Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress-Induced Immune Suppression Comparative Effectiveness Trial.

BACKGROUND AND AIMS: The pediatric Critical Illness Stress-induced Immune Suppression (CRISIS) trial compared the effectiveness of 2 nutraceutical supplementation strategies and found no difference in the development of nosocomial infection and sepsis in the overall population. We performed an exploratory post hoc analysis of interaction between nutraceutical treatments and host immune status related to the development of nosocomial infection/sepsis. METHODS: Children from the CRISIS trial were analyzed according to 3 admission immune status categories marked by decreasing immune competence: immune competent without lymphopenia, immune competent with lymphopenia, and previously immunocompromised. The comparative effectiveness of the 2 treatments was analyzed for interaction with immune status category. RESULTS: There were 134 immune-competent children without lymphopenia, 79 previously immune-competent children with lymphopenia, and 27 immunocompromised children who received 1 of the 2 treatments. A significant interaction was found between treatment arms and immune status on the time to development of nosocomial infection and sepsis ( P < .05) and on the rate of nosocomial infection and sepsis per 100 patient days ( P < .05). Whey protein treatment protected immune-competent patients without lymphopenia from infection and sepsis, both nutraceutical strategies were equivalent in immune-competent patients with lymphopenia, and zinc, selenium, glutamine, and metoclopramide treatment protected immunocompromised patients from infection and sepsis. CONCLUSIONS: The science of immune nutrition is more complex than previously thought. Future trial design should consider immune status at the time of trial entry because differential effects of nutraceuticals may be related to this patient characteristic.

Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers.

Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis.

Mothers' "liquid gold": a quality improvement initiative to support early colostrum delivery via oral immune therapy (OIT) to premature and critically ill newborns.

Early breast milk, known as colostrum ("liquid gold") provides immune benefits to infants, offering potential risk reduction for nosocomial infection (NI) and necrotizing enterocolitis (NEC), a serious gastrointestinal emergency. Provision of colostrum is recognized as oral immune therapy (OIT) and is valuable to all NICU infants unable to feed orally. A quality improvement project was initiated by the multidisciplinary NICU Quality Care Council at London Health Sciences Centres-Victoria (LHSC-VH) to obtain mothers' colostrum for early OIT. The initiative was driven by the Canadian EPIQ (Evidence-based Practice for Improving Quality) group as a means of reducing the rates of NEC and NI, two major morbidities in the NICU. The overall aim was to facilitate the availability of OIT to preterm and critically ill neonates as soon as possible after birth.

A randomized placebo-controlled trial of massage therapy on the immune system of preterm infants.

OBJECTIVES: The aim of this study was to investigate the effects of massage therapy (MT) on the immune system of preterm infants. The primary hypothesis was that MT compared with sham therapy (control) will enhance the immune system of stable premature infants by increasing the proportion of their natural killer (NK) cell numbers. METHODS: A randomized placebo-controlled trial of MT versus sham therapy (control) was conducted among stable premature infants in the NICU. Study intervention was provided 5 days per week until hospital discharge for a maximum of 4 weeks. Immunologic evaluations (absolute NK cells, T and B cells, T cell subsets, and NK cytotoxicity), weight, number of infections, and length of hospital stay were also evaluated. RESULTS: The study enrolled 120 infants (58 massage; 62 control). At the end of the study, absolute NK cells were not different between the 2 groups; however, NK cytotoxicity was higher in the massage group, particularly among those who received ≥5 consecutive days of study intervention compared with control (13.79 vs 10 lytic units, respectively; P = .04). Infants in the massage group were heavier at end of study and had greater daily weight gain compared with those in the control group; other immunologic parameters, number of infections, and length of stay were not different between the 2 groups. CONCLUSIONS: In this study, MT administered to stable preterm infants was associated with higher NK cytotoxicity and more daily weight gain. MT may improve the overall outcome of these infants. Larger studies are needed.

The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial.

