Luregn J. Schlapbach

Serum concentrations of lectin-pathway components in healthy neonates, children and adults: mannan-binding lectin (MBL), M-, L-, and H-ficolin, and MBL-associated serine protease-2 (MASP-2).

To cite this article: Sallenbach S, Thiel S, Aebi C, Otth M, Bigler S, Jensenius JC, Schlapbach LJ, Ammann RA. Serum concentrations of lectin‐pathway components in healthy neonates, childrens and adults: mannan‐binding lectin (MBL), M‐, L‐, and H‐ficolin, and MBL‐associated serine protease‐2 (MASP‐2).Pediatr Allergy Immunol 2011;: 424–430.

Association of a pool of HIV-1 with erythrocytes in vivo: a cohort study

BACKGROUND Treatment of HIV-1-infected individuals with antiretrovirals can result in sustained suppression of plasma viral RNA at concentrations below the detection limit of available assays. However, continuing virus replication has been detected in patients with viral RNA in plasma suppressed for months to years, and many cell types are known to act as reservoirs or carriers for the virus. In vitro, erythrocytes bind HIV-1 immune complexes, so we tested for a circulating pool of HIV-1 associated with erythrocytes in people with HIV-1 infection. METHODS We investigated 82 chronically HIV-1-infected individuals. Plasma, white cells, and erythrocytes were tested for HIV-1 RNA by RT-PCR. FINDINGS Erythrocyte-associated HIV-1 RNA was detected in 80 of 82 individuals. In 23, plasma HIV-1 RNA had been undetectable (<20 copies/mL) for up to 32 months; in corresponding erythrocyte samples, there were up to 82878 HIV-1 RNA copies per mL whole blood. HIV-1 associated with erythrocytes in vivo was shown to be infectious. Within the subgroup of patients with undetectable plasma viral load, higher numbers of HIV-1 associated with erythrocytes were correlated with a history of advanced clinical stages of HIV-1 infection (p=0.014). INTERPRETATION A pool of HIV-1 is associated with erythrocytes even after long-term suppression of viral RNA in plasma. This finding is direct evidence for continuing virus replication or release in these individuals. Quantification of this viral pool may help to judge suppression of HIV-1 replication in individuals with undetectable plasma HIV-1 RNA.

Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008

BackgroundWhile survival rates of extremely preterm infants have improved over the last decades, the incidence of neurodevelopmental disability (ND) in survivors remains high. Representative current data on the severity of disability and of risk factors associated with poor outcome in this growing population are necessary for clinical guidance and parent counselling.MethodsProspective longitudinal multicentre cohort study of preterm infants born in Switzerland between 240/7 and 276/7 weeks gestational age during 2000–2008. Mortality, adverse outcome (death or severe ND) at two years, and predictors for poor outcome were analysed using multilevel multivariate logistic regression. Neurodevelopment was assessed using Bayley Scales of Infant Development II. Cerebral palsy was graded after the Gross Motor Function Classification System.ResultsOf 1266 live born infants, 422 (33%) died. Follow-up information was available for 684 (81%) survivors: 440 (64%) showed favourable outcome, 166 (24%) moderate ND, and 78 (11%) severe ND. At birth, lower gestational age, intrauterine growth restriction and absence of antenatal corticosteroids were associated with mortality and adverse outcome (p < 0.001). At 360/7 weeks postmenstrual age, bronchopulmonary dysplasia, major brain injury and retinopathy of prematurity were the main predictors for adverse outcome (p < 0.05). Survival without moderate or severe ND increased from 27% to 39% during the observation period (p = 0.02).ConclusionsIn this recent Swiss national cohort study of extremely preterm infants, neonatal mortality was determined by gestational age, birth weight, and antenatal corticosteroids while neurodevelopmental outcome was determined by the major neonatal morbidities. We observed an increase of survival without moderate or severe disability.

Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study

BACKGROUND Severe infections kill more than 4·5 million children every year. Population-based data for severe infections in children requiring admission to intensive care units (ICUs) are scarce. We assessed changes in incidence and mortality of severe infections in critically ill children in Australia and New Zealand. METHODS We did a retrospective multicentre cohort study of children requiring intensive care in Australia and New Zealand between 2002 and 2013, with data from the Australian and New Zealand Paediatric Intensive Care Registry. We included children younger than 16 years with invasive infection, sepsis, or septic shock. We assessed incidence and mortality in the ICU for 2002-07 versus 2008-13. FINDINGS During the study period, 97 127 children were admitted to ICUs, 11 574 (11·9%) had severe infections, including 6688 (6·9%) with invasive infections, 2847 (2·9%) with sepsis, and 2039 (2·1%) with septic shock. Age-standardised incidence increased each year by an average of 0·56 cases per 100 000 children (95% CI 0·41-0·71) for invasive infections, 0·09 cases per 100 000 children (0·00-0·17) for sepsis, and 0·08 cases per 100 000 children (0·04-0·12) for septic shock. 260 (3·9%) of 6688 patients with invasive infection died, 159 (5·6%) of 2847 with sepsis died, and 346 (17·0%) of 2039 with septic shock died, compared with 2893 (3·0%) of all paediatric ICU admissions. Children admitted with invasive infections, sepsis, and septic shock accounted for 765 (26·4%) of 2893 paediatric deaths in ICUs. Comparing 2008-13 with 2002-07, risk-adjusted mortality decreased significantly for invasive infections (odds ratio 0·72, 95% CI 0·56-0·94; p=0·016), and for sepsis (0·66, 0·47-0·93; p=0·016), but not significantly for septic shock (0·79, 0·61-1·01; p=0·065). INTERPRETATION Severe infections remain a major cause of mortality in paediatric ICUs, representing a major public health problem. Future studies should focus on patients with the highest risk of poor outcome, and assess the effectiveness of present sepsis interventions in children. FUNDING National Medical Health and Research Council, Australian Resuscitation Outcomes Consortium, Centre of Research Excellence (1029983).

Differential Role of the Lectin Pathway of Complement Activation in Susceptibility to Neonatal Sepsis

BACKGROUND. The incidence of bacterial sepsis during the neonatal period is high. Mannan-binding lectin (MBL), L-ficolin, and H-ficolin recognize microorganisms and activate the complement system via MBL-associated serine proteases (MASPs). This study investigated whether cord blood concentrations of the lectin pathway proteins are associated with neonatal sepsis. METHODS. This was a case-control study including 47 infants with culture-proven sepsis during the first month of life and 94 matched controls. MBL, L-ficolin, H-ficolin, MASP-2, and MASP-3 levels were measured in cord blood with use of enzyme-linked immunosorbent assay and time-resolved immunofluorometric assay. Multivariate logistic regression was performed. RESULTS. Infants with gram-positive sepsis had significantly lower H-ficolin cord blood concentrations than controls (multivariate odds ratio [OR], 4.00; 95% confidence interval [CI], 1.51-10.56; P = .005), whereas infants with gram-negative sepsis had lower MBL cord blood concentrations (OR, 2.99; 95% CI, 0.86-10.33; P = .084). When excluding patients with postoperative sepsis, multivariate analysis confirmed that low H-ficolin was associated with a significantly higher risk of gram-positive sepsis (OR, 3.71; 95% CI, 1.26-10.92; P = .017) and late-onset sepsis (OR, 3.14; 95% CI, 1.07-9.21; P = .037). In contrast, low MBL was associated with a significantly higher risk of gram-negative sepsis (OR, 4.39; 95% CI, 1.10-17.45; P = .036) and early-onset sepsis (OR, 3.87; 95% CI, 1.05-14.29; P = .042). The concentrations of all the lectin pathway proteins increased with gestational age (P < .01). CONCLUSIONS. These preliminary results indicate that low MBL concentrations are a susceptibility factor for gram-negative sepsis, and low H-ficolin concentrations indicate susceptibility to gram-positive sepsis. The decreased expression of lectin pathway proteins in neonates must be considered to be an additional form of neonatal immunodeficiency.

Serum levels of mannose-binding lectin and the risk of fever in neutropenia pediatric cancer patients

Fever in neutropenia (FN) is a frequent complication in pediatric oncology. Deficiency of mannose‐binding lectin (MBL), an important component of innate immunity, is common due to genetic polymorphisms, but its impact on infections in oncologic patients is controversial. This study investigated whether MBL serum levels at cancer diagnosis are associated with the development of FN in pediatric cancer patients.

