Neuroendocrine cell hyperplasia of infancy (NEHI)

INTRODUCTION — Neuroendocrine cell hyperplasia of infancy (NEHI), initially described as persistent tachypnea of infancy, is a rare lung disease first defined in 2005 [1]. The etiology is unknown, but genetic mechanisms may play a role. NEHI typically presents in otherwise healthy infants during the first months to year of life with persistent tachypnea, crackles, and hypoxemia. Characteristic findings on chest computed tomography (CT) include hyperinflation and ground-glass opacities in a characteristic geographic distribution, without other parenchymal abnormalities. Pulmonary symptoms and hypoxemia tend to improve with time but may persist for years.

The clinical presentation, diagnosis, and treatment of NEHI are discussed in this topic review. The characteristics and diagnosis of other interstitial lung diseases of infancy and childhood are discussed separately. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)".)

EPIDEMIOLOGY — The incidence and prevalence of NEHI are unknown, but it is clearly rare. Available data derive from small- to moderate-sized case series. The original report of this disorder in 2005 included 15 cases from two referral centers [1]. In an 11-center study reported by the Children's Interstitial and Diffuse Lung Disease Research Network in North America (chILDRN), NEHI cases (n = 18) represented 10 percent of all lung biopsies from children less than two years of age [2]. A study from a large referral center identified 19 cases (14 percent) from among 138 lung biopsy cases accrued over a 10-year period [3]. Twenty-three NEHI cases were included in a separate study testing chest CT diagnostic criteria [4], and 37 cases were included in a manuscript focusing on infant pulmonary function testing (PFT) [5]. The largest report to date collated 199 NEHI cases from 11 centers in the United States and Canada [6]. In the initial report from the chILDRN registry in the United States, which requires informed consent from participants, NEHI comprised the largest category, with 155 (23 percent) of all cases [7]. Importantly, there is undoubtedly a significant overlap of cases included in all of these publications, making the total number of NEHI cases in North America unknown at this time. Additional published cases have now been reported from Finland, Brazil, the United Kingdom, China, Poland, Australia, New Zealand, Ecuador, Spain, Germany, France, Mexico, and Japan [8].

It is suspected that the prevalence of NEHI may be greater than currently estimated. At a pediatric center that was not a historic referral center or included in the above studies, there were 8 cases (8.3 percent) of NEHI out of 93 cases of childhood interstitial lung disease identified through a retrospective review. Most of these NEHI cases were not previously recognized, and the patients had been diagnosed with other specific or nonspecific types of chronic lung disease [9].

In the original series of 15 cases reported by Deterding et al, there was a slight male predominance [1]. This pattern was also observed in the multicenter report (66 percent male) [6] but not in all subsequent reports.

PATHOGENESIS — The etiology of NEHI is unknown, but genetic mechanisms are likely to play a role, as suggested by familial patterns seen in some cases. As an example, a heterozygous mutation in NKX2-1 was identified in an individual with confirmed NEHI and pediatric and adult family members with histories of childhood lung disease [10]. The mutation results in a nonconservative amino acid substitution in the homeodomain in a codon extensively conserved through evolution. Two cases of definite NEHI in infants in a subsequent generation support the association of the variant with NEHI [11]. NKX2-1 mutations were not identified in eight other unrelated subjects with NEHI [10], but cases with likely NEHI have subsequently been rarely identified [12].

Although lung biopsies in NEHI are characterized by prominent pulmonary neuroendocrine cells in the distal airways, it is unclear whether these cells are directly involved in the pathogenesis of NEHI or are simply a marker of the disorder. The correlation between neuroendocrine cell prominence and the severity of small airway obstruction on infant pulmonary function tests (PFTs) in NEHI patients suggests a potential causal role [3]. However, the density of the neuroendocrine cells would not appear, in and of themselves, to result in anatomic narrowing of the airways involved, and, indeed, the small airways appear patent histologically.

Pulmonary neuroendocrine cells have complex roles in a variety of developmentally and disease-associated contexts. Postnatally, pulmonary neuroendocrine cells are providers of a lung stem cell niche that is important in airway epithelial regeneration and lung carcinogenesis. These cells are oxygen sensors involved in neonatal adaptation and have roles as airway chemoreceptors and in chemotransmission of the hypoxic stimulus [13]. There is no known association between NEHI and the adult lung disease diffuse idiopathic pulmonary neuroendocrine cell hyperplasia [14].

No common infectious etiologies have been identified. The absence of active neuroendocrine cell proliferation in lung biopsies and lack of correlation with airway injury suggests that neuroendocrine cell prominence in NEHI is not due to an infectious or inflammatory process [3].

