As with idiopathic nasal polyposis, the NPs observed in CF comprise a heterogeneous range of disorders. A weakness of this investigation is that these data represent a modest pilot study with few subjects and thus do not enable us to accurately predict the relative frequency of each condition. It remains possible that other presentations may also occur. This is important to consider in making the correct diagnosis and determining treatment options. In general, these studies suggest that as with idiopathic NPs, the most common presentations are eosinophilic and non-eosinophilic disorders, with slightly more than half of patients presenting without eosinophils. The presence of eosinophilia in CF NPs has previously been noted; Neely et al15
commented that CF NPs “frequently” had marked eosinophilia. In contrast to these 2 studies. Tos et al9
found predominantly plasma cells and lymphocytes in their 11 CF NPs, with only 1 sample demonstrating eosinophilia. As noted above, non-eosinophilic NPs in patients without CF are thought to result from anatomic defects or inflammatory processes of the nares that obstruct the sinus ostia. This obstruction leads to recurrent protracted infections, ultimately leading to remodeling of the airways with glandular hyperplasia, fibrosis, and the presence of a chronic inflammatory (mononuclear cell) infiltrate.3
This disease frequently responds to surgery or other interventions that open the sinus ostia and prevent recurrent infection. This pathology is consistent with the non-eosinophilic disease observed in more than half of our CF NP samples. In patients with CF, this disease could reflect either the occlusion of the sinus ostia by inspissated mucus or, more likely, the inability to clear the thickened mucus characteristic of CF and the secondary development of a vicious circle involving infection, remodeling, glandular hyperplasia, and recurrent infection.
We initiated these studies with the expectation that we would identify eosinophilia in at least a subset of CF patients. There was heterogeneity in the eosinophil numbers we observed in the CF NPs. Five of the subjects displayed eosinophilic infiltrate with an average of 5 eosinophils per HPF (see ), which is similar to our previous findings in non-CF NPs, in which we observed an average of 9.3 eosinophils per HPF in samples with a marked eosinophilic infiltrate.3
In the remaining 7 CF NPs, the eosinophil average was 0.26 eosinophils per HPF (see ), consistent with the non-eosinophilic group (2.9 eosinophils per HPF) of non-CF NPs we identified.3
In non-CF NPs, the presence of eosinophilia often correlates with the presence of allergic rhinitis or asthma. As allergens do not readily enter the sinus space,16
the mechanism driving eosinophilia is not obvious. It has been argued that the eosinophilia reflects an underlying tendency of the sinuses to produce a Th2 inflammatory reaction to immune insults.3,11,17
Patients with CF are uniquely predisposed to develop a Th2 immune response to fungi that colonize their lower airways, and up to 20% of CF patients, as noted, develop allergic bronchopulmonary aspergillosis.13
Although none of our patients presented with allergic fungal sinusitis, it remains possible that the subjects with eosinophilia could still be displaying a Th2 response to pathogens, including fungi, that had colonized their sinus cavities.
The most striking feature in these NPs was the presence of neutrophils in 4 of 10 samples — something that we almost never observe in idiopathic NPs of non-CF patients. The presence of neutrophils likely reflects trafficking of the cells in response to chemotactic stimuli different from those found in the NPs of non-CF patients. The distinguishing feature of CF lower airway disease is the almost universal colonization with bacteria — typically, gram-negative organisms. Although this is not the focus of the present study, it is reasonable to argue that CF similarly predisposes patients to colonization of the sinuses with bacteria and biofilm formation. Neutrophilia would then reflect the migration of these cells from the vasculature in response to this process. A role for PMNs is further supported by our studies regarding granulocyte biomarker expression in sinus secretions. As sinus secretions were obtained during routine clinic visits and not as a part of the polypectomy, we cannot directly correlate expression of mediators in mucus samples with polyp histology. Despite this caveat, as with the NPs, markedly elevated concentrations of myeloperoxidase were seen in half of these specimens, and again, this is something not routinely observed in non-CF chronic sinus disease. Van Zele et al18
found elevated levels of myeloperoxidase (as well as CXCL8 [IL-8]) in CF-derived sinus secretions, also pointing to a prominent role for PMNs. Even more impressive were our extracellular DNA concentrations, which were elevated in all of the CF specimens and to an extent higher than those we have observed in non-CF disease. Extracellular DNA is primarily derived from granulocytes, secreted as a component of neutrophils and eosinophils (mitochondrial-derived and nuclear-derived DNA nets, respectively) as part of their antibacterial response.14,19
In addition, extracellular DNA reflects cellular necrosis and the presence of inhibitors of phagocytosis of apoptotic bodies.20
These striking elevations in DNA content contribute to the viscosity of secretions and the inability to clear them (even with surgery and postsurgical irrigations) and will thereby contribute to the infection-remodeling-infection process. Elevations in DNA content are also consistent with reports that in attempts to reduce viscosity in the lung, CF secretions respond best to DNase.21-23
This approach is being tested as a therapeutic option following sinus surgery. Administration of dornase alpha between 4 weeks and 12 months after surgery was associated with improved nasal symptoms and rhinoscopic findings.22
A recent double-blind placebo-controlled study found that dornase alpha improved quality-of-life outcome measures in subjects who had previously undergone sinus surgery.24
As found in non-CF NPs, these samples all demonstrated a mononuclear infiltrate. As noted, Tos et al9
also prominently found plasma cells in CF NPs. These are also seen in non-CF NPs, implying the development of secondary lymphoid tissue and antibody production. The target of these antibodies was not the subject of this study, but could include colonizing bacteria or other pathogens. Along with plasma cells and lymphocytes, large numbers of mast cells were seen in many of these NPs (6 of 10). This finding is consistent with those of Henderson and Chi25
demonstrating the presence of mast cells in CF NPs, 30% of which appeared to have undergone spontaneous degranulation. Although typically associated with allergic processes, mast cells are a component of fibrotic disorders reflecting a synergistic feedback process wherein mast cells provide fibroblast-targeting growth factors and fibroblasts respond in kind as sources of mast cell growth factors. This process is consistent with our finding of mast cells within areas of thickened stroma ().
Our findings demonstrate that CF NPs are not a distinct subtype, but rather, exhibit features of the well-described subtypes of non-eosinophilic sinusitis and chronic hyperplastic eosinophilic sinusitis. The striking feature of CF NPs was the frequent association of both eosinophilic and non-eosinophilic diseases with the presence of neutrophilia — something virtually never observed in idiopathic NPs. Even when not present in the NP itself, evidence of neutrophilic inflammation was universally present in the mucous secretions, as manifested through the presence of extracellular DNA. These data suggest the need for investigating appropriately targeted therapeutic approaches based upon each patient's unique histologic presentation.