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Noneosinophilic asthma: A distinct clinical and pathologic phenotype

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The use of induced sputum to assess airway inflammation in large and diverse populations with asthma has led to the recognition that significant numbers of patients do not have evidence of eosinophilic airway inflammation. The absence of a sputum eosinophilia has been noted in patients across the range of asthma severity; it has also been reported in patients presenting with an asthma exacerbation. However, whether noneosinophilic asthma represents a pathologically distinct and clinically important asthma phenotype remains unclear. In this review, we present recent evidence suggesting that noneosinophilic asthma represents a stable phenotype associated with a distinct lower airway pathology and structure. We suggest that this lower airway inflammation develops in response to etiologic factors acting through the innate immune pathway and that elements of this immune response contribute to airway dysfunction. Finally, we argue that noneosinophilic asthma is associated with clinically important differences in natural history and treatment response. We particularly highlight evidence that noneosinophilic asthma is associated with a reduced short-term and long-term response to corticosteroid therapy.

Section snippets

Defining noneosinophilic asthma

There are 4 important elements to this diagnosis: the presence of typical symptoms, objective evidence of variable airflow obstruction and/or airway hyperresponsiveness, the consistent absence of a sputum eosinophil count, and the absence of an alternative explanation for the symptoms and findings on investigation (Table I). Values for the upper limit of the eosinophil count that constitutes noneosinophilic disease have varied between studies. Green et al19 used <1.9%, the upper limit of the

Stability of noneosinophilic asthma

There is limited evidence from longitudinal studies to address the question of whether noneosinophilic asthma is a consistent phenotype over time. Simpson et al32 have recently shown that the absence of a sputum eosinophilia is a consistent finding at 4 weeks and 5 years after first sputum induction, and Green et al16 identified a subgroup of patients with refractory asthma who had predominantly noneosinophilic sputum on repeated observations made over a period of 12 months. However, 70% of

Histopathologic features of noneosinophilic asthma

In a study of patients with severe asthma, Wenzel et al24 have shown that noneosinophilic disease defined histologically by the absence of eosinophils in the mucosa was associated with normal thickness of the subepithelial basement membrane and a lower number of CD3+ cells and macrophages, compared with severe eosinophilic asthma. These differences were present despite the use of comparable doses of corticosteroid therapy by patients in each group. Berry et al21 reported similar differences in

Mechanisms of airway inflammatory response and disordered airway function

It has been suggested that the different inflammatory profiles now recognized in asthma populations are a result of different patterns of antigen exposure in the airways.36 Thus, eosinophilic disease is considered a consequence of allergen mediated activation of mast cells and T cells in the airway with release of TH2 cytokines. In contrast, neutrophilic inflammation is the product of innate and cell mediated immune responses. Numerous etiologic factors are believed to evoke responses along

Is noneosinophilic asthma clinically important?

The view that noneosinophilic asthma represents a clinically important asthma phenotype would be strengthened if there were evidence of differences in epidemiology, natural history, or treatment response. These possibilities have not been explored extensively, and much of the available work is limited by the population size and the uncontrolled, observational nature of the studies. However, there is growing evidence that noneosinophilic asthma is associated with a difference in epidemiology,

Conclusion

There does seem to be sufficient evidence to support the existence of a subgroup of patients with asthma who have stable noneosinophilic and often neutrophilic disease. In comparison with eosinophilic asthma, patients with noneosinophilic asthma have differences in airway histopathology, airway structure, mechanisms of airway dysfunction, potential etiologic factors, response to treatment, and perhaps prognosis. The identification of this phenotype at the time of diagnosis is important, because

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    (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

    Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

    Disclosure of potential conflict of interest: I. D. Pavord has received grant support from GlaxoSmithKline and is on the speakers' bureau for GlaxoSmithKline and AstraZeneca. P. Haldar has declared that he has no conflict of interest.

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