Late-onset group B streptococcus infections and severe bronchopulmonary dysplasia in an extremely preterm born infant.

This case report is about a boy born extremely preterm at gestational age of 24 weeks, with extremely low birth weight, developing severe bronchopulmonary dysplasia and in need of mechanical ventilation for 155 days. He also had five recurrent infections with group B streptococcus (GBS) within 4 months from birth, and his respiratory condition clearly deteriorated with every GBS infection. It was difficult to wean him from mechanical ventilation. Finally he was extubated when he was 7 months old and kept out of mechanical ventilation after receiving high-dose methylprednisolone, given according to international recommendations. After GBS was cultured for the fifth time, he received oral rifampicin along with intravenous penicillin and after this treatment, GBS did not occur again. At the age of 22 months, the boy no longer needed any respiratory support and he was about 6 months late in his neurological development.

Two pediatric cases of Pneumocystis jirovecii pneumonia diagnosed by polymerase chain reaction of gastric lavage.

Detecting Pneumocystis jirovecii by bronchoalveolar lavage or lung biopsy is the gold standard for diagnosis of P. jirovecii pneumonia (PJP); however, these techniques are not always applicable in children because of their high invasiveness. We report two pediatric cases of PJP diagnosed by polymerase chain reaction (PCR) of gastric lavage that were successfully treated. To date, there are no reported cases of using PCR of gastric lavage to diagnose PJP. On the day of PJP onset, both the infants required respiratory support and infiltrative shadows were observed in both lung fields on chest radiography. Furthermore, their (1 â†’ 3)-ß-D glucan levels were elevated. P. jirovecii was detected by PCR of gastric lavage and trimethoprim-sulfamethoxazole was administered for 3 weeks, following which their condition improved. They were long-term steroid users, but without any prophylaxis. PCR of gastric lavage in cases of suspected PJP may help in confirming the diagnosis in children who have mild to moderate airway symptoms, or have difficulty with invasive examination like bronchoscopy.

Exosomal microRNA predicts and protects against severe bronchopulmonary dysplasia in extremely premature infants.

Premature infants are at high risk for developing bronchopulmonary dysplasia (BPD), characterized by chronic inflammation and inhibition of lung development, which we have recently identified as being modulated by microRNAs (miRNAs) and alterations in the airway microbiome. Exosomes and exosomal miRNAs may regulate cell differentiation and tissue and organ development. We discovered that tracheal aspirates from infants with severe BPD had increased numbers of, but smaller, exosomes compared with term controls. Similarly, bronchoalveolar lavage fluid from hyperoxia-exposed mice (an animal model of BPD) and supernatants from hyperoxia-exposed human bronchial epithelial cells (in vitro model of BPD) had increased exosomes compared with air controls. Next, in a prospective cohort study of tracheal aspirates obtained at birth from extremely preterm infants, utilizing independent discovery and validation cohorts, we identified unbiased exosomal miRNA signatures predictive of severe BPD. The strongest signal of reduced miR-876-3p in BPD-susceptible compared with BPD-resistant infants was confirmed in the animal model and in vitro models of BPD. In addition, based on our recent discovery of increased Proteobacteria in the airway microbiome being associated with BPD, we developed potentially novel in vivo and in vitro models for BPD combining Proteobacterial LPS and hyperoxia exposure. Addition of LPS led to a larger reduction in exosomal miR 876-3p in both hyperoxia and normoxia compared with hyperoxia alone, thus indicating a potential mechanism by which alterations in microbiota can suppress miR 876-3p. Gain of function of miR 876-3p improved the alveolar architecture in the in vivo BPD model, demonstrating a causal link between miR 876-3p and BPD. In summary, we provide evidence for the strong predictive biomarker potential of miR 876-3p in severe BPD. We also provide insights on the pathogenesis of neonatal lung disease, as modulated by hyperoxia and microbial product-induced changes in exosomal miRNA 876-3p, which could be targeted for future therapeutic development.

Administration of Bifidobacterium breve PS12929 and Lactobacillus salivarius PS12934, two strains isolated from human milk, to very low and extremely low birth weight preterm infants: a pilot study.

