lactoferrin and Sepsis

Neonates who have undergone gastrointestinal surgery are particularly susceptible to infectious complications in the postoperative period. This may be due in part to disruption of the integrity of the gut and its altered intestinal microflora. Lactoferrin is a whey protein found in milk and is an important innate mammalian defence mechanism. Lactoferrin has been reported to have antimicrobial and anti-inflammatory properties. It has also been reported to help establish a healthy gut microflora and aid in the intestinal immune system. Lactoferrin supplementation has been reported to decrease sepsis in preterm infants. There may be a role for lactoferrin to reduce the incidence of sepsis, thus reducing morbidity and mortality and improving enteral feeding in postoperative term neonates.. The primary objective of this review was to evaluate the efficacy of administering lactoferrin on the incidence of sepsis and mortality in term neonates after gastrointestinal surgery. The secondary objective was to assess the impact of administering lactoferrin on time to full enteral feeds, the intestinal microflora, duration of hospital stay, and mortality before discharge in the same population.. The Cochrane Neonatal Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase Ovid, CINAHL, the WHO ICTRP and ClinicalTrials.gov trials registries. The date of the last search was February 2023. There were no restrictions to language, publication year or publication type. We checked references of potentially relevant studies and systematic reviews.. We planned to include randomised controlled trials that studied infants born at 37 or more weeks of gestation who had one or more episodes of gastrointestinal surgery within 28 days of birth, and compared administration of lactoferrin with a placebo.. We used standard Cochrane methodological procedures. We planned to use the GRADE approach to assess the certainty of evidence for each outcome.. We identified no published randomised controlled studies that assessed the efficacy of lactoferrin for the postoperative management of term neonates following gastrointestinal surgery.. There is currently no evidence available from randomised controlled trials to show whether lactoferrin is effective or ineffective for the postoperative management of term neonates after gastrointestinal surgery. There is a need for randomised controlled trials to be performed to assess the role of lactoferrin in this setting.

Topics: Animals; Digestive System Surgical Procedures; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Milk; Sepsis

This study aimed to systematically review and meta-analyze the role of lactoferrin supplementation to prevent late-onset sepsis (LOS) in preterm infants.. Database search include PubMed, Web of Science, and Cochrane central for randomized clinical trial (RCTs). The Cochrane Grading of Recommendations Assessment, Development, and Evaluation methodology was used for summarizing the results.. Ten RCTs involving 3,679 infants were included. Lactoferrin supplementation with or without probiotics decreased all LOS (relative risk [RR]: 0.56; 95% confidence interval [CI]: 0.36-0.86;. Low to moderate quality evidence suggests that lactoferrin supplementation reduces LOS in preterm infants. Further research is needed to improve the certainty in the evidence.

Topics: Administration, Oral; Age of Onset; Bronchopulmonary Dysplasia; Cause of Death; Enteral Nutrition; Enterocolitis, Necrotizing; Humans; Infant; Infant Mortality; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Mycoses; Probiotics; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Sepsis

In this commentary, we summarize the current evidence from randomized controlled trials on enteral lactoferrin supplementation in preterm neonates. Our recently completed systematic review includes 12 randomized controlled trials performed all over the world. Our meta-analysis suggests clinical benefit in decreasing late-onset sepsis, late-onset fungal sepsis, length of stay in the hospital and urinary tract infections. There were no adverse effects. There was no statistically significant decrease in necrotizing enterocolitis, mortality or neurodevelopmental impairment in lactoferrin supplemented preterm infants. There was significant statistical heterogeneity in the effects of lactoferrin on late-onset sepsis between larger and smaller studies, which may reflect either small study biases, differences in the effectiveness, dose or duration of supplemental lactoferrin products, or differences in underlying population risk, or any or all of these.

Topics: Dietary Supplements; Enteral Nutrition; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Randomized Controlled Trials as Topic; Sepsis; Urinary Tract Infections

Newborn infants, especially those born preterm, are at risk of infections in early life. In preterm infants, necrotizing enterocolitis (NEC), a devastating inflammatory gut condition, and late-onset sepsis (LOS) are important causes of serious morbidity and are the commonest reasons for death after the first week of life. Fresh breast milk from the infant's mother reduces the risks of these serious pathologies in a dose-dependent fashion. Considerable effort has been expended to better understand which specific components of human milk are likely to exert the greatest functional benefits, particularly those that have immune modulatory or anti-infectious properties. Lactoferrin is a whey glycoprotein present in especially high concentrations in colostrum and early milk. Studies show that lactoferrin impacts on immune function and, through a multitude of mechanisms, reduces the risk of viral, fungal, and bacterial infections. Supplemental enteral bovine lactoferrin has been tested in a series of randomized clinical trials, many of which suggested important reductions in LOS in preterm or low-birth-weight infants. However, the largest trial to date - the Enteral Lactoferrin in Neonates (ELFIN) trial - recruited 2,203 infants and failed to show any significant reductions in LOS or NEC. Challenges in conducting clinical research and the translational relevance of these studies for clinical practice will be considered.

Topics: Enterocolitis, Necrotizing; Female; Gastrointestinal Microbiome; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Milk, Human; Sepsis

Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later.. We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials.. In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates.. We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence.. Meta-analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95% CI 0.74 to 0.91; typical RD -0.04, 95% CI, -0.06, -0.02; NNTB 25, 95% CI 17 to 50; 12 studies, 5425 participants, low-certainty evidence) and decreased length of hospital stay (MD -2.38, 95% CI, -4.67, -0.09; 3 studies, 1079 participants, low-certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95% CI, 0.78, 0.97; typical RD -0.03, 95% CI, -0.05, -0.0; 9 studies, 4702 participants, low-certainty evidence). There were no differences in NEC stage II or III (typical RR 1.10, 95% CI, 0.86, 1.41; typical RD -0.00, 95% CI, -0.02, 0.01; 7 studies, 4874 participants; low-certainty evidence) or 'all-cause mortality' (typical RR 0.90, 95% CI 0.69, 1.17; typical RD -0.00, 95% CI, -0.01, 0.01; 11 studies, 5510 participants; moderate-certainty evidence). One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (one study, 292 participants, low-certainty evidence). Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.25, 95% CI 0.14 to 0.46; RD -0.13, 95% CI -0.18 to -0.08; NNTB 8, 95% CI 6 to 13; 3 studies, 564 participants; low-certainty evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; 1 study, 496 participants; very low-certainty evidence), but not 'all-cause mortality' (very low-certainty evidence). Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low-certainty evidence). Investigators reported no adverse effects in the included studies.. We found low-certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreases late-onset sepsis but not NEC ≥ stage II or 'all cause mortality' or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects. Low- to very low-certainty evidence suggests that lactoferrin supplementation of enteral feeds in combination with probiotics decreases late-onset sepsis and NEC ≥ stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality. The presence of publication bias and small studies of poor methodology that may inflate the effect size make recommendations for clinical practice difficult.

Topics: Administration, Oral; Bacterial Infections; Cause of Death; Chronic Disease; Enteral Nutrition; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Lung Diseases; Mycoses; Numbers Needed To Treat; Probiotics; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Sepsis

Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer's disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in

Topics: Anemia; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Biomarkers; Humans; Inflammation; Iron; Lactoferrin; Sepsis

Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial.. Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs).. A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics.. Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.

Topics: Anti-Infective Agents; Cross Infection; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Male; Sepsis; Treatment Outcome

Newborn infants are at a high risk for infection due to an under-developed immune system, and human milk has been shown to exhibit substantial anti-infective properties that serve to bolster neonatal defenses against multiple infections. Lactoferrin is the dominant whey protein in human milk and has been demonstrated to perform a wide array of antimicrobial and immunomodulatory functions and play a critical role in protecting the newborn infant from infection. This review summarizes data describing the structure and important functions performed by lactoferrin in protecting the neonate from infection and contributing to the maturation of the newborn innate and adaptive immune systems. We also briefly discuss clinical trials examining the utility of lactoferrin supplementation in the prevention of sepsis and necrotizing enterocolitis in newborn infants. The data reviewed provide rationale for the continuation of studies to examine the effects of lactoferrin administration on the prevention of sepsis in the neonate.

Topics: Anti-Infective Agents; Dietary Supplements; Enterocolitis, Necrotizing; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Immunologic Factors; Infant, Newborn; Infant, Newborn, Diseases; Lactoferrin; Milk, Human; Sepsis

Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. Primary objective 1. To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates Secondary objectives 1. To determine the effects of lactoferrin supplementation to enteral feeds to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later2. To determine the adverse effects of lactoferrin supplementation for prophylaxis of neonatal sepsis and/or NECWhen data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants)3. Type of feeding: breast milk versus formula milk SEARCH METHODS: We used the search strategy of the Cochrane Neonatal Review Group (CNRG) to update our search in December 2016. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trial registries and conference proceedings.. Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates.. Review authors used standard methods of the CNRG.. This review includes six RCTs. Trial results show that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical risk ratio (RR) 0.59, 95% confidence interval (CI) 0.40 to 0.87; typical risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 17, 95% CI 10 to 50; six trials, 886 participants; low-quality evidence) and NEC stage II or III (typical RR 0.40, 95% CI 0.18 to 0.86; typical RD -0.04, 95% CI -0.06 to -0.01; NNTB 25, 95% CI 17 to 100; four studies, 750 participants; low-quality evidence). Lactoferrin supplementation did not have an effect on "all-cause mortality" (typical RR 0.65, 95% CI 0.37 to 1.11; typical RD -0.02, 95% CI -0.05 to 0; six studies, 1041 participants; low-quality evidence).Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants; low-quality evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants; low-quality evidence), but not "all-cause mortality" (low-quality evidence).Lactoferrin supplementation to enteral feeds with or without probiotics decreased bacterial and fungal sepsis but not CLD or length of hospital stay (low-quality evidence). Investigators reported no adverse effects and did not evaluate long-term neurological outcomes and PVL.. Evidence of low quality suggests that lactoferrin supplementation to enteral feeds with or without probiotics decreases late-onset sepsis and NEC stage II or III in preterm infants without adverse effects. Completed ongoing trials will provide data from more than 6000 preterm neonates, which may enhance the quality of the evidence. Clarification regarding optimal dosing regimens, types of lactoferrin (human or bovine), and long-term outcomes is needed.

Topics: Administration, Oral; Bacterial Infections; Cause of Death; Chronic Disease; Enteral Nutrition; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Lung Diseases; Mycoses; Numbers Needed To Treat; Probiotics; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Sepsis

Neonatal sepsis and necrotizing enterocolitis (NEC) are two most important neonatal problems in nursery which constitute the bulk of neonatal mortality and morbidity. Inflammatory mediators secondary to sepsis and NEC increases morbidity, by affecting various system of body like lung, brain and eye, thus causing long term implications. Lactoferrin (LF) is a component of breast milk and multiple actions that includes antimicrobial, antiviral, anti-fungal and anti-cancer and various other actions. Few studies have been completed and a number of them are in progress for evaluation of efficacy and safety of LF in the prevention of neonatal sepsis and NEC in field of neonatology. In future, LF prophylaxis and therapy may have a significant impact in improving clinical outcomes of vulnerable preterm neonates. This review analyse the role of lactoferrin in prevention of neonatal sepsis and NEC, with emphasis on mechanism of action, recent studies and current studies going on around the globe.

Topics: Anti-Infective Agents; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Lactoferrin; Neonatology; Sepsis

Bacterial infections, with the most severe form being sepsis, can often not be treated adequately leading to high morbidity and lethality of infected patients in critical care units. In particular, the increase in resistant bacterial strains and the lack of new antibiotics are main reasons for the worsening of the current situation, As a new approach, the use of antimicrobial peptides (AMPs) seems to be promising, combining the ability of broad-spectrum bactericidal activity and low potential of induction of resistance. Peptides based on natural defense proteins or polypeptides such as lactoferrin, Limulus anti-lipopolysaccharide factor (LALF), cathelicidins, and granulysins are candidates due to their high affinity to bacteria and to their pathogenicity factors, in first line lipopolysaccharide (LPS, endotoxin) of Gram-negative origin. In this review, we discuss literature with the focus on the use of AMPs from natural sources and their variants as antibacterial as well as anti-endotoxin (anti-inflammatory) drugs. Considerable progress has been made by the design of new AMPs for acting efficiently against the LPS-induced inflammation reaction in vitro as well as in vivo (mouse) models of sepsis. Furthermore, the data indicate that efficient antibacterial compounds are not necessarily equally efficient as anti-endotoxin drugs and vice versa. The most important reason for this may be the different molecular geometry of LPS in bacteria and in free form. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

Topics: Amino Acid Sequence; Animals; Anti-Bacterial Agents; Antigens, Differentiation, T-Lymphocyte; Antimicrobial Cationic Peptides; Arthropod Proteins; Disease Models, Animal; Drug Design; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Humans; Lactoferrin; Lipopolysaccharides; Mice; Molecular Sequence Data; Sepsis

The early postnatal period is a critical time for gastrointestinal (GI) and immune development. Neonates fed mother's milk have more rapid GI and immune development than fed-formula infants. In addition, clinical and epidemiologic data provide strong evidence that breastfeeding reduces the incidence and/or severity of infectious diseases. Lactoferrin is a 77 kDa, iron-binding glycoprotein that is present at high concentration in human milk compared with bovine milk and infant formula. It is a multifunctional protein that mediates many of the physiological processes in which breastfed infants have advantages over their formula-fed peers, including promoting GI and immune development, protection from infections, and improved cognitive development. Feeding bovine lactoferrin or recombinant human lactoferrin was well tolerated and stimulated intestinal cell proliferation and increased villus length and crypt depth in piglets. Lactoferrin also influenced both systemic and GI immune development by stimulating a balanced T-helper-1/T-helper-2 cytokine immune response. Further, there was a tendency for immune cells to secrete more anti-inflammatory cytokines in an unstimulated state, while being primed for a robust pro-inflammatory response when presented with a bacterial trigger in piglets fed lactoferrin. These findings support clinical studies demonstrating benefits of dietary lactoferrin in the prevention of infections, late onset sepsis, and necrotizing enterocolitis.

