Endotypes of chronic rhinosinusitis: Impact on management.

Following the trend in asthma, endotypes for chronic rhinosinusitis with nasal polyps have been established, with type 2 immune reactions representing >80% of nasal polyp cases in Europe and the United States. Endotyping is without doubt useful to predict the natural course of disease, to determine pharmacotherapy and the extent of surgery, and lately also to select patients for treatment with type 2 biologics. However, with the opening of this new era of treatment, limitations of the current possibilities in subgrouping patients also became apparent, as (1) mixed endotypes often can be found and (2) predictions as to the best biologic to be used in an individual patient are not yet possible. Some of the questions to address in the near future are discussed.

Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2-mediated inflammatory disease associated with significant clinical, social, and economic burdens and high unmet therapeutic need. Dupilumab, a fully human monoclonal antibody targeting the interleukin-4 receptor α (IL-4Rα) subunit, demonstrated efficacy and acceptable safety in CRSwNP and other type 2 diseases (eg, atopic dermatitis and asthma). We now report the local effects of dupilumab on type 2 inflammatory biomarkers in nasal secretions and nasal polyp tissues of patients with CRSwNP in a randomized, placebo-controlled, phase 2 trial (NCT01920893). METHODS: Cytokines, chemokines, and total immunoglobulin E (IgE) levels were measured using immunoassay techniques in nasal secretions and nasal polyp tissue homogenates of CRSwNP patients receiving dupilumab 300 mg or placebo weekly for 16 weeks. RESULTS: With dupilumab, type 2 biomarker concentrations decreased in nasal secretions (least squares mean area under the curve from 0 to 16 weeks for the change from baseline) vs placebo for eotaxin-3 (-30.06 vs -0.86 pg/mL; P = 0.0008) and total IgE (-7.90 vs -1.86 IU/mL; P = 0.022). Dupilumab treatment also decreased type 2 biomarker levels in nasal polyp tissues at Week 16 vs baseline for eosinophilic cationic protein (P = 0.008), eotaxin-2 (P = 0.008), eotaxin-3 (P = 0.031), pulmonary and activation-regulated chemokine (P = 0.016), IgE (P = 0.023), and IL-13 (P = 0.031). CONCLUSIONS: Dupilumab treatment reduced multiple biomarkers of type 2 inflammation in nasal secretions and polyp tissues of patients with CRSwNP, demonstrating that antagonism of IL-4Rα signaling suppresses IL-4-/IL-13-dependent processes, such as mucosal IgE formation, as well as the expression of chemokines attracting inflammatory cells to the nasal mucosa.

Lactate dehydrogenase as an indicator of severe illness in neonatal intensive care patients: a longitudinal cohort study.

AIM: Lactate dehydrogenase (LDH) increases in several critical conditions that cause cell damage and could potentially be used for early detection of serious illness in the newborn. Our aim was to investigate the relationship between the early clinical course of NICU infants and LDH in plasma at admission. METHODS: LDH was measured in a cohort of patients consecutively admitted to a major NICU in Hanoi. The infants were classified as 'obviously needing intensive care during the first week' (n = 83) or 'not receiving intensive care measures during the first week' (n = 260) by a senior neonatologist blinded to the LDH and lactate activity. RESULTS: LDH differed significantly between the groups in infants born after 32 gestational weeks. LDH differed with the vitality of the patient (F = 26.25, p < 0.0001) at admittance and correlated with lactate (R = 0.496, p < 0.0001). Also, the predictive value for obvious need of intensive care was higher for LDH than for lactate assessed by area under the curve calculated with ROC-curves [0.82 (0.77-0.88) vs. 0.67 (0.60-0.75)]. CONCLUSION: There is a strong relationship between bad clinical condition of infants during first week of life and elevated plasma LDH. The results suggest that LDH might be a valuable support in decision making in the neonatal period.

Endoscopic Sinus Surgery for Type-2 CRS wNP: An Endotype-Based Retrospective Study.

OBJECTIVES: Nasal polyps are often characterized by type 2 inflammation and disease recurrence. We developed a new surgical technique, referred to as reboot approach, which aims to maximally remove all sinus mucosa and allow healthy re-epithelialization from the preserved nasal mucosa. We here review type 2 endotype chronic rhinosinusitis with nasal polyps (CRSwNP) patients who underwent classical mucosa-sparing endoscopic sinus surgery (ESS) or the reboot approach. METHODS: Retrospective case-control study of 50 consecutive CRSwNP patients who underwent endoscopic sinus surgery between 2015 and 2017, either as a classical non-reboot ESS (n = 20); a partial reboot approach removing the mucosa of the ethmoidal, sphenoidal, and maxillary sinuses (n = 18); or a complete reboot approach including Draf III and removal of all frontal sinus mucosa (n = 12). Polyp recurrence over the follow-up period of 2 years served as the primary outcome. RESULTS: All patients demonstrated a type 2 inflammation of the mucosal tissue harvested during surgery. In the classical approach group (n = 20), nine patients relapsed within 2 years (45%); in the partial reboot group, three out of 18 patients (17%) relapsed; and in the full reboot group one out of 12 patients (8%) relapsed. The relapse rates were significantly different between the non-reboot and the reboot groups (P = 0.02) but also between all treatment groups (P = 0.038). CONCLUSION: Complete removal of diseased mucosa from the paranasal sinuses (reboot approach) significantly reduces the recurrence of nasal polyps for 30 months postoperatively compared to the current mucosa-sparing approach in type 2 inflammatory CRSwNP. LEVEL OF EVIDENCE: 3b Laryngoscope, 129:1286-1292, 2019.

Emerging biologics for the treatment of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a prevalent chronic inflammatory disease of the nasal and paranasal cavities and is known to seriously impair quality of life in affected patients. CRS appears to be a heterogeneous group of diseases with different inflammatory and remodeling patterns, suggesting that not only different clinical phenotypes but also pathophysiological endotypes occur. CRS with nasal polyps (CRSwNP) is considered a more severe phenotype, especially when associated with comorbid asthma, as patients having this condition often do not respond to conventional treatment, including topical and systemic corticosteroids or surgery. Recently, studies with biologic agents have shown various effects in severe airway disease; specifically in Th2-biased CRSwNP, these effects were very promising. The greatest challenge for the future is to define the different endotypes of CRSwNP using easily accessible biomarkers to select the patients who have the best chance of a positive therapeutic response to innovative approaches.