Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation.

After infection, many factors coordinate the population expansion and differentiation of CD8+ effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8+ T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8+ effector cells. Long-lived memory CD8+ cells ultimately expressed a small subset of genes shared by natural killer T and γδ T cells. Although distinct inflammatory milieu and T cell precursor frequencies influenced the differentiation of CD8+ effector and memory populations, core transcriptional signatures were regulated similarly, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Our results provide insights into the transcriptional regulation that influence memory formation and CD8+ T cell immunity.

The transcriptional landscape of αß T cell differentiation.

The differentiation of αßT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4(+)CD8(+) stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4(+) or CD8(+) lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation.

Identification of transcriptional regulators in the mouse immune system.

The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage-specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.

Factors associated with D-lactic acidosis in pediatric intestinal failure: A case-control study.

BACKGROUND: D-lactic acidosis (DLA) is a serious complication of short bowel syndrome (SBS) in children with intestinal failure (IF). Malabsorbed carbohydrates are metabolized by bacteria in the intestine to D-lactate which can lead to metabolic acidosis and neurologic symptoms. METHODS: A retrospective chart review was performed in children ≤18 years old with SBS who had one of the following criteria: unexplained metabolic acidosis, neurologic signs or symptoms, history of antibiotic therapy for small bowel bacterial overgrowth, or high clinical suspicion of DLA. Cases had serum D-lactate concentration >0.25 mmol/L; controls with concentrations ≤0.25 mmol/L. RESULTS: Of forty-six children, median age was 3.16 (interquartile range (IQR): 1.98, 5.82) years, and median residual bowel length was 40 (IQR: 25, 59) cm. There were 23 cases and 23 controls. Univariate analysis showed that cases had significantly lower median bicarbonate (19 vs. 24 mEq/L, p = 0.001), higher anion gap (17 vs. 14 mEq/L, p < 0.001) and were less likely to be receiving parenteral nutrition, compared with children without DLA. Multivariable analysis identified midgut volvulus, history of intestinal lengthening procedure, and anion gap as significant independent risk factors. Midgut volvulus was the strongest independent factor associated with DLA (adjusted odds ratio = 17.1, 95% CI: 2.21, 133, p = 0.007). CONCLUSION: DLA is an important complication of pediatric IF due to SBS. Patients with IF, particularly those with history of midgut volvulus, having undergone intestinal lengthening, or with anion gap acidosis, should be closely monitored for DLA.

The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets.

During infection, naive CD8(+) T cells differentiate into effector cells, which are armed to eliminate pathogens, and memory cells, which are poised to protect against reinfection. The transcriptional program that regulates terminal differentiation into short-lived effector-memory versus long-lived memory cells is not clearly defined. Through the use of mice expressing reporters for the DNA-binding inhibitors Id2 and Id3, we identified Id3(hi) precursors of long-lived memory cells before the peak of T cell population expansion or upregulation of cell-surface receptors that indicate memory potential. Deficiency in Id2 or Id3 resulted in loss of distinct CD8(+) effector and memory populations, which demonstrated unique roles for these inhibitors of E-protein transcription factors. Furthermore, cytokines altered the expression of Id2 and Id3 differently, which provides insight into how external cues influence gene expression.

The Challenges of Parenthood for Female Surgeons: The Current Landscape and Future Directions.

Although surgical training programs have nearly reached gender parity, pregnancy and parenthood remain challenging for female surgeons, with obstetric risks related to occupational demands, stigma, inconsistent and brief parental leaves, a paucity of postpartum support for lactation and childcare, and little mentorship on work-family integration. This work environment causes many to postpone starting a family, which leads to higher risks of infertility among female surgeons compared to their male peers. Perception of work-family incompatibility jeopardizes recruitment and retention of our surgical workforce, as it deters medical students from the profession, increases risk of resident attrition, and leads to burnout and career dissatisfaction. The challenges of parenthood for female surgeons was the focus of a Hot Topics session during the 2022 Academic Surgical Congress, the discussion of which is presented herein with recommendations for policy change to better support maternal-fetal health and the needs of surgeons with young children.