Topics: Animals; Breast Feeding; Cattle; Enterocolitis, Necrotizing; Gastrointestinal Tract; Humans; Immune System; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Lactoferrin; Milk; Models, Animal; Sepsis; Swine; Translational Research, Biomedical

To discuss the potential clinical benefits of lactoferrin in preterm and term infants, as well as in young children and to review information on the burden of neonatal sepsis. Current evidence on the mechanisms that explain the role of human milk in the neonatal and infant anti-infective responses will be briefly reviewed and preclinical research data on the potential mechanisms of action by which lactoferrin may impact infant gut health, gut immune development and functions, including the lactoferrin effects on the neonatal microbiome, will be examined. Finally, updated translational research on lactoferrin will be presented and discussed and the current evidence from prospective randomized controlled trials in neonates, infants, and toddlers will be analyzed. These randomized controlled trials demonstrate that lactoferrin has a clinically significant impact on feeding, the microbiome, and clinical outcomes in neonates and infants.

Topics: Anti-Infective Agents; Candidiasis; Child, Preschool; Enterocolitis, Necrotizing; Gastrointestinal Tract; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Intensive Care, Neonatal; Lactoferrin; Microbiota; Milk, Human; Sepsis

Necrotizing enterocolitis (NEC) is the most common acquired disease of the gastrointestinal tract (GIT) in premature infants and newborns. It is defined as an ulcerative inflammation of the intestinal wall. The clinical signs of incipient NEC are often very discrete, and range from localized intestinal symptoms to generalized signs of sepsis. NEC is classified depending on its severity into disease states according to the modified Bell's Classification. Treatment of NEC ranges, depending on its severity, from a conservative therapeutic approach to surgery with resection of the affected parts of the intestine. Mortality is considerably high in extremely small preterm infants reaching up to 42% of the affected children. Measures such as breastfeeding or alternatively nutrition with pasteurized human donor milk from a milk bank, administration of probiotics, avoidance of histamine type II receptor antagonists, and restrictive antibiotic treatment should be considered early on for prevention of NEC.

Topics: Breast Feeding; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infusions, Parenteral; Lactoferrin; Probiotics; Risk Factors; Sepsis

Sepsis and necrotizing enterocolitis (NEC) cause significant morbidity and mortality in the newborn. Their ill effects persist in spite of appropriate and effective antibiotic therapy. Lactoferrin as an adjunct to antibiotics in the treatment of sepsis or NEC in the newborn may improve the clinical outcomes by enhancing the host defense and modulating the inflammatory response. This review focuses on the various aspects of lactoferrin use in the newborn.

Topics: Anti-Bacterial Agents; Antifungal Agents; Antiviral Agents; Child Development; Enterocolitis, Necrotizing; Fetal Organ Maturity; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature, Diseases; Lactoferrin; Sepsis

Late-onset sepsis occurs in 15-25% of very low birth weight neonates. Early diagnosis and therapy optimize patient outcomes. Despite these efforts, mortality remains high (18-36%) and survivors suffer significant neurological and pulmonary morbidity. Although rapid diagnostics are improving, more are needed. Current therapy remains antibiotics and supportive care. Adjunctive therapies have either limited data (e.g., pentoxifylline) or have been found ineffective (e.g., granulocyte transfusions, granulocyte macrophage colony-stimulating factor/granulocyte colony-stimulating factor, and intravenous immunoglobulin). Preventive strategies that have proven beneficial include infection control measures (e.g., hand hygiene and universal precautions), early enteral feeds with human milk, early removal of central lines, catheter infection prevention bundles, antibiotic stewardship and focused quality improvement measures. Promising strategies to prevent late-onset sepsis include oral lactoferrin, and pathogen-specific monoclonal antibodies but more evidence is required to make practice recommendations.

Topics: Anti-Infective Agents; Disease Management; Drug Administration Schedule; Enteral Nutrition; Hand Hygiene; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Milk, Human; Sepsis; Survival Analysis; Time Factors

Lactoferrin, a normal component of human colostrum and milk, can enhance host defense and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. Primary objective To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates. Secondary objectives1. To determine the effects of oral lactoferrin used to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later.2. To determine the adverse effects of oral lactoferrin in the prophylaxis of neonatal sepsis and/or NEC.When data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks.2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants).3. Type of feeding: breast milk versus formula milk.. We used the search strategy of the Cochrane Neonatal Review Group (CNRG) and updated our search in July 2014. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, EMBASE, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trials registries and conference proceedings.. Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates.. Review authors used standard methods of the CNRG.. Four RCTs are included in this review. Oral lactoferrin supplementation decreased late-onset sepsis (typical risk ratio (RR) 0.49, 95% confidence interval (CI) 0.32 to 0.73; typical risk difference (RD) -0.09, 95% CI -0.14 to -0.04; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 25; four trials, 678 participants, moderate-quality evidence), NEC stage II or greater (typical RR 0.30, 95% CI 0.12 to 0.76; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence), and "all-cause mortality" (typical RR 0.30, 95% CI 0.12 to 0.75; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence).Oral lactoferrin supplementation with a probiotic decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants, low-quality evidence) and NEC stage II or greater (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants, low-quality evidence), but not "all-cause mortality."Oral lactoferrin with or without probiotics decreased fungal sepsis but not chronic lung disease or length of hospital stay (from one study, low-quality evidence). No adverse effects were reported. Long-term neurological outcomes or periventricular leukomalacia was not evaluated.. Evidence of moderate to low quality suggests that oral lactoferrin prophylaxis with or without probiotics decreases late-onset sepsis and NEC stage II or greater in preterm infants without adverse effects. Completion of ongoing trials will provide evidence from more than 6000 preterm neonates and may enhance the quality of the evidence. Clarifications regarding optimum dosing regimens, type of lactoferrin (human or bovine), and long-term outcomes are still needed.

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Probiotics; Randomized Controlled Trials as Topic; Sepsis

There is an intense interest among neonatal caregivers as to whether lactoferrin given enterally may reduce the incidence of necrotizing enterocolitis in preterm infants. This review presents scientific and clinical evidence that lactoferrin alleviates or prevents this life-threatening disease.. Preclinical studies in neonatal rats showed that lactoferrin given orally before enteral infection with pathogenic Escherichia coli reduced bacteremia and mortality. A multicentered clinical trial found that very low-birth weight preterm infants given bovine lactoferrin had a significant reduction in late-onset sepsis; there was also a trend towards a diminished incidence of necrotizing enterocolitis. Although multicentered trials of lactoferrin use in preterm infants are near completion, regulatory burdens required to bring lactoferrin to the bedside may limit its availability.. Extremely preterm infants should receive colostrum, a natural lactoferrin concentrate, immediately after birth and, ideally, continue on breast milk throughout the hospital stay. This practice appears well tolerated, but additional experience will tell us whether this practice reduces the prevalence of necrotizing enterocolitis.

Topics: Animals; Colostrum; Enteral Nutrition; Enterocolitis, Necrotizing; Gastrointestinal Tract; Humans; Immunity, Innate; Incidence; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Inflammation; Lactoferrin; Randomized Controlled Trials as Topic; Sepsis

Preterm neonates are at risk to acquire infections. In addition to the high mortality associated with sepsis, these patients are at risk for long-term disabilities, particularly neurodevelopment impairment. Several interventions have been evaluated to reduce rates of infections in neonates but have not proven efficacy. Lactoferrin (LF), a milk glycoprotein with anti-inflammatory, immunomodulatory and anti-microbial properties, has the potential to prevent infections in young children. We performed a review of current and ongoing clinical trials of LF for prevention of neonatal sepsis, and found eleven registered clinical trials that include more than 6,000 subjects. Few of these trials have finished; despite their small sample size, the preliminary results show a trend towards a positive protective effect of LF on neonatal infections. Larger trials are underway to confirm the findings of these initial studies. This information will help to define LF's role in clinical settings and, if proven effective, would profoundly affect the treatment of low birth weight neonates as a cost-effective intervention worldwide.

Topics: Animals; Cattle; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Lactoferrin; Male; Randomized Controlled Trials as Topic; Recombinant Proteins; Sepsis

Neonatal sepsis remains a feared cause of morbidity and mortality in the neonatal period. Maternal, neonatal, and environmental factors are associated with risk of infection, and a combination of prevention strategies, judicious neonatal evaluation, and early initiation of therapy are required to prevent adverse outcomes. This article reviews recent trends in epidemiology and provides an update on risk factors, diagnostic methods, and management of neonatal sepsis.

Topics: Adaptive Immunity; Anti-Infective Agents; Antibodies, Monoclonal; Antifungal Agents; Bacterial Infections; Biomarkers; Blood Cell Count; C-Reactive Protein; Candidiasis; Escherichia coli Infections; Fluconazole; Genomics; Humans; Immunity, Innate; Immunoglobulins, Intravenous; Infant, Newborn; Infant, Newborn, Diseases; Lactoferrin; Polymerase Chain Reaction; Predictive Value of Tests; Proteomics; Risk Factors; Sepsis; Streptococcal Infections; Streptococcus agalactiae

Neonatal sepsis and necrotizing enterocolitis (NEC) are associated with significant mortality and morbidity. Inflammation secondary to sepsis and NEC increases morbidity, especially those related to the lung, brain and eye. Therapeutic strategies that target inflammation and decrease the emergence of antibiotic resistance are urgently needed. Lactoferrin (Lf) is a multifunctional protein that modulates inflammation, cell growth and differentiation and has broad antimicrobial activity. Studies evaluating the efficacy and safety of Lf in the prevention of neonatal sepsis and NEC are currently in progress, and one completed study shows significant promise. In this article, the functions of this multifunctional molecule and current clinical evidence for its use in the newborn are reviewed. Lf prophylaxis and therapy may have a significant impact in improving clinical outcomes of vulnerable preterm neonates.

Topics: Animals; Anti-Infective Agents; Clinical Trials as Topic; Enterocolitis, Necrotizing; Humans; Immunomodulation; Infant, Newborn; Lactoferrin; Mice; Sepsis; Treatment Outcome

Neonatal sepsis causes a huge burden of morbidity and mortality and includes bloodstream, urine, cerebrospinal, peritoneal, and lung infections as well as infections starting from burns and wounds, or from any other usually sterile sites. It is associated with cytokine - and biomediator-induced disorders of respiratory, hemodynamic, and metabolic processes. Neonates in the neonatal intensive care unit feature many specific risk factors for bacterial and fungal sepsis. Loss of gut commensals such as Bifidobacteria and Lactobacilli spp., as occurs with prolonged antibiotic treatments, delayed enteral feeding, or nursing in incubators, translates into proliferation of pathogenic microflora and abnormal gut colonization. Prompt diagnosis and effective treatment do not protect septic neonates form the risk of late neurodevelopmental impairment in the survivors. Thus prevention of bacterial and fungal infection is crucial in these settings of unique patients. In this view, improving neonatal management is a key step, and this includes promotion of breast-feeding and hygiene measures, adoption of a cautious central venous catheter policy, enhancement of the enteric microbiota composition with the supplementation of probiotics, and medical stewardship concerning H2 blockers with restriction of their use. Additional measures may include the use of lactoferrin, fluconazole, and nystatin and specific measures to prevent ventilator associated pneumonia.

Topics: Anti-Infective Agents; Central Venous Catheters; Contraindications; Cross Infection; Fluconazole; Histamine H2 Antagonists; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Lactoferrin; Milk, Human; Nystatin; Pneumonia, Ventilator-Associated; Probiotics; Sepsis

Newborns are at increased risk of infection due to genetic, epigenetic, and environmental factors. Herein we examine the roles of the neonatal innate immune system in host defense against bacterial and viral infections. Full-term newborns express a distinct innate immune system biased toward T(H)2-/T(H)17-polarizing and anti-inflammatory cytokine production with relative impairment in T(H)1-polarizing cytokine production that leaves them particularly vulnerable to infection with intracellular pathogens. In addition to these distinct features, preterm newborns also have fragile skin, impaired T(H)17-polarizing cytokine production, and deficient expression of complement and of antimicrobial proteins and peptides (APPs) that likely contribute to susceptibility to pyogenic bacteria. Ongoing research is identifying APPs, including bacterial/permeability-increasing protein and lactoferrin, as well as pattern recognition receptor agonists that may serve to enhance protective newborn and infant immune responses as stand-alone immune response modifiers or vaccine adjuvants.

Topics: Antimicrobial Cationic Peptides; Bacterial Infections; Blood Proteins; Cytokines; Humans; Immunity, Innate; Infant, Newborn; Inflammasomes; Lactoferrin; Lectins, C-Type; Receptors, Cytoplasmic and Nuclear; Sepsis; Signal Transduction; Toll-Like Receptors; Virus Diseases

Much has been learned in recent years about the mechanisms by which breastfeeding improves child health and survival. However, there has been little progress in using these insights to improve pediatric care. The aim of this study was to review all clinical studies of lactoferrin (LF) in children in an effort to determine which interventions may improve pediatric care or require further research. We conducted a systematic and critical review of published literature and found 19 clinical studies that have used human or bovine LF for different outcomes: iron metabolisms and anemia (6 studies), fecal flora (5 studies), enteric infections (3 studies), common pediatric illnesses (1 study), immunomodulation (3 studies), and neonatal sepsis (1 study). Although the efficacies have varied in each trial, the main finding of all published studies is the safety of the intervention. Protection against enteric infections and neonatal sepsis are the most likely biologically relevant activities of LF in children. Future studies on neonatal sepsis should answer critically important questions. If the data from these sepsis studies are proven to be correct, it will profoundly affect the treatment of low birth weight neonates and will aid in the reduction of child mortality worldwide.

