High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity.

Thymic stromal lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1-24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as 'high TSLP' or 'low TSLP' for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long-term impact of viral respiratory illnesses during early infancy and beyond childhood.

Respiratory Comorbidities Associated with Bronchiectasis in Patients with Common Variable Immunodeficiency in the USIDNET Registry.

BACKGROUND: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development. OBJECTIVE: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID. METHODS: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis. RESULTS: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population. CONCLUSION: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication.

The lung in inborn errors of immunity: From clinical disease patterns to molecular pathogenesis.

In addition to being a vital organ for gas exchange, the lung is a crucial immune organ continuously exposed to the external environment. Genetic defects that impair immune function, called inborn errors of immunity (IEI), often have lung disease as the initial and/or primary manifestation. Common types of lung disease seen in IEI include infectious complications and a diverse group of diffuse interstitial lung diseases. Although lung damage in IEI has been historically ascribed to recurrent infections, contributions from potentially targetable autoimmune and inflammatory pathways are now increasingly recognized. This article provides a practical guide to identifying the diverse pulmonary disease patterns in IEI based on lung imaging and respiratory manifestations, and integrates this clinical information with molecular mechanisms of disease and diagnostic assessments in IEI. We cover the entire IEI spectrum, including immunodeficiencies and immune dysregulation with monogenic autoimmunity and autoinflammation, as well as recently described IEI with pulmonary manifestations. Although the pulmonary manifestations of IEI are highly relevant for all age groups, special emphasis is placed on the pediatric population, because initial presentations often occur during childhood. We also highlight the pivotal role of genetic testing in the diagnosis of IEI involving the lungs and the critical need to develop multidisciplinary teams for the challenging evaluation of these rare but potentially life-threatening disorders.

Innate IFN-lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life.

INTRODUCTION: IFN lambda (type III-IFN-λ1) is a molecule primarily produced by epithelial cells that provides an important first-line defence against viral respiratory infections and has been linked to the pathogenesis of viral-induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN-lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. METHODS: IFN-lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN-lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. RESULTS: Our in vitro experiments showed that the poly(I:C)-induced innate production of IFN lambda in human infant AECs is regulated by (a) p38-MAPK/NF-kB dependent mechanism; and (b) exposure to pro-inflammatory signals such as IL1ß. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus-induced IFN-lambda airway secretion; (b) subjects with RSV infection showed the highest IFN-lambda airway levels; and (c) individuals with the highest virus-induced IFN-lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). CONCLUSION: IFN-lambda responses to dsRNA in the human infant airway epithelium are regulated by p38-MAPK and NF-kB signalling. High in vivo IFN-lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children.

Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.

OBJECTIVE: 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed. APPROACH AND RESULTS: A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non-high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed. CONCLUSIONS: ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.

The lung in inborn errors of immunity.

The lungs are integral to immune defense, and inborn errors of immunity (IEI) often manifest as lung disease. Lung complications of IEI can involve the airways, alveolar spaces, interstitium, vasculature, and pleura. Accurate identification of these lung disease patterns requires a thorough clinical history, physical examination, and high-resolution computed tomography (HRCT), as lung imaging patterns guide further respiratory and immunological evaluations. Respiratory assessment may also include pulmonary function tests, bronchoscopy with bronchoalveolar lavage, and, in some cases, lung biopsy. Additionally, molecular diagnosis of underlying immune defects, typically through comprehensive clinical phenotyping, functional immune studies, and genetic testing, is crucial for informing patient management and guiding targeted therapies. Importantly, given the complexity of IEI, a multidisciplinary approach is necessary. Furthermore, ongoing research is required to refine therapies and improve outcomes for lung complications.

Cytokine Storm Syndrome Responsive to IL-1 Inhibition in Trisomy 21.

