Serum biomarkers in neuroendocrine cell hyperplasia of infancy.

BACKGROUND: Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease of unknown origin associated with hyperplasia of pulmonary neuroendocrine cells (PNECs). Diagnosis is based on the characteristic clinical picture and typical radiological imaging, and, in some cases, on lung biopsies. To date, no biochemical indicators of the disease have been identified. AIM: We aimed to determine biomarkers that could be useful in the management of children diagnosed with NEHI. METHODS: Patients with NEHI and healthy children were enrolled. Concentrations of serum biomarkers secreted by PNECs (calcitonin gene-related peptide and gastrin-releasing peptide) and biomarkers of the destruction of alveolar capillary membrane (surfactant proteins A and D [SP-A and SP-D]; glycoprotein Krebs von den Lungen-6 [KL-6]; metalloproteinases 7 and 9 [MMP-7 and MMP-9]; tissue inhibitor of metalloprotease 1) were measured. RESULTS: Fifty-two children with NEHI and 23 healthy children were included in the study. The median age of children with NEHI was 3.9 years. There were no differences in serum levels of biomarkers secreted by PNECs between groups. KL-6 levels were significantly higher in children with NEHI than in healthy ones (median 119.6 vs. 92.1 U/mL, p = 0.003); however, concentrations of KL-6 were low in both groups. No significant differences existed between groups for the remaining biomarkers associated with the destruction of the alveolar-capillary membrane. CONCLUSIONS: Measurement of serum biomarkers released by PNECs and those associated with the destruction of the alveolar-capillary membrane does not appear to be useful in the management of children with NEHI.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

Interstitial Lung Disease in Children: "Specific Conditions of Undefined Etiology" Becoming Clearer.

BACKGROUND: Children's interstitial lung disease (chILD) is a rare group of pediatric lung diseases affecting the lung interstitium diffusely. In this work, we focused our attention on a specific infant group of chILD, also known as "specific conditions of undefined aetiology", including pulmonary interstitial glycogenosis (PIG) and neuroendocrine cell hyperplasia of infancy (NEHI). METHODS: PubMed was searched to conduct this narrative review. We searched for articles in English using the following keywords: (1) neuroendocrine cell hyperplasia of infancy; (2) NEHI; (3) pulmonary interstitial glycogenosis; (4) PIG; (5) chILD. RESULTS: An increasing interest and insight into these two conditions have been reported. The updated literature suggests that it is possible to look at these disorders as a continuum of diseases, rather than two different entities, since they share a pulmonary dysmaturity. CONCLUSIONS: NEHI and PIG are featured by dysmaturity of airway development and consequent respiratory distress. Understanding the underlying pathogenic mechanisms would lead to identifying new targeted therapies to ameliorate the mortality and morbidity of these rare conditions.

Case report: Rare lung disease of infancy diagnosed with the assistance of a home pulse oximetry baby monitor.

Neuroendocrine cell hyperplasia of infancy (NEHI) is a rare childhood interstitial lung disease characterized by a gradual onset of tachypnea, hypoxemia, and failure to thrive in the first 2 years of life. NEHI is challenging to diagnose and can masquerade as common respiratory infections and reactive airway disease. Timely diagnosis is essential to optimize management of comorbidities, improve outcomes, and prevent unnecessary interventions. We report a case of a 14-month-old male who was hospitalized multiple times with recurrent episodes of presumed bronchiolitis. However, early on, the parents had detected unexplained nighttime hypoxemia with a wearable home pulse oximetry baby monitor. While recurrent respiratory infections are common in infancy, our patient had numerous persistent symptoms refractory to traditional treatments, which prompted further workup and ultimately led to the diagnosis of NEHI. The home baby monitor provided useful information that accelerated workup for a presentation that did not fit the usual picture of recurrent bronchiolitis, bronchospasm, or pneumonia. These devices that monitor infant cardiopulmonary status and oxygenation are becoming increasingly popular for home use. There is controversy over their clinical utility due to the frequency of false alarms, excessive parental reliance on these devices, and lack of Food and Drug Administration oversight to ensure accuracy and effectiveness of these devices. Our case provides an example of how in certain clinical settings, information from these devices might serve as a complementary tool in the pediatrician's medical decision-making and possibly lead to a rare diagnosis such as NEHI.