Topics: Child; Child Health Services; Clinical Trials as Topic; Communicable Diseases; Feces; Gastrointestinal Diseases; Humans; Immunomodulation; Infant, Newborn; Iron Metabolism Disorders; Lactoferrin; Sepsis

Sepsis-related morbidity and mortality is an increasing concern in all neonatal ICUs (NICUs). Sepsis occurs in 20-40% of all preterm patients, and although much is known on the origin, the incidence is reported to be constantly increasing. Many risk factors account for the increased risk of sepsis in preterms, including use of broad-spectrum antibiotics selecting resistant microflora and pathogenic gut colonization, parenteral nutrition, acid inhibitors and steroids, as well as the systematic and long-lasting use of invasive management and in-dwelling lines. As treatment does not prevent severe long-term neurodevelopmental impairment and sequelae in septic premature neonates, the best strategy is to avoid infections rather than to treat them.. Published results from several recent randomized controlled trials currently show a level I evidence that fluconazole for prevention of fungal sepsis, probiotics for prevention of necrotizing enterocolitis, and bovine lactoferrin for prevention of bacterial sepsis should be considered as preventive strategies in NICUs.. In this article, the current evidence in favour of lactoferrin use in preterm neonates will be reviewed and the areas of further research and future improvements will be discussed in order to illustrate the implications of the recent findings for clinical practice or research.

Topics: Anti-Infective Agents; Chemoprevention; Enterocolitis, Necrotizing; Fluconazole; Humans; Infant, Newborn; Lactoferrin; Premature Birth; Probiotics; Randomized Controlled Trials as Topic; Sepsis

Lactoferrin, a normal component of human colostrum, milk, tears and saliva can enhance host defence and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates.. We used the search strategy of the Cochrane Neonatal Review Group (CNRG) including searches of CENTRAL (The Cochrane Library), MEDLINE and PREMEDLINE, EMBASE and CINAHL. We also searched trials registries and the conference proceedings of Pediatric Academic Society. Searches updated in July 2011.. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin at any dose or duration for the prophylaxis of sepsis or NEC in preterm neonates.. Data collection and analysis were performed according to the standard methods of the CNRG.. One trial (Manzoni 2008) that randomized 472 very low birth weight infants was eligible. A statistically significant reduction in late-onset sepsis was observed in the groups that received either lactoferrin alone (RR 0.34, 95% CI 0.17 to 0.70) or in combination with Lactobacillus rhamnosus GG (RR 0.27, 95% CI 0.12 to 0.60).In subgroup analyses, infants weighing less than 1000 g and those fed exclusively on maternal milk had a significant reduction in late-onset sepsis after oral lactoferrin supplementation alone. In the group supplemented with oral lactoferrin and Lactobacillus rhamnosus, infants weighing less than 1000 g had a significant reduction in late-onset sepsis, a result not seen in infants fed maternal milk exclusively.Prophylaxis with oral lactoferrin alone did not reduce the incidence of NEC (RR 0.33, 95% CI 0.09 to 1.17), but a significant reduction in NEC with a combination of lactoferrin and Lactobacillus rhamnosus GG was noted (RR 0.05, 95% CI 0.00 to 0.90).No adverse effects due to lactoferrin were observed in this study. Long-term neurological outcomes were not assessed in this trial.. Oral lactoferrin prophylaxis reduces the incidence of late-onset sepsis in infants weighing less than 1500 g and most effective in infants weighing less than 1000 g. There is no evidence of efficacy of oral lactoferrin (given alone) in the prevention of NEC in preterm neonates.Well designed, randomized trials should address dosing, duration, type of lactoferrin (bovine or human) prophylaxis in prevention of sepsis and NEC. The effect of exclusive maternal milk feeding should be clarified.

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Sepsis

Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity in spite of appropriate antibiotic therapy. Enhancing host defence and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis and/or NEC may improve clinical outcomes.. The primary objective is to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis and/or NEC.. Relevant trials in any language were searched in July 2011 in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, PREMEDLINE, EMBASE, CINAHL, web sites: www.clinicaltrials.gov and www.controlled-trials.com, abstracts from the annual meeting of Pediatric Academic Societies (1990 to July 2011), by contacting authors who have published in this field, from the reference lists of identified clinical trials and in the reviewer's personal files.. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin (at any dose or duration) used as an adjunct to antibiotic therapy compared with antibiotic therapy alone (with or without placebo) or other adjuncts to antibiotic therapy to treat neonates at any gestational age up to 44 weeks postmenstrual age with confirmed or suspected sepsis or necrotizing enterocolitis (Bell's Stage II or III).. We used the standardized methods of the Cochrane Neonatal Review Group (CNRG) for conducting a systematic review and for assessing the methodological quality of the studies (http://neonatal.cochrane.org/en/index.html). The titles and the abstracts of studies identified by the search strategy were independently assessed by the two review authors and full text version was obtained for assessment if necessary. Forms were designed for trial inclusion/exclusion and data extraction.. We did not identify any eligible neonatal trial evaluating lactoferrin for treatment of neonatal sepsis or NEC.. Currently there is no evidence to recommend or refute the use of lactoferrin for the treatment of neonatal sepsis or necrotizing enterocolitis as an adjunct to antibiotic therapy.. The safety and efficacy of different preparations and doses of lactoferrin need to be established in neonates. Well designed adequately powered randomized multicenter trials are needed to address the efficacy and safety of lactoferrin in the treatment of neonatal sepsis and necrotizing enterocolitis. These trials should evaluate long-term neurodevelopmental and pulmonary outcomes in addition to short-term outcomes.

Topics: Administration, Oral; Anti-Bacterial Agents; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis

Late-onset sepsis (LOS) affects a large proportion of pre-term neonates in neonatal intensive care units (NICUs) worldwide, with high morbidity and related mortality, and frequent occurrence of severe late neurodevelopmental impairment. Due to the frequency, severity and difficulties in early diagnosis and prompt therapy, prevention is crucial for decreasing the burden of infection-related complications in NICUs. It is well known that feeding with fresh maternal milk, hygiene measures and the cautious use of H2-blockers are related with a decreased risk of developing sepsis. However, evidence from randomised clinical trials exists only for fluconazole in the prevention of fungal infections in the NICU. Lactoferrin is the main whey protein in mammalian milk, and is involved in innate immune host defences. Notably, human lactoferrin can be found at increased concentrations in colostrum and in milk from mothers of premature neonates. Human (hLF) and bovine lactoferrin (bLF) share a high (77%) amino-acid homology, and the same N-terminal peptide responsible for antimicrobial activity, called lactoferricin. In vitro, bLF shows potent direct antimicrobial activity against all types of pathogens, which occurs via anti-cell wall actions and leads to disintegration of the micro-organism's membranes. bLF is also synergistic with many antimicrobials and antifungals, and promotes growth and differentiation of the immature gut. Based on this background data, a randomised clinical trial was recently conducted in very low birth weight pre-term neonates given bLF alone or with the probiotic Lactobacillus GG. The aim of the trial was to assess the ability of bLF to prevent late-onset sepsis of any origin in the studied infants during their stay in the NICU. This article discusses the preliminary data from this study, along with the proposed mechanisms of action of bLF in pre-term infants.

Topics: Age of Onset; Animals; Anti-Infective Agents; Cattle; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Premature Birth; Sepsis

Lactoferrin, a normal component of human colostrum, milk, tears and saliva can enhance host defence and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.. To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates.. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE and PREMEDLINE (1966 to Oct 2009), EMBASE (1980 to Oct 2009) and CINAHL (1982 to Oct 2009) were searched. Ongoing trials at www.clinicaltrials.gov and www.controlled-trials.com were searched. Conference proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Pediatric Research) were searched for abstracts 1990 from the journal 'Pediatric Research' and 'Abstracts Online'.. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin at any dose or duration for the prophylaxis of sepsis or NEC in preterm neonates.. Data collection and analysis were performed according to the standard methods of the CNRG.. One trial (Manzoni 2008) that randomized 472 very low birth weight infants was eligible. A statistically significant reduction in late-onset sepsis was observed in the groups that received either lactoferrin alone (RR 0.34, 95% CI 0.17, 0.70; RD -0.11, 95% CI -0.18, -0.05; NNT 9, 95% CI 5, 20) or in combination with Lactobacillus rhamnosus GG (RR 0.27, 95% CI 0.12, 0.60; RD -0.13, 95% CI -0.19, -0.06; NNT 8, 95% CI 5, 17).In subgroup analyses, infants weighing less than 1000 g and those fed exclusively on maternal milk had significant reduction in late-onset sepsis after oral lactoferrin supplementation alone. In the group supplemented with oral lactoferrin and Lactobacillus rhamnosus, infants weighing less than 1000 g had a significant reduction in late-onset sepsis, but not exclusively maternal milk fed infants.Prophylaxis with oral lactoferrin alone did not reduce the incidence of NEC (RR 0.33, 95% CI 0.09, 1.17; RD -0.04, 95% CI -0.08, 0.00), but a significant reduction in NEC with combination of lactoferrin with Lactobacillus rhamnosus GG was noted (RR 0.05, 95% CI 0.00, 0.90; RD -0.06, 95% CI -0.10, -0.02; NNT17, 95% CI 10, 50).No adverse effects due to lactoferrin were observed in this study. Long-term neurological outcomes were not assessed in this trial.. Oral lactoferrin prophylaxis reduces the incidence of late-onset sepsis in infants weighing less than 1500 g and most effective in infants weighing less than 1000 g. There is no evidence of efficacy of oral lactoferrin (given alone) in the prevention of NEC in preterm neonates.Well designed, randomized trials should address dosing, duration, type of lactoferrin (bovine or human) prophylaxis in prevention of sepsis and NEC. The effect of exclusive maternal milk feeding should be clarified.

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lacticaseibacillus rhamnosus; Lactoferrin; Probiotics; Sepsis

Because of inadequate sample sizes of randomized controlled trials, few immunologic interventions to treat or prevent neonatal sepsis have been reliably evaluated. International collaboration is essential in achieving timely, adequate samples to assess effects on mortality or disability-free survival reliably. Promising or possible therapeutic interventions in severe or gram-negative sepsis include exchange transfusions, pentoxifylline, and IgM-enriched intravenous immunoglobulin. Promising or possible prophylactic interventions include lactoferrin, with or without a probiotic; selenium; early curtailment of antibiotics after sterile cultures; breast milk; and earlier initiation of colostrum in high risk preterm infants. Prophylactic oral probiotics are safe and effective (P<.00001) in reducing all-cause mortality and necrotizing enterocolitis in preterm infants by over half, but do not reduce sepsis.

Topics: Anti-Bacterial Agents; Breast Feeding; Exchange Transfusion, Whole Blood; Glutamine; Humans; Immunoglobulins, Intravenous; Infant, Newborn; Lactoferrin; Oxidative Stress; Pentoxifylline; Probiotics; Protein C; Randomized Controlled Trials as Topic; Selenium; Sepsis

Sepsis-related morbidity and mortality is an increasing concern in all neonatal intensive care units, with reported incidences that are dramatically high regardless of the improvements in the quality of neonatal assistance. Antimicrobial resistance is also becoming a global and regional threat to public health. Neonatal sepsis include bloodstream, urine, cerebrospinal, peritoneal infections, and are classified as early-onset (occurring <3 days of life, EOS) and late-onset sepsis (LOS), i.e., infections arising after the perinatal period. Whereas prevention of EOS relies mainly on maternal-perinatal policies, attempts to reduce LOS incidence are a task merely for neonatologists but are hampered by non-specific clinical features, inadequate sensitivity of diagnostic tests, and late recognition. The frequent occurrence of late neurodevelopmental impairment after LOS challenges neonatologists to seek effective preventative strategies rather than more efficacious antibiotics for treatment. In the area of prevention, consistent evidence is accumulating on fluconazole--for prevention of fungal LOS--and, more recently, on bovine lactoferrin for prevention of both bacterial and fungal LOS: this innate immune system glycoprotein plays an important role in "in vivo" host defenses, and has been shown effective in a multicenter RCT recently published on VLBW neonates. Future studies are warranted to better elucidate the extent of the prevention provided by Ictoferrin and to identify the most suitable dosages to be administered.

Topics: Age of Onset; Animals; Bacterial Infections; Bacterial Translocation; Cattle; Fluconazole; Humans; Incidence; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Mice; Mycoses; Probiotics; Randomized Controlled Trials as Topic; Risk Factors; Sepsis

Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity in spite of appropriate antibiotic therapy. Enhancing host defence and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis and/or NEC may improve clinical outcomes.. The primary objective is to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis and/or NEC.. Relevant trials in any language were searched in June 2008 in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (1966 - June 2008), PREMEDLINE, EMBASE (1980 - June 2008), CINAHL (1982 - June 2008), web sites: www.clinicaltrials.gov and www.controlled-trials.com, abstracts from the annual meeting of Pediatric Academic Societies (1990- June 2008), by contacting authors who have published in this field, from the reference lists of identified clinical trials and in the reviewer's personal files.. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin (at any dose or duration) used as an adjunct to antibiotic therapy compared with antibiotic therapy alone (with or without placebo) or other adjuncts to antibiotic therapy to treat neonates at any gestational age up to 44 weeks postmenstrual age with confirmed or suspected sepsis or necrotizing enterocolitis (Bell's Stage II or III).. We used the standardized methods of the Cochrane Neonatal Review Group (CNRG) for conducting a systematic review and for assessing the methodological quality of the studies (http://neonatal.cochrane.org/en/index.html). The titles and the abstracts of studies identified by the search strategy were independently assessed by the two review authors and full text version was obtained for assessment if necessary. Forms were designed for trial inclusion/exclusion and data extraction.. Our search strategy did not identify any eligible trials or potentially eligible ongoing neonatal trials. One trial was excluded and three ongoing or soon to be started adult trials using lactoferrin for the treatment of infections were identified.. Currently there is no evidence to recommend or refute the use of lactoferrin for the treatment of neonatal sepsis or necrotizing enterocolitis as an adjunct to antibiotic therapy.. The safety and efficacy of different preparations and doses of lactoferrin needs to be established in neonates. Well designed adequately powered randomized multicenter trials are needed to address the efficacy and safety of lactoferrin in the treatment of neonatal sepsis and necrotizing enterocolitis. These trials should evaluate long-term neurodevelopmental and pulmonary outcomes in addition to short-term outcomes (e.g. mortality).