Background: Cytokine storm syndromes (CSS) are life-threatening systemic inflammatory disorders caused by immune system dysregulation. They can lead to organ failure and are triggered by various factors, including infections, malignancy, inborn errors of immunity, and autoimmune conditions. Trisomy 21 (TS21), also known as Down syndrome, is a genetic disorder associated with immune dysfunction, increased infection susceptibility, and inflammation. While TS21 has been linked to infectious-triggered hyperinflammation, its role as a primary cause of CSS has not been confirmed. Case Presentation. We present a case of a 16-year-old male with TS21 with fever, rash, joint pain, and abdominal symptoms. Extensive investigations ruled out infections, autoimmune conditions, malignancies, and inborn errors of immunity as triggers for a CSS. The patient's symptoms improved with treatment using IL-1 inhibition and corticosteroids. Conclusions: This case reinforces that TS21 is an immune dysregulation disorder and highlights the importance of considering CSS in TS21 patients, even when triggers are unclear. The positive response to IL-1 inhibition in this patient suggests that dysregulation of the IL-1 superfamily and the NLRP3 inflammasome may contribute to CSS in TS21. This finding raises the possibility of using IL-1 inhibition as a treatment approach for CSS in TS21 patients.

The bidirectional interplay of obstructive sleep apnea and viral respiratory infections in children: A novel opportunity for primary prevention.

Obstructive sleep apnea (OSA) and viral respiratory infections are highly prevalent conditions in children and a major cause of respiratory morbidity in this age group. Severe viral respiratory infections are a known risk factor for pediatric OSA, which is primarily caused by hypertrophy of upper airway lymphoid tissues (adenoids and tonsils). This review examines recent progress in understanding early-life development of lymphoid tissues in the human upper airway, with a particular focus on how respiratory viruses may influence this process and contribute to OSA pathogenesis. It also explores the bidirectional relationship between OSA and severe viral infections, highlighting the need for ongoing monitoring and novel primary prevention strategies to address these interconnected conditions.

Immune Biomarkers at Birth Predict Lower Respiratory Tract Infection Risk in a Large Birth Cohort.

Lower respiratory tract infections (LRTIs) remain the leading cause of infant morbidity and mortality worldwide and affect long-term respiratory health. Identifying immunological determinants of LRTI susceptibility may help stratify disease risk and identify therapies. This study aimed to identify neonatal immunological factors predicting LRTI risk in infancy. Cord blood plasma from 191 neonates from the Boston Birth Cohort was analyzed for 28 soluble immune factors. LRTI was defined as bronchiolitis, bronchitis, or pneumonia during the first year of life. Welch's t-test demonstrated significantly higher log10 transformed concentrations of IL-17 and IFNγ in the LRTI group compared to neonates without LRTI in the first year of life (p < 0.05). Risk associations were determined using multivariate survival models. There were 29 infants with LRTIs. High cord blood levels of IFNγ (aHR = 2.35, 95% CI 1.07-5.17), TNF-ß (aHR = 2.86, 95% CI 1.27-6.47), MIP-1α (aHR = 2.82, 95% CI 1.22-6.51), and MIP-1ß (aHR = 2.34, 95% CI 1.05-5.20) were associated with a higher risk of LRTIs. RANTES was associated with a lower risk (aHR = 0.43, 95% CI 0.19-0.97). Soluble immune factors linked to antiviral immunity (IFNγ) and cytokines mediating inflammatory responses (TNF-ß), and cell homing (MIP-1α/b), at birth were associated with an increased risk of LRTIs during infancy.

Infants hospitalized with lower respiratory tract infections during the first two years of life have increased risk of pediatric obstructive sleep apnea.