An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells.

E proteins are basic helix-loop-helix transcription factors that regulate many key aspects of lymphocyte development. Thymocytes express multiple E proteins that are thought to provide cooperative and compensatory functions crucial for T cell differentiation. Contrary to that, we report here that the E protein HEB was uniquely required at the CD4(+)CD8(+) double-positive (DP) stage of T cell development. Thymocytes lacking HEB showed impaired survival, failed to make rearrangements of variable-alpha (V(alpha)) segments to distal joining-alpha (J(alpha)) segments in the gene encoding the T cell antigen receptor alpha-chain (Tcra) and had a profound, intrinsic block in the development of invariant natural killer T cells (iNKT cells) at their earliest progenitor stage. Thus, our results show that HEB is a specific and essential factor in T cell development and in the generation of the iNKT cell lineage, defining a unique role for HEB in the regulation of lymphocyte maturation.

Antibiotic Therapy for Culture-Proven Bacterial Overgrowth in Children With Intestinal Failure Results in Improved Symptoms and Growth.

OBJECTIVES: To evaluate symptoms, enteral tolerance, growth, and antibiotic regimens in pediatric intestinal failure (IF) patients after treated with antibiotic therapy for small bowel bacterial overgrowth (SBBO). METHODS: Single-center retrospective review of children 0-18 years with IF with endoscopic cultures demonstrating >10 5 CFU/mL from 2010 to 2017. Symptoms, enteral tolerance, growth, and antibiotic regimens were evaluated at the time of endoscopy and 6 months later. RESULTS: Of 505 patients followed in our intestinal rehabilitation program, 104 underwent upper gastrointestinal endoscopy and 78 had positive duodenal cultures. Clinical data pre- and post-endoscopy were available for 56 patients. Compared to baseline, in the 6 months following targeted antibiotic treatment, children showed significant improvement in emesis or feeding intolerance (58.9% vs 23.2%, P < 0.001), abdominal pain (16.1% vs 7.1%, P = 0.02), high stool output (42.9% vs 19.6%, P = 0.002), and gross GI bleeding (19.6% vs 3.6%, P = 0.003). Mean BMI-for-age z scores increased significantly (-0.03 ± 0.94 vs 0.27 ± 0.82, P = 0.03); however, height-for-age z scores, weight-for-age z scores, and percent of calories from enteral intake were not significantly different after therapy. Antibiotic regimens remained highly variable. CONCLUSIONS: Children with IF and culture-positive SBBO showed significant improvement in symptoms and BMI-for-age z scores after duodenal culture with subsequent targeted antibiotic therapy. Longer follow-up may be needed to detect improvements in linear growth and percent of calories from enteral feeds. Antibiotic regimens remain highly variable. Long-term consequences of chronic antimicrobial therapy, including antimicrobial resistance, remain unknown. Prospective studies focused on standardizing duodenal sampling technique, correlating culture and pathology data, and evaluating antibiotic resistance patterns are needed.

Late-onset anorectal disease and psychosocial impact in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for the treatment of childhood cancer are not known. METHODS: A total of 25,530 survivors diagnosed between 1970 and 1999 (median age at cancer diagnosis, 6.1 years; age at survey, 30.2 years) and 5036 siblings were evaluated for late-onset anorectal disease, which was defined as a self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after the primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations was used to evaluate associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory 18 (BSI-18), and health-related quality of life, as defined by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS: By 45 years after the diagnosis, 394 survivors (fistula, n = 291; stricture, n = 116; anorectal SMN, n = 26) and 84 siblings (fistula, n = 73; stricture, n = 23; anorectal neoplasm, n = 1) had developed late-onset anorectal disease (adjusted rate ratio [RR] for survivors vs siblings, 1.2; 95% confidence interval [CI], 1.0-1.5). Among survivors, pelvic radiotherapy with ≥30 Gy within 5 years of the cancer diagnosis was associated with late-onset anorectal disease (adjusted RR for 30-49.9 Gy vs none, 1.6; 95% CI, 1.1-2.3; adjusted RR for ≥50 Gy vs none, 5.4; 95% CI, 3.1-9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains. CONCLUSIONS: Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity.