Topics: Administration, Oral; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis

Systemic infections in premature and term infants cause significant morbidity and mortality in spite of appropriate antimicrobial therapy. Consequently, immunotherapy has emerged as a potential adjuvant therapeutic modality to reduce the incidence and mortality associated with neonatal sepsis.. The most recent findings during the review period include systematic reviews of previously published trials evaluating the use of intravenous immunoglobulin and colony-stimulating factors in neonatal sepsis. In addition, the most recent trials describing the use of antistaphylococcal antibodies, probiotics, glutamine supplementation, recombinant human protein C, and lactoferrin in the prevention and treatment of neonatal sepsis have been reviewed.. Immunotherapy used as an adjuvant for the prevention and treatment of neonatal sepsis holds promise. Clinical trials specifically designed toward the neonatal population and appropriately powered to detect treatment differences are necessary prior to universal recommendation of these therapies in the nursery.

Topics: Colony-Stimulating Factors; Dietary Supplements; Glutamine; Humans; Immunoglobulins; Immunologic Factors; Immunotherapy; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Lactoferrin; Probiotics; Protein C; Recombinant Proteins; Sepsis; Treatment Outcome

Despite the use of potent antimicrobials, neonatal sepsis and necrotizing enterocolitis are associated with significant mortality and morbidity. The emergence of microbial antibiotic resistance is a grave concern. Inflammation secondary to sepsis and necrotizing enterocolitis increases pulmonary and cerebral morbidity. New strategies that target inflammation and reduce the emergence of antibiotic resistance are urgently needed. Lactoferrin has broad-spectrum antimicrobial and immunomodulatory activities. In animal models of colitis, lactoferrin reduces inflammatory injury. Lactoferrin also induces the receptor-mediated proliferation and differentiation of intestinal cells. A randomized, controlled trial of lactoferrin in premature neonates to prevent late-onset sepsis is currently in progress. Lactoferrin is a promising agent in the prevention of neonatal sepsis and necrotizing enterocolitis but needs further evaluation to confirm its safety, tolerability and efficacy.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Enterocolitis, Necrotizing; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature; Inflammation; Lactoferrin; Sepsis

Human sepsis is a spectrum of pathophysiological changes in the host system resulting from a generalized activation and systemic expression of the host's inflammatory pathways in response to infection. Since autopsy findings and routine histology in cases of suspected fatal sepsis are most often unspecific and unconvincing, a number of studies has recently dealt with different methods and markers to better define criteria for the postmortem diagnosis of sepsis. Research carried out on specimens obtained postmortem from sepsis-associated fatalities is an important tool to improve our understanding of inflammatory organ changes and the associated underlying pathophysiological mechanisms. One pitfall the investigator has to be aware of is how to select appropriate case material that constitutes the basis for the setting-up of reference values that derive from such studies. Since no scientific studies have investigated the value of cardiac blood samples in the present context, autopsy blood samples for the determination of biochemical sepsis markers have to derive from the femoral vein. In both sepsis cases as well as controls, the time of death has to be well defined.

Topics: Biomarkers; E-Selectin; Endothelial Cells; Forensic Pathology; Humans; Immunohistochemistry; Integrin alpha4beta1; Intercellular Adhesion Molecule-1; Lactoferrin; Leukocytes; Postmortem Changes; Sepsis; Vascular Endothelial Growth Factor A

To determine the impact of supplemental bovine lactoferrin on the gut microbiome and metabolome of preterm infants.. Cohort study nested within a randomised controlled trial (RCT). Infants across different trial arms were matched on several clinical variables. Bacteria and metabolite compositions of longitudinal stool and urine samples were analysed to investigate the impact of lactoferrin supplementation.. Thirteen UK hospitals participating in a RCT of lactoferrin.. 479 infants born <32 weeks' gestation between June 2016 and September 2017.. 10 990 stool and 22 341 urine samples were collected. Analyses of gut microbiome (1304 stools, 201 infants), metabolites (171 stools, 83 infants; 225 urines, 90 infants) and volatile organic compounds (314 stools, 117 infants) were performed. Gut microbiome Shannon diversity at 34 weeks corrected age was not significantly different between infants in the lactoferrin (mean=1.24) or placebo (mean=1.06) groups (p=0.11). Lactoferrin receipt explained less than 1% variance in microbiome compositions between groups. Metabolomic analysis identified six discriminative features between trial groups. Hospital site (16%) and postnatal age (6%) explained the greatest variation in microbiome composition.. This multiomic study identified minimal impacts of lactoferrin but much larger impacts of hospital site and postnatal age. This may be due to the specific lactoferrin product used, but more likely supports the findings of the RCT in which this study was nested, which showed no impact of lactoferrin on reducing rates of sepsis. Multisite mechanistic studies nested within RCTs are feasible and help inform trial interpretation and future trial design.

Topics: Enteral Nutrition; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis

Results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32 weeks gestation) reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC). The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the UK, aimed to further address this issue with a well powered double-blind placebo controlled trial of >2200 preterm infants. The results from ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. Of the 1093 infants, 316 (29%) in the intervention group developed late-onset sepsis versus 334 (31%) of 1089 in the control group, with an adjusted risk ratio of 0.95 (95% CI = 0.86-1.04;

Topics: Administration, Oral; Double-Blind Method; Enterocolitis, Necrotizing; Humans; Infant; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis; United Kingdom

We previously conducted two randomized controlled trials with bovine lactoferrin (bLF) for the prevention of late-onset sepsis (LOS) in infants with a birth weight <2500 g (Study 1) and <2000 g (Study 2). The aim of this study was to determine the preventative effects of bLF on culture-proven or probable LOS in infants with a birth weight <1500 g from both studies, and to determine the effect of bLF in relation to intake of human milk. Both trial designs had similar inclusion and exclusion criteria, the same dose of bLF [200 mg·(kg body mass)

Topics: Animals; Cattle; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Milk, Human; Pilot Projects; Sepsis

In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity, late-onset sepsis, or significant necrotizing enterocolitis. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions. Lactoferrin aids in creating an environment for growth of beneficial bacteria in the gut, thus reducing colonization with pathogenic bacteria. It is hypothesized that oral bovine lactoferrin (bLF), through its antimicrobial, antioxidant and anti-inflammatory properties, will reduce the rate of mortality or major morbidity in very low birth weight preterm infants.. Lactoferrin Infant Feeding Trial_Canada (LIFT_Canada) is a multi-centre, double-masked, randomized controlled trial with the aim to enroll 500 infants whose data will be combined with the data of the 1542 infants enrolled from Lactoferrin Infant Feeding Trial_Australia/New Zealand (LIFT_ANZ) in a pooled intention-to-treat analysis. Eligible infants will be randomized and allocated to one of two treatment groups: 1) a daily dose of 200 mg/kg bLF in breast/donor human milk or formula milk until 34 weeks corrected gestation or for a minimum of 2 weeks, whichever is longer, or until discharge home or transfer, if earlier; 2) no bLF with daily feeds. The primary outcome will be determined at 36 weeks corrected gestation for the presence of neonatal morbidity and at discharge for survival and treated retinopathy of prematurity. The duration of the trial is expected to be 36 months.. Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. LIFT_Canada is designed with the hope that the pooled results from Australia, New Zealand, and Canada may help to clarify the situation.. Clinical Trials.Gov, Identifier: NCT03367013, Registered December 8, 2017.

Topics: Anti-Infective Agents; Brain Injuries; Canada; Cerebral Palsy; Double-Blind Method; Enteral Nutrition; Enterocolitis, Necrotizing; Female; Hospital Mortality; Humans; Infant Formula; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intention to Treat Analysis; Lactoferrin; Male; Milk, Human; Sepsis

To determine the effect of bovine lactoferrin on prevention of late-onset sepsis (LOS) and neurodevelopment delay.. Randomized, double-blind, controlled trial in neonates with a birth weight of 500-2000 g in 3 neonatal units in Lima, Peru, comparing bovine lactoferrin 200 mg/kg/day with placebo administered for 8 weeks. The primary outcome was the first episode of culture-proven LOS or sepsis-associated death. Neurodevelopment delay was assessed by the Mullen Scales at 24 months corrected age.. Of the 414 infants enrolled, 209 received bovine lactoferrin and 205 received placebo. LOS or sepsis-associated death occurred in 22 infants (10.5%) in the bovine lactoferrin group vs 30 (14.6%) in the placebo group; there was no difference after adjusting for hospital and birth weight; hazard ratio 0.73 (95% CI, 0.42-1.26). For infants with birth weights of <1500 g the hazard ratio was 0.69 (95% CI, 0.39-1.25). The mean age-adjusted normalized Mullen composite score at 24 months was 83.3 ± 13.6 in the bovine lactoferrin group vs 82.6 ± 13.1 in the placebo group. Growth outcomes and rehospitalization rates during the 2-year follow-up were similar in both groups, except for significantly less bronchiolitis in the bovine lactoferrin group (rate ratio, 0.34; 95% CI, 0.14-0.86).. Supplementation with bovine lactoferrin did not decrease the incidence of sepsis in infants with birth weights of <2000 g. Growth and neurodevelopment outcomes at 24 months of age were similar. Neonatal bovine lactoferrin supplementation had no adverse effects.. ClinicalTrials.gov: NCT01525316.

Topics: Animals; Cattle; Double-Blind Method; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Lactoferrin; Male; Neurodevelopmental Disorders; Sepsis

Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice.. In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002.. We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86-1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention.. Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants.. UK National Institute for Health Research Health Technology Assessment programme (10/57/49).

Topics: Anti-Infective Agents; Cross Infection; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Male; Sepsis; Treatment Outcome; United Kingdom

To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit.. This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants.. Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants.. Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage.. isrctn.org: ISRCTN53107700.

Topics: Administration, Oral; Dietary Supplements; Enterocolitis, Necrotizing; Gastric Acid; Histamine H2 Antagonists; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Italy; Lacticaseibacillus rhamnosus; Lactoferrin; New Zealand; Probiotics; Proton Pump Inhibitors; Risk Factors; Sepsis

To evaluate the safety and explore the efficacy of recombinant human lactoferrin (talactoferrin [TLf]) to reduce infection.. We conducted a randomized, double blind, placebo-controlled trial in infants with birth weight of 750-1500 g. Infants received enteral TLf (n = 60) or placebo (n = 60) on days 1 through 28 of life; the TLf dose was 150 mg/kg every 12 hours. Primary outcomes were bacteremia, pneumonia, urinary tract infection, meningitis, and necrotizing enterocolitis (NEC). Secondary outcomes were sepsis syndrome and suspected NEC. We recorded clinical, laboratory, and radiologic findings, along with diseases and adverse events, in a database used for statistical analyses.. Demographic data were similar in the 2 groups of infants. We attributed no enteral or organ-specific adverse events to TLf. There were 2 deaths in the TLf group (1 each due to posterior fossa hemorrhage and postdischarge sudden infant death), and 1 death in the placebo group, due to NEC. The rate of hospital-acquired infections was 50% lower in the TLf group compared with the placebo group (P < .04), including fewer blood or line infections, urinary tract infections, and pneumonia. Fourteen infants in the TLf group weighing <1 kg at birth had no gram-negative infections, compared with only 3 of 14 such infants in the placebo group. Noninfectious outcomes were not statistically significantly different between the 2 groups, and there were no between-group differences in growth or neurodevelopment over a 1-year posthospitalization period.. We found no clinical or laboratory toxicity and a trend toward less infectious morbidity in the infants treated with TLf.. ClinicalTrials.gov: NCT00854633.

Topics: Administration, Oral; Bacteremia; Cross Infection; Double-Blind Method; Enterocolitis, Necrotizing; Female; Follow-Up Studies; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Male; Meningitis; Pneumonia; Protective Agents; Sepsis; Treatment Outcome; Urinary Tract Infections

To determine the immunologic effects of oropharyngeal colostrum administration in extremely premature infants.. We conducted a double-blind, randomized, placebo-controlled trial involving 48 preterm infants born before 28 weeks' gestation. Subjects received 0.2 mL of their mother's colostrum or sterile water via oropharyngeal route every 3 hours for 3 days beginning at 48 to 96 hours of life. To measure concentrations of secretory immunoglobulin A, lactoferrin, and several immune substances, urine and saliva were obtained during the first 24 hours of life and at 8 and 15 days. Clinical data during hospitalization were collected.. Urinary levels of secretory immunoglobulin A at 1 week (71.4 vs 26.5 ng/g creatinine, P = .04) and 2 weeks (233.8 vs 48.3 ng/g creatinine, P = .006), and lactoferrin at 1 week (3.5 vs 0.9 μg/g creatinine, P = .01) were significantly higher in colostrum group. Urine interleukin-1β level was significantly lower in colostrum group at 2 weeks (55.3 vs 91.8 μg/g creatinine, P = .01). Salivary transforming growth factor-β1 (39.2 vs 69.7 μg/mL, P = .03) and interleukin-8 (1.2 vs 4.9 ng/mL, P = .04) were significantly lower at 2 weeks in colostrum group. A significant reduction in the incidence of clinical sepsis was noted in colostrum group (50% vs 92%, P = .003).. This study suggests that oropharyngeal administration of colostrum may decrease clinical sepsis, inhibit secretion of pro-inflammatory cytokines, and increase levels of circulating immune-protective factors in extremely premature infants. Larger studies to confirm these findings are warranted.