RATIONALE: Lower respiratory tract infections (LRTI) during the first 2 years of life increase the risk of pediatric obstructive sleep apnea (OSA), but whether this risk varies by LRTI severity is unknown. METHODS: We analyzed data from 2962 children, aged 0-5 years, with early-life LRTI requiring hospitalization (severe LRTI, n = 235), treated as outpatients (mild LRTI, n = 394) and without LRTI (reference group, n = 2333) enrolled in the Boston Birth Cohort. Kaplan-Meier survival estimates and Cox proportional hazards models adjusted by pertinent covariables were used to evaluate the risk of pediatric OSA. RESULTS: Compared to children without LRTI, those with mild LRTI were at a higher risk of having OSA (hazard ratio [HR] 1.44, 95% confidence interval [CI]: 1.01-2.05), and those with severe LRTI were at the highest risk (HR 2.06, 95% CI: 1.41-3.02), independently of relevant covariables (including maternal age, race, gestational age, and type of delivery). Additional risk factors linked to a higher risk of OSA included prematurity (HR 1.34, 95% CI 1.01-1.77) and maternal obesity (HR 1.82, 95% CI 1.32-2.52). The time elapsed between LRTI and OSA diagnosis was similar in mild and severe LRTI cases, with medians of 23 and 25.5 months, respectively (p = .803). CONCLUSION: Infants with severe early-life LRTI have a higher risk of developing OSA, and surveillance strategies to identify OSA need to be particularly focused on this group. OSA monitoring should continue throughout the preschool years as it may develop months or years after the initial LRTI hospitalization.

Purine degradation pathway metabolites at birth and the risk of lower respiratory tract infections in infancy.

Background: Lower respiratory tract infections (LRTIs) are the leading cause of infant morbidity and mortality worldwide, and altered metabolite production is recognised as a critical factor in LRTI pathogenesis. Methods: This study aimed to identify prenatal metabolic changes associated with LRTI risk in infancy, using liquid chromatography-mass spectrometry unbiased metabolomics analysis on cord blood from 810 full-term newborns. Results: We identified 22 compounds linked to LRTIs in infancy, enriched for purine degradation pathway (PDP) metabolites. High cord blood PDP metabolites, including xanthine, hypoxanthine, xanthosine and inosine, were linked to reduced LRTI risk during infancy. Notably, a low xanthine to uric acid ratio at birth predicted a four-fold increased LRTI risk. Conclusion: This study is the first to reveal that high cord blood PDP metabolites identify newborns at lower LRTI risk, stratifying disease risk at birth. Moreover, our results prompt further study on PDP enzymes as pharmacological targets to decrease LRTI morbidity and mortality for at-risk newborns.

Pulmonary Calcifying Fibrous Tumor in a Pediatric Patient: A Case Report.

A calcifying fibrous tumor (CFT), also known as calcifying fibrous pseudotumor, is an uncommon non-cancerous neoplasm usually located in the gastrointestinal tract. Its location in the lung is extremely rare, and only a few case reports have been published. This case report describes our diagnostic approach in a 9-year-old male patient with an incidental pulmonary mass. The mass was initially misdiagnosed, requiring multiple imaging tests and interventions to obtain the definitive diagnosis of pulmonary CFT. This paper aims to contribute to the limited information available on pulmonary CFT by presenting detailed findings from computed tomography and magnetic resonance imaging.

Dietary intake assessment in a group of breastfeeding women in two populations of Antioquia, Colombia, 2021-2022 / Evaluación de ingesta dietética en un grupo de mujeres lactantes en dos poblaciones de Antioquia, Colombia, 2021-2022

Objectives: To describe the prevalence of the risk of under or overnutrition and the food intake pattern vis à vis the recommendations of the Ministry of Health and Social Protection and the Colombian Family Welfare Institute. Material and methods: Descriptive cross-sectional study carried out in healthy women receiving care in two hospitals of eastern Antioquia, with food and nutrition security in accordance with the Latin American and Caribbean Food Security Scale (ELCSA), in the first trimester of breastfeeding, assessed between 2021 and 2022. The clinical record was used as the source of information. The sociodemographic, clinical, anthropometric characteristics, as well as dietary and micronutrient intake, were measured. Descriptive statistics were used. The prevalence of deficient or excessive energy intake and the food consumption score (FCS) are presented. The EVINDI v5, PC-SIDE v1.0, Stata 16.1 and Jasp 0.16.4 software packages were used. Results: Overall, 30 breastfeeding women were included. The prevalence of the risk of deficient energy intake was 43 %, while the risk of excessive intake was 16 % and the risk of protein deficiency was 98 %. Intake exceeding the reference value for saturated fats was 86 %, and 72 % for simple carbohydrates. The consumption pattern was characterized by exceeding the recommendations for sugars (FCS = 1.29), milk and dairy products (FCS = 1.09), grains, roots, plantains and tubers (FCS = 1.04). Recommendations for the intake of fats (FCS = 0.70), meats, eggs, legumes, nuts, seeds (FCS = 0.49), fruits and vegetables (FCS = 0.41 were not met. Conclusions: The food intake pattern identified is far from meeting the national guidelines, limiting macro and micronutrient intake and contributing to the intergenerational malnutrition cycle. Additional research in the country is essential in order to identify other intake patterns and drive political action.

