Historical perspective on surfactant therapy: Transforming hyaline membrane disease to respiratory distress syndrome.

Lung surfactant is the first drug so far designed for the special needs of the newborn. In 1929, Von Neergard described lung hysteresis and proposed the role of surface forces. In 1955-1956, Pattle and Clements found direct evidence of lung surfactant. In 1959, Avery discovered that the airway's lining material was not surface-active in hyaline membrane disease (HMD). Patrick Bouvier Kennedy's death, among half-million other HMD-victims in 1963, stimulated surfactant research. The first large surfactant treatment trial failed in 1967, but by 1973, prediction of respiratory distress syndrome using surfactant biomarkers and promising data on experimental surfactant treatment were reported. After experimental studies on surfactant treatment provided insight in lung surfactant biology and pharmacodynamics, the first trials of surfactant treatment conducted in the 1980s showed a striking amelioration of severe HMD and its related deaths. In the 1990s, the first synthetic and natural surfactants were accepted for treatment of infants. Meta-analyses and further discoveries confirmed and extended these results. Surfactant development continues as a success-story of neonatal research.

Preterm prelabor rupture of membranes in singletons: maternal and neonatal outcomes.

OBJECTIVES: To determine the effect of gestational age at delivery on maternal and neonatal outcomes in preterm prelabor rupture of membranes (PPROM) and assess various predictors of neonatal and infant mortality in these pregnancies. METHODS: United States birth data from CDC-National Center for Health Statistics natality database for years 2004-2008 was used to identify singleton pregnancies with PPROM and delivery from 32 0/7 to 36 6/7 weeks. Controls were singletons at 37-40 weeks, without PPROM. Maternal and neonatal complications reported by all states were analyzed along with neonatal outcomes such as chorioamnionitis and hyaline membrane disease, reported by a subgroup of states. OR (95% CI) were calculated after adjusting for preeclampsia, diabetes, chronic hypertension, maternal race, and infant sex. RESULTS: There were 134,502 PPROM cases and similar number of controls. There was a significant decrease in need for prolonged ventilation, hyaline membrane disease, 5 min Apgar score <7, and NICU admission with advancing gestational age. Placental abruption decreased and chorioamnionitis and cord prolapse were not different between 34 and 37 weeks. We found reductions in early death, neonatal death, and infant mortality with advancing gestational age (p<0.001 for each). Gestational age at delivery was the strongest predictor for early death, neonatal death, and infant mortality in PPROM. These differences persisted after adjusting for antenatal steroid use. CONCLUSIONS: We provide population-based evidence showing a decrease in neonatal complications and death with advancing gestational age in PPROM. Gestational age at delivery in pregnancies with PPROM is the strongest predictor of mortality risk.

Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I.

The significant variability in the clinical manifestations of COL2A1-associated skeletal dysplasias makes it necessary to conduct a clinical and genetic analysis of individual nosological variants, which will contribute to improving our understanding of the pathogenetic mechanisms and prognosis. We presented the clinical and genetic characteristics of 60 Russian pediatric patients with type II collagenopathies caused by previously described and newly identified variants in the COL2A1 gene. Diagnosis confirmation was carried out by new generation sequencing of the target panel with subsequent validation of the identified variants using automated Sanger sequencing. It has been shown that clinical forms of spondyloepiphyseal dysplasias predominate in childhood, both with more severe clinical manifestations (58%) and with unusual phenotypes of mild forms with normal growth (25%). However, Stickler syndrome, type I was less common (17%). In the COL2A1 gene, 28 novel variants were identified, and a total of 63% of the variants were found in the triple helix region resulted in glycine substitution in Gly-XY repeats, which were identified in patients with clinical manifestations of congenital spondyloepiphyseal dysplasia with varying severity, and were not found in Stickler syndrome, type I and Kniest dysplasia. In the C-propeptide region, five novel variants leading to the development of unusual phenotypes of spondyloepiphyseal dysplasia have been identified.

Evidence of an active Cushing reflex in a preterm neonate with hyaline membrane disease: a case report.