Analysis of surgically excised breast masses in 119 pediatric patients.

PURPOSE: Breast masses in children and adolescents are uncommon and the vast majority are benign. There are currently limited analyses of breast masses in this population and clinical management is highly variable between institutions and providers. The purpose of our study is to analyze the demographics, pathology and management of 119 pediatric patients with breast masses; one of the largest studies to date. METHODS: We performed a retrospective review of patients who underwent excision of a breast mass at a single pediatric center from June 2009 to November 2013. Demographics, imaging, pathology and management were reviewed. RESULTS: Average patient age was 15.3 years, average mass size was 3.15 cm and 20.3 % had a family history of breast cancer. 68 % of patients had pre-operative ultrasound, and 31.9 % underwent a period of observation. The most common indication for resection was patient and family anxiety. All masses were benign, with fibroadenoma being the most common histopathology (75.2 %). CONCLUSIONS: In our cohort there were no cases of malignancy. Only 31.9 % of patients underwent some form of observation and patient or family anxiety was the most common indication for proceeding with surgery. This suggests that patient anxiety may result in unnecessary operation. Our data may help reassure patients, families and providers that the risk of malignancy is low and could help develop more optimal management strategies.

Id2 influences differentiation of killer cell lectin-like receptor G1(hi) short-lived CD8+ effector T cells.

CD8(+) T cells play a crucial role in the clearance of intracellular pathogens through the generation of cytotoxic effector cells that eliminate infected cells and long-lived memory cells that provide enhanced protection against reinfection. We have previously shown that the inhibitor of E protein transcription factors, Id2, is necessary for accumulation of effector and memory CD8(+) T cells during infection. In this study, we show that CD8(+) T cells lacking Id2 did not generate a robust terminally differentiated killer cell lectin-like receptor G1 (KLRG1)(hi) effector population, but displayed a cell-surface phenotype and cytokine profile consistent with memory precursors, raising the question as to whether loss of Id2 impairs the differentiation and/or survival of effector memory cells. We found that deletion of Bim rescued Id2-deficient CD8(+) cell survival during infection. However, the dramatic reduction in KLRG1(hi) cells caused by loss of Id2 remained in the absence of Bim, such that Id2/Bim double-deficient cells form an exclusively KLRG1(lo)CD127(hi) memory precursor population. Thus, we describe a role for Id2 in both the survival and differentiation of normal CD8(+) effector and memory populations.

Association between neurodevelopmental outcomes and concomitant presence of NEC and IVH in extremely low birth weight infants.

OBJECTIVE: To quantify the association between necrotizing enterocolitis (NEC) and neurodevelopmental disability (NDI) in extremely low birth weight (ELBW) infants with intraventricular hemorrhage (IVH). STUDY DESIGN: ELBW survivors born 2011-2017 and evaluated at 16-26 months corrected age in the Vermont Oxford Network (VON) ELBW Follow-Up Project were included. Logistic regression determined the adjusted relative risk (aRR) of severe NDI in medical or surgical NEC compared to no NEC, stratified by severity of IVH. RESULTS: Follow-up evaluation occurred in 5870 ELBW survivors. Compared to no NEC, medical NEC had no impact on NDI, regardless of IVH status. Surgical NEC increased risk of NDI in patients with no IVH (aRR 1.69; 95% CI 1.36-2.09), mild IVH (aRR 1.36;0.97-1.92), and severe IVH (aRR 1.35;1.13-1.60). CONCLUSIONS: ELBW infants with surgical NEC carry increased risk of neurodevelopmental disability within each IVH severity stratum. These data describe the additive insult of surgical NEC and IVH on neurodevelopment, informing prognostic discussions and highlighting the need for preventative interventions.

