Bronchopulmonary dysplasia in adults: Exploring pathogenesis and phenotype.

This review highlights both the longstanding impact of bronchopulmonary dysplasia (BPD) on the health of adult survivors of prematurity and the pressing need for prospective, longitudinal studies of this population. Conservatively, there are an estimated 1,000,000 survivors of BPD in the United States alone. Unfortunately, most of the available literature regarding outcomes of lung disease due to prematurity naturally focuses on pediatric patients in early or middle childhood, and the relative amount of literature on adult survivors is scant. As the number of adult survivors of BPD continues to increase, it is essential that both adult and pediatric pulmonologists have a comprehensive understanding of the pathophysiology and underlying disease process, including the molecular signaling pathways and pro-inflammatory modulators that contribute to the pathogenesis of BPD. We summarize the most common presenting symptoms for adults with BPD and identify the critical challenges adult pulmonologists face in managing the care of survivors of prematurity. Specifically, these challenges include the wide variability of the clinical presentation of adult patients, comorbid cardiopulmonary complications, and the paucity of longitudinal data available on these patients. Adult survivors of BPD have even required lung transplantation, indicating the high burden of morbidity that can result from premature birth and subsequent lung injury. In addition, we analyze the disparate symptoms and management approach to adults with "old" BPD versus "new" BPD. The aim of this review is to assist pulmonologists in understanding the underlying pathophysiology of BPD and to improve clinical recognition of this increasingly common pulmonary disease.

Green Cytoplasmic Neutrophilic Inclusion Bodies in a Patient With Aspiration Pneumonia and Bowel Perforation.

Blue-green cytoplasmic neutrophilic inclusion bodies, previously described as "green crystals of death," are a rare but likely underreported finding in critically ill patients. This finding is associated with high mortality, ranging from 31% to 100% in published case studies. These inclusion bodies have been most strongly associated with acute liver injury and lactic acidosis, but they have also been reported in critically ill patients secondary to other etiologies. Here, we report a case of blue-green neutrophilic inclusion bodies in a patient with aspiration pneumonia and severe pneumoperitoneum secondary to bowel perforation. These blue-green neutrophilic inclusion bodies offer high prognostic value for physicians, and their presence should be considered a "critical result," indicating the severity of the patient's illness.

The Mortality of Congenital Syphilis.

OBJECTIVES: To document the case-fatality rate (CFR) of congenital syphilis diagnosed by molecular tools and rabbit infectivity testing (RIT) of clinical specimens in addition to standard evaluation and to compare that with the CFR using the Centers for Disease Control and Prevention (CDC) surveillance case definition. STUDY DESIGN: Prospective, single site, cohort study of all cases of syphilis among mothers and their infants from 1984 to 2002. The diagnosis of congenital syphilis was determined using IgM immunoblotting, polymerase chain reaction, and RIT of fetal or infant specimens in addition to clinical, laboratory, and radiographic criteria. Data were retrospectively reviewed to ascertain fetal and neonatal mortality. RESULTS: During the 18-year study, there were 191 cases of congenital syphilis confirmed by abnormalities on clinical, laboratory, or radiographic evaluation and/or positive serum IgM immunoblot, blood polymerase chain reaction, or blood/cerebrospinal fluid RIT. Of the 191 cases, 59 died for a CFR of 31%. Of the 59 deaths, 53 (90%) were stillborn and 6 (10%) died in the neonatal period. The majority (74%, 39/53) of stillbirths occurred in the third trimester. The CDC surveillance case definition correctly identified all infants with congenital syphilis, but the CDC CFR was 10% which underestimated the CFR by more than 300%. CONCLUSIONS: Our findings corroborate the high sensitivity of the CDC surveillance definition for congenital syphilis but highlight its poor estimation of its associated mortality. The CFR among infected progeny of pregnant women with syphilis was 31%, due mostly to demise in the third trimester and as such highlights the need for detection and appropriate treatment of syphilis during pregnancy.

Clinical challenges to the concept of ectogestation.

Since the publication of the successful animal trials of the Biobag, a prototypical extrauterine support for extremely premature neonates, numerous ethicists have debated the potential implications of such a device. Some have argued that the Biobag represents a natural evolution of traditional newborn intensive care, while others believe that the Biobag would create a new class of being for the patients housed within. Kingma and Finn argued in Bioethics for making a categorical distinction between fetuses, newborns and 'gestatelings' in a Biobag on the basis of a conceptual distinction between ectogenesis versus ectogestation. Applying their arguments to the clinical realities of newborn intensive care, however, demonstrates the inapplicability of their ideas to the practice of medicine. Here, I present three clinical examples of the difficulty and confusion their argument would create for clinicians and offer a possible remedy: namely, discarding the term 'artificial womb' in favour of 'Biobag'.

A global point prevalence survey of antimicrobial use in neonatal intensive care units: The no-more-antibiotics and resistance (NO-MAS-R) study.