Neuroendocrine cell hyperplasia of infancy: Feasibility of objective evaluation with quantitative CT.

OBJECTIVE: To describe quantitative CT parameters of children with a typical pattern for NEHI and compare them to controls. MATERIALS AND METHODS: Eleven patients (7 boys) with NEHI and an available chest CT concordant NEHI were identified. Eleven age-, sex-, height-matched, with CT technique-matching were identified for comparison. An open-source software was used to segment the lung parenchyma into lobes using the fissures. Quantitative parameters such as low attenuation areas, mean lung density, kurtosis, skewness, ventilation heterogeneity, lung mass, and volume were calculated for both controls and cases. RESULTS: Analysis of the lung parenchyma showed that patients with NEHI had a lower mean lung density (-615 HU vs -556 HU, p = 0.03) with higher ventilation heterogeneity (0.23 vs 0.19, p = 0.04), lung mass (232 g vs 146 g, p = 0.01) and volume (595 mL vs 339 mL, p = 0.008) compared to controls. Most lobes followed this trend, except the middle lobe that showed only a higher lung mass (32.9 g vs 19.6 g, p = 0.02) and volume (77.4 vs 46.9, p = 0.005) in patients with NEHI compared to controls. CONCLUSION: Quantitative CT is a feasible technique in children with a typical pattern for NEHI and is associated with differences in attenuation, ventilation heterogeneity, and lung volume.

Airway basal stem cells generate distinct subpopulations of PNECs.

Pulmonary neuroendocrine cells (PNECs) have crucial roles in airway physiology and immunity by producing bioactive amines and neuropeptides (NPs). A variety of human diseases exhibit PNEC hyperplasia. Given accumulated evidence that PNECs represent a heterogenous population of cells, we investigate how PNECs differ, whether the heterogeneity is similarly present in mouse and human cells, and whether specific disease involves discrete PNECs. Herein, we identify three distinct types of PNECs in human and mouse airways based on single and double positivity for TUBB3 and the established NP markers. We show that the three PNEC types exhibit significant differences in NP expression, homeostatic turnover, and response to injury and disease. We provide evidence that these differences parallel their distinct cell of origin from basal stem cells (BSCs) or other airway epithelial progenitors.

Early onset children's interstitial lung diseases: Discrete entities or manifestations of pulmonary dysmaturity?

Interstitial lung diseases in children (chILD) are rare and diverse. The current classifications include a group of early onset chILD specific to infancy, namely neuro-endocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG) and the alveolar capillary-congenital acinar dysplasia (ACD-CAD) spectrum, as well as alveolar growth disorders. NEHI and PIG cells are seen in the normal developing foetal lung. We hypothesise that these conditions are in fact overlapping manifestations of pulmonary dysmaturity, respectively of airway, mesenchymal and vascular elements, rather than discrete clinical conditions in their own right. Clinically, these present as respiratory distress in early life. Mild cases rightly never undergo lung biopsy, and for these the clinical description 'persistent tachypnoea of infancy' has been proposed. In terms of pathology, we reviewed current literature, which showed that NEHI cells decline with age, and are not specific to NEHI, which we confirmed by unpublished re-analysis of a second dataset. Furthermore, specific genetic disorders which affect pulmonary maturation lead to a histological picture indistinguishable from NEHI. PIG and ACD-CAD are also associated with pulmonary growth disorders, and manifestations of PIG and NEHI may be present in the same child. We conclude that, contrary to current classifications, NEHI, PIG, and ACD-CAD should be considered as overlapping manifestations of pulmonary dysmaturation, frequently associated with disorders of alveolar growth, rather than as separate conditions. Identification of one of these patterns should be the start, not the end of the diagnostic journey, and underlying in particular genetic causes should be sought.

Exacerbations in neuroendocrine cell hyperplasia of infancy are characterized by increased air trapping.

Neuroendocrine cell Hyperplasia of Infancy (NEHI) presents with tachypnea, retractions, hypoxemia, and often failure to thrive. The radiologic and physiologic findings in infants with NEHI have been well described with a distinct geographic pattern of ground-glass opacities on chest computerized tomography imaging and profound air-trapping on infant pulmonary function testing. Despite gradual improvement over time, unexplained exacerbation has been observed but not well characterized. We present physiological and radiological changes of increased air-trapping during acute exacerbations in two older children with NEHI who had previously experienced significant clinical improvement. These cases illustrate previously undescribed manifestations of NEHI in older children.

