Annelies van Zwol

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

BACKGROUND Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each days delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each days delay). INTERPRETATION We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING F Hoffmann-La Roche.

Long-term effects of neonatal glutamine-enriched nutrition in very-low-birth-weight infants

Several studies in very-low-birth-weight (VLBW) infants have investigated the effect of parenteral or enteral glutamine supplementation on morbidity, mortality, and outcome in the neonatal period. No evidence of toxicity of glutamine supplementation was found in these clinical trials, but the results for efficacy on a limited number of outcomes have been mixed. The use of glutamine supplementation in VLBW infants has not become routine. Some authors suggest that further study in this area is no longer warranted. In this review, more recent research in the area of glutamine supplementation is described, which suggests additional studies are warranted.

Neurodevelopmental outcomes of very low‐birth‐weight infants after enteral glutamine supplementation in the neonatal period

Aim: To determine the effect of neonatal glutamine‐enriched enteral nutrition in very low birth weight (VLBW) infants on neurodevelopmental outcome at 2 years of age.

Glutamine-enriched enteral nutrition in very low birthweight infants and allergic and infectious diseases at 6 years of age

In a previous randomised controlled trial, we found that glutamine-enriched enteral nutrition in 102 very low birthweight (VLBW) infants decreased both the incidence of serious infections in the neonatal period and the risk of atopic dermatitis during the first year of life. We hypothesised that glutamine-enriched enteral nutrition in VLBW infants in the neonatal period influences the risk of allergic and infectious disease at 6 years of age. Eighty-eight of the 102 infants were eligible for the follow-up study (13 died, 1 chromosomal abnormality). Doctor-diagnosed allergic and infectious diseases were assessed by means of validated questionnaires. The association between glutamine-enriched enteral nutrition in the neonatal period and allergic and infectious diseases at 6 years of age was based on univariable and multivariable logistic regression analyses. Seventy-six of the 89 (85%) infants participated, 38 in the original glutamine-supplemented group and 38 in the control group. After adjustment, we found a decreased risk of atopic dermatitis in the glutamine-supplemented group: adjusted odds ratio (aOR) 0.23 [95% CI 0.06, 0.95]. No association between glutamine supplementation and hay fever, recurrent wheeze and asthma was found. A decreased risk of gastrointestinal tract infections was found in the glutamine-supplemented group (aOR) 0.10 [95% CI 0.01, 0.93], but there was no association with upper respiratory, lower respiratory or urinary tract infections. We concluded that glutamine-enriched enteral nutrition in the neonatal period in VLBW infants decreased the risk of atopic dermatitis and gastrointestinal tract infections at 6 years of age.

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

The impact of neuraminidase inhibitors (NAIs) on influenza‐related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection.

Cytokine responses in very low birth weight infants receiving glutamine-enriched enteral nutrition.

Objective: Very low birth weight (VLBW) infants receiving glutamine-enriched enteral nutrition may present with a lower infection rate, which may result from enhanced antimicrobial innate or Th1 cytokine responses. We investigated whether glutamine-enriched enteral nutrition in VLBW infants increased these cytokine responses following in vitro stimulation of whole blood cells. Methods: In a double-blind, placebo-controlled, randomized controlled trial, VLBW infants (gestational age <32 weeks and/or birth weight <1500 g) received enteral glutamine supplementation (0.3 g · kg−1 · day−1) or isonitrogenous placebo supplementation (alanine) between days 3 and 30 of life. Cytokine responses following in vitro whole blood cell stimulation with anti-(α)CD3/αCD28 or lipopolysaccharide were analyzed by cytometric bead array at 3 time points: before the start of the study, at day 7 of life, and at day 14 of life. Results: Baseline patient and nutritional characteristics were not different between groups. At least 2 blood samples were analyzed in 25 of 52 (48%) and 38 of 50 (76%) infants in the glutamine-supplemented and control groups, respectively. Glutamine-enriched enteral nutrition was not associated with significant alterations in cytokine responses (interferon-γ, tumor necrosis factor-α, interleukin [IL]-2, IL-4, IL-5, and IL-10) of peripheral blood cells upon stimulation with either anti-αCD3/αCD28 or lipopolysaccharide. Conclusions: We hypothesize that glutamine-enriched enteral nutrition decreases the infection rate in VLBW infants by influencing the mucosal and not the systemic immune system.

Clinical Features of a Dutch Cohort of Critically Ill Children Due to the 2009 New Influenza A H1N1 Pandemic

Objective: This study describes the clinical course, treatment, and outcome of 13 critically ill children due to infection with new influenza A H1N1, admitted to 2 pediatric intensive care units (PICUs) in the northwestern part of the Netherlands. Methods: Retrospective case series, conducted in 2 PICUs in Amsterdam, the Netherlands. Results: A total of 13 children with a new influenza A H1N1 infection were admitted at 2 Dutch PICUs. The majority of these children were 12 to 16 years old and had an underlying disease. All children required mechanical ventilatory support. Shock was present in 7 of 13 (54%) children. Two children were transferred to a supraregional PICU with facilities for extracorporeal membrane oxygenation. Conclusions: In a Dutch cohort of 13 critically ill children due to infection with new influenza (H1N1), respiratory (100%) and circulatory (54%) failure characterized the course of this infection in most of these children. All children survived.

Cytokine profiles in 1‐yr‐old very low‐birth‐weight infants after enteral glutamine supplementation in the neonatal period

In a previous study, we found that glutamine‐enriched enteral nutrition in 102 very low‐birth‐weight (VLBW) infants decreased both the incidence of serious neonatal infections and atopic dermatitis during the first year of life. The aims of this follow‐up study were to determine whether these beneficial effects are attended by changes in Th1 and Th2 cytokine profiles at age 1 yr. Furthermore, we studied changes in cytokine profiles during the first year of life in these VLBW infants. In total, 89 infants were eligible for the follow‐up study (12 died, 1 exclusion due to a chromosomal abnormality). Th1 (IFN‐γ, TNF‐ α and IL‐2) and Th2 cytokine (IL‐10, IL‐5, and IL‐4) profiles following in vitro whole blood stimulation were measured at 1 yr. Cytokine profiles were measured in 59/89 (66%) infants. Glutamine‐enriched enteral nutrition in neonatal period did not influence cytokine profiles at 1 yr. Cytokine profiles were not different in infants with and without allergic or infectious diseases. The beneficial effect of glutamine‐enriched enteral nutrition on the incidence of serious neonatal infections and atopic dermatitis during the first year of life is not related to changes in the Th1 and Th2 cytokine profiles. Both Th1 and Th2 cytokine profiles increased during the first year of life in this cohort of VLBW infants.