Precision medicine in united airways disease: A "treatable traits" approach.

United airways disease (UAD) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma-allergic rhinitis is the archetypal UAD, but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a "treatable traits" approach for the classification and management of UAD, wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD.

Comorbid "treatable traits" in difficult asthma: Current evidence and clinical evaluation.

The care of patients with difficult-to-control asthma ("difficult asthma") is challenging and costly. Despite high-intensity asthma treatment, these patients experience poor asthma control and face the greatest risk of asthma morbidity and mortality. Poor asthma control is often driven by severe asthma biology, which has appropriately been the focus of intense research and phenotype-driven therapies. However, it is increasingly apparent that extra-pulmonary comorbidities also contribute substantially to poor asthma control and a heightened disease burden. These comorbidities have been proposed as "treatable traits" in chronic airways disease, adding impetus to their evaluation and management in difficult asthma. In this review, eight major asthma-related comorbidities are discussed: rhinitis, chronic rhinosinusitis, gastroesophageal reflux, obstructive sleep apnoea, vocal cord dysfunction, obesity, dysfunctional breathing and anxiety/depression. We describe the prevalence, impact and treatment effects of these comorbidities in the difficult asthma population, emphasizing gaps in the current literature. We examine the associations between individual comorbidities and highlight the potential for comorbidity clusters to exert combined effects on asthma outcomes. We conclude by outlining a pragmatic clinical approach to assess comorbidities in difficult asthma.

Profile of difficult to treat asthma patients referred for systematic assessment.

AIM: We determined the proportion of asthma patients under specialist care who remain difficult-to-treat and might benefit from systematic assessment. We additionally report the characteristics and indications for referral in 90 patients who received systematic assessment for difficult asthma. METHODS: We conducted a three-month prospective audit of our hospital's general asthma clinic. We then analyzed consecutive patients over 18 months referred on for systematic assessment of difficult asthma. RESULTS: Over 3 months, 22/166 patients (13.3%) in the general asthma clinic were considered likely to benefit from systematic assessment of difficult asthma. These patients had higher inhaled steroid requirements (890 ± 604 mg), lower lung function (FEV1: 65 ± 18%), and more often received GINA step 5 treatment (22.7%). However, 7/22 (32%) of suitable patients were not referred for assessment, mainly due to patient factors. Over 18 months, 90 patients received systematic assessment for difficult asthma, on account of poor symptom control (62%), frequent exacerbations (44%), poor lung function (42%), patient factors (29%), and diagnostic uncertainty (26%). There was a high disease burden with a mean (±SD) asthma control test score and asthma quality of life questionnaire score of 14 ± 5 and 4.26 ± 1.45 respectively. 80% fulfilled criteria for severe asthma. The majority were either atopic (66.7%) or eosinophilic (54.4%); only 15.6% were neither. Patients had a median of three extra-pulmonary comorbidities, of which most were previously unrecognised. CONCLUSION: One-in-eight asthma patients already under specialist care were suitable for systematic assessment of difficult asthma, but a third of these were not referred due to patient factors. Diagnostic uncertainty and patient factors were important indications for systematic assessment. Most patients who underwent systematic assessment exhibited severe asthma phenotypes potentially responsive to targeted treatment, but also had multiple comorbidities. Our results highlight the importance of management strategies to address patient factors, severe asthma biology, and concurrent contributory conditions.

Elevated total serum immunoglobulin E (>1000 IU/mL): implications?

Atopic eczema, allergic broncho-pulmonary aspergillosis, helminthic infections and rare primary immunodeficiencies are known to elevate total serum immunoglobulin E (IgE) above 1000 IU/mL. However, of 352 patients with IgE >1000 IU/mL seen in our hospital over a 5-year period, less than 50% had these conditions. Markedly elevated IgE levels in the rest of the patients were associated with asthma, allergic rhinitis and food allergy, instances where the test is of limited diagnostic utility.

Do we need transbronchial lung biopsy if we have bronchoalveolar lavage Xpert® MTB/RIF?

BACKGROUND: Studies evaluating the role of transbronchial lung biopsy (TBLB) in diagnosing pulmonary tuberculosis (PTB) date back decades and have shaped current practice. However, with the recent advent of bronchoalveolar lavage (BAL) Xpert® MTB/RIF, it is time to re-evaluate the role of TBLB. OBJECTIVE: To assess the impact of BAL and TBLB with the addition of BAL Xpert on diagnostic PTB yields and time to treatment initiation in sputum-scarce or acid-fast bacilli (AFB) smear-negative PTB patients. METHODS: We retrospectively reviewed all sputum-scarce or AFB smear-negative patients who underwent both BAL and TBLB for suspected PTB between March 2011 and October 2013. Xpert was performed on all BAL specimens. RESULTS: Of 158 patients included in our analysis, 44 were culture-proven PTB. Ninety-four per cent of the patients had AFB smear-negative BAL samples. The sensitivity and specificity of Xpert in AFB smear-negative BAL samples were respectively 60% and 98%. The addition of BAL Xpert expedited the institution of PTB treatment while having diagnostic yields comparable to those of conventional BAL with TBLB. CONCLUSIONS: The use of BAL Xpert may obviate the need for TBLB in increasing the diagnostic yield of PTB in sputum-scarce or AFB smear-negative patients.