Recurrent Nerve Injury After Total Thyroidectomy: Risk Factor Analysis of a Targeted NSQIP Data Set.

BACKGROUND: Recurrent laryngeal nerve (RLN) injury is a significant complication after thyroidectomy. Understanding risk factors for RLN injury and the associated postoperative complications may help inform quality improvement initiatives. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) thyroidectomy-targeted database was utilized for patients undergoing total thyroidectomy between 2016 and 2017. Univariable and multivariable regression were used to identify factors associated with RLN injury. RESULTS: A total of 6538 patients were identified. The overall rate of RLN injury was 7.1% (467/6538). Of these, 4129 (63.1%) patients had intraoperative neuromonitoring (IONM), with an associated RLN injury rate of 6.5% (versus 8.2% without). African American and Asian race, non-elective surgery, parathyroid auto-transplantation, and lack of RLN monitoring were all significantly associated with nerve injury on multivariable analysis (P<.05). Patients with RLN injury were more likely to experience cardiopulmonary complications, re-intubation, longer length of stay, readmission, and reoperation. Patients who had IONM and sustained RLN injury remained at risk for developing significant postoperative complications, although the extent of cardiopulmonary complications was less severe in this cohort. DISCUSSION: Recurrent laryngeal nerve injury is common after thyroidectomy and is associated with significant morbidity, despite best practices. Attention to preoperative characteristics may help clinicians to further risk stratify patients prior to thyroidectomy. While IONM does not mitigate all complications, use of this technology may decrease severity of postoperative complications.

Impact of concomitant necrotizing enterocolitis on mortality in very low birth weight infants with intraventricular hemorrhage.

OBJECTIVE: To evaluate the impact of necrotizing enterocolitis (NEC) on mortality in very low birth weight (VLBW) infants with intraventricular hemorrhage (IVH). STUDY DESIGN: Data were collected on VLBW infants born 2014-2018 at Vermont Oxford Network (VON) centers. NEC and IVH were categorized by severity. Adjusted risk ratios (ARR) for in-hospital mortality were calculated. RESULTS: This study included 187 187 VLBW infants. Both medical and surgical NEC increased mortality risk compared to those without NEC. Stratification by IVH severity modified this effect (no IVH: ARR 3.04 (95%CI 2.74-3.38) for medical NEC and 4.17 (3.84-4.52) for surgical NEC; mild IVH: ARR 2.14 (1.88-2.44) for medical NEC and 2.49 (2.24-2.78) for surgical NEC; severe IVH: ARR 1.14 (1.03-1.26) for medical NEC and 1.10 (1.02-1.18) for surgical NEC). CONCLUSION: The relative impact of NEC on mortality decreased as IVH severity increased. Given the frequent coexistence of NEC and IVH, these data inform multidisciplinary management of these complex patients.

Transcriptional regulator Id2 controls survival of hepatic NKT cells.

Natural killer T cells expressing an invariant T-cell receptor (iNKT) regulate activation of both innate and adaptive immunity in many contexts. iNKT cells accumulate in the liver and rapidly produce prodigious amounts of numerous cytokines upon activation, impacting the immune response to viral infection, immunosurveillance for malignant cells, and liver regeneration. However, little is known about the factors controlling iNKT homeostasis, survival and hepatic localization. Here, we report that the absence of the transcriptional regulator Id2 resulted in a severe, intrinsic defect in the accumulation of hepatic iNKT cells. Id2-deficient iNKT cells showed increased cell death in the liver, although migration and functional activity were not impaired in comparison to Id2-expressing iNKT cells. Id2-deficient iNKT cells exhibited diminished expression of CXCR6, a critical determinant of iNKT cell accumulation in the liver, and of the anti-apoptotic molecules bcl-2 and bcl-X(L), compared to Id2-sufficient iNKT cells. Furthermore, survival and accumulation of iNKT cells lacking Id2 expression was rescued by deficiency in bim, a key pro-apoptotic molecule. Thus, Id2 was necessary to establish a hepatic iNKT cell population, defining a role for Id2 and implicating the Id targets, E protein transcription factors, in the regulation of iNKT cell homeostasis.