CLINICAL PRESENTATION — NEHI presents in otherwise healthy infants with chronic tachypnea and retractions, generally of insidious onset, in the first few months to year of life [15]. The vast majority of reported cases were born after an uncomplicated full-term pregnancy [6], but rare cases in preterm infants have been documented [1,3]. The patient may come to medical attention after apparent viral upper respiratory infections, but in most cases, the respiratory symptoms predate the acute illness [3,16,17]. Other infants come to medical attention because of failure to thrive [15]. It is likely that some infants with mild NEHI do not come to medical attention or their respiratory symptoms are mistakenly attributed to more common disorders such as gastroesophageal reflux or aspiration.

Tachypnea is the most consistently reported clinical feature; chronic subglottic, intercostal, and subcostal retractions are also common. Cough is not a prominent chronic feature. The infants are otherwise well-appearing. Hypoxemia has been universal in some series [1,3] but was present in only 57 to 78 percent of cases in other reports [9,16-18]. These latter reports did not specify whether oxygenation was systematically assessed during feeding and sleep.

On physical examination, inspiratory crackles are the most prominent finding but are not universally present [1,2,9,17]. Wheezing is occasionally noted, typically in association with superimposed viral illness. Chest wall deformity with increased anteroposterior diameter of the chest appears to be a common finding but is probably underreported [16,18], and, occasionally, pectus excavatum is also observed. Clubbing has not been reported.

Many infants with NEHI experience difficulty gaining weight or failure to thrive, with prevalence ranging from 20 to 89 percent in series that used different reporting criteria [1,3,16,17,19]. Further, a decline in growth trajectory has been reported to precede diagnosis of NEHI [19]. Gastroesophageal reflux is a common comorbid condition. This has been attributed to the respiratory physiology of NEHI and is not considered a causal factor. No other extrapulmonary manifestations have been consistently described, though evaluation for developmental delays may be warranted [19].

EVALUATION

Diagnostic approach — The first step in the evaluation of an infant presenting with chronic tachypnea is to exclude more common causes of the symptoms, such as acute or chronic infection, asthma, immunodeficiency, cystic fibrosis, and congenital heart disease, through a thorough history, physical examination, and chest radiography. In infants with NEHI, chest radiographs may be normal or may reveal hyperinflation and perihilar opacities, which are findings that are also consistent with viral infection [1,16,17].

Laboratory testing typically includes screening for immunodeficiency and evaluation of acid-base status to exclude metabolic acidosis as a cause of tachypnea. Thyroid function testing should be considered, particularly in infants with low muscle tone or failure to thrive, because of the possible association of interstitial lung disease with hypothyroidism in individuals with pathogenic variants in the NKX2-1 gene. Variants in this gene are an established cause of brain-lung-thyroid syndrome, and a variant has also been associated with NEHI in one family, although none of the affected individuals had hypothyroidism at the time that they presented with pulmonary disease [10]. Other sporadic cases associated with NKX2-1 disruption have also rarely been observed, though not all have been published [12]. One child with disruption in the FOXP1 gene has also been reported to have NEHI and intellectual disability [20]. (See 'Pathogenesis' above and "Genetic disorders of surfactant dysfunction", section on 'NKX2-1 sequence variants'.)

Other causes of interstitial lung disease syndrome presenting in this age group may include pulmonary hypoplasia, pulmonary interstitial glycogenosis, genetic disorders of surfactant production and metabolism, and interstitial lung disease associated with immunodeficiency or autoinflammatory disorders. This diagnostic process is detailed separately. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Diagnostic approach'.)

The most revealing part of the evaluation for interstitial lung disease is chest CT (see 'Chest computed tomography' below). Most infants with NEHI have unique findings on CT that distinguish the disorder from other interstitial lung diseases of infancy (table 1). In infants with typical clinical features of NEHI, the CT can establish the diagnosis. Additional testing such as infant pulmonary function tests (PFTs) and lung biopsy may be performed to support the diagnosis in patients with atypical features, as outlined below, though clinical observation may also be considered depending on the severity and clinical course.

Chest computed tomography — On chest CT (performed with thin slices, or "high-resolution"), infants with NEHI have distinctive and specific findings that may be used to establish a confident diagnosis without lung biopsy in the appropriate clinical context. Findings include well-demarcated geographic ground-glass opacities centrally and in the right middle lobe and lingula (image 1). Air-trapping is often demonstrated when expiratory images are performed. Importantly, no bronchiectasis or other airway or parenchymal abnormalities are seen.

