*Chiara Migliorati1, Alberto Terminiello 2 & Paolo Del Greco 2
1 SOSD Broncopneumologia, Ospedale Pediatrico Meyer IRCCS, Firenze
2 SCDU Pediatria, Università del Piemonte Orientale, AOU Maggiore della Carità, Novara
We report the news regarding the diagnostic process in the Neuroendocrine Cell Hyperplasia of Infancy (NEHI), emerged from a recent European multicenter retrospective observational study. [1]
Diagnostic workup in neuroendocrine cell hyperplasia of infancy (NEHI): Population and methods of the proposed study: Population and methods
The study included 378 children from 17 countries, predominantly of males (63.5%), Caucasians (97.4%) and term births (90.3%). All children included in the study underwent high-resolution chest computed tomography (HRCT) at a median age of 8 months and receives a NEHI diagnosis at a median age of 9 months.
The diagnosis was formulated according to the guidelines of the American Thoracic Society, considering the main clinical criteria (persistent tachypnea, retractions, hypoxemia, crackles, or a combination thereof), associated with typical findings for HRCT, such as the presence of ground glass opacities in the middle lobe and tongue (in cases of less widespread disease) or extended to paramediastinic regions (more extensive changes). [2;3;4]
Exclusion criteria included incomplete clinical documentation (less than 80% of available information) and presence of genetic variants related to other diseases.
Age at diagnosis, clinical manifestations and the diagnostic process were compared between countries that had enrolled at least 10 patients. In addition, the clinical score proposed by Liptzin et al [5] was applied, based on ten criteria, each of which was given a point value: onset of symptoms before 12 months of age, poor growth, absence of digital hippocracy, no cough or wheezing, Chest wall abnormalities, crackles, hypoxemia, tachypnea and thoracic retractions. A total score of 7 out of 10 was considered indicative of NEHI.
NEHI Diagnosis: Results: Results
Data collected confirms that the diagnosis of NEHI is based on:
– Clinical picture: Tachypnea has been shown to be the least variable symptom between countries involved. Other frequent signs were chest shrinkage, crackles, hypoxemia and failure to thrive. Cough and wheezing were reported in about 40% of cases, although their prevalence may be overestimated, as many diagnoses are made in a peri-infectious context. There was also a high incidence of chest wall abnormalities (e.g. pectus excavatum or carenatum), potentially secondary to chronic respiratory retractions. The Liptzin Score [5] has been shown to be effective at diagnosing suspicion, with a sensitivity of more than 93%. In 86.5% of the cases, patients obtained a score of 7. However, 13.5% of patients with confirmed diagnosis had a score below 7, showing that a negative score does not allow to exclude the diagnosis. A correlation has also been reported between high scores and greater extent of alterations in the chest CT.
– Chest X-ray: although it is the most common initial survey to assess persistent respiratory symptoms, it is characterized by poor sensitivity in detecting interstitial diseases. [6] It is therefore not a valid diagnostic tool for NEHI, as it does not allow an adequate evaluation of the pulmonary interstitium or paramediastinal regions. In a non negligible percentage (30,4%) of patients involved in the study affected by NEHI, chest radiography was found to be normal, pointing out that such examination, if negative, is not able to exclude the diagnosis.
– Pulmonary ultrasound: although it is highly sensitive, it has a low specificity; its diagnostic use therefore remains limited.
– Chest CT: is the reference survey for the identification of ground glass opacities in the middle lobe and lingula. [6] In the study, ground glass opacities limited to the middle lobe and lingula were found in 21.5% of patients with NEHI. In 78.5% of the affected patients, these abnormalities had a more extensive localization, to the middle lobe, lingula but also to other paramediastinal regions. Atypical localisations have been found in some cases, apparently not related to a worse clinical picture. [7]
– Lung biopsy: not a routine test, as it is positive in only 50-70% of cases. There was no correlation between the opacity density and the number of pulmonary neuroendocrine cells (PNECs) detected in the biopsy material. [8] In addition, performing the biopsy may lead to diagnostic delays, so it is indicated only in patients with atypical clinical presentation.