Objetivos: describir la prevalencia del riesgo de deficiencia o exceso en la ingesta de nutrientes y el patrón de consumo de alimentos de acuerdo con las recomendaciones establecidas por el Ministerio de Salud y Protección Social y el Instituto Colombiano de Bienestar Familiar. Materiales y métodos: se realizó un estudio transversal descriptivo en mujeres sanas que fueron atendidas en dos hospitales del oriente antoqueño, con seguridad alimentaria y nutricional (SAN) según la Escala Latinoamericana y Caribeña de Seguridad Alimentaria (ELCSA), en el primer trimestre de lactancia, evaluadas entre los años 2021 y 2022. La fuente de información fue la historia clínica. Se midieron las características sociodemográficas, clínicas, antropométricas y la ingesta dietética y de micronutrientes. Se empleó estadística descriptiva. Se presenta la prevalencia de déficit o exceso de ingesta calórica y el índice de relación de consumo (IRC). Se utilizaron los software EVINDI v5, PCSIDE v1.0, Stata 16.1 y Jasp 0.16.4. Resultados: se incluyeron 30 mujeres lactantes. La prevalencia de riesgo de deficiencia en la ingesta usual de energía fue 43 % y exceso 16 %; el riesgo de deficiencia proteica fue 98 %. El consumo superior al valor de referencia para grasa saturada fue 86 % y carbohidratos simples 72 %. El patrón de consumo se caracterizó por superar las recomendaciones para azúcares (IRC = 1,29), leche y derivados (IRC = 1,09), cereales, raíces, plátanos y tubérculos (IRC = 1,04). No cumplieron las recomendaciones en la ingesta de grasas (IRC = 0,70), carnes, huevos, leguminosas, frutos secos y semillas (IRC = 0,49), frutas y verduras (IRC = 0,41). Conclusiones: el patrón alimentario identificado dista de las guías nacionales, lo que limita el consumo de macro y micronutrientes, y contribuye al círculo intergeneracional de la malnutrición. Es fundamental realizar nuevas investigaciones en el país para identificar otros patrones de consumo e impulsar acciones de política al respecto.

Increase in pediatric recurrent fever evaluations during the first year of the COVID-19 pandemic in North America.

The impact of the COVID-19 pandemic on new diagnoses of recurrent fevers and autoinflammatory diseases is largely unknown. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA/AID Working Group aimed to investigate the impact of the COVID-19 pandemic on the number of pediatric patients evaluated for recurrent fevers and autoinflammatory diseases in North America. The absolute number of new outpatient visits and the proportion of these visits attributed to recurrent fever diagnoses during the pre-pandemic period (1 March 2019-29 February 2020) and the first year of the COVID-19 pandemic (1 March 2020-28 February 2021) were examined. Data were collected from 27 sites in the United States and Canada. Our results showed an increase in the absolute number of new visits for recurrent fever evaluations in 21 of 27 sites during the COVID-19 pandemic compared to the pre-pandemic period. The increase was observed across different geographic regions in North America. Additionally, the proportion of new visits to these centers for recurrent fever in relation to all new patient evaluations was significantly higher during the first year of the pandemic, increasing from 7.8% before the pandemic to 10.9% during the pandemic year (p < 0.001). Our findings showed that the first year of the COVID-19 pandemic was associated with a higher number of evaluations by pediatric subspecialists for recurrent fevers. Further research is needed to understand the reasons behind these findings and to explore non-infectious triggers for recurrent fevers in children.

Corrigendum: Increase in pediatric recurrent fever evaluations during the first year of the COVID-19 pandemic in North America.