BACKGROUND: The Cushing reflex does not appear to have been described in preterm neonates. This case report shows the presence of an active Cushing reflex in a 32-week preterm neonate with hyaline membrane disease. CASE PRESENTATION: The 1.94 kg Caucasian infant was delivered by caesarean section following concerns about possible maternal infection and fetal compromise. Chest X-ray showed mild-to-moderate hyaline membrane disease and treatment was initiated with supplemental oxygen and nasal continuous positive airway pressure. It is probable that a pneumothorax occurred at 5-6 hours of age, with progression during the day. Interstitial air, pneumomediastinum, and tension pneumothorax were diagnosed on subsequent X-ray, and ultrasound of the brain showed a grade IV intraventricular hemorrhage. A review of the nurses' recordings of heart rate, blood pressure, and respiratory rate showed a progressive increase in blood pressure accompanied by slowing of the heart rate and irregular respiration. These are features of the Cushing reflex that is elicited in response to raised intracranial pressure. CONCLUSION: While well-described in older children and adults, in neonates the Cushing reflex has mainly been described in animal experiments and infants who have developed hydrocephalus. It is likely that in this case, the reflex was elicited as a result of a progressive increase in intracranial pressure due to the combination of elevated intrathoracic pressure, obstructed venous return from the brain, and concurrent intraventricular hemorrhage.

The burden of hyaline membrane disease, mortality and its determinant factors among preterm neonates admitted at Debre Tabor General Hospital, North Central Ethiopia: A retrospective follow up study.

BACKGROUND: Hyaline membrane disease (HMD) is a leading cause of morbidity and mortality in preterm newborn babies. Though, there are studies related to Hyaline membrane disease inclusive of all neonates, studies related to the burden among preterm neonates were limited. In addition, increasing neonatal mortality in Ethiopia could be related to increase in the burden of hyaline membrane disease among preterm neonates. Therefore, this study was aimed to assess the burden of hyaline membrane disease, mortality and its associated factors among preterm neonate admitted at neonatal intensive care unit, North Central Ethiopia. METHODOLOGY: An institution-based retrospective follow-up study was conducted among 535 preterm neonates admitted at neonatal intensive care unit from January 1, 2014-December 30, 2017. Data were entered into EPi-data 4.2.0.0 and transferred to STATA version 14 statistical software for statistical analysis. Binary logistic regression was used for the analysis. All variables with P-value < 0.25 during bi-variable analysis were considered for multivariable logistic regression. Level of statistical significance was declared at P value ≤0.05. RESULTS: In the current study, proportion of hyaline membrane disease was 40% (95% CI; 35.8, 44.3) of which 49.5% died. Preterm neonate born with Gestational age of less than 34 weeks of age (Adjusted odd ratio (AOR = 2.64; 95 CI: 1.49, 4.66)), 5th minute Apgar score less than 7 (AOR = 2.2; 95% CI: 1.20, 4.07), and newborn with birth weight of less than 1500 gram (AOR = 2.4, 95% CI: 1.3, 4.3) were predictors of hyaline membrane disease. CONCLUSIONS: The mean gestational age (±) was 33.46 (±2.55) weeks. The incidence of hyaline membrane disease among preterm admissions was high. Preterm neonate born with gestational age of less than 34 weeks of age, asphyxiated newborns and newborn with birth weight of less than 1500 gram were predictors of hyaline membrane disease. So, emphasis should be given on early screening, follow up and timely interventions for preterm neonate.

Radiologic Features of Type II and Type XI Collagenopathies.