Topics: Colostrum; Creatinine; Double-Blind Method; Enteral Nutrition; Hospitals, University; Humans; Immunoglobulin A, Secretory; Infant, Extremely Low Birth Weight; Infant, Newborn; Interleukin-1beta; Interleukin-8; Lactoferrin; Republic of Korea; Saliva; Sepsis; Transforming Growth Factor beta1

Lactoferrin (LF) is a broad-spectrum antimicrobial and immunomodulatory milk glycoprotein.. To determine the effect of bovine LF on the prevention of the first episode of late-onset sepsis in Peruvian infants.. We conducted a pilot randomized placebo-controlled double blind study in infants with a birth weight (BW) less than 2500g in 3 Neonatal Units in Lima. Patients were randomized to receive bovine LF 200mg/kg/d or placebo for 4 weeks.. One hundred and ninety neonates with a BW of 1591 ± 408 g and a gestational age of 32.1 ± 2.6 weeks were enrolled. Overall, 33 clinically defined first late-onset sepsis events occurred. The cumulative sepsis incidence in the LF group was 12/95 (12.6%) versus 21/95 (22.1%) in the placebo group, and 20% (8/40) versus 37.5% (15/40) for infants less than or equal to 1500 g. The hazard ratio of LF, after adjustment by BW, was 0.507 (95% CI: 0.249-1.034). There were 4 episodes of culture-proven sepsis in the LF group versus 4 in the placebo group. Considering that children did not received the intervention until the start of oral or tube feeding, we ran a secondary exploratory analysis using time since the start of the treatment; in this model, LF achieved significance. There were no serious adverse events attributable to the intervention.. Overall sepsis occurred less frequently in the LF group than in the control group. Although the primary outcome did not reach statistical significance, the confidence interval is suggestive of an effect that justifies a larger trial.

Topics: Anti-Infective Agents; Double-Blind Method; Humans; Immunologic Factors; Infant, Newborn; Lactoferrin; Peru; Pilot Projects; Placebos; Sepsis; Treatment Outcome

Talactoferrin alfa is a recombinant form of the human glycoprotein, lactoferrin, which has been shown to have a wide range of effects on the immune system. This phase II/III clinical trial compared talactoferrin with placebo, in addition to standard of care, in patients with severe sepsis.. Multicenter, randomized, placebo-controlled, phase II/III clinical study.. Seventy-seven centers in 10 countries.. Adult (> 18 yr) patients admitted to one of the participating centers with severe sepsis who were receiving antimicrobial therapy and able to take liquid medication by mouth or feeding tube.. Patients were randomized to receive either talactoferrin (1.5 g, 15 mL) or placebo three times a day orally or by another enteral route for 28 days or until ICU discharge.. The study was terminated after 305 patients had been enrolled (153 talactoferrin and 152 placebo) because of futility and safety concerns identified by the Data Safety Monitoring Board. There were no significant differences between groups in baseline characteristics including age, sex, site of infection, and severity scores. Twenty-eight-day mortality was higher in talactoferrin-treated patients although this difference was not statistically significant (24.8% vs 17.8% placebo; p = 0.117). The difference was largely the result of differences in patients with shock (talactoferrin, 33/105 [31.4%] vs placebo, 21/104 [20.2%]; p = 0.064); no mortality difference was seen in patients without shock (talactoferrin, 5/48 [10.4%] vs placebo, 6/48 [12.5%]; p = 0.806). In-hospital (43/153 [28.1%] vs 27/152 [17.8%]; p = 0.037) and 3-month (46/153 [30.1%] vs 31/152 [20.4%]; p = 0.036) mortality rates were significantly higher in talactoferrin-treated patients than in patients in the placebo group. The occurrence of treatment-related adverse or serious adverse events was similar between groups.. Administration of oral talactoferrin was not associated with reduced 28-day mortality in patients with severe sepsis and may even be harmful.

Topics: Adult; Aged; Aged, 80 and over; Anti-Infective Agents; APACHE; Double-Blind Method; Female; Humans; Lactoferrin; Male; Middle Aged; Sepsis; Shock, Septic

To evaluate the efficacy of bovine lactoferrin (BLF) in preventing first episode of late-onset sepsis (LOS) in low birth weight (LBW) neonates.. In this study conducted from May 2012 to July 2013 in the neonatal intensive care unit (NICU) of a tertiary care hospital, inborn asymptomatic neonates, <2000 g, admitted to NICU in first 12 h of birth with no maternal risk factors for sepsis were randomized to receive BLF or placebo from 1st to 28th day of life. The incidence of culture-proven sepsis and sepsis-attributable mortality after 72 h of life was recorded. Increasing doses of BLF were used with higher birth weights.. Incidence of first episode of culture-proven LOS was significantly lower in the BLF group vs. placebo [2/63 (3.2%) vs. 9/67(13.4%); risk ratio, 0.211; 95% CI, 0.044-1.019; p = 0.036]. Statistically significant reduction in the sepsis-attributable mortality was also seen after use of prophylactic BLF [0/63 (0%) vs. 5/67 (7.5%); p = 0.027].. BLF supplementation in LBW neonates reduced the incidence of first episode of LOS.

Topics: Animals; Anti-Infective Agents; Cattle; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Incidence; India; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Lactoferrin; Male; Risk Factors; Sepsis; Treatment Outcome

Lactoferrin (LF) is effective in the prevention of sepsis in very low birth weight (VLBW) neonates. T-regulatory cells (Tregs) are important subsets of T lymphocytes that control pathogen-specific immune responses and are essential for intestinal immune homoeostasis. The aim of the present study is to determine whether oral LF at a dosage of 200 mg/d reduces nosocomial sepsis episodes and necrotizing enterocolitis (NEC) in premature infants and to evaluate the possible effects of LF on Treg levels.. In this prospective, placebo-controlled, double-blind, randomized trial, infants either VLBW or born before 32 weeks were assigned to receive either placebo (n = 25), or 200 mg LF (n = 25) daily throughout hospitalization. Episodes of culture proven nosocomial sepsis and NEC were recorded. The level of FOXP3 + CD4 + CD25hi lymphocytes was studied by flow cytometry at birth and discharge. A third comparison was made with healthy term neonates (n = 16).. Fewer sepsis episodes were observed in LF-treated infants (4.4 vs. 17.3/1,000 patient days, p = 0.007) with none developing NEC, without statistical significance. Treg levels at birth and discharge were similar, while preterm infants showed significantly lower levels than term controls. However, individual increases in Treg levels were higher in the LF group.. LF prophylaxis reduced nosocomial sepsis episodes. Treg levels in preterm infants were lower than in term infants and an increase of Treg levels under LF prophylaxis was observed. Increase in Treg levels can be the mechanism for protective effects of LF on nosocomial sepsis.

Topics: Administration, Oral; Anti-Infective Agents; Cross Infection; Double-Blind Method; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Lactoferrin; Lymphocyte Count; Male; Prospective Studies; Sepsis; T-Lymphocytes, Regulatory

Lactoferrin is a glycoprotein with anti-infective and anti-inflammatory properties found in secretions and immune cells. Talactoferrin alfa, a recombinant form of human lactoferrin, has similar properties and plays an important role in maintaining the gastrointestinal mucosal barrier integrity. In experimental animal models, administration of talactoferrin reduces translocation of bacteria from the gut into the systemic circulation and mortality from sepsis. Our objective was to determine if talactoferrin could reduce 28-day all-cause mortality in patients with severe sepsis and to assess its safety.. Prospective, randomized, double-blind, placebo-controlled, multicenter phase 2 trial.. Adult ICUs and emergency departments in the United States.. One hundred ninety-four adults within 24 hrs of the onset of severe sepsis.. Enterally administered talactoferrin 1.5g or placebo every 8 hrs for up to 28 days or until discharge from the ICU.. Modified intention-to-treat analysis was used to assess the primary (28-day all-cause mortality) and secondary endpoints. The all-cause mortality at 28 days was 26.9% in the placebo group and 14.4% in the talactoferrin group (two-sided p = 0.052), representing a 12.5% absolute and a 46.5% relative reduction in mortality, meeting the protocol-specified primary endpoint. Reduction in all cause mortality was sustained at 6 months (p = 0.039). These reductions in mortality were observed across a wide spectrum of subgroups. The drug was well tolerated with a safety profile similar to that of placebo.. Enteral administration of talactoferrin reduced 28-day all-cause mortality in patients with severe sepsis. This reduction in mortality was sustained at 6 months. Talactoferrin was very well tolerated.

Topics: Adult; Aged; APACHE; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hospital Mortality; Humans; Infusions, Parenteral; Intensive Care Units; Lactoferrin; Male; Middle Aged; Placebos; Prospective Studies; Recombinant Proteins; Sepsis; Treatment Outcome

Sepsis is a common and severe complication in premature neonates, particularly those with very low birth weight (VLBW) (<1500 g). Whether lactoferrin, a mammalian milk glycoprotein involved in innate immune host defenses, can reduce the incidence of sepsis is unknown. In animal models, the probiotic Lactobacillus rhamnosus GG (LGG) enhances the activity of lactoferrin but has not been studied in human infants.. To establish whether bovine lactoferrin (BLF), alone or in combination with LGG, reduces the incidence of late-onset sepsis in VLBW neonates.. Prospective, multicenter, double-blind, placebo-controlled, randomized trial conducted in 11 Italian tertiary neonatal intensive care units. Patients were 472 VLBW infants enrolled from October 1, 2007, through July 31, 2008, and assessed until discharge for development of sepsis.. Infants were randomly assigned to receive orally administered BLF (100 mg/d) alone (n = 153), BLF plus LGG (6 x 10(9) colony-forming units/d) (n = 151), or placebo (n = 168) from birth until day 30 of life (day 45 for neonates <1000 g at birth).. First episode of late-onset sepsis, ie, sepsis occurring more than 72 hours after birth with isolation of any pathogen from blood or from peritoneal or cerebrospinal fluid.. Demographic, clinical, and management characteristics of the 3 groups were similar, including type of feeding and intake of maternal milk. Incidence of late-onset sepsis was significantly lower in the BLF and BLF plus LGG groups (9/153 [5.9%] and 7/151 [4.6%], respectively) than in the control group receiving placebo (29/168 [17.3%]) (risk ratio, 0.34; 95% confidence interval, 0.17-0.70; P = .002 for BLF vs control and risk ratio, 0.27; 95% confidence interval, 0.12-0.60; P < .001 for BLF plus LGG vs control). The decrease occurred for both bacterial and fungal sepsis. No adverse effects or intolerances to treatment occurred.. Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of a first episode of late-onset sepsis in VLBW neonates.. isrctn.org Identifier: ISRCTN53107700.

Topics: Double-Blind Method; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care, Neonatal; Lacticaseibacillus rhamnosus; Lactoferrin; Logistic Models; Male; Probiotics; Risk Factors; Sepsis

Modulation of intestinal microbiome by administering probiotics, prebiotics, or both may prevent morbidity and mortality in premature infants.. To assess the comparative effectiveness of alternative prophylactic strategies through a network meta-analysis (NMA) of randomized clinical trials.. MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, and Google Scholar from inception until May 10, 2023.. Eligible trials tested probiotics, prebiotics, lactoferrin, and combination products for prevention of morbidity or mortality in preterm infants.. A frequentist random-effects model was used for the NMA, and the certainty of evidence and inferences regarding relative effectiveness were assessed using the GRADE approach.. All-cause mortality, severe necrotizing enterocolitis, culture-proven sepsis, feeding intolerance, time to reach full enteral feeding, and duration of hospitalization.. A total of 106 trials involving 25 840 preterm infants were included. Only multiple-strain probiotics were associated with reduced all-cause mortality compared with placebo (risk ratio [RR], 0.69; 95% CI, 0.56 to 0.86; risk difference [RD], -1.7%; 95% CI, -2.4% to -0.8%). Multiple-strain probiotics alone (vs placebo: RR, 0.38; 95% CI, 0.30 to 0.50; RD, -3.7%; 95% CI, -4.1% to -2.9%) or in combination with oligosaccharides (vs placebo: RR, 0.13; 95% CI, 0.05 to 0.37; RD, -5.1%; 95% CI, -5.6% to -3.7%) were among the most effective interventions reducing severe necrotizing enterocolitis. Single-strain probiotics in combination with lactoferrin (vs placebo RR, 0.33; 95% CI, 0.14 to 0.78; RD, -10.7%; 95% CI, -13.7% to -3.5%) were the most effective intervention for reducing sepsis. Multiple-strain probiotics alone (RR, 0.61; 95% CI, 0.46 to 0.80; RD, -10.0%; 95% CI, -13.9% to -5.1%) or in combination with oligosaccharides (RR, 0.45; 95% CI, 0.29 to 0.67; RD, -14.1%; 95% CI, -18.3% to -8.5%) and single-strain probiotics (RR, 0.61; 95% CI, 0.51 to 0.72; RD, -10.0%; 95% CI, -12.6% to -7.2%) proved of best effectiveness in reduction of feeding intolerance vs placebo. Single-strain probiotics (MD, -1.94 days; 95% CI, -2.96 to -0.92) and multistrain probiotics (MD, -2.03 days; 95% CI, -3.04 to -1.02) proved the most effective in reducing the time to reach full enteral feeding compared with placebo. Only single-strain and multistrain probiotics were associated with greater effectiveness compared with placebo in reducing duration of hospitalization (MD, -3.31 days; 95% CI, -5.05 to -1.58; and MD, -2.20 days; 95% CI, -4.08 to -0.31, respectively).. In this systematic review and NMA, moderate- to high-certainty evidence demonstrated an association between multistrain probiotics and reduction in all-cause mortality; these interventions were also associated with the best effectiveness for other key outcomes. Combination products, including single- and multiple-strain probiotics combined with prebiotics or lactoferrin, were associated with the largest reduction in morbidity and mortality.

