Neuroendocrine cell hyperplasia of infancy (NEHI) is a rare lung disorder that primarily affects young children, causing persistent breathing difficulties and low oxygen levels in the blood. Although this condition was first described less than two decades ago, it represents one of the more common forms of childhood interstitial lung disease and is often underdiagnosed.

Epidemiology

Neuroendocrine cell hyperplasia of infancy was first classified and formally described by medical professionals in 2005, making it a relatively recently recognized condition.^[1] Because of its recent discovery and the challenges involved in diagnosis, it is difficult to estimate the exact number of children affected by this disorder in the United States or globally. Many cases likely go unrecognized because doctors and specialists are still learning about this condition.

Despite its rarity, NEHI is considered one of the most common forms of childhood interstitial lung disease, which is a group of rare disorders affecting the lungs in children.^[1] The condition remains significantly underdiagnosed, partly because the symptoms can look like other more common childhood illnesses such as asthma or recurring respiratory infections.

NEHI predominantly occurs in infants during their first two years of life, with symptoms typically appearing when babies are around three months old on average.^[3] Most children diagnosed with NEHI are born at full term, meaning they completed a normal pregnancy period. Interestingly, only one case of NEHI in a premature infant has been documented in medical literature to date.^[3]

Causes

The underlying cause of NEHI remains poorly understood at this time, and much more research is needed to answer fundamental questions about why this condition develops.^[1] What scientists do know is that when lung tissue from NEHI patients is examined under a microscope using a special staining technique called bombesin staining, it reveals an unusually high number of pulmonary neuroendocrine cells in the airways.^[1]

Pulmonary neuroendocrine cells are specialized cells that normally exist in the lining of the airways, either alone or grouped together in clusters called neuroepithelial bodies. These cells are thought to play a role in lung development, though their exact function is not entirely clear.^[1] In children with NEHI, the number of these cells and the clusters they form is always significantly increased compared to healthy lungs. However, researchers have not yet determined why these cells multiply in such high numbers or what role this increase plays in causing the breathing difficulties that children experience.

There is some evidence suggesting that NEHI may have a genetic component, as the condition has been found to run in some families.^[1] This family connection suggests there may be an inherited basis for the disorder. However, despite ongoing research efforts, scientists have not yet identified a specific gene abnormality or mutation that causes NEHI. Environmental factors may also influence whether a child develops NEHI, but much more research must be done before doctors can understand these potential environmental triggers.

Risk Factors

Given that the exact cause of NEHI remains unclear, identifying specific risk factors for developing the condition is challenging. However, certain patterns have emerged from the documented cases. The most significant risk factor appears to be age, as NEHI almost exclusively affects infants within their first two years of life, particularly during the first year.^[2]

Family history may represent another risk factor, as NEHI has been observed to occur in multiple members of the same family in some instances.^[1] This familial clustering suggests that children born into families where NEHI has already occurred may have a higher risk of developing the condition themselves, although the exact inheritance pattern has not been established.

Being born at full term appears to be the norm for children with NEHI, though this does not mean that being full-term is itself a risk factor. Rather, it indicates that premature birth does not seem to be associated with the condition, as only one premature infant case has been documented.^[3] Beyond these observations, no other clear risk factors such as maternal health conditions, environmental exposures, or lifestyle factors have been definitively linked to NEHI development.

Symptoms

Children with NEHI typically experience a characteristic set of breathing-related symptoms that begin during infancy. The most common symptoms include rapid and difficult breathing, which medical professionals call tachypnea.^[1] Parents often notice that their baby breathes faster than normal and seems to work harder to breathe than other infants their age.

Low levels of oxygen in the blood, a condition known as hypoxemia, is another hallmark of NEHI.^[1] When doctors examine children with NEHI using a stethoscope, they typically hear crackling sounds, called crackles, in the lungs. Some children may also wheeze, although wheezing is not as characteristic of NEHI as the other symptoms. The wheezing can lead doctors to initially suspect asthma, which can delay the correct diagnosis.