Deficiency of mannose-binding lectin-associated serine protease-2 associated with increased risk of fever and neutropenia in pediatric cancer patients

Background: Mannose-binding lectin-associated serine protease-2 (MASP-2) is an essential component of the lectin pathway of complement activation. MASP-2 deficiency is common because of genetic polymorphisms, but its impact on susceptibility to infection is largely unknown. The aim of the present study was to determine whether children with cancer and MASP-2 deficiency develop more frequent or more severe episodes of fever and severe chemotherapy-induced neutropenia (FN). Methods: Serum MASP-2 was measured by enzyme-linked immunosorbent assay at the time of diagnosis in children treated with chemotherapy for cancer. Association of FN episodes with MASP-2 concentration was analyzed using Poisson regression accounting for chemotherapy intensity and duration. Results: Median MASP-2 in 94 children was 527 ng/mL (interquartile range, 367–686). Nine (10%) children had MASP-2 deficiency (<200 ng/mL). During a cumulative chemotherapy exposure time of 82 years, 177 FN episodes were recorded. MASP-2 deficient children had a significantly increased risk of developing FN (multivariate risk ratio, 2.08; 95% confidence interval, 1.31–3.21; P = 0.002), translating into significantly prolonged cumulative duration of hospitalization and of intravenous antimicrobial therapy. They experienced significantly more episodes of FN without a microbiologically defined etiology, and there was a trend toward more frequent episodes of FN with bacteremia. Conclusion: In this study, MASP-2 deficiency was associated with an increased risk of FN in children treated with chemotherapy for cancer. MASP-2 deficiency represents a novel risk factor for chemotherapy-related infections.

Congenital H-ficolin deficiency in premature infants with severe necrotising enterocolitis

In a recent issue of Gut , Muller et al reported on excessive colitis in a murine model of mannan-binding lectin (MBL) deficiency.1 They showed that absence of MBL can lead to uncontrolled intestinal inflammation detrimental to the host. MBL is a pattern-recognition molecule activating the complement system by the lectin pathway. H-ficolin is structurally closely related to MBL and can activate the lectin pathway of complement independently of MBL. While low levels of MBL occur in 10% of Caucasians, H-ficolin deficiency is extremely rare: studies involving over 100 000 adults found no case of H-ficolin deficiency, suggesting it exerts crucial functions for the human immune system.2 The first report on the so far only patient diagnosed with H-ficolin deficiency was published only recently,3 describing a patient with repeated infections who presented …

H-ficolin serum concentration and susceptibility to fever and neutropenia in paediatric cancer patients

H‐ficolin (Hakata antigen, ficolin‐3) activates the lectin pathway of complement similar to mannose‐binding lectin. However, its impact on susceptibility to infection is currently unknown. This study investigated whether the serum concentration of H‐ficolin at diagnosis is associated with fever and neutropenia (FN) in paediatric cancer patients. H‐ficolin was measured by time‐resolved immunofluorometric assay in serum taken at cancer diagnosis from 94 children treated with chemotherapy. The association of FN episodes with H‐ficolin serum concentration was analysed by multivariate Poisson regression. Median concentration of H‐ficolin in serum was 26 mg/l (range 6–83). Seven (7%) children had low H‐ficolin (< 14 mg/l). During a cumulative chemotherapy exposure time of 82 years, 177 FN episodes were recorded, 35 (20%) of them with bacteraemia. Children with low H‐ficolin had a significantly increased risk to develop FN [relative risk (RR) 2·24; 95% confidence interval (CI) 1·38–3·65; P = 0·004], resulting in prolonged duration of hospitalization and of intravenous anti‐microbial therapy. Bacteraemia occurred more frequently in children with low H‐ficolin (RR 2·82; CI 1·02–7·76; P = 0·045). In conclusion, low concentration of H‐ficolin was associated with an increased risk of FN, particularly FN with bacteraemia, in children treated with chemotherapy for cancer. Low H‐ficolin thus represents a novel risk factor for chemotherapy‐related infections.

Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia

BackgroundVasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia.MethodsCopeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30), chorioamnionitis (n = 33) and asphyxia (n = 25) were compared to a control group of preterm and term (n = 155) neonates.ResultsMedian copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419). Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p < 0.0001). Neonates born after vaginal compared to cesarean delivery had elevated copeptin levels (p < 0.0001). Copeptin correlated strongly with umbilical artery pH (Spearmans Rho -0.50, p < 0.0001), umbilical artery base excess (Rho -0.67, p < 0.0001) and with lactate at NICU admission (Rho 0.54, p < 0.0001). No difference was found when comparing copeptin cord blood concentrations between neonates with EOS and controls (multivariate p = 0.30). The highest copeptin concentrations were found in neonates with asphyxia (median 993 pmol/l). Receiver-operating-characteristic curve analysis showed that copeptin cord blood concentrations were strongly associated with asphyxia: the area under the curve resulted at 0.91 (95%-CI 0.87-0.96, p < 0.0001). A cut-off of 400 pmol/l had a sensitivity of 92% and a specifity of 82% for asphyxia as defined in this study.ConclusionsCopeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS.