Don’t hold your breath. Understanding asthma could take a while…


Let’s face it, asthma has been around for more than ‘a bit’. It’s often considered as a 21st century epidemic, but as early as c.3000 BC, E.sinica (ephedra) was used to treat asthma by Shen Nong, the ‘Father of Chinese Herbal Medicine’. Not long after (relatively speaking…), the Ebers Papyrus (c.1550 BC), a text containing the worldly knowledge of Thoth, the Egyptian god of learning, described a “disorder of the metu”, ducts that were thought to distribute air and water to the lungs, amongst other organs. Interestingly, to alleviate wheezing and panting, many ancient civilisations inhaled the smoke of burning ephedra, which contains ephedrine, a beta-agonist. Brings a whole new meaning to a relaxing smoke, doesn’t it? Hippocrates (c.460-377 BC) was one of the earliest physicians to make the link between respiratory disease and the environment, whilst Pliny the Elder (AD 23-79) described pollen as an irritant of asthma, prescribing ephedra in red wine (hurrah!), or drinking the blood of wild horses, fox liver in red wine or millipedes soaked in honey (no thanks, I just ate). Why, then, given that the condition has existed for more than 5000 years, are we still unable to accurately define asthma and treat it effectively?

One explanation is the increasing recognition that asthma (particularly severe asthma) is a heterogeneous disease. As early as the 1950s, it was noted that not all asthmatics expressed the eosinophilia phenotype1 and correspondingly, inhaled corticosteroids (ICSs) were ineffective in disease control. Yet it wasn’t until the late 1990s that asthma phenotyping really signalled a break away from the ‘one size fits all’ approach of ICS therapy2, when it was proposed that asthma was divided into two inflammatory subtypes (those with or without eosinophilia) by Wenzel et al. The advent of further biomarker discoveries led to the designation of ‘Type 2-associated asthma’ (Type 2high), characterised by the increased expression of the cytokines IL-4, IL-5 and IL-13. Recent evidence, however, suggests that directing therapies according to the Type 2high signature might have limited efficacy, suggesting that further, more complex, patho-biological features have yet to be elucidated4,5, in addition to the biomarkers already used to assign Type 2high status (Table 1).Diane 7-12-15 Picture 1

It follows that assigning sub-phenotypes to patients may go some way to address some of the diagnostic and therapeutic challenges faced in the clinic today. Different phenotypes will have different therapeutic consequences, whilst other pulmonary diseases which mimic asthma can be differentiated, sometimes resulting in a reversal of diagnosis, or re-assessment of therapy. How this should be approached is of some debate. The least invasive form of phenotype identification is that of cluster analysis, such as that performed by Serrano-Pariente et al.6, in which three clusters of near fatal asthma phenotypes were identified. Cluster 1, the largest, encompassing older patients with the clinical and therapeutic classical criteria of severe asthma; cluster 2 was marked by a higher proportion of respiratory arrest, impaired consciousness and mechanical ventilation (the latter being a whopping 98%). The final cluster tended to include younger patients, sensitive to certain allergens. The reasoning of such clustering, based on variables including (but not exclusive to) demographics, clinical and functional characteristics, spirometric and immunological studies is to improve the design of therapeutic strategies for each phenotype.

A somewhat more controversial approach is to biopsy the patient, by video-assisted thoracoscopic surgery (VATS)(Figure 1)7. Doing so gives detailed insight into all areas of the lung (including the distal airways, an area where knowledge is relatively limited), providing information on individual phenotype which can then guide therapy and improve patient outcome. It also allows differentiation from asthma mimics, but it carries risks, not least those of general anaesthesia and acute exacerbation of the underlying disease.

Diane 7-12-15 Picture 2

Figure 1. Examples of distal lung disease in “atypical” severe asthma and differential diagnoses from video-assisted thoracoscopic surgery procured tissue. a) Small airway with massive lymphocytic bronchiolitis (arrowheads) often found in severe asthma with an autoimmune background (100× magnification). b) Small interstitial poorly defined granulomas (arrows) with epitheloid histiocytes/giant cells (arrowheads) in asthmatic granulomatosis, note the absence of vasculitis (100× magnification). c) Granulomatous inflammation in eosinophilic granulomatosis with polyangiitis, note the presence of prominent tissue eosinophilia, vasculitis (arrow) and necrotising granulomatous inflammation (arrowheads) (200× magnification). d) Aspiration granuloma, note a well-formed, non-necrotising granuloma entirely replaces an airway lumen (arrow), with foreign-body giant cell reaction to vegetable material (arrowhead) (100× magnification).7

A less invasive procedure is that of sputum examination, from which an evaluation of treatment can be made, for example the inclusion of immunosuppressants (methotrexate and sulfasalazine) or antifungals (oral itraconazole) or biologics (omal-izumab, the anti-IgE monoclonal antibody). Sputum also provides a useful source of asthma biomarkers, used in both phenotyping and also as indicators of therapeutic response. It is by linking the clinical phenotypes of asthma with mechanisms of disease data obtained through the integration of genetic, transcriptomic and proteomic technologies, that the diagnosis and treatment of asthma may be improved. It is hoped that this will lead towards tailored, therapeutic strategies for asthma, with any luck before the passing of another five millennia!

Blog written by Diane Lee

  1. Brown HM, et al. Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet 1958; 2: 1245–1247.

 

  1. Wenzel SE, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160: 1001–1008.

 

  1. Woodruff PG, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009; 180: 388–395

 

  1. Bel EH, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371: 1189–1197.

 

  1. De Boever EH, et Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial. J Allergy Clin Immunol 2014; 133: 989–996.

 

  1. Serrano-Pariente J, et al., Identification and characterization of near-fatal asthma phenotypes by cluster analysis. Eur J Allergy Clin Immunol 2015; 70: 1139-1147.

 

  1. Doberer D, et al., Should lung biopsies be performed in patients with severe asthma? Eur Respir Rev 2015; 24: 525–539
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s