Topics: Enterocolitis, Necrotizing; Humans; Infant; Infant, Newborn; Infant, Premature; Lactoferrin; Morbidity; Network Meta-Analysis; Oligosaccharides; Prebiotics; Probiotics; Sepsis

Topics: Dietary Supplements; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Lactoferrin; Sepsis

Topics: Antiviral Agents; Humans; Lactoferrin; Sepsis; South America; Viruses

Lactoferrin (LF) is a protective protein present in milk with anti-infective and immune-modulating properties.. The aim of this study was to determine the association of maternal LF intake and mother's own milk intake in the first 10 days of life on the prevention of late-onset sepsis (LOS), necrotizing enterocolitis (NEC), or death in the first 8 weeks of life in newborns with a birth weight <2,000 g.. A retrospective cohort study was conducted, with the exposure being the consumption of mother's own LF and mother's own milk in the first 10 days of life, and the outcome being LOS, NEC, or death during days 11 and 56 of life, analyzed by Cox regression.. Two hundred and ninety-nine infants were enrolled, including 240 with human LF intake information. The average daily human LF intake over days 4-10 of life was 283 mg/kg/day (IQR 114-606 mg/kg/day). The hazard ratio (HR) of mother's own milk LF intake ≥100 mg/kg/day in days 4-10 for LOS, NEC, or death was 0.297 (95% CI 0.156-0.568, p < 0.001); the adjusted HR was 0.752 (95% CI 0.301-1.877, p = 0.541). The adjusted HR of mother's own milk cumulative intake (days 4-10) of 54-344 mL/kg (25-75 quartiles) for LOS, NEC, or death was 0.414 (95% CI 0.196-0.873, p = 0.02). Infants who developed an event (LOS, NEC, or death) had significantly less median daily human LF intake than those that did not (89 vs. 334 mg/kg/day, respectively, p < 0.0001).. Consumption of higher amounts of mother's own milk in the first days of life is associated with less infection, NEC, and death. Early human milk intake should be strongly encouraged in all newborns.

Topics: Enterocolitis, Necrotizing; Female; Humans; Infant; Infant, Newborn; Lactoferrin; Milk, Human; Mothers; Neonatal Sepsis; Retrospective Studies; Sepsis

Preterm infants are at a high risk of developing late-onset sepsis (LOS). Lactoferrin is one of the most abundant endogenous antimicrobial proteins expressed in breast milk, stools, and blood, and a candidate for preventive intervention. Large clinical trials have recently investigated whether enteral supplementation with bovine lactoferrin reduces LOS.. To characterize lactoferrin levels in preterm infants with and without LOS during the first month of life.. Very preterm and term infants were recruited and serial biosamples collected during the first month of life. Lactoferrin levels were determined by immunoassay in cord blood and peripheral blood on days 1, 7, 14, 21, and 28; in the stools on days 1 and 28; and in the mother's breast milk on days 7 and 21. Furthermore, we assessed the capacity of the peripheral blood to release lactoferrin in response to an in vitro challenge with live Staphylococcus epidermidis, lipopolysaccharide, and fibroblast-stimulating lipopeptide 1.. Plasma lactoferrin levels were higher in cord blood and day 1 peripheral blood and declined during the first month of life. Plasma lactoferrin levels were similar in term infants and in preterm infants with (n = 32) and without LOS (n = 53). S. epidermidis-induced lactoferrin levels were lower following the sepsis episode.. Endogenous lactoferrin expression in preterm infants does not appear to affect their risk of developing LOS. These findings are in line with the lack of benefit recently observed in large trials of enteral supplementation with bovine lactoferrin to prevent LOS.

Topics: Female; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Lactoferrin; Sepsis

This study was aimed to uncover proteins that are differentially expressed in sepsis. Data-independent acquisition (DIA) was used for analysis to identify differentially expressed proteins in peripheral blood mononuclear cells (PBMCs) of patients. A total of 24 non-septic intensive care unit (ICU) patients, 11 septic shock patients and 27 patients diagnosed with sepsis were recruited for the mass spectrometry (MS) discovery. PBMCs were isolated from routine blood samples and digested into peptides. A DIA workflow was developed using a quadrupole-Orbitrap liquid chromatography LC-MS system, and mass spectra peaks were extracted by Skyline software. Orthogonal partial least-squares discriminant analysis (OPLS-DA) and partial least-squares discriminant analysis (PLS-DA) were applied to distinguish the patient groups at the level of fragment ion and peptide. Differentially expressed proteins in the patient groups were verified by enzyme-linked immunosorbent assay (ELISA). Receiver-operating characteristic (ROC) curves were used to evaluate the protein expression. A total of 1062 fragment ions and 122 proteins were identified in the MS-DIA analysis conducted by Skyline software. Using gene ontology clustering analysis, we discovered that 51 of the 122 identified proteins were associated with biological processes, including carbon metabolism, biosynthesis of antibiotics, platelet activation, bacterial invasion of epithelial cells and complement, and coagulation cascades. Among them, five proteins (high-mobility group box1 [HMGB1], matrix metalloproteinase 8 [MMP8], neutrophil gelatinase-associated lipocalin [NGAL], lactotransferrin [LTF] and grancalcin [GCA]) were identified by ELISA as closely related to the development of sepsis. The ROC curves displayed good sensitivity and specificity.

Topics: Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Cells, Cultured; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; HMGB1 Protein; Humans; Immunity; Lactoferrin; Leukocytes, Mononuclear; Lipocalin-2; Male; Mass Spectrometry; Matrix Metalloproteinase 8; Middle Aged; Proteome; Sepsis

Lactoferrin (LF), an iron-binding glycoprotein distributed widely in the biological fluids of mammals, is believed to play an important role in host defenses against infection. Previous studies in animal models and humans demonstrated that combined administration of LF and probiotic lactic acid bacteria (LAB) can prevent sepsis. In this study, we genetically engineered a probiotic LAB strain, Lactococcus lactis, to produce recombinant bovine LF based on the green fluorescent protein (GFP)-fused expression system. Western blotting confirmed that the genetically modified L. lactis strain (designated NZ-GFP-bLF) produced a protein corresponding to a fusion of GFP and bLF in the presence of nisin, an inducer of target gene expression. The protein synthesized by NZ-GFP-bLF was fluorescent and thus we monitored the time-dependent change in the production level of the recombinant protein using fluorometric analysis. The utility of NZ-GFP-bLF in preventing sepsis was determined by investigating its anti-inflammatory property in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells. Pretreatment of RAW 264.7 cells with NZ-GFP-bLF significantly attenuated the LPS-induced mRNA expression and protein production of 3 proinflammatory cytokines (IL-1α, IL-6, and tumor necrosis factor-α) compared with pretreatment with a vector control strain of L. lactis. Our results suggest that NZ-GFP-bLF holds promise for the development of a new prophylaxis for sepsis.

Topics: Animals; Cattle; Green Fluorescent Proteins; Interleukin-1alpha; Interleukin-6; Lactococcus lactis; Lactoferrin; Lipopolysaccharides; Mice; Microorganisms, Genetically-Modified; RAW 264.7 Cells; Recombinant Proteins; Sepsis; Tumor Necrosis Factor-alpha

Lactoferrin (Lf) is one of the major proteins of all exocrine secretions with a role in the antinfective process. Our aim was to evaluate how plasma Fl levels may change in response to infection in newborn preterm infants.. A total of 15 (8 females, 7 males) newborn preterm infants with a postnatal age >72 h of life, underwent to blood culture and others markers of infection, for suspected sepsis, were enrolled in the study.. We found that Lf serum concentration was significantly lowest in four neonates (26.7%) with confirmed sepsis than in 11 (73.3%) with clinical sepsis. The AUC was 0.90 (95%CI: 0.63-0.99). The optimal cutoff for Lf was <1.2 μg/ml with a sensibility of 100% and a specificity of 81.8%. Lf serum concentration was positively correlated with WBC or neutrophil (Spearman rho = 0.69 and 0.49, respectively).. Serum Lf could prove a promising, sensitive and specific marker in the diagnostic approach to infants with suspected sepsis, thanks to its role in defense mechanisms and physiological functions of the immune system. Low levels of Lf in sepsis may suggest an immature response due to suboptimal leukocites activity in newborn preterm infants.

Topics: Biomarkers; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lactoferrin; Male; Predictive Value of Tests; Sensitivity and Specificity; Sepsis

Topics: Blood Banks; Bronchopulmonary Dysplasia; Child Development; Chromosomes, Human, Pair 18; Enterocolitis, Necrotizing; Fetal Blood; Hematinics; Humans; Hypoxia, Brain; Infant; Infant, Newborn; Lactoferrin; Sepsis; Trisomy; Trisomy 18 Syndrome

Topics: Female; Humans; Lactoferrin; Male; Sepsis

Topics: Administration, Oral; Anti-Infective Agents; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature, Diseases; Infection Control; Lactoferrin; Sepsis

The role of endotoxin in the genesis of sepsis has long been recognized and multiple treatments aimed at neutralizing it have been studied. Endotoxin can be bound by antibodies (whose role as a therapeutic agent is unlikely), binding proteins such as BPI or human lactoferrin (effectiveness debated and promising respectively) and phospholipid emulsion (which has not improved outcomes in a recent study). Alternatively, the action of endotoxin could be blocked by lipid A analogs (initial study showed no overall benefit and another large trial is near completion targeting a subpopulation of that study). Finally, endotoxin can be bound by polymyxin B embedded in hemoperfusion cartridges. The later treatment has been used for more than a decade in Japan. Since both pre-clinical rationale and studies support the targeting of endotoxin to ameliorate the pro-inflammatory and pro-coagulation response of severe sepsis, this therapeutic intervention is being pursued.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies; Antimicrobial Cationic Peptides; Blood Proteins; Clinical Trials as Topic; Endotoxins; Humans; Lactoferrin; Lipid A; Polymyxin B; Sepsis

An episode of sepsis occurs in 20 to 40% of all preterm patients, and such figures have been reported constantly increasing in Neonatal Intensive Care Units. Neonatal sepsis include bloodstream, urine, cerebrospinal, peritoneal infections, infections starting from burns and wounds, or from any other usually sterile sites. Many specific risk factors account for the increased risk of sepsis, including employment of broad-spectrum antibiotics selecting resistant microflora, parenteral nutrition, acid inhibitors and steroids, as well as the systematic and long-lasting use of invasive management. In preterm neonates, loss of gut commensals such as bifidobacteria and lactobacilli, due to the difficulties in oral feeding, or a slower acquisition of them, translates into an increased susceptibility to pathogenic gut colonization. Prompt diagnosis, effective treatment, and specific prophylaxis with antibacterial and antifungal drugs are the milestones of management of these life-threatening events. This article discusses the recent advances in prevention and shows how fluconazole for prevention of fungal sepsis, probiotics for prevention of necrotizing enterocolitis, and bovine lactoferrin for prevention of bacterial sepsis may be considered as effective preventive strategies.

Topics: Antifungal Agents; Fluconazole; Humans; Infant, Newborn; Infant, Premature, Diseases; Lactoferrin; Probiotics; Sepsis

Topics: Cross Infection; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Lacticaseibacillus rhamnosus; Lactoferrin; Probiotics; Sepsis

The investigation of results of treatment included the observation of 2250 patients with pyo-necrotic diseases of soft tissues. For the early diagnosis of sepsis the indices of C-reactive protein, oligopeptides and lactoferrin of blood were used. In the presence of one or more symptoms of the systemic inflammatory reaction the level of the indices was increased from 1.1-3.1 up to 4-7 times depending on the degree of the systemic response severity. When the inflammatory process was local the data of the markers remain normal. These markers allow the confirmation of the clinical diagnosis of sepsis, assessment of the degree of the systemic inflammatory reaction and prognosis of the disease.

Topics: Biomarkers; C-Reactive Protein; Diagnosis, Differential; Follow-Up Studies; Humans; Immunoenzyme Techniques; Lactoferrin; Oligopeptides; Prognosis; Reproducibility of Results; Retrospective Studies; Sepsis; Severity of Illness Index; Time Factors

Neonatal sepsis causes significant mortality and morbidity. Coagulase-negative staphylococci (CoNS) and Candida frequently cause neonatal sepsis at >72 h of age. Lactoferrin, which is present in human milk, is a component of innate immunity and has broad-spectrum antimicrobial activity. The synergistic effects of lactoferrin with antibiotics against neonatal isolates have not been systematically evaluated. Here, eight clinical strains (seven neonatal) of CoNS and three strains (two neonatal) of Candida albicans were studied. MIC50 and MIC90 values of human recombinant lactoferrin (talactoferrin; TLF), vancomycin (VAN) and nafcillin (NAF) against CoNS, and of TLF, amphotericin B (AMB) and fluconazole (FLC) against C. albicans, were evaluated according to established guidelines. Antimicrobial combinations of TLF with NAF or VAN against CoNS, and TLF with AMB or FLC against C. albicans, were evaluated by a checkerboard method with serial twofold dilutions. Synergy was evaluated by the median effects principle, and combination indices and dose reduction indices were reported at 50, 75 and 90% inhibitory effect at several drug-dose ratios. It was found that TLF acted synergistically with NAF and VAN against CoNS, and with AMB and FLC against C. albicans, at multiple dose effects and drug-dose ratios with few exceptions. In synergistic combinations, drug reduction indices indicated a significant reduction in doses of antibiotics, which may be clinically relevant. Thus TLF acts synergistically with anti-staphylococcal and anti-Candida agents commonly used in neonatal practice and is a promising agent that needs to be evaluated in clinical studies.

Topics: Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Candidiasis; Coagulase; Drug Synergism; Humans; Infant, Newborn; Lactoferrin; Microbial Sensitivity Tests; Recombinant Proteins; Sepsis; Staphylococcal Infections; Staphylococcus

Plasma lactoferrin dynamics was investigated in 120 of the 2250 patients with local and generalized soft tissue infections. Systemic symptoms were observed in 15% of the patients with soft tissue infections, syndrome of systemic inflammatory response in 13%, and sepsis in 42%. In 89% of the patients with systemic inflammatory reactions the blood lactoferrin level was 1.1-1.3 times the normal one within 72 hours after the onset of therapy; it dropped to the normal value in 12-15 days. Normalization of blood lactoferrin in patients with mild and moderate systemic inflammatory reactions roughly coincided with the disappearance of symptoms of generalized infection. It occurred 5-6 days after the septic process was resolved in patients with severe inflammatory reactions. Normal blood lactoferrin levels were characteristic of a mild inflammatory reaction and local forms of infection. A rise in blood lactoferrin above 1400 ng/ml combined with the syndrome of systemic inflammatory reaction over 72 hr in duration was regarded as a diagnostic criterion of sepsis. It is suggested that monitoring blood lactoferrin during treatment of systemic inflammatory reactions and sepsis be used for the choice of therapeutic strategy and the assessment of efficiency of its efficiency.

