Neuroendocrine Cell Hyperplasia of Infancy

NEHI, persistent shortness of breath in infancy, Neuroendocrine Hyperplasia of Infancy

Neuroendocrine cell hyperplasia of infancy is a rare lung disorder that mainly affects babies and young children, causing rapid breathing and low oxygen levels in the blood, though most children gradually improve as they grow.

Table of contents

• What is NEHI?
• Signs and Symptoms
• What Causes NEHI?
• How is NEHI Diagnosed?
• Treatment and Management
• Long-Term Outlook

What is NEHI?

Neuroendocrine cell hyperplasia of infancy, commonly known as NEHI, is a relatively rare disorder of the lungs that was first classified and described in 2005^[1]. Because it is a newly recognized condition, it is difficult to estimate exactly how many children have this disorder. However, NEHI is considered one of the most common forms of childhood interstitial lung disease (chILD), a group of rare disorders that affect the tissues in the lungs^[1][2].

The condition is named after the observation that children with NEHI have an increased number of pulmonary neuroendocrine cells (PNECs) in their lung tissue. These are cells normally present in the lining of the airways that are thought to be involved in lung development^[1]. Despite being one of the most common forms of chILD, NEHI is still underdiagnosed^[1].

NEHI predominantly occurs in infants within their first two years of life, with most cases appearing around three months of age. Most patients are born full-term, with only one premature infant case documented to date^[3].

Signs and Symptoms

Children with NEHI often have rapid and difficult breathing, low levels of oxygen in the blood (a condition called hypoxemia), and crackling sounds that are heard when a doctor listens to the chest with a stethoscope^[1]. The clinical signs include tachypnea (rapid breathing), persistent shortness of breath, retractions (when the skin pulls in around the ribs during breathing), and crackling sounds in the lungs^[3].

Wheezing may also occur, although it is not a typical feature of NEHI^[1]. Because these symptoms overlap with more common childhood conditions, children may be initially diagnosed with asthma or prolonged respiratory infections^[1]. However, an important clue that helps doctors suspect NEHI is that children with this condition generally do not respond to asthma treatments and corticosteroids (medications that reduce inflammation)^[1].

NEHI typically appears insidiously during the first year of life, subtly masquerading as one of the more common lung diseases of childhood^[2]. The condition typically manifests with chronic tachypnea, retractions, hypoxemia, and failure to thrive (poor weight gain)^[2].

What Causes NEHI?

The cause of NEHI is poorly understood at this point in time^[1]. The disorder represents an interstitial and diffuse lung disease with an unknown cause in pediatric populations^[3].

When a biopsy (removal of a small tissue sample for examination) is performed and examined with a special stain called bombesin staining, NEHI patients show an increased number of pulmonary neuroendocrine cells in their lung tissue. The high numbers of these cells lead to the NEHI diagnosis, but the role of these cells in causing NEHI remains unclear^[1].

In the airways of children with NEHI, these cells are usually present alone or in clusters called neuroepithelial bodies (NEBs). These cells and cell clusters are thought to be involved in lung development. In NEHI, the number of PNECs and NEBs in the airways is always significantly increased^[1].

NEHI has been found to run in some families, which suggests there is some genetic basis for this disorder. However, a gene abnormality has not been identified to date. Environmental causes may also influence the development of NEHI, but much more research must be done to answer these questions^[1].

How is NEHI Diagnosed?

The diagnosis of NEHI is challenging and requires a systematic approach^[2]. When any form of chILD is suspected, there are several tests that are commonly performed to help with the diagnosis^[1].

Laboratory work is often performed to rule out other causes of these symptoms, such as cystic fibrosis or immunodeficiency^[1]. A bronchoscopy with bronchoalveolar lavage (BAL) is often performed, which involves passing a tube into the lungs to collect fluid samples. This test can look for infection, inflammation, and signs of aspiration into the lungs^[1].

A high-resolution computed tomography (CT) scan of the lungs is often useful and is a major imaging approach for assisting in the diagnosis of NEHI. This scan shows a characteristic pattern called ground glass opacities, which are hazy areas on the scan. The lungs also show areas that are inflated to different extents, with some areas being overinflated and some underinflated, creating a mosaic pattern on the CT scan^[1][3].

An Infant Pulmonary Function Test (infant PFT) has become more important in diagnosing NEHI, though this test is not always used because it requires specialized equipment that is not always available to doctors. These tests usually show trapping of air in the lungs in NEHI patients with characteristic results^[1].

If all of these tests show characteristic findings of NEHI, the child may receive a diagnosis of NEHI Syndrome without needing a biopsy. However, if any of the results or symptoms are not typical, the only way to conclusively confirm the NEHI diagnosis is through a lung biopsy^[1].

The biopsy tissue typically has little or no inflammation. When stained with the particular bombesin stain, it demonstrates an abnormally increased number of pulmonary endocrine cells within the small airways^[1].

Treatment and Management

The treatment for NEHI is mainly supportive, meaning it focuses on managing symptoms and helping the child stay as healthy as possible^[1]. There is no consensus on specific therapy for NEHI, and management generally consists of supportive care^[6].

Children with NEHI often have labored breathing, which uses more calories than normal breathing and can be accompanied by gastroesophageal reflux (GERD), a condition where stomach contents flow back into the food pipe. As a result, poor weight gain (failure to thrive) is often seen with NEHI. Optimizing the child’s nutritional status to promote adequate growth is important for overall health^[1].

Oxygen supplementation may also be required. The amount of oxygen needed varies widely among NEHI patients. Some need oxygen 24 hours a day, while others will only wear it at night and during illness, and some do not require it at all^[1].

Common colds and flu can be more severe in NEHI patients, so limiting exposure to respiratory infections is important. Seasonal flu shots and prevention of Respiratory Syncytial Virus are recommended^[1].

Proper immunization, avoidance of environmental pollutants, and treatment of recurrent infections are also part of managing the condition^[6].

Long-Term Outlook

Most NEHI patients decrease their need for oxygen over time, and most eventually grow out of the need for supplementation^[1]. This is because neuroendocrine cells do not multiply or get larger in size while the lungs continue to grow. This allows the lung disease to have less effect on lung function with age, although children will always have the same amount of neuroendocrine cells as they were born with^[6].

The condition is described as non-progressive, meaning it does not typically worsen over time^[6]. Prior to the findings of the hyperplasia of neuroendocrine cells, the condition was known as tachypnea of infancy, as most children outgrow the need for oxygen supplementation within two to seven years^[6].

An accurate diagnosis is the key to guiding appropriate clinical management^[3]. The clinical manifestations of NEHI frequently resemble other interstitial pulmonary disorders, which can result in underdiagnosis, misdiagnosis, and delays in treatment if healthcare providers are not familiar with the condition^[3].