OBJECTIVES: Nosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population. DESIGN: Randomized, double-blinded, comparative effectiveness trial. SETTING: Eight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PATIENTS: Two hundred ninety-three long-term intensive care patients (age 1-17 yrs) expected to require >72 hrs of invasive care. INTERVENTIONS: Patients were stratified according to immunocompromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n = 149), or daily enteral whey protein (n = 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat. MEASUREMENTS AND MAIN RESULTS: There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p = .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .011). CONCLUSION: Compared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient.

Safety and efficacy of fish oil-enriched parenteral nutrition regimen on postoperative patients undergoing major abdominal surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: To evaluate the safety and efficacy of a fish oil-enriched parenteral nutrition regimen in patients undergoing major abdominal surgery, a meta-analysis of randomized controlled trials was conducted. METHODS: An electronic search of PubMed, MEDLINE, EMBASE, Academic Search Premier, and China National Knowledge Infrastructure databases was performed in March 2009. RevMan 5.0 was used for statistical analysis. RESULTS: The combined analysis showed that a fish oil-enriched parenteral nutrition regimen had a positive treatment effect on length of hospital stay (weighed mean difference = -2.98, P < .001), length of intensive care unit stay, postoperative infection rate (odds ratio = 0.56, P = .04), and serum levels of aspartate aminotransferase, alanine aminotransferase, and alpha-tocopherol on postoperative day 6 in these patients. The regimen increased the plasma levels of eicosapentaenoic acid (standardized mean difference = 3.11, P < .001) and docosahexaenoic acid and upregulated the leukotriene B(5) production in leukocytes on postoperative day 6. No significant differences were found between the 2 groups in postoperative mortality; incidence of postoperative cardiac complications; serum levels of bilirubin, triglyceride, or arachidonic acid; or the liberation of leukotriene B(4). No serious adverse events related to fish oil treatment were reported. CONCLUSIONS: Based on the meta-analysis, fish oil-supplemented parenteral nutrition was safe, improved clinical outcomes, and altered the fatty acid pattern as well as leukotriene synthesis. More laboratory parameters should be considered in future meta-analyses.

Rationale and design of the pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial.

Despite implementation of CDC recommendations and bundled interventions for preventing catheter-associated blood stream infection, ventilator-associated pneumonia, or urinary catheter-associated infections, nosocomial infections and sepsis remain a significant cause of morbidity and mortality in critically ill children. Recent studies suggest that acquired critical illness stress-induced immune suppression (CRISIS) plays a role in the development of nosocomial infection and sepsis. This condition can be related to inadequate zinc, selenium, and glutamine levels, as well as hypoprolactinemia, leading to stress-induced lymphopenia, a predominant T(H)2 monocyte/macrophage state, and subsequent immune suppression. Prolonged immune dysfunction increases the likelihood of nosocomial infections associated with invasive devices. Although strategies to prevent common complications of critical illness are routinely employed (eg, prophylaxis for gastrointestinal bleeding, thrombophlebitis), no prophylactic strategy is used to prevent stress-induced immune suppression. This is the authors' rationale for the pediatric CRISIS prevention trial (NCT00395161), designed as a randomized, double-blind, controlled clinical investigation to determine if daily enteral supplementation with zinc, selenium, and glutamine as well as parenteral metoclopramide (a dopamine 2 receptor antagonist that reverses hypoprolactinemia) prolongs the time until onset of nosocomial infection or sepsis in critically ill children compared to enteral supplementation with whey protein. If effective, this combined nutritional and pharmacologic approach may lessen the excess morbidity and mortality as well as resource utilization associated with nosocomial infections and sepsis in this population. The authors present the design and analytic plan for the CRISIS prevention trial.

Leukodepletion of autologous whole blood has no impact on perioperative infection rate and length of hospital stay.