Topics: Biomarkers; Diagnosis, Differential; Follow-Up Studies; Humans; Immunoenzyme Techniques; Lactoferrin; Necrosis; Prospective Studies; Sepsis; Soft Tissue Infections

The treatment of children affected by severe congenital neutropenia (SCN) with G-CSF strongly reduces the risk of sepsis by reversing neutropenia. However, SCN patients who respond to the treatment with the growth factor still have an elevated risk of succumbing to sepsis. Because the disease is usually caused by heterozygous mutations of ELA2, a gene encoding for neutrophil elastase (NE), we have investigated in G-CSF-responder and nonresponder patients affected by SCN the expression of polypeptides that constitute the antimicrobial machinery of these cells. In peripheral blood-derived neutrophils of patients with heterozygous mutations of ELA2 who were treated with G-CSF, NE was nearly absent as detected by immunofluorescence and immunoblotting, suggesting that production of the mutant protein interferes with normal gene expression. This defect was associated with abnormal expression of other granule-associated proteins such as myeloperoxidase, lactoferrin, cathepsin G, and human-neutrophil-peptide. Moreover, in one patient with partial response to G-CSF, we observed an impairment of neutrophil antimicrobial activity against Candida albicans, and, to a lower extent against Escherichia coli. Thereby, we propose that the treatment with G-CSF is not sufficient to correct all of the functional deficiency of neutrophils, and this might account for the consistent risk of infections observed in SCN patients.

Topics: Candida albicans; Cathepsin G; Cathepsins; Escherichia coli; Granulocyte Colony-Stimulating Factor; Humans; Infant; Infant, Newborn; Lactoferrin; Leukocyte Elastase; Mutation; Neutropenia; Neutrophils; Peptides; Peroxidase; Sepsis; Serine Endopeptidases

Previous studies demonstrated that lactoferrin (LF), given intravenously (i.v.), 24 h before lethal Escherichia coli ( E. coli) infection, protects mice against mortality. The aim of this investigation was to determine whether downregulation of serum TNF alpha activity and increase of neutrophil number in the circulation and bone marrow by LF could contribute to the protective action of LF against E. coli-induced sepsis.. CBA female mice, 10-12 week old, weight 20-22 g, were used.. Mice were given 10 mg LF i.v. either 2 h or 24 h before i.v. administration of lethal dose of E. coli (5 x 10(8)).. Serum activities of TNF alpha and IL-1 were determined by bioassays 2 h following E. coli or LF injection. The blood and bone marrow smears were stained with Giemsa and May-Grünwald reagents and reviewed histologically.. LF given 24 h before E. coli caused a 60% reduction of TNF alpha released into circulation. However, pretreatment of mice with LF 2 h before bacterial challenge resulted in strong (15 fold) increase of TNF alpha serum level. Analysis of bone marrow cell composition revealed a significant increase in neutrophil lineage cell content (myelocytes, bands and mature neutrophils) following 24 h pretreatment with LF (51.8% of the total cell count), versus PBS control (32.7%) and 2 h LF pretreatment (35.8%). The percentage of neutrophils (bands and mature forms) in the peripheral blood rose to 47.4% versus 32% and 32%, respectively. Intravenous administration of LF increased also interleukin 1 (IL-1) concentration in the circulation of noninfected mice.. This investigation has added more information regarding the mechanism of the protective action of LF in E. coli-induced bacteremia by revealing the phenomenon of accelerated neutrophil recruitment and down-regulation of E. coli-induced TNF alpha serum level.

Topics: Animals; Bacteremia; Bone Marrow; Dose-Response Relationship, Drug; Escherichia coli; Escherichia coli Infections; Female; Interleukin-1; Lactoferrin; Mice; Mice, Inbred CBA; Neutrophils; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

Forty patients with severe sepsis or septic shock recently received C1 inhibitor. In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-alpha(1)-antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved in the activation of neutrophils in human sepsis. Elevated levels of EA and LF were found in 65 and 85% of the septic patients, respectively. Patients with elevated EA levels had higher organ dysfunction scores, higher levels of cytokines, and higher levels of complement activation products than patients with normal EA levels. C1 inhibitor therapy reduced EA as well as complement activation and IL-8 release in the patients with elevated EA on admission. We conclude that neutrophil activation in human sepsis correlates with the severity of organ dysfunction and involves complement and interleukin-8 as agonists. The effect of C1 inhibitor therapy on neutrophils may provide an explanation for the beneficial, although mild, effects of this treatment on organ dysfunction in sepsis.

Topics: Adult; Aged; alpha 1-Antitrypsin; Biomarkers; Complement Activation; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Cytokines; Female; Humans; Interleukin-8; Lactoferrin; Leukocyte Elastase; Male; Middle Aged; Multiple Organ Failure; Neutrophils; Sepsis; Serpins; Shock, Septic

We hypothesized that systemic release of endogenous leukocyte-derived polypeptide antimicrobial defensins (polymorphonuclear leukocyte-specific) and lactoferrin (polymorphonuclear leukocyte and epithelial cell derived) occurs in nonneutropenic children with severe sepsis.. We performed a prospective cross-sectional and longitudinal study in a university children's hospital pediatric intensive care unit. Ninety-two consecutive children meeting criteria for sepsis and 14 critically ill children without sepsis (controls) were enrolled, and plasma defensins and lactoferrin concentrations were measured on Days 1 and 3 of sepsis.. Nonneutropenic sepsis patients (n = 71) had increased defensins and lactoferrin plasma concentrations compared with critically ill control patients [defensins, 450 ng/ml vs. 150 ng/ml; lactoferrin, 332 ng/ml vs. 176 ng/ml (median values); P < 0.05] and neutropenic sepsis patients [n = 21; defensins, 450 ng/ml vs. 50 ng/ml; lactoferrin, 332 ng/ml vs. 20 ng/ml (median values); P < 0.05]. Neutropenic sepsis patients had similar plasma defensin concentrations and a decrease in plasma lactoferrin concentrations compared with control patients (P < 0.05). Defensins and lactoferrin plasma concentrations correlated to total white blood cell and absolute neutrophil count (P < 0.05). There was no association between plasma defensin concentration and organ failure or outcome; however, increased plasma lactoferrin concentrations were observed with the development of organ failure (P < 0.05).. These data suggest that increased circulating defensins and lactoferrin release are dependent in part on neutrophil count and might play a role in host defense in children with severe sepsis.

Topics: Adolescent; Child; Child, Preschool; Cross-Sectional Studies; Defensins; Female; Humans; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Lactoferrin; Male; Neutropenia; Prospective Studies; Sepsis; Severity of Illness Index

To determine whether lactoferrin (LF) and lysozyme (LZ) can be used as immunohistochemical postmortem markers of sepsis, pulmonary tissue sections from autopsy cases of sepsis-related fatalities (n = 13) and control cases of non-septic fatalities (n = 14) were evaluated for differences in leucocytic immunoreactivity. LF and LZ were investigated in paraffin sections using the AEC technique. The immunohistochemical expression of both markers was scored, evaluating the quantity of immunopositive cells and the intensity of the intracellular immunoreactivity. There was a statistically significant association between an enhanced expression of LF on pulmonary leucocytes in sepsis-related fatalities in contrast to non-sepsis cases (P < 0.001), whereas no such difference could be observed for LZ immunoreactivity between the two study groups. Pneumonic tissue alterations had no significant influence on LF and LZ immunoreactivity, thus suggesting differences between the degranulation of these non-specific antibacterial agents in local and systemic inflammatory processes. While the variability of LZ immunoreactivity, possibly reflecting a non-specific release from lysosomes according to the length of the postmortem interval, limits its application to the postmortem diagnosis of sepsis, the immunohistochemical detection of an enhanced expression of LF can contribute to the postmortem discrimination between sepsis and non-septic fatalities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Cause of Death; Child; Child, Preschool; Female; Humans; Immunoenzyme Techniques; Lactoferrin; Leukocytes; Lung; Male; Middle Aged; Muramidase; Sepsis

To investigate interactions between the endothelium and leukocytes in patients with sepsis, we measured soluble adhesion molecules (sE-selectin and sICAM-1), von Willebrand factor antigen (vWf:Ag), myeloperoxidase (MPO), and lactoferrin (Lacto-f) as plasma markers of endothelial and neutrophil activation. We tested whether the five proteins were predictors of clinical severity, which was evaluated by simplified acute physiological score (SAPS), number of organ failures (MOF), acute lung injury (ALI), and subsequent final outcome. Levels of the five plasma markers were higher in patients with severe infection (n = 25) than in patients without sepsis (n = 7) and healthy volunteers (n = 9). In the study population, levels of sE-selectin, sICAM-1, and vWf:Ag were higher for nonsurvivors as well as for patients with septic shock or with bacteremia, and they were correlated with SAPS and MOF. Survival outcome was predicted with high sensitivity and specificity by initial plasma levels of sICAM-1 and vWf:Ag. The initial sICAM-1 level appeared to be an independent prognostic variable, based on a logistic regression analysis. Unlike sE-selectin, sICAM-1 remained at high levels indefinitely in nonsurvivors. We conclude that, unlike neutrophil activation markers, levels of endothelium-derived soluble adhesion molecules and vWf:Ag in severe sepsis syndrome are correlated with the severity of illness and may be considered as predictors of survival outcome.

Topics: Adult; Aged; Aged, 80 and over; APACHE; Bacteremia; Biomarkers; E-Selectin; Endothelium, Vascular; Female; Follow-Up Studies; Forecasting; Humans; Intercellular Adhesion Molecule-1; Lactoferrin; Leukocytes; Logistic Models; Male; Middle Aged; Multiple Organ Failure; Neutrophil Activation; Peroxidase; Prognosis; Sensitivity and Specificity; Sepsis; Shock, Septic; Survival Rate; Treatment Outcome; von Willebrand Factor

Breast milk has been shown to prevent gut-origin infections in neonates through undefined mechanisms. Putative protective factors in breast milk include immunoglobulin (Ig)A, IgG, and lactoferrin. We examined their role in bacterial translocation in neonatal rabbits.. IgA, IgG, and lactoferrin were isolated from rabbit breast milk through gel filtration and ion-exchange chromatography. Neonates were randomized to receive breast milk, formula alone, or formula supplemented with IgA, IgG, or lactoferrin. Quantitative cultures were performed on day 7 for bacterial translocation. Hematoxylin-eosin-stained sections of distal ileum were examined by light microscopy. Transmucosal bacterial passage was determined in vitro, and the ileal mucosal membranes were examined by confocal microscopy.. IgA supplementation abrogated bacterial translocation. IgG and lactoferrin had no significant effect. Neonates that received IgA or breast milk gained more weight than those in the other groups. IgA reduced transmucosal bacterial passage in vitro. In contrast to the normal-appearing distal ileum of neonates fed breast milk, intestinal epithelium from neonates that received formula or formula with IgG or IgA demonstrated prominent vacuoles by light microscopy. Those fed formula alone or formula with lactoferrin had slightly shortened villi.. IgA supplementation prevents bacterial translocation by enhancing gut mucosal barrier function.

Topics: Animals; Animals, Newborn; Animals, Suckling; Bacteria; Biological Transport; Female; Immunoglobulin A; Immunoglobulin G; Infant Food; Intestinal Mucosa; Lactoferrin; Lymph Nodes; Mesentery; Milk; Rabbits; Sepsis; Weight Gain

Neutrophil activation is thought to play a crucial role in the pathogenesis of sepsis. During activation, neutrophils adhere to and migrate through the endothelium. Therefore, the amount of circulating neutrophils does not adequately reflect the total amount of neutrophils that are involved in the pathophysiologic process of this condition. In this study we test the hypothesis that the severity of sepsis is associated with the total body mass of neutrophils as reflected in the plasma concentration of soluble Fc gamma receptor type III (sFc gammaRIII). Nineteen patients with sepsis (12 male, seven female, median age of 69 years, range 29-87 years) were included in this study. Ten healthy volunteers served as controls. Plasma sFc gammaRIII concentrations were measured by ELISA. Other parameters that were studied were leucocyte count, plasma concentrations of lactoferrin and soluble L-selectin, and surface expression of CD11b and CD66b on circulating neutrophils. Disease activity was measured using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Soluble Fc gammaRIII levels were elevated in sepsis patients whereas soluble L-selectin levels were moderately decreased compared with healthy controls. Markers of cell activation were significantly increased in sepsis patients. Soluble Fc gammaRIII correlated with disease severity as measured by the APACHE score (P<0.05, r=0.53), whereas the other parameters did not correlate with the APACHE score. In conclusion, this study demonstrates that soluble Fc gammaRIII is a useful marker for disease severity in patients with sepsis.