Children with NEHI may present with what appears to be recurrent respiratory infections because the symptoms can overlap significantly with common childhood illnesses.^[2] This similarity to more familiar conditions often leads to initial misdiagnosis. However, a key distinguishing feature is that children with NEHI generally do not respond to typical asthma treatments or corticosteroids, which are anti-inflammatory medications commonly used for respiratory problems.^[1]

The labored breathing associated with NEHI uses more calories than normal breathing, which can lead to feeding difficulties and poor weight gain, a condition doctors call failure to thrive.^[1] Many children with NEHI also experience gastroesophageal reflux, where stomach contents flow back into the esophagus. The combination of increased calorie needs and potential feeding difficulties makes maintaining adequate nutrition a significant challenge for these infants. The chronic respiratory symptoms, including persistent shortness of breath and chest retractions (when the skin pulls in around the ribs during breathing), can significantly affect a child’s overall quality of life and development.^[2]

Prevention

Because the exact cause of NEHI is not yet understood, there are currently no known methods to prevent the condition from developing. Without understanding the genetic or environmental factors that trigger the excessive growth of pulmonary neuroendocrine cells, doctors cannot recommend specific preventive measures that would stop NEHI from occurring in the first place.

However, once a child has been diagnosed with NEHI, there are important steps that families can take to prevent complications and reduce the severity of symptoms. One of the most crucial preventive measures is limiting the child’s exposure to respiratory infections.^[1] Common colds and flu can be more severe in NEHI patients, potentially causing dangerous drops in oxygen levels or worsening breathing difficulties.

Seasonal flu vaccinations are important for children with NEHI and should be given according to the schedule recommended by their healthcare provider.^[1] Prevention of Respiratory Syncytial Virus, a common cause of respiratory infections in infants, is also particularly important for these children. Parents should practice good hand hygiene, keep their child away from people who are sick when possible, and avoid crowded places during cold and flu season to minimize infection risk.

Maintaining optimal nutrition is another critical preventive measure, though it relates more to preventing complications rather than preventing the disease itself. Ensuring that children with NEHI receive adequate calories and nutrients supports their overall health and helps them maintain the energy needed for the increased work of breathing.^[1] Some families may need to work with nutritionists or feeding specialists to develop strategies for meeting their child’s increased caloric needs. Proper nutrition can help prevent failure to thrive, which is a common complication of NEHI that can affect a child’s growth and development.

Pathophysiology

The pathophysiology of NEHI involves complex changes in the normal structure and function of the lungs, though many aspects remain incompletely understood. At the cellular level, the defining characteristic of NEHI is an abnormal proliferation of pulmonary neuroendocrine cells throughout the small airways of the lungs.^[1] These specialized cells, which are normally present in small numbers, multiply to significantly higher levels in children with NEHI.

In healthy lungs, pulmonary neuroendocrine cells exist as single cells or in small clusters called neuroepithelial bodies scattered along the airway lining. They are believed to play a role in lung development and may function as sensors that respond to chemical or mechanical stimuli in the airways.^[1] In NEHI, both the individual cells and the clusters become markedly increased in number. Despite this dramatic increase, the precise role these cells play in causing the breathing difficulties remains unclear. Scientists do not yet know whether the cells themselves directly cause problems or whether their presence is a marker of some other underlying process affecting the lungs.

When doctors examine lung tissue from NEHI patients under a microscope, they typically find little or no inflammation, which distinguishes this condition from many other lung diseases.^[1] This absence of significant inflammation is an important clue that NEHI works differently from conditions where the immune system attacks the lungs or where infection causes tissue damage.

High-resolution CT scans of the lungs reveal characteristic patterns that reflect the functional abnormalities in NEHI. The scans typically show areas described as ground glass opacities, which appear as hazy regions suggesting that air spaces are not functioning normally.^[1] Additionally, the lungs display a mosaic pattern where some areas appear overinflated while others appear underinflated. This uneven inflation suggests that air is not distributing evenly throughout the lungs, leading to inefficient gas exchange.

Pulmonary function tests in NEHI patients typically demonstrate air trapping, meaning that air gets trapped in the lungs and cannot be exhaled properly.^[1] This trapped air contributes to the overinflation seen in some lung regions and reduces the efficiency of breathing. The combination of uneven air distribution, air trapping, and abnormal gas exchange ultimately results in the low oxygen levels that characterize this condition. The increased work of breathing needed to compensate for these functional abnormalities explains why children with NEHI breathe rapidly and show signs of respiratory effort such as retractions.