BACKGROUND: Global assessment of antimicrobial agents prescribed to infants in the neonatal intensive care unit (NICU) may inform antimicrobial stewardship efforts. METHODS: We conducted a one-day global point prevalence study of all antimicrobials provided to NICU infants. Demographic, clinical, and microbiologic data were obtained including NICU level, census, birth weight, gestational/chronologic age, diagnoses, antimicrobial therapy (reason for use; length of therapy), antimicrobial stewardship program (ASP), and 30-day in-hospital mortality. FINDINGS: On July 1, 2019, 26% of infants (580/2,265; range, 0-100%; median gestational age, 33 weeks; median birth weight, 1800 g) in 84 NICUs (51, high-income; 33, low-to-middle income) from 29 countries (14, high-income; 15, low-to-middle income) in five continents received ≥1 antimicrobial agent (92%, antibacterial; 19%, antifungal; 4%, antiviral). The most common reasons for antibiotic therapy were "rule-out" sepsis (32%) and "culture-negative" sepsis (16%) with ampicillin (40%), gentamicin (35%), amikacin (19%), vancomycin (15%), and meropenem (9%) used most frequently. For definitive treatment of presumed/confirmed infection, vancomycin (26%), amikacin (20%), and meropenem (16%) were the most prescribed agents. Length of therapy for culture-positive and "culture-negative" infections was 12 days (median; IQR, 8-14) and 7 days (median; IQR, 5-10), respectively. Mortality was 6% (42%, infection-related). An NICU ASP was associated with lower rate of antibiotic utilization (p = 0·02). INTERPRETATION: Global NICU antibiotic use was frequent and prolonged regardless of culture results. NICU-specific ASPs were associated with lower antibiotic utilization rates, suggesting the need for their implementation worldwide. FUNDING: Merck & Co.; The Ohio State University College of Medicine Barnes Medical Student Research Scholarship.

Antibiotic exposure and growth patterns in preterm, very low birth weight infants.

BACKGROUND: Antibiotic exposure in term infants has been associated with later obesity. Premature, very-low-birth-weight (birth weight ≤ 1500 g) infants in the neonatal intensive care unit frequently are exposed to antibiotics. Our hypothesis was that in preterm infants, there is a positive linear and dose-dependent relationship between antibiotic exposure and growth from birth through 12 months' corrected age. METHODS: Retrospective analysis of prospectively collected data of all antibiotic use among inborn, preterm (≤32 weeks' gestation), very-low-birth-weight infants admitted to the neonatal intensive care unit at Parkland Memorial Hospital and followed in the Low Birth Weight Clinic at Children's Medical Center, Dallas, TX. Antibiotic use was quantified by days of therapy which was compared with weight and length parameters at birth, 36 weeks' postmenstrual age, and 2, 4, 6, and 12 months' corrected age. The change in weight and length z-scores from birth to all subsequent age points was calculated. Stepwise multivariate regression analysis was performed to determine predictors of weight, length, and weight-for-length delta z-scores from birth to each subsequent age point. RESULTS: During the 18-month study, 161 infants received a median of 11 (IQR, 5.5-19.5) antibiotic days of therapy which was not associated with weight or length delta z-scores from birth through 12 months' corrected age. CONCLUSION: Association of prolonged antibiotic use and neonatal morbidities and mortality may override the potential association with increased weight gain in the NICU and beyond.

Recent Trends in RSV Immunoprophylaxis: Clinical Implications for the Infant.

Respiratory syncytial virus (RSV) remains the leading cause for hospitalizations in infants worldwide, resulting in significant health and financial burden. Since 1998, the humanized monoclonal antibody palivizumab remains the only available option licensed for the prevention of severe RSV disease in high-risk children, namely premature infants and those with chronic lung disease and congenital heart disease. In 2014, the American Academy of Pediatrics modified the recommendations on the use of RSV prophylaxis in these high-risk children, and limited its use to premature infants born at < 28 weeks' gestational age (wGA). Following this last guidance update, studies have confirmed that premature infants of 29 to 34 wGA remain at high risk for severe RSV disease, especially those of younger chronologic age. New and more cost-effective strategies are being developed that would help alleviate both the health and financial burden associated with severe RSV disease.

Early Antibiotic Exposure and Adverse Outcomes in Preterm, Very Low Birth Weight Infants.

OBJECTIVES: To determine whether antibiotic use in the first 14 postnatal days in preterm, very low birth weight (birth weight of ≤1500 g) infants is associated with risk after 14 days of age for late-onset sepsis, necrotizing enterocolitis (NEC), or death after controlling for severity of illness using the Clinical Risk Index in Babies II score, and determine whether duration of antibiotic exposure was associated with risk of adverse outcomes. STUDY DESIGN: This retrospective cohort study included very low birth weight infants born at ≤326/7 weeks of gestation admitted to the neonatal intensive care unit from September 2010 to June 2014. Infants were excluded if they had major congenital anomalies or culture-proven sepsis, NEC, or death during the first 14 days of life. Antibiotic exposure was recorded as days of therapy and length of therapy in days. RESULTS: Of 374 infants, 70 (19%) had late-onset sepsis, NEC, or death after 14 days of age. The median number of antibiotic days of therapy and length of therapy were 5.5 and 3.0, respectively. In multivariate analysis after controlling for severity of illness, each antibiotic day of therapy was associated with a 1.24 times increased risk of sepsis, NEC, or death (OR, 1.24; 95% CI, 1.17-1.31). Risk was similar when length of therapy was used (OR, 1.47; 95% CI, 1.32-1.64). CONCLUSIONS: After controlling for severity of illness, each day of antibiotic therapy provided to preterm, very low birth weight infants in the first 2 weeks of age is associated with an increased risk of late-onset sepsis, NEC, or death.

Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study.

BACKGROUND: Antibiotics are used frequently in the neonatal intensive care unit. We aimed to inform antibiotic stewardship strategies in a level 3 neonatal intensive care unit by surveillance and assessment of all antibiotic use during a 14-month period, identifying scenarios where antibiotic use can be reduced, and implementing interventions while monitoring safety. METHODS: The SCOUT study is an observational study in the level 3 neonatal intensive care unit at Parkland Hospital, Dallas, TX, USA. All antibiotic use in infants admitted to the neonatal intensive care unit between March 1, 2012, and Nov 30, 2012 (9 months), was monitored and analysed. After the baseline period (Oct 3, 2011, to Nov 30, 2012), continuation of empirical antibiotic therapy for ruled-out sepsis courses beyond 48 h, pneumonia, and "culture-negative" sepsis were selected as targets for antibiotic stewardship interventions. During the intervention period (Oct 1, 2013, to June 30, 2014), empirical antibiotic therapy was set to discontinue after 48 h in the electronic medical record and the duration of therapy for pneumonia and culture-negative sepsis was limited to 5 days. Antibiotic use, defined as days of therapy per 1000 patient-days, was compared between the baseline and intervention periods. The primary outcome was the change in total antibiotic days of therapy per 1000 patient-days between the baseline and intervention periods. Safety outcomes measured were instances in which infants received 5 or more days of therapy and subsequently had antibiotic therapy reinstituted within 14 days for any indication; a composite of late-onset sepsis, necrotising enterocolitis (modified Bell stage ≥2), or death in infants 32 weeks' gestation or younger; prevalence of multidrug-resistant organism colonisation; and length of hospital stay. FINDINGS: 2502 infants were admitted to the neonatal intensive care unit during the two study periods (1607 in the baseline period and 895 in the intervention period). Antibiotic use declined from 343·2 days of therapy per 1000 patient-days during the baseline period to 252·2 days of therapy per 1000 patient-days in the intervention period (p<0·0001), representing an overall decrease of 27%. No difference in safety outcomes was observed between the intervention and baseline periods. INTERPRETATION: Thorough assessment of antibiotic consumption in a neonatal intensive care unit can inform high-yield stewardship targets tailored to the individual centre. Effective interventions to reduce antibiotic use can then be designed and implemented in a collaborative manner. FUNDING: The Gerber Foundation.

Prospective surveillance of antibiotic use in the neonatal intensive care unit: results from the SCOUT study.

BACKGROUND: Prolonged or unnecessary antibiotic use is associated with adverse outcomes in neonates. Our objectives were to quantify all antibiotic use in a Level-III neonatal intensive care unit and to identify scenarios where their use could be reduced. METHODS: Surveillance and evaluation of all antibiotic use provided to every infant admitted to a Level-III neonatal intensive care unit from 10/3/11 to 11/30/12 was performed. Types of antibiotics, reasons for their initiation, discontinuation and duration, as well as clinical, laboratory and outcome data were recorded. Antibiotic use was quantified by days of therapy (DOT) per 1000 patient-days (PD). RESULTS: A total of 1607 infants were included. The total antibiotic use was 9165 DOT (343.2 DOT/1000 PD; 5.7 DOT/infant). Seventy-two percent of infants received 1 (43%) or more (29%) courses of antibiotics. Gentamicin (46%), ampicillin (39%) and oxacillin (8%) were the most frequently used agents. Ninety-four percent of antibiotic use (323 DOT/1000 PD) was empiric therapy for suspected infection. Sixty-three percent (216.2 DOT/1000 PD) was discontinued at approximately 48 hours when cultures were sterile (68%>48 hours, 32%≤48 hours). Twenty-six percent of all antibiotic use (89.4 DOT/1000 PD) was therapy for ≥5 days despite sterile cultures; pneumonia (16%) and "culture-negative" sepsis (8%) were the major contributors. Five percent (17.4 DOT/1000 PD) of antibiotic use was for culture-proven sepsis, 5% (16.6 DOT/1000 PD) was penicillin prophylaxis for group B Streptococcus and 1% (3.5 DOT/1000 PD) was preprocedural prophylaxis. CONCLUSIONS: Narrow-spectrum therapy accounted for >92% of antibiotic use and would not be monitored by most stewardship programs. Only 5% of antibiotic usage was due to culture-proven infection. Pneumonia and "culture-negative" sepsis were frequent reasons for prolonged therapy; further study of these conditions may allow reduction in treatment duration.