– Genetic analysis: although no specific gene variants are known for NEHI, molecular analysis may contribute to the exclusion of alternative diagnoses (e.g. mutations in the NKX2.1 and FOXP1 genes). [9; 10]
– Echocardiography: was performed in almost all the patients involved in the study, proving an example of good diagnostic uniformity. It found minor heart defects and no pulmonary hypertension.
– Bronchoscopy: performed in about half of the patients, it should be reserved for cases with specific indications (for example, infections or tracheobronchial abnormalities).
– Pulmonary function tests: indicate a marked increase in residual functional capacity [11], but studies on larger populations are necessary to assess their reliability.
– Blood tests and other investigations: they generally show modest alterations and present high variability between the different centers, making it difficult to draw definitive conclusions about their usefulness in the diagnosis of NEHI. Patients with NEHI may also have comorbidities, such as gastroesophageal reflux disease or obstructive apnea syndrome [5], which should therefore always be excluded with dedicated tests if the patients present symptoms compatible with them.
Limitations of the study
The distribution of patients enrolled in different countries was not proportional to the total population of each nation, and the role of possible ethnic and environmental influences is still poorly defined. In addition, the retrospective nature of the study led to a partial incompleteness of the data collected; in particular, the clinical score for NEHI was not calculated in all patients included in the analysis.
Conclusions
Currently, the diagnosis of NEHI is based on clinical evaluation and chest imaging (chest CT). Other investigations, such as lung biopsy and bronchoscopy should be reserved for patients with atypical clinical presentation. There is a need to define shared recommendations in order to trace basic minimum diagnostic requirements to avoid the use of tests with limited diagnostic value.
References
[1] Diagnostic Evaluation and Clinical Findings in Children with Persistent Tachypnea of Infancy/Neuroendocrine Cell Hyperplasia of Infancy Marczak, Honorata et al. CHEST, Volume 0, Issue 0
[2] Deterding RR, Fan LL, Morton R, Hay TC, Langston C. Persistent tachypnea of infancy (PTI)-a new entity Pediatr Pulmonol. 2001; Suppl 23:72-73
[3] Deterding, RR, Pye, C., Fan, LL and Langston, C. (2005), Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia. Pediatr. Pulmonol., 40: 157-165. https://doi.org/10.1002/ppul.20243
[4] Kurland G, Deterding RR, Hagood JS, et al. An official american thoracic society clinical practice guideline: Classification, evaluation, and management of childhood interstitial lung disease in infancy Am J Respir Crit Care Med. 2013; 188(3):376-394
[5] Liptzin DR, Pickett K, Brinton JT, et al. Neuroendocrine cell hyperplasia of infancy. Clinical score anda comorbidities. Ann Am Thorac Soc. 2020;17(6);724-728
[6] Nathan N, Griese M, michel K, et al. Diagnostic Workup of Childhood Interstitial Lung Disease, Eur Resp Rev 2023; 32(167): 220188
[7] Rauch D, Wetzke M, Reu S, et al. Persistent tachypnea of infancy: Usual and aberrant, Am J Respir Crit Care Med. 2016;193(4):438-447
.[8] Miraftabi P., Kirjavainen T., Lohi J. Martelius L. The original histopathologic description of neuroendocrinecell hyperplasia of infancy is not applicable to every patientwith the disease.
[9] Nevel R.J. , Garnett ET, Worrel JA, et al. Persistent lung disease in adults with NKX2.1 mutation and familial neuroendocrine cell hyperplasia of infancy Ann Am Thorac Soc. 2016;13(8):1299-1304
[10] Myers A, du Souich C, Yang CL, et al. FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?. Am J Med Genet Part A. 2017; 173A: 3172–3181. https://doi.org/10.1002/ajmg.a.38462
[11] Breuer O, Cohen-Cymberknoh M, Picard E, et al. The Use of Infant Pulmonary Function Tests in the Diagnosis of Neuroendocrine Cell Hyperplasia of Infancy, Chest, 2021; 160(4):1397-1405Pages 1397-1405
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