Topics: Adult; Aged; Aged, 80 and over; Female; Flow Cytometry; Humans; L-Selectin; Lactoferrin; Male; Middle Aged; Receptors, IgG; Sepsis; Solubility

Typical alterations of the white blood cell count are often missed during the acute course of infectious diseases. Activiation and degranulation of granulocytes are followed by elevation of E alpha 1 PI and lactoferrin plasma concentrations under these conditions. The aim of our study was the evaluation of the diagnostic significance of these granulocyte parameters in relation with the absolute granulocyte count in infected pediatric patients. A total number of 106 patients at the age of 1 day to 16 years were studied. 25 children suffered from viral, 26 from localized and 23 from systemic bacterial infections, 32 children exhibiting no signs of infection served as controls. Results of the study are given as medians and ranges. Total granulocyte count was elevated above controls (4.8; 2.2-12.7/nl) only in patients with localized bacterial infections (13.3; 5.5-36.5/nl). E alpha 1 PI and lactoferrin plasma concentrations correlated well (r = 0.72) and were found to be significantly elevated in patients with localized bacterial infections (856; 363-4820 micrograms/l and 748; 206-2078 micrograms/l) and septicemia respectively (661; 256-2078 micrograms/l and 871; 160-9550 micrograms/l). A clearcut differentiation of septic and locally infected patients was given by the ratio of E alpha 1 PI and total granulocyte counts. Significantly elevated E alpha 1 PI concentrations of patients exhibiting viral infections (295; 86-690 micrograms/l) may suggest effective granulocyte activation under this condition. Finally we conclude that E alpha 1 PI and lactoferin plasma concentration related to total granulocyte counts in infected patients may serve as a helpful indicator of granulocyte activation during the acute course of the disease.

Topics: Adolescent; Bacterial Infections; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Lactoferrin; Leukocyte Count; Male; Sepsis; Serine Proteinase Inhibitors; Serpins; Viremia; Virus Diseases

Human lactoferrin (HLf) is an iron-binding protein and a host-defence component at the mucosal surface. Recently, a specific receptor for HLf has been identified on a strain of Staphylococcus aureus associated with toxic shock syndrome. We have looked for the occurrence of 125I-HLf binding among 489 strains of S. aureus isolated from various clinical sources. HLf binding was common among S. aureus strains associated with furunculosis (94.3%), toxic shock syndrome (94.3%), endocarditis (83.3%) and septicaemia (82.8%) and other (nasal, vaginal or ocular) infections (96.1%) with a mean binding (in fmol) of 29.1, 21.9, 16.9, 22.2 and 29.2 respectively; the differences between mean HLf binding values of 29.1-29.2, 21.9-22.2 and 16.9 were significant. Furunculosis-associated (low-invasive or localised) isolates were high-to-moderate binders of HLf; 50% gave positive results at a threshold of greater than 31 fmol of 125I-HLf bound. In contrast, endocarditis-associated (high-invasive or systemic) isolates demonstrated low binding and did not bind 125I-HLf at the above threshold level. S. aureus recognised human or bovine Lf. However, bound 125I-HLf was more effectively inhibited in a dose-dependent manner by unlabelled bovine Lf than by homologous HLf. Binding of 125I-HLf to staphylococci was optimal with organisms grown in agar compared with those from broth cultures. The binding capacity of S. aureus was abolished when strains were grown on carbohydrate- and salt-rich agar media. HLf-binding ability of S. aureus did not correlate with fibronectin, fibrinogen, immunoglobulin G or laminin binding.

Topics: Culture Media; Endocarditis; Fibrinogen; Fibronectins; Furunculosis; Immunoglobulin G; Lactoferrin; Laminin; Sepsis; Shock, Septic; Staphylococcus aureus

Using a whole blood in vitro model, we have investigated the effect of Escherichia coli (E. coli), Streptococcus agalactiae (group B streptococci, GBS) and tumor necrosis factor alpha (TNF) on the generation of lactoferrin (LF), interleukin-1 beta (IL-1) and tissue thromboplastin (TPL) in healthy newborns at term and their mothers. E. coli (at a final concentration of 10(7)/ml) significantly increased the release of LF in whole blood from newborns after 20 as well as 60 min stimulation, and in samples from their mothers after 60 min stimulation. A significant increase in the release of LF was observed in both newborns and their mothers after 20 and 60 min stimulation with TNF (at a final concentration of 1000 pg/ml). A combination of TNF/E. coli or TNF/GBS never gave any significant additional stimulatory effect. After stimulation with E. coli or GBS (both at a final concentration of 10(7)/ml) for 60 min a significant increase in production of TNF and TPL was observed in newborns. In newborns a significant increase in production of TNF and TPL was observed also after 20 min stimulation with E. coli. TNF (at a final concentration of 1000 pg/ml) significantly increased the generation of TPL after 20 and 60 min stimulation in both groups. There was a tendency for a greater release of LF and generation of TNF and TPL in samples from newborns compared with their mothers, but the differences were not statistically significant. E. coli, GBS and TNF had no significant effect on the production of IL-1.

Topics: Escherichia coli; Female; Humans; In Vitro Techniques; Infant, Newborn; Interleukin-1; Lactoferrin; Sepsis; Streptococcus agalactiae; Thromboplastin; Tumor Necrosis Factor-alpha

The prevention of enterogenic infection by human lactoferrin was tested in five neutropenic patients receiving chemotherapy for acute myelogenous leukemia. Lactoferrin did not significantly delay the onset of infection but reduced its duration and severity as judged from the course of fever. Compared with nine matched controls, lactoferrin-treated patients had a lower incidence of bacteremia on the whole and of gram-negative bacteremia in particular.

Topics: Adolescent; Adult; Agranulocytosis; Female; Fever; Humans; Lactoferrin; Lactoglobulins; Leukemia, Myeloid, Acute; Male; Middle Aged; Neutropenia; Sepsis

Total serum iron, plasma lactoferrin and circulating leukocytes were measured in piglets during the early phase of severe gram-negative septicemia and endotoxemia in 3 experimental settings: intravenous (i.v.) infusion of lipopolysaccharide (LPS) (n = 8), i.v. infusion of live Escherichia coli (n = 7) and intraperitoneal (i.p.) infusion of E. coli (n = 6). Iron dropped significantly during the first 30 min of LPS infusion from a median of 32 microM to 13.4 microM. A similar decrease in serum iron was demonstrated in the 2 other groups with minimum values at 120 min after the start of E. coli infusion. Plasma levels of lactoferrin increased significantly 120 min after the start of LPS infusion (median 6 mg/l) when compared to preinfusion values (0.25 mg/l). After i.v. infusion of E. coli a significant rise of plasma lactoferrin was demonstrated already 30 min after bacterial infusion (to 2.1 mg/l) compared to preseptic values (0.8 mg/l). This increase was accompanied with a significant drop of circulating leukocytes (to 7.3 x 10(9)/l) compared to before the infusion (17 x 10(9)/l) in the pigs given E. coli i.v. After i.p. E. coli infusion no significant change of plasma lactoferrin was observed. The rapid fall of total serum iron seen during endotoxemia and E. coli septicemia may in part be explained by the release of lactoferrin from granulocytes and the clearance of iron-bound lactoferrin in the blood or peritoneal cavity.

Topics: Animals; Escherichia coli Infections; Female; Iron; Lactoferrin; Lactoglobulins; Leukocytes; Lipopolysaccharides; Male; Sepsis; Swine; Toxemia

The levels of plasma lactoferrin (LF) in response to endotoxin and Escherichia coli infusions in piglets were studied to obtain exact time relation of plasma LF increase in relation to start of endotoxin and E. coli infusions. A new enzyme-linked immunoassay of swine LF is presented. 13 piglets had a 10-fold rapid increase of plasma LF concentrations after 0.25 mg/kg endotoxin intravenous infusion. The initial rise was 3.4 mg/l/h. 14 piglets, receiving 1 x 10(11) E. coli intravenously, showed a higher increase of plasma LF concentrations, amounting to 6-9 mg/l/h. Thus, plasma LF was an early marker of septicemia and endotoxemia.

Topics: Anesthesia; Animals; Endotoxins; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Escherichia coli Infections; Female; Halothane; Lactoferrin; Lactoglobulins; Leukocyte Count; Male; Sepsis; Swine; Toxemia

In healthy subjects normal plasmalactoferrin (PLf) concentrations were found to be 0.206 +/- 0.06 mg/l in 49 men and 0.148 +/- 0.06 mg/l in 62 women. A highly significant correlation of PLf with the number of circulating neutrophils (PMN) and a PLf/PMN relationship suggesting proportionality was demonstrated. Among 73 patients absolute PLf concentrations were significantly increased in septicemia, cirrhosis of the liver and tumors with liver metastases, decreased in localized infection, tumors without liver involvement, iron deficiency and acute hepatitis B, and normal in acute myocardial infarction. The PLf/PMN ratio, on the other hand, was normal in liver cirrhosis, hepatitis B and in a part of the patients with septicemia and tumor disease with liver involvement. The ratio was increased in a part of the septicemic patients, and decreased in the remaining disease types. Positive PLf/PMN correlations were found in myocardial infarction, septicemia and liver cirrhosis, whereas a very close, negative correlation existed in acute hepatitis B. These findings are discussed on the basis of existing knowledge on lactoferrin physiology, the intravascular fate of PMN and the RES function.

Topics: Anemia, Hypochromic; Female; Hepatitis B; Humans; Lactoferrin; Lactoglobulins; Leukocyte Count; Liver Cirrhosis; Liver Neoplasms; Male; Myocardial Infarction; Neutrophils; Reference Values; Sepsis; Sex Factors

Topics: Burns; Humans; Lactoferrin; Publishing; Sepsis

The interrelationships between various components of the non-immune inflammatory response (white cell count, plasma lactoferrin, C-reactive protein, ferritin, iron and iron-binding capacity), were studied serially in a variety of inflammatory conditions including acute lobar pneumonia, active pulmonary tuberculosis, rheumatoid arthritis on gold therapy and sepsis in the face of marrow hypoplasia induced by chemotherapy. Lactoferrin concentrations paralleled the white count in all groups. They were highest in pneumonia and tuberculosis, mildly elevated in rheumatoid arthritis and markedly decreased in neutropenic sepsis. Very high initial lactoferrin concentrations were associated with a poor prognosis in acute pneumonia. C-reactive protein and ferritin concentrations remained elevated through the period of study in acute pneumonia and neutropenic sepsis, while they gradually normalised over weeks in subjects with tuberculosis or rheumatoid arthritis on therapy. In pneumonia and tuberculosis moderate hypoferraemia and a reduced iron-binding capacity were evident. In contrast, a raised percentage saturation was present in neutropenic sepsis, probably related to erythroid marrow suppression. Comparisons between ferritin, lactoferrin and C-reactive protein in the various groups supported the concept that ferritin behaves in part as an acute phase reactant and that hypoferraemia in inflammation is due to deviation of iron into ferritin stores. The suggestion that lactoferrin is responsible for the hypoferraemia and hyperferritinaemia was not supported by the present data. Iron deficiency appeared to limit the hyperferritinaemic response in rheumatoid arthritis, while erythropoietic inhibition by chemotherapy dampened the hypoferraemic response in neutropenic sepsis.

Topics: Arthritis, Rheumatoid; C-Reactive Protein; Ferritins; Humans; Inflammation; Iron; Lactoferrin; Lactoglobulins; Leukocyte Count; Pneumonia; Sepsis; Tuberculosis, Pulmonary

The importance of the mammary gland as a potential immunological organ is characterized in this literature survey by the following aspects: immunoglobulins in colostrum and mother's milk, immunological active cells in colostrum and mother's milk, nonspecific factors in the mother's milk. The importance of the early nursing is emphasized from the immunological point of view.

Topics: Antibody Formation; Antibody Specificity; Bacteria; Bacterial Infections; Colostrum; Complement System Proteins; Female; Humans; Immunity, Cellular; Immunoglobulin A, Secretory; Immunoglobulins; Infant, Newborn; Infections; Intestinal Absorption; Lactoferrin; Milk, Human; Pregnancy; Sepsis

The number of granulocytic stem cells (CFU-C) was measured in the peripheral blood of surviving and nonsurviving burned humans. It has been shown that the number of CFU-C in the peripheral blood of survivors increases over time and is elevated compared to the number found in normal humans. The number found in nonsurvivors, however, falls significantly in the later stages of burn injury, suggesting perhaps a defect in stem cell production and/or differentiation in patients with severe thermal injuries. The mechanism is unclear but its delineation may have an important bearing on understanding the nature of infectious complications following thermal injury.

Topics: Adult; Aged; Burns; Colony-Forming Units Assay; Granulocytes; Humans; Lactoferrin; Middle Aged; Polysaccharides, Bacterial; Prostaglandins E; Sepsis; Stem Cells

Serum lactoferrin concentrations were elevated in 22 out of 49 newborn infants with suspected and verified severe bacterial as well as viral infections, suggesting that this protein resembled an acute phase reactant. In the infants suspected of having septicemia, high concentrations of C-reactive protein appeared to indicate a severe bacterial infection. Like lactoferrin, however, haptoglobin, orosomucoid, alpha 1-antitrypsin and alpha 1-antichymotrypsin discriminated only poorly or not at all between infants with severe bacterial infections and those in which such infections were unlikely. Thus, serum CRP concentrations remained the most valuable of the acute phase reactants tested as an aid in ruling out septicemia in the neonatal period.

Topics: Acute Disease; Acute-Phase Proteins; Bacterial Infections; Blood Proteins; C-Reactive Protein; Humans; Immunoglobulin M; Infant, Newborn; Lactoferrin; Lactoglobulins; Sepsis

Serum lactoferrin concentrations were elevated in almost all children with meningococcal septicemia, in whom the disease had been clinically apparent for less than 18 hours, while the concentrations were normal or only moderately elevated in patients who had had the disease longer before being admitted. Concentrations of C-reactive protein (CRP) were markedly elevated, even with a time lapse of less than six hours, making this the most suitable parameter for the early diagnosis of severe meningococcal infection. Following an operative injury on children the lactoferrin concentrations changed very little. More than six hours after an operation, however, a marked increase in CRP-values was observed, possibly indicating differentiation of this response from that of bacterial infection. The concomitant study of serum alpha 1-antitrypsin, alpha 1-antichymotrypsin, orosomucoid and haptoglobin did not uncover results of great significance with regard to early changes.

Topics: Acute Disease; alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; C-Reactive Protein; Chymotrypsin; Haptoglobins; Humans; Infant, Newborn; Lactoferrin; Lactoglobulins; Meningococcal Infections; Orosomucoid; Sepsis; Time Factors