The utility of CT for the diagnosis of NEHI was evaluated in a series of 23 children with biopsy-proven NEHI and six children with other forms of interstitial lung disease [4]. When evaluated by two expert radiologists, the specificity of CT for the diagnosis of NEHI was 100 percent. The sensitivity of CT was incomplete, as the expert radiologists did not suggest NEHI in up to 22 percent of the cases. These results have subsequently been confirmed in a study in which the amount of ground-glass opacity also correlated with disease severity, as defined by continuous oxygen use [21]. Similar findings were reported in a study utilizing semiautomated image analysis of 21 NEHI cases and 10 age-matched controls [21]. In addition, it has been reported that children with NEHI have different airway and lung shape compared with controls, manifested as increased anteroposterior diameter [22].

Pulmonary function tests — Infant PFT in NEHI patients reveals a mixed physiologic pattern, including profound air trapping, as shown by [3,5,17,23]:

●Reductions in the forced expiratory volume in 0.5 seconds (FEV_0.5) and forced vital capacity (FVC). FEF₇₅ and FEF₈₅ (forced expiratory flow at 75 and 85 percent of FVC has been exhaled, respectively) are particularly reduced.

●Marked elevations in functional residual capacity (FRC), residual volume (RV), and RV/total lung capacity (TLC).

In a case-control study, FRC ≥150 percent predicted was highly specific for NEHI, when compared with infants with wheezing, prematurity, or no lung disease [23]. However, the specificity of infant PFT findings compared with other forms of childhood interstitial lung disease, including bronchiolitis obliterans, has not been evaluated. PFT abnormalities have not been systematically studied in older children with NEHI, although our experience suggests that this physiologic pattern can persist in at least some cases [10].

Bronchoscopy and bronchoalveolar lavage — Bronchoscopy has a well-established role in the evaluation of a variety of pulmonary symptoms and conditions [24]. However, bronchoscopy does not specifically diagnose NEHI, and cytologic analysis of fluid from bronchoalveolar lavage in NEHI patients is generally macrophage-predominant, without an excess of neutrophils or lymphocytes [25]. Because infection and aspiration may rarely be seen in infants with NEHI [1,3], bronchoscopy may have a role to evaluate for such potential comorbid or superimposed processes after the diagnosis of NEHI is established.

Lung biopsy — Lung biopsy (obtained via video-assisted thoracoscopic surgery [VATS]) is considered the gold standard for NEHI diagnosis, although it is increasingly accepted to make the diagnosis based on typical findings in chest CT rather than lung biopsy.

If lung biopsy is undertaken, more than one biopsy site is recommended. This is because of wide intra- and intersubject variability in neuroendocrine cell number, which cannot be predicted by the appearance of the region on CT [3,26]. The histopathologic evaluation should be performed by a pediatric pathologist experienced in this diagnosis and interpreted in context with the clinical and radiographic findings.

In contrast with the clinical severity of the disorder, lung biopsies in NEHI often show minimal to no pathologic alterations on initial evaluation by hematoxylin and eosin staining and, in some cases, are initially interpreted as normal. Architecture and lung development appear normal, with only mild, nonspecific changes including mild smooth muscle hyperplasia of the airways and mildly increased alveolar macrophages. Interstitial involvement is absent, and there is little or no inflammation.

The primary histopathologic abnormality in NEHI is increased neuroendocrine cells, which are identified based on immunopositivity to bombesin and serotonin. Staining with neuron-specific enolase, calcitonin, synaptophysin, or chromogranin is less reliable in demonstrating the increased neuroendocrine cells. The neuroendocrine cells appear in the distal respiratory bronchioles and as aggregates in the alveolar ducts, termed neuroendocrine bodies; this finding generated the descriptive name of NEHI [1,2]. Immunohistochemical assessment requires an adequate biopsy with at least 10 to 15 airways for evaluation. Morphometric quantification of bombesin staining may be required. Histologic criteria for NEHI diagnosis have been validated [27]. Two individual airways with more than a 10 percent bombesin-immunopositive area or cell number of the airway epithelium is also suggestive of the diagnosis [2,3]. Although airway architecture is generally normal, a minor degree of airway injury is consistent with the diagnosis. Patchy mild inflammation or fibrosis (bronchiolitis) may be present, especially following a viral infection, but is generally too mild to explain the significant respiratory symptoms [3].

The presence of increased numbers of neuroendocrine cells is not sufficient for the diagnosis, because neuroendocrine cell prominence is associated with a variety of other conditions, including bronchopulmonary dysplasia, airway injury, sudden infant death syndrome (SIDS), pulmonary hypertension, and cystic fibrosis. Nonetheless, neuroendocrine cells are more prominent in NEHI than in these other lung disorders [3]. To fully distinguish NEHI from these other conditions, the histopathologic findings must be correlated with clinical and radiologic information.