Long-term assessment of bilirubin and transaminase trends in pediatric intestinal failure patients during the era of hepatoprotective parenteral nutrition.

PURPOSE: This study aimed to characterize the relationship between hepatoprotective parenteral nutrition (PN) dependence and long-term serum liver tests in children with intestinal failure (IF). METHODS: A retrospective review was performed of children with severe IF (> 90 consecutive days of PN) who were followed from 2012 to 2019 at a multidisciplinary intestinal rehabilitation program. Patients were stratified into three groups based on level of PN dependence at most recent follow up: EN (achieved enteral autonomy), mixed (parenteral and enteral nutrition), and PN (> 75% of caloric intake from PN). PN at any point for this cohort was hepatoprotective, defined as soy-based lipids < 1.5 g/kg/day, combination (soy, medium chain fatty acid, olive and fish oil) lipid emulsion, or fish oil-based lipid emulsion. Kaplan-Meier analysis and a generalized estimating equation (GEE) model were utilized to estimate time to normalization and trends, respectively, of two serum markers of liver health: direct bilirubin (DB) and alanine aminotransferase (ALT). RESULTS: The study included 123 patients (67 EN, 32 mixed, 24 PN). Median follow up time was 4 years. Based on the Kaplan Meier curve, 100% of EN and mixed group patients achieved normal DB levels by 3 years, while 32% of the PN group had elevated DB levels (Fig. 1). At 5 years, 16% of EN patients had elevated ALT levels compared to 73% of PN patients (p < 0.001, Fig. 2). The PN group's ALT levels were 1.76-fold above normal at 3 years (95%CI 1.48-2.03) and 1.65-fold above normal at 5 years (95%CI 1.33-1.97, Fig. 3). CONCLUSIONS: While serum bilirubin levels tend to normalize, long-term PN dependence in the era of hepatoprotective PN is associated with a persistent transaminase elevation in an overwhelming majority of patients. These data support continued vigilant monitoring of liver health in children with intestinal failure. LEVEL OF EVIDENCE: III.

Long-Term Outcomes and Disease Burden of Neonatal Onset Short Bowel Syndrome.

PURPOSE: The study aims to describe long-term outcomes and disease burden of neonatal onset short bowel syndrome (SBS). METHODS: Utilizing the WHO criteria for adolescence, patients 10-19 years of age with neonatal onset SBS requiring parenteral nutrition (PN) for >90 days and followed by our multidisciplinary intestinal rehabilitation center between 2009 and 2018 were included for analysis. RESULTS: Seventy adolescents with SBS were studied. Median (IQR) age at last follow up in our center was 15 (11, 17) years. There was 0% mortality in the cohort, and 94% remained transplant free. Fifty-three patients (76%) achieved enteral autonomy. Three patients were weaned from PN without transplantation after six years of follow-up and another four after ten years of care at our multidisciplinary center. Disease burden remained higher in adolescents receiving PN, including inpatient hospitalizations (p < 0.01), procedures (p = 0.01), clinic visits (p < 0.01), and number of prescribed medications (p < 0.01). CONCLUSION: Survival for adolescents with neonatal onset SBS is excellent. Of the cohort studied, there was no mortality, and more than 75% achieved enteral autonomy. Disease burden remains high for adolescents who remain dependent on PN. However, achievement of enteral autonomy is feasible with long-term multidisciplinary rehabilitation. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level II.

Long-term outcomes of severe surgical necrotizing enterocolitis.