BACKGROUND: Several mechanisms have been proposed as possible causes of transfusion-related immunomodulation (TRIM) after allogeneic transfusion. If one of these mechanisms, the release of mediators of immunity and inflammation ("biologic response modifiers"[BRMs]) from disintegrating blood cells during storage of blood products, really causes TRIM, it should in principle also occur after autologous transfusion. As a consequence, prestorage leukoreduction of autologous blood should be able to prevent the clinical consequences of TRIM after autologous transfusion. STUDY DESIGN AND METHODS: This hypothesis was investigated in a multicenter, double-blind, randomized controlled trial. A total of 1089 patients scheduled for total hip arthroplasty and eligible for preoperative autologous blood donation were randomly assigned to receive autologous whole blood (AWB) either unmodified or leukoreduced when transfusion was indicated. RESULTS: Neither the primary study outcome, that is, the overall postoperative infection rate (17.3% vs. 17.6%, p = 0.59), nor several secondary outcomes like median length of hospital stay (14 days vs. 14 days, p = 0.17) were significantly different between groups, whether analyzed according to the intention-to-treat principle or "as treated." CONCLUSION: This trial provides strong evidence, from clinically relevant outcome data, that leukoreduction of AWB does not improve postoperative patient outcome and that the release of BRMs from disintegrating blood cells during storage cannot explain the immunomodulatory effect of blood transfusion.

Novel nonantibiotic therapies for pneumonia: cytokines and host defense.

Effective host defense against bacterial infection is dependent on the activation and recruitment of phagocytic cells. The initiation, maintenance, and resolution of this inflammatory response in the setting of bacterial pneumonia is dependent on the expression of cytokines. As the complexities of the host-pathogen interaction are further dissected and unraveled, immunologic manipulation of cytokine expression will likely become an important adjuvant therapy in the treatment of serious lung infections.

[Initial experience with monoclonal antibodies in therapy of life threatening nosocomial infections in the neonatal period]. / Erste Erfahrungen mit monoklonalen Antikörpern bei der Therapie lebensbedrohlicher Nosokomialinfektionen im Neugeborenenalter.

Despite the use of modern broad spectrum antibiotics nosocomial infections are an unsolved problem, especially in the field of neonatal intensive care (preterm babies and newborns). In patients with septic shock human monoclonal antibodies in combination with appropriate antibiotics have proven effective and compatible for children older than one year. So far, there have been no reports in the literature on the application of such kind of antiendotoxin immunotherapy for pre-term babies and newborns. We describe the effectiveness of monoclonal antibodies in two newborns. Already 12 respectively 16 hours after application of the human monoclonal IgM antibodies (Centoxin) and appropriate antibiotics, the clinical condition of our patients stabilized. Consecutively further clinical symptoms improved rapidly.

Passive immunisation of children with bovine colostrum containing antibodies to human rotavirus.

The efficacy of a 10-day course of bovine colostrum with high antibody titre against the four known human rotavirus serotypes in protecting children against rotavirus infection was examined in patients admitted to hospital. Children aged 3 to 15 months were blocked in pairs according to ward accommodation (ie, isolation or open area). Each block contained 1 treated and 1 control child. The allocation to treatment or control (an artificial infant formula) was randomised. 9 of 65 control children but none of 55 treated children acquired rotavirus infection during the treatment period (p less than 0.001). The importance of protecting against rotavirus infection was highlighted by the fact that parents of symptomatic rotavirus-positive children sought medical attention seven times more often than did parents of symptomatic rotavirus-negative children (p less than 0.05).

PIP: One of the main reasons for hospital admission of infants and young children is infectious diarrhea usually caused by a rotavirus infection. Infants can also acquire rotavirus in hospital neonatal and pediatric wards; the infection can also be transmitted to adult members of the family. The most protection against rotavirus is the presence of an antibody in the lumen of the small intestine. However, both adults and children can be immunized against rotavirus through the ingestion of an antibody containing a modified rotavirus. A study was conducted on 120 children, aged 3 - 15 months. The aim of the study was to produce a preparation of bovine colostrum with a high antibody titre against the 4 known human rotavirus. 65 of the children were placed in a control group, while the remaining 55 were placed in a treatment group. A colostrum was produced by introducing a vaccine containing all 4 human rotavirus into 25 pregnant Freisian cows. The colostrum was then administered to the children, orally. Stool specimens were collected before admission, during the study and after discharge. The result of the study are as follows: 14% of the control group (9 of 65) acquired rotavirus during the study; 8 of the 9 patients probably acquired the infection on admission to the hospital. None of the treatment group were infected.