Genetic testing — No genetic tests are routinely helpful in making the diagnosis of NEHI. However, testing for mutations in NKX2-1 should be considered in infants with hypothyroidism or a familial pattern of interstitial lung disease. Mutations in NKX2-1 have been associated with a syndrome of neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome, known as brain-lung-thyroid syndrome [28]. In addition, a heterozygous mutation in NKX2-1 was associated with NEHI in a single family and a few other nonfamilial cases [10,12] (see "Genetic disorders of surfactant dysfunction", section on 'NKX2-1 sequence variants'). NEHI has also been reported in a child with intellectual disability in association with a variant in the FOXP1 gene [20,29].

DIAGNOSIS — The possibility of NEHI is suspected in an otherwise healthy infant presenting with tachypnea, retractions, and hypoxemia in the first few months to year of life. The symptoms are chronic or sometimes gradually progressive but may first come to medical attention during an intercurrent upper respiratory illness. The diagnosis is made by excluding other causes of the symptoms and the presence of typical findings on CT of the chest, sometimes supported by data from infant pulmonary function tests (PFTs) [5,23,24]. A lung biopsy is not required to make the diagnosis except in patients with atypical clinical or CT findings. (See 'Chest computed tomography' above and 'Lung biopsy' above.)

TREATMENT — There is no specific treatment for NEHI, and management largely consists of general supportive and preventive care. Supplemental oxygen has been required for the vast majority of cases [1,16,30]. Asthmatic symptoms are not part of the early disease process but occasionally occur and should be treated as for other children with asthma. Many children will require nutritional supplementation. Treatment of comorbidities such as gastroesophageal reflux is recommended. Immunizations should be rigorously maintained, including annual influenza vaccine starting at six months of age and pneumococcal vaccines using schedules for children at increased risk. Genetic counseling and family support are important components of care, as for all families who experience the diagnosis of a rare disease [24,31]. (See "Seasonal influenza in children: Prevention with vaccines".)

There have been no controlled trials of therapy in children with NEHI. Glucocorticoids are considered not to have been helpful in most cases [1,17,32]. Therefore, establishment of the diagnosis of NEHI, distinguishing it from other chronic lung diseases affecting infants and young children, helps avoid the complications of such medications.

PROGNOSIS — The natural history of NEHI and long-term outcomes have not been well established. Respiratory symptoms generally improve with time but may persist for years. The need for supplemental oxygen is variable, and some patients require oxygen for several years [1,2,5,17,19,32]. In one study, one-half of the subjects had discontinued daytime and nighttime supplemental oxygen by 32 and 87.5 months of age, respectively; failure to thrive was associated with a longer duration of supplemental oxygen use [19]. Most patients eventually become asymptomatic at rest, but some continue to have exercise intolerance or develop symptoms during respiratory infections. Case reports suggest that sudden exacerbations are associated with air trapping and may occur in the absence of an obvious respiratory infection [33]. In one series, six of nine infants developed a phenotype consistent with nonatopic asthma [17]. The CT abnormalities may improve but do also persist for years in at least some cases [10,16], but the time course of radiologic resolution in relationship to clinical parameters has not been systematically evaluated. No deaths or need for lung transplantation have been reported.

Because NEHI has only been recognized recently, there are no descriptions of the condition as these individuals reach adulthood. In light of this uncertainty, patients should have long-term follow-up, including strong counseling to support tobacco abstinence.

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Neuroendocrine cell hyperplasia of infancy (NEHI) is a rare, nonprogressive lung disease that presents in infants in the first months to year of life with chronic or slowly progressive tachypnea, hypoxemia, retractions, and crackles. (See 'Clinical presentation' above.)

●Pathogenesis – The etiology of NEHI is unknown, but genetic mechanisms are likely to play a role, as suggested by familial patterns seen in some cases. Growing understanding of pulmonary neuroendocrine cell biology and further discovery of genetic mechanisms provide promise for improved diagnostic and treatment approaches for this disease. (See 'Pathogenesis' above.)

●Diagnosis – In patients with typical clinical findings, the diagnosis can be established by chest CT. Radiologic findings include homogeneous ground-glass opacities on CT in the right middle lobe, lingula, and central portions of the lung (image 1). Other findings or architectural distortion or bronchiectasis are absent. (See 'Chest computed tomography' above.)

Lung biopsy is generally reserved for cases with atypical clinical or imaging features to distinguish NEHI from other forms of interstitial lung disease that present in infancy (table 1). (See 'Diagnosis' above.)

●Management – There is no specific treatment for NEHI. Management consists of supportive care, including supplemental oxygen and supplemental nutrition as needed, treatment for gastroesophageal reflux, rigorous attention to immunizations, and family support. (See 'Treatment' above.)

●Prognosis – Respiratory symptoms and hypoxemia generally improve over the course of years, with considerable variability among patients in functional impairment and clinical course. No deaths or need for lung transplantation have been reported. (See 'Prognosis' above.)