Rare Lung Diseases: Interstitial Lung Diseases and Lung Manifestations of Rheumatological Diseases.

The concept of Childhood Interstitial Lung Disease (ChILD) is relatively young. There has been tremendous progress in this field in the last decade. The key advance has been the recognition of interstitial lung diseases that are often distinct and occur mainly in infants. Diagnosis is challenging because the incidence is low and no single center in the world has enough cases to promote experience and clinical skills. This has led to formation of international groups of people interested in the field and the "Children's interstitial and diffuse lung disease research network" (ChILDRN) is one such group which contributed to the progress of this field. Clinically, these disorders overlap with those of other common respiratory disorders. Hence, clinical practice guidelines emphasize the additional role of chest imaging, genetic testing and lung biopsy in the diagnostic evaluation. Genetic testing, in particular, has shown tremendous progress in this field. Being noninvasive, it has the potential to help early recognition in a vast majority. Despite progress, definitive therapeutic modalities are still lacking and supportive care is still the backbone of management in the majority. Early recognition of the definitive diagnosis helps in the management, even if, in a significant number, it helps in avoiding unnecessary therapy. Also discussed in this article, is the pulmonary manifestation of rheumatic diseases in children. The incidence and spectrum of pulmonary involvement in rheumatic conditions vary and can be result of the primary disease or its management or due to an concurrent infection.

European protocols for the diagnosis and initial treatment of interstitial lung disease in children.

Interstitial lung disease in children (chILD) is rare, and most centres will only see a few cases/year. There are numerous possible underlying diagnoses, with specific and non-specific treatment possibilities. The chILD-EU collaboration has brought together centres from across Europe to advance understanding of these considerations, and as part of this process, has created standard operating procedures and protocols for the investigation of chILD. Where established consensus documents exist already, for example, for the performance of bronchoalveolar lavage and processing of lung biopsies, these have been adopted. This manuscript reports our proposals for a staged investigation of chILD, starting from when the condition is suspected to defining the diagnosis, using pathways dependent on the clinical condition and the degree of illness of the child. These include the performance of genetic testing, echocardiography, high-resolution CT, bronchoscopy when appropriate and the definitive investigation of lung biopsy, in order to establish a precise diagnosis. Since no randomised controlled trials of treatment have ever been performed, we also report a Delphi consensus process to try to harmonise treatment protocols such as the use of intravenous and oral corticosteroids, and add-on therapies such as hydroxychloroquine and azithromycin. The aim is not to dictate to clinicians when a therapeutic trial should be performed, but to offer the possibility to collaborators of having a unified approach when a decision to treat has been made.

"A remarkable experience of god, shaping us as a family": parents' use of faith following child's rare disease diagnosis.

A child's chronic illness can lead parents to utilize different types of coping, including religious beliefs and practices. Previous studies have generally focused on life-shortening diagnoses. The present study explored parental use of faith when the diagnosis was not life-shortening, using grounded-theory qualitative methodology. Data were collected using semi-structured telephone interviews with N = 12 parents of children diagnosed with Neuroendocrine Hyperplasia of Infancy (NEHI); approximately 50% of the diagnosed population in the United States at the time of the interview. Participants used faith to cope and make meaning in five ways: parents believed NEHI happened for a reason; beliefs provided resilience; parents were sustained by faith communities; beliefs affected parents' behavior; and beliefs developed over time. The results suggest that chaplains develop means for universal screening for spiritual struggle; educating congregational clergy how to support families in which a child has a chronic illness; and assisting parents construct meaning of their experience.

Research in progress: put the orphanage out of business.

Paediatric interstitial lung disease (ILD) is rare and diverse, meaning no single centre will see sufficient children to perform the studies needed to make progress. This EU FP-7 grant will standardise the evaluation of these rare conditions by establishing pan-European multidisciplinary expert panels and establish consensus on treatment protocols and standard operating procedures across Europe. We will work with patient groups to determine optimal treatment end-points and biomarkers. A biobank will be established as a Europe-wide resource for mechanistic studies. Ultimately we aim to do the first randomised controlled trial of a pharmacological treatment in paediatric ILD.