- fers in its response to histamine induced broncho- lator responsiveness in the absence of an good clin- spasm which is effectively reversed with ipratropi- ical response to such antiasthmatic treatment. In 120 ROMANIAN JOURNAL OF PEDIATRICS – VOL. LXIV, NO. 2, YEAR 2015 contrast to those with asthma, exercise does not in- TREATMENT duce bronchospasm and can even cause bronchodi- latation in patients with CF who have bronchodila- Many patients with CF exacerbations also have tor responsiveness in the absence of asthma. (4, 6, airway hyperresponsiveness and an improvenment 8-10) in lung function in hospitalized patients has been shown with regular nebulized salbutamol. β-adrenergic agoniste enhance ciliary beat frequen- ATOPY cy and may affect secretion. (11,14,15) Ter- Serum total IgE can be a guide to patient’s atop- butaline has been shown to stimulate chloride ic status. Positive prick testing or serum radio- secretion in the lumen and may increase hydration allergosorbent tests (RAST) will indicate atopic of the airway. (10) increases muco- status when the common aeroallergens such as ciliary clearance, diaphragmatic contractility and house dust mite, cat, dog, grass and tree pollens, are central nervous system drive to the respiratory cen- tested. A reaction to does not necesarly ters, and may also be anti-infl ammatory, at least in denote atopy. It should not therefore form part of the context of asthma in the non CF patient. Some atopic screening in CF. The prevalence of atopy in studies have shown theophylline to be benefi cial in CF is in fact similar to that in the non CF popula- CF asthma. (10) tion. (1-6) It has been stated that atopic CF patients Inhaled are very widely pre- have worse lung disease. scribed in CF, often without much justifi cation. In- fants are sometime prescribed them prior to diag- nosis because their symptoms have been attributed DIFFERENTIAL DIAGNOSIS to asthma. Another reason inhaled steroids are pre- In a CF patient with intractable wheezing cer- scribed to known CF patients is the mistaken belief tain condition need to be excluded and form part of that the noise the patient or family is describing is the differential diagnosis of CF asthma. They can related to bronchospasm, not airway secretions. coexist too. Moust would believe that giving inhaled steroids to Tracheo-bronchomalacia needs to be excluded reduce CF – related infl ammation is not a correct by fl exible bronchoscopy. The importance of this strategy. Therefore, the only indication for using diagnosis is that it can mimic asthma symptoms, them in CF is if the patient has asthma. (1,11,14) but may be worsened by bronchodilators relaxing A stepwise treatment approach for asthma has the smoth muscle. been proposed by all international guidelines. In Gastro-oesophageal refl ux is common in infants patients with uncontrolled asthma, step-up treat- with CF, but the problem persist in many older chil- ment should be considered. (7) In patients with CF dren and adults. It is well established that refl ux is asthma the treatment follows the standard step- associated with bronchospasm and wheezing. A 24 wise progression used in asthma: short-acting bron- hour ph study needs to be performed to confi rm the chodilator, inhaled corticosteroid, long-acting β diagnosis. (3,5) agonist, theophyllines (which may aid mucociliary Allergic bronchopulmonary aspergillosis must clearance), leukotriene receptor antagonist (limited be excluded, although sometimes the diagnosis is evidence in CF, but may decrease eosinophilic in- diffi cult. The classical case is easy to diagnose. fl ammation), oral steroids. The response to anti- However many of the symptoms and signs of ABPA asthma therapy in an individual may be as helpful are common and mimic CF lung disease. Cystic Fi- in the diagnosis of CF asthma (4,6,7,10,14-16) brosis Foundation consensus Conference proposed criteria for classic ABPA, minimal diagnostic crite- CONCLUSION ria and recommendations for screening (12,13). Severe small airways disease is diffi cult to de- There is no consensus on how to defi ne CF asth- fi ne precisely. Children have intractable wheezing ma. The overlap between the symptoms of CF lung and often expectoration is minimal even disease and those of asthma, and the fact that both though the are full of secretions. High resolu- condition are characterized by bronchial reactivity, tions computer tomography (HRCT) may be useful variable airway obstruction and infective exacerba- in patient who are not responding to standard treat- tions, complicates the precise diagnosis of asthma ments. It reveals extensive small airways disease in CF. manifest by distal air trapping due to fi xed oblitera- Factors that support diagnosis of cystic fi brosis tive . (4,6,11,12) asthma are: history of recurrent wheezing, positive ROMANIAN JOURNAL OF PEDIATRICS – VOL. LXIV, NO. 2, YEAR 2015 121 family history atopy, patient s history of atopy (ec- from the North American and European databases, zema, hay fever,food allergy), positive skin prick it seems that labeling a CF patients with concomi- tests or serum radioallergosorbent tests (RAST) to tant asthma infl uenced drug prescribing. (4,6) aeroallergens (excluding Aspergillus), high serum Identifying patients with signifi cant co-existing IgE (excluding ABPA). Pulmonary function tests asthma is, however, important as they may benefi t (spirometry, bronchodilator responsiveness, BHR), from specifi c asthma medications, in particular in- other diagnose excluded (gastroesophageal refl ux, haled steroids. (11) malacic airways, ABPA, obliterative bronchiolitis) Whether wheezing is due to concomitant asthma and the response to antiasthma medication may or not, the treatment follows the standard step-wise also help the diagnosis. (4,6,7) progression used in asthma. However it still be diffi cult to determine who Whatever the therapy prescribed by the physi- has CF and asthma and who has asthma like symp- cian, it should only be continued if the benefi ts are toms of prolonged exhalation, wheeze, and crack- objectively proven. les due to underlying lung infl ammation. A analysis

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