Type II collagen is a major component of the cartilage matrix. Pathogenic variants (ie, disease-causing aberrations) in the type II collagen gene (COL2A1) lead to an abnormal structure of type II collagen, causing a large group of skeletal dysplasias termed type II collagenopathies. Because type II collagen is also located in the vitreous body of the eyes and inner ears, type II collagenopathies are commonly associated with vitreoretinal degeneration and hearing impairment. Type II collagenopathies can be radiologically divided into two major groups: the spondyloepiphyseal dysplasia congenita (SEDC) group and the Kniest-Stickler group. The SEDC group is characterized by delayed ossification of the juxtatruncal bones, including pear-shaped vertebrae. These collagenopathies comprise achondrogenesis type 2, hypochondrogenesis, SEDC, and other uncommon subtypes. The Kniest-Stickler group is characterized by disordered tubular bone growth that leads to "dumbbell" deformities. It comprises Kniest dysplasia and Stickler dysplasia type 1, whose radiographic manifestations overlap with those of type XI collagenopathies (a group of disorders due to abnormal type XI collagen) such as Stickler dysplasia types 2 and 3. This phenotypic overlap is caused by type II and type XI collagen molecules sharing part of the same connective tissues. The authors describe the diagnostic pathways to type II and type XI collagenopathies and the associated differential diagnoses. In addition, they review the clinical features and genetic bases of these conditions, which radiologists should know to participate in multidisciplinary care and translational research. Online supplemental material is available for this article. ©RSNA, 2020.

Neonatal acute liver failure with pulmonary yellow hyaline membrane and kernicterus

Background Neonatal acute liver failure (NALF) is a rare and life-threatening condition. It causes bilirubin to accumulate to a dangerous level in the body, causing permanent damage to vital organs such as the brain and lungs. In many cases, the etiology of NALF remains unknown. Case presentation We described a case of an 8-day-old baby girl who presented with poor oral intake, lethargy, and jaundice. Her clinical condition rapidly deteriorated with progression to multi-organ failure, and despite intensive resuscitation efforts, she expired. At autopsy, the most significant findings were liver necrosis, yellow hyaline membrane deposition in the lungs, and bilirubin deposition in the brain (kernicterus). Conclusions NALF is a rare and potentially fatal condition necessitating prompt recognition and disease-specific treatment approaches. Toxic accumulation of bilirubin in the lungs can lead to hypoxia and precipitate further ischemic injury to the liver.

A survey on criteria for intubation in moderate to late preterm infants with respiratory distress.

BACKGROUND: Majority of preterm infants do well with continuous positive airway pressure (CPAP) as the sole respiratory management; but some require endotracheal intubation and surfactant administration. While intubation is needed predominantly in extremely preterm infants (<28 weeks); some of the more mature preterm infants also require it. Currently, there are no clear guidelines regarding indications for endotracheal intubation in such infants. AIMS: To understand the current practice regarding "criteria for intubation" in moderate to late preterm infants with respiratory distress. METHODS: A survey of neonatologists in Australia New Zealand Neonatal Network (ANZNN) was conducted between April and June 2019. RESULTS: At least one neonatologist each from 29 of the 30 tertiary ANZNN Neonatal Intensive Care Units (NICUs) responded to the survey. In total, 118/200 (59%) neonatologists responded. The most common criteria for intubation were CPAP = 8 cmH2 O (61%), pH < 7.2 (55%), pCO2 > 70 mmHg (48%), FiO2 > 40% (40%), chest retractions (48%), more than two episodes of apnea requiring intervention (54%), and chest X-ray (CXR) showing moderate-severe hyaline membrane disease (HMD, 49%). CONCLUSION: While there were variations in practice, nearly 50% of the neonatologists shared a common threshold with regards to the CPAP level, FiO2 , blood gas parameters, and clinical and radiological findings. The results of this survey will help in designing future randomized controlled trials (RCTs) on this subject.

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.

BACKGROUND: COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes. METHODS: We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation. FINDINGS: All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet-fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes. INTERPRETATION: The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet-fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy. FUNDING: None.

Risk Factors of Respiratory Diseases Among Neonates in Neonatal Intensive Care Unit of Qena University Hospital, Egypt.

