Elevated Cord Blood Levels of Mannose-Binding Lectin-Associated Serine Protease-2 (MASP-2) in Infants with Necrotizing Enterocolitis – a Case-Control Study

Abstract

Background: While the general prognosis for premature infants has improved in recent years, morbidity and mortality due to necrotizing enterocolitis (NEC) remain high. Several innate immunity polymorphisms have been proposed to explain susceptibility to NEC, but the data are conflicting. Mannose-binding lectins (MBL) are soluble pattern-recognition receptors that bind MBL-associated serine protease-2 (MASP-2), thereby activating the complement system by the so-called lectin-pathway. Deficiency of either MBL or MASP-2 due to single nucleotide polymorphisms is common. While MBL deficiency has been associated with neonatal sepsis and pneumonia, the role of the lectin pathway regarding NEC remains unknown. AIM: To investigate whether cord blood MBL and MASP-2 levels are associated with both the development and the severity of NEC. Methods: Case-control study including 32 infants with radiologically confirmed NEC and 64 controls. The controls were matched for gestational age, intrauterine growth retardation, prenatal steroid administration, birth asphyxia and chorioamnionitis. MBL and MASP-2 were measured in cord blood using ELISA. Low (high) MBL levels were defined as <700ng/ml (=/>700ng/ml) according to the literature. Low (high) MASP-2 levels were defined as <30ng/ml (=/>30ng/ml) using receiver-operating-characteristics analysis. Multivariate logistic regression was performed. Results: Of the 32 NEC cases (median gestational age 30.5 weeks, range 25–39), 19 (59%) were managed conservatively, 13 (41%) were operated and 5 (16%) died. MBL cord blood concentration correlated positively with gestational age (p=0.024), while no age-dependent effect was found for MASP-2. MASP-2 cord blood concentration ranged from undetectable (<5ng/ml) to 277ng/ml. 18 of 32 (56%) NEC cases had high MASP-2 levels (>30ng/ml) compared to 22 of 64 (34%) controls (univariate OR 2.46; 95%-CI 1.03–5.85; p=0.043). Multivariate analysis confirmed that high cord blood MASP-2 levels were significantly associated with an increased risk of NEC (OR 3.00; 95%-CI 1.17–7.93; p=0.027). MBL levels were not associated with NEC (for low MBL: multivariate OR 1.25; 95%-CI 0.49 to 3.22; p=0.64). No association was found between MBL and MASP-2 levels and NEC severity. Conclusions: Infants developing NEC had significantly more frequently high MASP-2 cord blood levels compared to controls. Elevated MASP-2 levels may favour complement-mediated inflammation and could thereby predispose to NEC. In contrast, the extremely low levels of MASP-2 found in most premature infants compared to the values reported from older children suggest that the lectin pathway of complement activation is often not fully functional at birth which may represent a protective mechanism against NEC.