To the Editor
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a debilitating
inflammatory disease of the sinonasal cavities.1Concomitant CRSwNP and asthma, together with hypersensitivity reactions
to cyclooxygenase-1 (COX-1) inhibitors, is a particular phenotype known
as aspirin exacerbated respiratory disease (AERD), which is associated
with greater disease severity.2
In this study, we attempted to characterize clinical, laboratory, and
transcriptomic differences between patients with AERD (N=13) and CRSwNP
patients without AERD (N=13).
We compared patient demographics and clinical characteristics
(Table 1 ). A more severe clinical phenotype with asthma
presence and a higher number of sinus surgeries was noticed in AERD
patients. LM scores in AERD were significantly higher compared to CRSwNP
patients (20 (IQR 16-23) vs. 14 (IQR 14-18), respectively, P = 0.0065,Figure 1A ). Peripheral blood eosinophil counts were not
significantly different between the groups (Figure E1A ).
However, blood eosinophil counts had a positive correlation with LM
scores in CRSwNP patients (R = 0.65, P = 0.018, Figure E1C ),
while this correlation was absent in AERD (R = -0.33, P = 0.26,Figure E1B) . Neutrophil counts were higher in the polyp tissues
of AERD patients (8.5 cells per hpf (IQR 3-25) vs. 2.5 cells (IQR 2-5)
in CRSwNP (P = 0.026, Figure 1B ). Analysis of the inflammatory
cell infiltrates on histologic slides showed that both groups had
abundant but similar eosinophil counts (Figure 1C ).
We then conducted the whole-transcriptomic sequencing, followed by
pairwise comparisons of gene expression between the AERD and CRSwNP
polyps. A stringent analysis of the transcriptomic data using a false
discovery correction (FDR) narrowed down the differentially expressed
genes (DEGs) to 10 protein-coding genes significantly downregulated in
AERD compared to CRSwNP (Figure 1D , Table E1). In
AERD, there was a downregulation of the genes coding for epidermal
differentiation marker (CALM3, CRNN), keratinsation (CNFN ,KRT13 , SPINK5 ), secreted mucin protein MUC2,and epidermal barrier marker genes (SPINK5, CRNN, A2ML1) .
Functional analysis of significant DEGs using Ingenuity Pathway Analysis
highlighted biological pathways enriched with AERD status such as
organismal injury (N = 264, P = 1.66 x 10-6),
inflammatory responses (N = 147, p = 5.95 x 10-20),
humoral immune response (N = 34, p =5.95 x 10-20), and
cell morphology (N = 73, p = 4.45 x 10-14;Figure 1E-G ).
Taken together, these findings underline the key differences in patients
with CRSwNP, with and without AERD. Compared to CRSwNP patients, we
observed that AERD patients were likely to have a more severe clinical
disease. This was associated with a downregulation of genes responsible
for the epithelial barrier function. AERD has a strong type-2
inflammation, but a simultaneous increase in the presence of neutrophils
suggests that AERD is characterized by mixed Th17 along with Th1 and Th2
immune responses assocaited with eosinophils3 While
blood eosinophils were not sufficiently predictive of type 2
inflammation in patients with chronic rhinosinusitis without nasal
polyps,4 here we show that peripheral blood
eosinophilia was significantly associated with LM scores in CRSwNP
patients. This finding was not relevant to AERD patients, indicating
that other cells, perhaps neutrophils, contribute to the severity of the
polyp burden in AERD. The presence of a mixed eosinophilic and
neutrophilic inflammation has recently been reported in a more severe
phenotype of CRSwNP.5 Such phenotype is likely due to
the presence of Charcot-Leyden crystals that attract neutrophils and
lead to a greater barrier dysfunction and bacterial
colonization.5,6 Our observations also suggest that
the clinical characteristics of AERD, as a more severe phenotype of
CRSwNP, are linked to a distinct dysregulation of epithelial barrier
function in AERD polyps, offering a basis for further mechanistic
studies on epithelial remodeling and inflammation of the upper and lower
airways.