PURPOSE: We sought to describe long-term outcomes of infants with severe surgical necrotizing enterocolitis (NEC). METHODS: Data were collected on infants with surgical NEC (2009-2018). Severe surgical NEC was defined by extensive bowel loss with residual bowel length <30 cm, and "NEC totalis" was identified per operative report. Post-operative management and long-term outcomes were assessed, including enteral autonomy, severe neurodevelopmental disability, and educational attainment. RESULTS: Of 268 infants with surgical NEC, 41 (15%) had severe surgical NEC, and 14/41 were identified as "NEC totalis". Zero severe NEC vs. 8 (57%) "NEC totalis" patients were placed on comfort measures following initial surgery (p < 0.001). Twenty-five patients (93%) with severe NEC survived vs 3/6 with "NEC totalis" (p < 0.001). The 28 survivors (68%) were followed for a median (IQR) duration of 8(4,10) years. Nine (32%) with severe NEC were weaned from parenteral nutrition. Eight (29%) had ≥1 marker for severe neurodevelopmental disability, and 11/16(69%) (7-16 years) were attending school at last follow-up. CONCLUSION: Long-term survival is excellent following initial discharge, and achievement of enteral autonomy is feasible in patients with severe surgical NEC. The majority of patients who survive do not have severe neurodevelopmental disability and participate in school. Given current survivals and outcomes, focus on measured residual bowel length may be more appropriate than the subjective term "NEC-totalis." TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: Level II.

Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort analysis.

OBJECTIVE: We sought to describe changes in the incidence and mortality of necrotizing enterocolitis (NEC) and associated surgical management strategies for very low birth weight (VLBW) infants. METHODS: Data were prospectively collected on VLBW infants (≤1500 g or < 29 weeks) born 2006 to 2017 and admitted to 820 U.S. centers. NEC was defined by the presence of at least one clinical and one radiographic finding. Trends analyses were performed to assess changes in incidence and mortality over time. RESULTS: Of 473,895 VLBW infants, 36,130 (7.6%) were diagnosed with NEC, of which 21,051 (58.3%) had medical NEC and 15,079 (41.7%) had surgical NEC. Medical NEC decreased from 5.3% to 3.0% (p < 0.0001). Surgical NEC decreased from 3.4% to 3.1% (p = 0.06). Medical NEC mortality decreased from 20.7% to 16.8% (p = 0.003), while surgical NEC mortality decreased from 36.6% to 31.6% (p < 0.0001). In the surgical cohort, the use of primary peritoneal drainage (PPD) versus initial laparotomy rose from 23.2% to 46.8%. CONCLUSION: The incidence and mortality of both medical and surgical NEC have decreased over time. Changes in surgical management during this time period included the increased utilization of primary peritoneal drainage. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level II.

Tracheostomy in Very Low Birth Weight Infants: A Prospective Multicenter Study.

OBJECTIVES: In this study, we benchmark outcomes and identify factors associated with tracheostomy placement in infants of very low birth weight (VLBW). METHODS: Data were prospectively collected on infants of VLBW (401-1500 g or gestational age of 22-29 weeks) born between 2006 and 2016 and admitted to 796 North American centers. Length of stay (LOS), mortality, associated surgical procedures, and comorbidities were assessed, and infants who received tracheostomy were compared with those who did not. Multivariable logistic regressions were performed to identify risk factors for tracheostomy placement and for mortality in those receiving tracheostomy. RESULTS: Of 458 624 infants of VLBW studied, 3442 (0.75%) received tracheostomy. Infants with tracheostomy had a median (interquartile range) LOS of 226 (168-304) days and a mortality rate of 18.8%, compared with 58 (39-86) days and 8.3% for infants without tracheostomy. Independent risk factors associated with tracheostomy placement included male sex, birth weight <1001 g, African American non-Hispanic maternal race, chronic lung disease (CLD), intraventricular hemorrhage, patent ductus arteriosus ligation, and congenital neurologic, cardiac, and chromosomal anomalies. Among infants who received tracheostomy, male sex, birth weight <751 g, CLD, and congenital anomalies were independent predictors of mortality. CONCLUSIONS: Infants of VLBW receiving tracheostomy had twice the risk of mortality and nearly 4 times the initial LOS of those without tracheostomy. CLD and congenital anomalies were the strongest predictors of tracheostomy placement and mortality. These benchmark data on tracheostomy in infants of VLBW should guide discussions with patient families and inform future studies and interventions.