The preterm infant gut has been described as immature and colonized by an aberrant microbiota. Therefore, the use of probiotics is an attractive practice in hospitals to try to reduce morbidity and mortality in this population. The objective of this pilot study was to elucidate if administration of two probiotic strains isolated from human milk to preterm infants led to their presence in feces. In addition, the evolution of a wide spectrum of immunological compounds, including the inflammatory biomarker calprotectin, in both blood and fecal samples was also assessed. For this purpose, five preterm infants received two daily doses (~10(9) CFU) of a 1:1 mixture of Bifidobacterium breve PS12929 and Lactobacillus salivarius PS12934. Bacterial growth was detected by culture-dependent techniques in all the fecal samples. The phylum Firmicutes dominated in nearly all fecal samples while L. salivarius PS12934 was detected in all the infants at numerous sample collection points and B. breve PS12929 appeared in five fecal samples. Finally, a noticeable decrease in the fecal calprotectin levels was observed along time.

Oropharyngeal colostrum administration in extremely premature infants: an RCT.

OBJECTIVE: To determine the immunologic effects of oropharyngeal colostrum administration in extremely premature infants. METHODS: 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. RESULTS: 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-1ß level was significantly lower in colostrum group at 2 weeks (55.3 vs 91.8 µg/g creatinine, P = .01). Salivary transforming growth factor-ß1 (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). CONCLUSIONS: 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.

Extremely hypotrophic newborn of mother with systemic lupus erythematosus and antiphospholipid syndrome.

The case presented describes a high-risk pregnancy of a woman with systemic lupus erythematosus (SLE) with multiple lesions of central nervous system (CNS), vasculitis, secondary epilepsy and antiphospholipid syndrome (APS). At gestational age 28 weeks and 3 days the pregnancy was urgently terminated via caesarean section and an extremely hypotrophic immature newborn with a birth weight of 580 g was born. The high disease activity in the mother at the time of conception and the histologically proven chronic placental insufficiency due to APS are presumably the causes for the extensive hypotrophy of the neonate. The significant comorbidity of the newborn, including respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, osteopathy of prematurity, transient hypothyroidism and hypocortisolism, vesicoureteral reflux, and hypertonic-hyperexcitation syndrome complicated his three-month stay in NICU. A positive titre of transplacentally transferred anticardiolipin and anti-ß2 glycoprotein antibody was detected in the child and persisted through the following 30 months. During the three-year follow-up, significantly delayed neuropsychological development with microcephaly (-4 SD) and short stature of the child was observed. Finally, the authors discuss possible causes of neuropsychological consequences in children of mothers with SLE and APS and emphasize the need for long-term monitoring and specialized care to improve development of these children.

Early administration of oropharyngeal colostrum to extremely low birth weight infants.

BACKGROUND: Human milk reduces morbidities in extremely low birth weight (ELBW) infants. However, clinical instability often precludes ELBW infants from receiving early enteral feeds. This study compared clinical outcomes before and after implementing an oropharyngeal colostrum (COL) protocol in a cohort of inborn (born at our facility) ELBW infants. STUDY DESIGN: This is a retrospective cohort study of inborn ELBW infants admitted to the Duke Intensive Care Nursery from January 2007 to September 2011. In November 2010, we initiated a COL protocol for infants not enterally fed whose mothers were providing breastmilk. Infants received 0.1 mL of fresh COL to each cheek every 4 hours for 5 days beginning in the first 48 postnatal hours. We assessed demographics, diagnoses, feeding history, and mortality and for the presence of medical necrotizing enterocolitis (NEC), surgical NEC, and spontaneous perforation. Between-group comparisons were made using Fisher's exact test or Wilcoxon rank sum testing where appropriate. RESULTS: Of the 369 infants included, 280 (76%) were born prior to the COL protocol (Pre-COL Cohort [PCC]), and 89 (24%) were born after (COL Cohort [CC]). Mortality and the percentage of infants with surgical NEC and spontaneous perforations were statistically similar between the groups. The CC weighed an average (interquartile range) of 1,666 (1,399, 1,940) g at 36 weeks versus 1,380 (1,190, 1,650) g for the PCC (p<0.001). In a multivariable analysis with birth weight as a covariable, weight at 36 weeks was significantly greater (37 g; p<0.01). CONCLUSIONS: Initiating oropharyngeal COL in ELBW infants in the first 2 postnatal days appears feasible and safe and may be nutritionally beneficial. Further research is needed to determine if early COL administration reduces neonatal morbidity and mortality.