Background: Respiratory diseases in newborns are considered major causes of neonatal morbidity and mortality especially in developing countries. Its causes are diverse and require early detection and management. This study aimed for detection of the prevalence and risk factors of respiratory diseases in addition to outcome among neonates admitted in neonatal intensive care unit. Methods: Our study was a prospective observational study that was undertaken at the neonatal intensive care unit of Qena University Hospital, Egypt from July 2017 to July 2018. Demographic and clinical data of newborns and their mothers were evaluated and tabulated. Results: In this period, 312 neonates were admitted to the neonatal intensive care unit, out of them 145 suffered respiratory diseases giving a prevalence of (46.5%), and (55.9%) were males. The mean neonatal age at admission was 4.33 ± 7.19 days and mean gestational age was 34.49 ± 3.31 weeks. The most common detected respiratory diseases were respiratory distress syndrome (RDS; 49.6%), transient tachypnea of newborn (TTN; 22%), neonatal pneumonia (17.2%) and meconium aspiration syndrome (MAS; 6.21%). Premature rupture of membrane (PROM), maternal diabetes and fetal prematurity had the highest risk factors for respiratory diseases occurrence in neonates. Neonatal mortality rate was 26.2%, mainly due to hyaline membrane disease and pneumonia. Conclusion: Respiratory diseases constitute major part of total admission in neonatal intensive care unit especially RDS, TTN, pneumonia and MAS. Prematurity and maternal diabetes were the most important risk factors associated with respiratory diseases. Respiratory distress syndrome carried the highest risk of mortality and TTN carried the highest survival rate.

Clinical and Molecular Characterization and Discovery of Novel Genetic Mutations of Chinese Patients with COL2A1-related Dysplasia.

COL2A1-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular phenotypes of Chinese patients with COL2A1-related dysplasia and to explore their phenotype-genotype relations. Clinical data were collected, physical examinations were conducted, and X-ray radiography and genetic analyses were performed in ten families involving 29 patients with COL2A1-related dysplasia. Nine mutations were identified in COL2A1, including five novel (c.816+6C>T, p.Gly246Arg, p.Gly678Glu, p.Gly1014Val and p.Ter1488Gln) and four reported previously (p.Gly204Val, p.Arg275Cys, p.Gly504Ser and p.Arg719Cys). Based on clinical features and molecular mutations, the ten families were classified into five definite COL2A1-related disorders: four families with spondyloepiphyseal dysplasia congenita (SEDC), three with osteoarthritis with mild chondrodysplasia (OSCPD), one with Czech dysplasia, one with Kniest dysplasia, and one with epiphyseal dysplasia, multiple, with myopia and deafness (EDMMD). Based on genetic testing results, prenatal diagnosis and genetic counseling were accomplished for one female proband with OSCDP. Chinese patients with OSCDP, Czech dysplasia and EDMMD caused by COL2A1 mutations were first reported, expanding the spectrum of COL2A1 mutations and the phenotype of COL2A1-related disorders and providing further evidence for the phenotype-genotype relations, which may help improve procreative management of COL2A1-related disorders.

The influence of maternal ethnicity on neonatal respiratory outcome.

OBJECTIVE: Higher rates of neonatal morbidity and mortality at term combined with earlier spontaneous delivery have led to the hypothesis that babies born to South Asian born (SA-born) women may mature earlier and/or their placental function decreases earlier than babies born to Australian and New Zealand born (Aus/NZ-born) women. Whether babies born to SA-born women do better in the preterm period, however, has yet to be evaluated. In this study we investigated respiratory outcomes, indicative of functional maturity, of preterm babies born to SA-born women compared with those of Aus/NZ-born women to explore this hypothesis further. STUDY DESIGN AND SETTING: This retrospective cohort study was conducted at Monash Health. PATIENTS: Data were collected from neonatal and birth records of moderate-late preterm (32-36 weeks) infants born between 2012 and 2015 to SA-born and Aus/NZ-born women. OUTCOME MEASURES: Rates of nursery admissions and neonatal respiratory outcomes were compared. RESULTS: Babies born to Aus/NZ-born women were more likely to be admitted to a nursery (80%) compared with SA-born babies (72%, p=0.004). Babies born to SA-born mothers experienced significantly less hyaline membrane disease (7.8%), required less resuscitation at birth (28.6%) and were less likely to require ventilation (20%) than babies born to Aus/NZ-born mothers (18%, 42.2%, 34.6%; p<0.001). There was no difference in the duration of ventilation or length of stay in hospital. CONCLUSIONS: Moderate-late preterm babies born to SA-born women appear to have earlier functional maturity, as indicated by respiratory outcomes, than Aus/NZ-born babies. Our findings support the hypothesis of earlier fetal maturation in SA-born women.

