‘Indirect’ challenges from science to clinical practice

Abstract

Indirect challenges act to provoke bronchoconstriction by causing the release of endogenous mediators and are used to identify airway hyper-responsiveness. This paper reviews the historical development of challenges, with exercise, eucapnic voluntary hyperpnoea (EVH) of dry air, wet hypertonic saline, and with dry powder mannitol, that preceded their use in clinical practice. The first challenge developed for clinical use was exercise. Physicians were keen for a standardized test to identify exercise-induced asthma (EIA) and to assess the effect of drugs such as disodium cromoglycate. EVH with dry air became a surrogate for exercise to increase ventilation to very high levels. A simple test was developed with EVH and used to identify EIA in defence force recruits and later in elite athletes. The research findings with different conditions of inspired air led to the conclusion that loss of water by evaporation from the airway surface was the stimulus to EIA. The proposal that water loss caused a transient increase in osmolarity led to the development of the hypertonic saline challenge. The wet aerosol challenge with 4.5% saline, provided a known osmotic stimulus, to which most asthmatics were sensitive. To simplify the osmotic challenge, a dry powder of mannitol was specially prepared and encapsulated. The test pack with different doses and an inhaler provided a common operating procedure that could be used at the point of care. All these challenge tests have a high specificity to identify currently active asthma. All have been used to assess the benefit of treatment with inhaled corticosteroids. Over the 50 years, the methods for testing became safer, less complex, and less expensive and all used forced expiratory volume in 1 sec to measure the response. Thus, they became practical to use routinely and were recommended in guidelines for use in clinical practice.

Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics

“…Exercise, mannitol and eucapnic voluntary hyperventilation (EVH) are stimuli believed to exert their effect by dehydration of the epithelial lining fluid, causing pro-inflammatory mediator release with subsequent bronchoconstriction in susceptible subjects (Anderson, 2016). Levels of CC16 have been shown to increase in both plasma and urine after exercise (Romberg et al 2011, Tufvesson et al 2013, and in urine after mannitol inhalation challenge and EVH (Bolger et al 2011b, Kippelen et al 2013).…”

The usefulness of bronchial challenge tests in the diagnosis of occupational asthma

“…Test prowokacyjny z mannitolem W ostatnim czasie obserwuje się większe zainteresowanie testem prowokacyjnym z użyciem mannitolu, który ze względu na dużą swoistość, prostą metodykę i stosunkowo krótki czas wykonania badania znajduje zastosowanie w diagnostyce astmy oskrzelowej, również tej o podłożu zawodowym [31]. W wielu krajach są dostępne komercyjne zestawy z mannitolem do oceny BHR, niestety test ten nie jest jeszcze rutynowo wykorzystywany w Polsce [13,32,33].…”

“…O wielkości nadreaktywności świadczyła dawka mannitolu PD 15 , która powodowała znamienne zmniejszenie wartości FEV 1 o 15%. Według badaczy wartość PD 15 dla mannitolu jest właściwym punktem cut-off w klasyfikacji BHR [33,36].…”

“…Główne zalety testu prowokacyjnego z mannitolem to: prosta technika badania (nie jest wymagany specjalistyczny sprzęt), stosunkowo krótki czas wykonywania (około 20 min, podczas gdy czas wykonania testu nadreaktywności oskrzeli z metacholiną to prawie 1 godz.) i bezpieczeństwo pacjenta [2,33]. Anderson oceniła kilka testów prowokacyjnych pośrednich i stwierdziła, że w porównaniu z testem wysiłkowym zmiany FEV 1 w teście z mannitolem są obserwowane dużo wcześniej (badanie spirometryczne wykonuje się po każdej zainhalowanej dawce), a technika badania nie wymaga aż tak dużego wysiłku badanej osoby [34].…”

Nebulised hypertonic saline for acute bronchiolitis or ‘there and back again’ to use Tolkien's subtitle for The Hobbit

“…However, this trial was also subject to many of the design shortcomings that have already been mentioned. In view of the current uncertainty, it is perhaps prudent to add epinephrine when using HS, as the later is known to cause bronchoconstriction .…”