[This corrects the article DOI: 10.3389/fped.2023.1240242.].

Systemic Autoinflammatory Diseases: A Growing Family of Disorders of Overlapping Immune Dysfunction.

Systemic autoinflammatory diseases (SAIDs) are characterized by unprovoked exaggerated inflammation on a continuum from benign recurrent oral ulceration to life-threatening strokes or amyloidosis, with renal failure as a potential sequela. The ability to discriminate these diagnoses rests on the genetic and mechanistic defect of each disorder, considering potential overlapping autoinflammation, autoimmunity, and immune deficiency. A comprehensive and strategic genetic investigation influences management as well as the consequential expected prognoses in these subsets of rare diseases. The ever-expanding therapeutic armamentarium reflects international collaborations, which will hasten genetic discovery and consensus-driven treatment.

TSLP bronchoalveolar lavage levels at baseline are linked to clinical disease severity and reduced lung function in children with asthma.

Rationale: Thymic stromal lymphopoietin (TSLP) is increasingly recognized as a key molecule in asthma pathogenesis and as a promising therapeutic target in adults. In contrast, in asthmatic children the clinical relevance of TSLP secretion in the lower airways has been remarkably understudied. We tested the hypothesis that pulmonary TSLP levels in asthmatic children correlate with clinical severity, airway inflammation and lower airway obstruction. Methods: Bronchoalveolar lavage (BAL) samples and relevant clinical data were collected from asthmatic children undergoing clinically indicated bronchoscopy at Children's National Hospital in Washington D.C. Protein levels of TSLP, IL-5, IL-1ß, and IL-33 were quantified in BAL at baseline and correlated with individual severity and clinical features including spirometry, serum IgE and eosinophils, BAL neutrophil and eosinophil counts. Results: We enrolled a total of 35 asthmatic children (median age: 9 years). Pediatric subjects with severe asthma had greater TSLP BAL levels at baseline relative to mild or moderate asthmatic subjects (p = 0.016). Asthmatic children with the highest TSLP levels (>75th percentile) had higher IL-5 and IL-1ß BAL levels and greater lower airway obstruction (lower FEV1/FVC ratios). Conclusion: Our study demonstrates for the first time that higher pulmonary TSLP levels obtained at baseline are linked to asthma disease severity in a subset of children. These data indicate that TSLP may play a key role in the pathogenesis of pediatric asthma and thus provide initial support to investigate the potential use of anti-TSLP biologics to treat severe uncontrolled asthmatic children.

The Next Frontier of Prematurity: Predicting Respiratory Morbidity During the First Two Years of Life in Extremely Premature Babies.

Background Advances in perinatal and neonatal medicine have led to an increasing number of infants surviving extreme prematurity (≤27 weeks gestational age, GA). The goal of this study was to examine the respiratory outcomes after neonatal intensive care unit (NICU) discharge of this vulnerable population. We hypothesized that the rates of respiratory hospitalizations are disproportionally higher in the subset of infants born ≤27 weeks GA relative to premature infants born 28-32 weeks GA. Methodology A retrospective longitudinal study of severe premature children (≤32 weeks GA, n = 183) was conducted. We subdivided our sample into extremely preterm infants (≤27 weeks GA; n = 101) and those born very preterm (28-32 weeks GA; n = 82). Our main outcome was the presence of respiratory hospitalizations within 24 months of NICU discharge. Results Extremely premature infants had more than three times higher odds of respiratory hospitalization at 24 months relative to infants born 28-32 weeks GA (adjusted odds ratio = 3.4; 95% confidence interval = 1.8, 6.4; p < 0.01). The increased risk of respiratory hospitalization in extremely premature infants was independent of GA. Regression models identified that the duration of supplemental oxygen and Black/African American ethnicity were significant predictors of respiratory hospitalizations in both prematurity groups independent of gender and birth weight. Conclusions The results support that babies born ≤27 weeks GA represent a distinct high-risk group of severely premature infants that needs novel preventive strategies and targeted interventions to improve their respiratory outcomes after NICU discharge.