Transcriptional Changes in Chronic Rhinosinusitis with Asthma Favor a Type 2 Molecular Endotype Independent of Polyp Status

Figures & data

Table 1 Baseline Demographic Data for Patients with CRS Enrolled in This Study (N =34)

	CRS (n=15)	CRS-A (n=19)	p-value
Age			0.12
- Mean (SD)	52.60 (17.07)	42.79 (18.23)
- Range (Min-Max)	52 (21–73)	58 (15–73)
Gender			0.70
- Female	6	10
- Male	9	9
Nasal polyposis
-Yes	7	10	1
-No	8	9
Migraines
-Yes	4	0	0.03
-No	11	19
Diabetes Mellitus
-Yes	3	1	0.30
-No	12	18
GERD
-Yes	5	7	1
-No	10	12
AERD
-Yes	0	1	1
-No	15	18
Cystic Fibrosis
-Yes	0	0	1
-No	15	19
Atopy
-Yes	9	13	0.88
- No	6	6
Tobacco Use
-Yes	0	2	1
- No	15	17
Lund-MacKay			0.25
-Mean (SD)	10.20 (5.00)	12.42 (6.11)
-Range (Min-Max)	17 (3–20)	21 (3–24)
Lund-Kennedy			0.52
-Mean (SD)	5.12 (3.46)	6.12 (4.92)
-Range (Min-Max)	12 (0–12)	20 (0–20)

Abbreviations: AERD, aspirin-exacerbated respiratory disease; CRS, chronic rhinosinusitis; CRSsNP-A, asthma-related chronic rhinosinusitis without nasal polyposis; CRSsNP, non-asthma chronic rhinosinusitis without nasal polyposis; CRSwNP-A, asthma-related chronic rhinosinusitis with nasal polyposis; CRSwNP, non-asthma chronic rhinosinusitis with nasal polyposis; GERD, gastroesophageal reflux disease.

Table 2 Patient-Reported Outcome Measure (PROM) Comparisons

	CRSsNP (N=8)	CRSsNP-A (N=9)	p-value	CRSwNP (N=7)	CRSwNP-A (N=10)	p-value
Baseline SNOT-22
-Mean (SD)	57.80 (7.40)	50.50 (15.83)	0.29	56.25 (20.58)	65.00 (23.28)	0.52
-Range (Min-Max)	17 (49–66)	45 (24–69)		45 (26–71)	71 (31–102)
RSDI Physical Subdomain
-Mean (SD)	17.4 (8.32)	16.125 (8.37)	0.80	25.00 (9.30)	26.40 (12.48)	0.85
-Range (Min-Max)	21 (5–26)	25 (2–27)		22 (15–37)	30 (11–41)
RSDI Emotional Subdomain
-Mean (SD)	14.6 (4.16)	10.25 (11.49)	0.35	20.40 (11.41)	20.60 (11.84)	0.98
-Range (Min-Max)	11 (9–20)	33 (0–33)		29 (9–38)	29 (0–29)
RSDI Functional Subdomain
-Mean (SD)	18.50 (4.04)	10.0 (8.28)	0.03	18.20 (10.71)	24.20 (13.46)	0.46
-Range (Min-Max)	9 (14–23)	26 (2–28)		28 (8–36)	34 (1–35)
RSDI Total
-Mean (SD)	50.80 (12.99)	36.38 (26.76)	0.22	63.80 (29.28)	69.60 (36.20)	0.79
-Range (Min-Max)	31 (35–66)	80 (8–88)		76 (35–111)	87 (12–99)
PHQ-2
-Mean (SD)	1.33 (0.82)	1.38 (1.85)	0.96	2.60 (1.67)	2.40 (2.51)	0.89
-Range (Min-Max)	2 (0–2)	5 (0–5)		4 (1–5)	0 (0–6)

Abbreviations: CRSsNP-A, asthma-related chronic rhinosinusitis without nasal polyposis; CRSsNP, non-asthma chronic rhinosinusitis without nasal polyposis; CRSwNP-A, asthma-related chronic rhinosinusitis with nasal polyposis; CRSwNP, non-asthma chronic rhinosinusitis with nasal polyposis; PHQ-2, Patient Health Questionnaire 2; SNOT-22, SinoNasal Outcomes Test 22; RSDI, Rhinosinusitis Disability Index; SD, standard deviation.

Table 3 Inflammatory Gene Expression Ratio Comparisons in the Peripheral Blood of Patients with CRSsNP-A vs CRSsNP

Gene	CRSsNP-A/CRSsNP Gene Expression Ratio	p-value
HLA-DRB3*	1.36	0.04
CASP2**	0.91	0.02
NFATC3**	0.89	0.04
NFKB1**	0.79	0.02

Notes: *Upregulated genes; **downregulated genes.

Abbreviations: CRSsNP-A, asthma-related chronic rhinosinusitis without nasal polyposis; CRSsNP, non-asthma chronic rhinosinusitis without nasal polyposis.

Table 4 Inflammatory Gene Expression in the Peripheral Blood of Patients with CRSwNP-A vs CRSwNP

Gene	CRSwNP-A/CRSwNP Gene Expression Ratio	p-value
CCL4*	1.49	0.01
IKBKB*	1.20	0.04
IKZF2*	1.37	0.02
ILF3*	1.17	0.02
B2M**	0.85	0.003
C9**	0.61	0.02
CAMP**	0.50	0.008
CD1A**	0.73	0.02
CD82**	0.79	0.04
CX3CL1**	0.75	0.04
CXCL13**	0.67	0.04
HLA-DPA1**	0.84	0.04
IL18RAP**	0.58	0.02
IL28A**	0.67	0.04
IRF1**	0.76	0.01
KIR3DL2**	0.75	0.01
KIR3DL3**	0.49	0.03
MAPK11**	0.72	0.01
PDGFB**	0.70	0.04
PSMB8**	0.83	0.01
S100A8**	0.61	0.02
XCR1**	0.63	0.01

Notes: *Upregulated genes; **downregulated genes.

Abbreviations: CRSwNP-A, asthma-related chronic rhinosinusitis with nasal polyposis; CRSwNP, non-asthma chronic rhinosinusitis with nasal polyposis.

Figure 1 Genetic transcriptional changes in peripheral blood favor a type 2 inflammatory profile among patients with CRSsNP-A compared to CRSsNP. (A) HLA-DRB3 is significantly upregulated in CRSsNP-A compared to CRSsNP (Th2, p<0.02). (B) CASP2 (Th2, p<0.04), NFATC3 (Th2, p<0.04), and NFKB1 (Th2, p<0.02) are downregulated in CRSsNP-A compared to CRSsNP.

Figure 2 Upregulated genetic transcriptional changes in peripheral blood favor a type 2 inflammatory profile among patients with CRSwNP-A compared to CRSwNP. CCL4 (Th2, p<0.01), IKBKB (Th2, p<0.04), IKZF2 (Th2, p<0.02), and ILF3 (Th2, p<0.02) are significantly upregulated in CRSwNP-A compared to CRSwNP.

Figure 3 Downregulation of genes predominantly associated with Th1 and Th17 inflammation in peripheral blood favor an overall type 2 profile in patients with CRSwNP-A compared to CRSwNP.