Cytokine profiles of preterm neonates with fungal and bacterial sepsis.

BACKGROUND: Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight (ELBW) infants, is lacking. We hypothesized that cytokine profiles in the first 21 d of life in ELBW infants with FS differ from those with bacterial sepsis (BS) or no sepsis (NS). METHODS: In a secondary analysis of the National Institute of Child Health and Human Development Cytokine study, three groups were defined-FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3 ± 1, 7 ± 2, 14 ± 3, and 21 ± 3 and sepsis group was explored. RESULTS: Of 1,066 infants, 89 had FS and 368 had BS. As compared with BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (P < 0.05). Analyses controlling for covariates showed significant group differences over time for interferon-γ (IFN-γ), interleukin (IL)-10, IL-18, transforming growth factor-ß (TGF-ß), and tumor necrosis factor-α (TNF-α) (P < 0.05). CONCLUSION: Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-ß, and TNF-α in FS, BS, or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.

Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ.

BACKGROUND: Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. METHODOLOGY/PRINCIPAL FINDINGS: We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon-γ. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-γ. CONCLUSION/SIGNIFICANCE: Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero. Ex vivo treatment of leukocytes from premature neonates with interferon-γ reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis.

T cell cytokines and the risk of blood stream infection in extremely low birth weight infants.

Cytokines mediate the host immune response to infectious micro-organisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6, and IL-10) and inflammatory cytokines (Interferon-γ [INF-γ], tumor necrosis factor-ß [TNF-ß], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the five sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (p=0.01), and higher levels of the regulatory cytokines, IL-6 (p=0.01) and IL-10 (p<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population.

[Leukemoid reaction in extremely immature preterm infants]. / Leukämoide Reaktion bei extrem unreifen Frühgeborenen.

Extremely immature preterm infants rarely present with a leukocytosis exceeding 30,000/microL. The pathogenetic sequence leading to leukemoid reactions in non-malignant diseases remains to be elucidated. Potential triggers for leukemoid reactions in premature infants include prenatal corticosteroids, chorioamnionitis and funisitis or systemic infection. In the two-year period from 2006 to 2007 all infants with a gestational age of less than 26 weeks were screened for leukocytosis. Among our cases, one preterm infant presented with a leukocyte count of 229,300/microL at the age of 48 hours, lasting throughout the first three weeks of life. Impairment of microcirculation and resulting organ dysfunction were not observed. Thus, invasive therapeutic procedures, which are routinely initiated in hyperleukocytosis in accompanying malignant diseases, may not have the same significance in extremely immature preterm infants and should be executed in these patients on an individual basis and with extreme caution.

Measles-mumps-rubella and varicella vaccine responses in extremely preterm infants.

OBJECTIVE: Extremely preterm infants mount lower antibody responses than term infants to several vaccines. The objective of this study was to measure the immunogenicity of measles-mumps-rubella and varicella vaccines in preterm and term children. METHODS: Immune status before immunization and immune response after immunization with measles-mumps-rubella and varicella vaccines at 15 months of age were compared in 32 infants, 16 of whom were preterm (< 29 weeks' gestation) and 16 of whom were term (> or = 37 weeks' gestation) at birth. Blood was drawn before vaccination and 3 to 6 weeks thereafter. Measles antibody was measured by plaque reduction neutralization assay. Mumps and rubella immunoglobulin G were measured in available sera by enzyme-linked fluorescent immunoassay. Varicella immunoglobulin G was measured in available sera by glycoprotein enzyme-linked immunosorbent assay. Values that were above or below the assay limits were assigned values double or half those limits, respectively. The primary outcome was the geometric mean antibody titer. RESULTS: Preterm children had lower mumps and rubella geometric mean titers than did term children before vaccine, and nearly all children were seronegative for each of the 4 vaccine antigens before immunization. Measles, mumps, rubella, and varicella geometric mean titers were similar between groups after vaccine. All children were seropositive for measles after vaccine, whereas 13 of 14 preterm and 11 of 13 term children were seropositive for mumps, 13 of 14 preterm and 13 of 13 term children were seropositive for rubella, and 11 of 16 preterm and 9 of 15 term children were seropositive for varicella. CONCLUSIONS: Preterm children mounted antibody responses that were similar to those of term children after measles-mumps-rubella and varicella vaccines at 15 months of age.