Uso convencional de surfactante en recién nacidos con enfermedad de membrana hialina / Conventional use of surfactant in newborns with hyaline membrane disease

La enfermedad de membrana hialina se debe a la deficiencia de surfactante en los pulmones de los recién nacidos especialmente los menores de 37 semanas de gestación. El manejo materno con corticoides prenatales en este grupo, disminuye la morbimortalidad asociada a esta patología neonatal. Se analiza desde el punto de la evidencia actualmente existente la administración de surfactante a estos prematuros y se revisa el tipo de surfactante a administrar, cuando es el mejor momento para administrarlo, la dosis y la forma de administrarlo.

Hyaline membrane disease is due to surfactant deficiency in the lungs of newborns, especially those younger than 37 weeks gestation. Maternal management with prenatal corticosteroids in this group reduces the morbidity and mortality associated with this neonatal pathology. The administration of surfactant to these preterm infants is analyzed from the point of the currently existing evidence and the type of surfactant to be administered is reviewed, when is the best time to administer it, the dose and the form of administration.

Pulmonary Hyalinising Granuloma: A report of two cases.

Pulmonary hyalinising granuloma (PHG) is a rare fibrosclerosing inflammatory lung condition of unknown aetiology. It is characterised by solitary or multiple pulmonary nodules that are usually found incidentally while imaging the chest for other reasons. We report two cases of histologically proven PHG diagnosed at the Royal Hospital, Muscat, Oman. The first case was a 71-year-old male patient who presented in 2010 with a dry cough, weight loss and bilateral pulmonary nodules. The second case was a 58-year-old male patient who presented in 2012 and was found to have incidental bilateral pulmonary nodules on chest X-ray. Both patients were started on prednisolone and on follow-up the PHG nodules remained stable. Although there is no definitive treatment, PHG generally has an excellent prognosis.

Orthodontic Treatment in a Patient With Kniest Dysplasia: A Case Study and Review of Literature.

Kniest dysplasia is a rare autosomal dominant chondrodysplasia that is characterized by distinct musculoskeletal and craniofacial irregularities. These craniofacial abnormalities include cleft palate, midface anomalies, tracheomalacia, and hearing loss. This article illustrates a case of Kniest dysplasia that presented for orthodontic treatment. The purpose of this literature review is to describe clinical manifestations, radiographic features, histopathological features, genetic mutation, and management of Kniest dysplasia.

Predictors of Neonatal mortality in Neonatal intensive care unit at referral Hospital in Southern Ethiopia: a retrospective cohort study.

BACKGROUND: The first one month of life; the neonatal period is the most risky time for child survival. In Ethiopia, neonatal mortality is unacceptably high, and the trend in reduction is slower as compared to infant and child mortality. The magnitude and associated factors of neonatal mortality in a tertiary care facility were not well documented. Therefore, the aim of this study was to determine neonatal mortality and predictors among neonates admitted to neonatal intensive care unit of Wolaita Sodo University Teaching and Referral Hospital, South Ethiopia. METHODS: A retrospective cohort study design was done among neonates admitted to neonatal intensive care unit of a University Teaching and Referral Hospital from 2015 to 2017. Data were collected using data extraction checklist from the medical registry. The main outcome was the occurrence of death within the first four weeks. The survival time was calculated in days between the date of admission and the date of death. Kaplan-Meier survival was used to depict the pattern of death in 28 days and Cox-Proportional model was used to identify the predictors of the neonatal mortality. RESULTS: A total of 964 neonates which contributed to 5889 neonates-days were included in the study. There were 159 neonatal deaths during the follow-up time. Overall, the neonatal mortality incidence was 27 per 1000 neonates-days. Predictors of neonatal mortality were: multiple birth, mothers who did not attend antenatal care visits, neonates born by cesarean section, not initiated breast feeding within 1 h of birth, neonates resuscitated, hyaline membrane disease and perinatal asphyxia. CONCLUSION: Neonatal mortality at neonatal intensive care unit was high. Managing neonatal complications, initiating breast feeding within 1 h of birth, promoting antenatal care visits, improving quality of services and ensuring continuum of care are recommended to increase survival of neonates.