Rethinking chronic rhinosinusitis phenotypes

It is the currently accepted practice to sort chronic rhinosinusitis (CRS) into 2 phenotypes distinguished solely according to the presence (CRSwNP) or absence (CRSsNP) of nasal polyps (NPs). This dichotomy was based in part on the relative ease of determining whether NPs are present and the seeming distinct immune and pathologic presentations of these 2 conditions.¹ Thus the presence of NPs suggests the presence of an eosinophilic disease with a prominent T_H2 cytokine signature and, in particular, the presence of the most important cytokine driving eosinophilic inflammation: IL-5. In contrast, defining the immune and pathologic basis underlying CRSsNP has been more controversial but is less likely to be characterized by eosinophils and a T_H2/IL-5 signature.²

However, this concept that the presence of NPs alone could be the basis for assuming the presence of an IL-5^high eosinophilic process has been rife with controversy. This controversy included the striking observation that although NPs in European studies were seemingly universally eosinophilic in nature, those evaluated in China were equally universally neutrophilic. Also, for those of us practicing elsewhere, the extent of eosinophilia can be quite variable. For example, at the University of Virginia, pathologic examination of 76 consecutive surgically derived polyps demonstrates a split of 84.2%/15.8% between those that are predominantly eosinophilic and neutrophilic, respectively (unpublished data). Therefore the study by Wang et al³ in the current issue of the Journal is a valuable advance in our understanding of these regional differences in CRS pathology and immune profiles and, more importantly, begins to force a rethinking of how CRS should be subgrouped.

The timing for this rethinking is especially appropriate because although in 2016 there are still no US Food and Drug Administration–approved therapeutics for CRS, we are on the cusp of major pharmacologic advances. However, the specific mechanistic-based targeting of CRS therapeutics will require demonstrating the presence of an appropriate histologic and immune signature that will predict efficacy. For example, just as in asthma, where there was from the beginning a compelling literature that corticosteroid efficacy is dependent on the presence of eosinophils, this will almost certainly also be true in patients with CRS, in whom highly variable responsiveness to corticosteroids is also observed.⁴ Also, similarly, preliminary studies evaluating the benefit of anti–IL-5 in patients with CRS have shown that, as with asthma, the presence of an eosinophil^highIL-5^high state is required to predict responsiveness.⁵

The problem is that although in Europe, Australia, the United States, and Japan CRSwNP is most often an IL-5^high state, large numbers of these polyps display neither IL-5 (17% in Benelux in the current study) nor a high eosinophil peroxidase/myeloperoxidase ratio (approximately 30% in Benelux). These subjects will be unlikely to respond to IL-5 antagonism or perhaps to steroid irrigation or other T_H2 antagonists. Also, obviously, the response rate with these agents in Chengzu, China, will be even lower. What is also intriguing is that many of the subjects in the current study without NPs displayed a T_H2^high signature with increased levels of IL-5 (30% in Benelux) along with high concentrations of eosinophil cationic protein (approximately 40%). The absence of polyps in these patients reflects either the location of the inflammation in the sinus (away from any sinus ostia) or merely that the NPs have not been developed yet. Either way, these are presumably patients who will respond to therapies targeting these immune processes, and more importantly, this suggests that they have an endotype identical to those with T_H2^high/IL-5^high/eosinophil^high CRSwNP.

Although early studies argued that CRSsNP seemed to be a T_H1- or perhaps even T_H17-prominent disease,¹ more recent studies have not been able to confirm this and, alternatively, suggest that this condition is most often not associated with any particular T-effector signature.⁶ The current study confirms that a plurality of these subjects do not demonstrate cytokines associated with any T-effector signature. What is again interesting is that the pattern of inflammation and cytokines observed in patients with CRSsNP is quite similar to that observed in patients with noneosinophilic CRSwNP disease. Again, this suggests that the IL-5^low/eosinophil^low signature represents a distinct endotype (or perhaps distinct endotypes) that might be present in most CRSsNP samples and, outside of China, a significant minority of CRSwNP samples. Therefore a compelling argument can be made that it is time to move past the subgrouping of CRS solely on the basis of whether polyps exist but instead demand that pathology be obtained from patients with CRS, especially those undergoing surgery, to permit initiation of appropriate endotype-specific treatments.

Another question arising from this article is what is driving these distinct presentations of CRS. Presumably, there are genetic and environmental factors involved. However, what is particularly intriguing is that these presentations are not fixed but are evolving over time.^7,8 It has been argued that there have been distinct “allergy” epidemics: those for allergic rhinitis (1870–1920), asthma (1960–1990), and food allergy (1990–present) and perhaps a fourth epidemic if we include eosinophilic esophagitis.⁹ Eosinophilic esophagitis seemingly did not exist or at least barely registered just a generation ago. It seems plausible that just as eosinophils did not used to attack the esophagus, perhaps until recently, they seldom attacked the sinuses. CRS itself is less frequent in China, with a prevalence of 2.1% to 8% compared with the 7% to 27% prevalence reported in Europe.¹⁰ Perhaps the seemingly unique presentation of noneosinophilic CRS in China represents the historic frequency of neutrophilic/IL-5^low CRS in all human populations. The actual prevalence of this particular phenotype might be similar in China and Belgium and, indeed, might be comparatively low. If true, like Thailand and Korea,^7,8 China will soon see an epidemic of eosinophilic CRS, which will become the most prominent presentation observed there as well.

In summary, this study makes several important advances in our understanding of CRS. CRS can present as at least 2 distinct diseases that can be defined histologically and immunologically by the presence or absence of an eosinophil^high/IL-5^high state. Currently, there are striking regional differences in the prevalence of these 2 phenotypes. In combination with studies showing the temporal evolution of noneosinophilic into eosinophil-predominant diseases, an intriguing implication is that eosinophilic CRS is a new disease created by a modern hygiene-associated lifestyle, and the sinuses can now join the ranks of the nose (allergic rhinitis), lung (asthma), and gut (eosinophilic esophagitis) as organs routinely afflicted with a T_H2/eosinophilic disease. This study also demonstrates that, although at varying frequencies, an eosinophil^low/IL-5^low process can be present in both patients with CRS and those with CRSwNP, and similarly, eosinophil^high/IL-5^high tissue samples can be identified in both of these traditional presentations. These endotypes will define individualized therapeutics, including predicting efficacy to anti–IL-5, other eosinophil antagonists, and likely corticosteroids. Thus the current study begins to make a compelling argument that it might be time to move past the defining of CRS purely on the basis of whether there are NPs and instead require pathologic (and perhaps immunologic) analysis of tissue samples as the proper basis for subgrouping/endotyping.