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Neuroendocrine Cell Hyperplasia of Infancy: Clinical Score and Comorbidities

Deborah R. Liptzin, MD,1 Kaci Pickett, MS,2 John T. Brinton, PhD,2 Amit Agarwal, MD,3 Martha P.
Fishman, MD,4 Alicia Casey,4 MD, Christopher T. Towe, MD,5 Jane B. Taylor, MD,6 Geoffrey
Kurland, MD,6 James S. Hagood, MD,7 Jennifer Wambach, MD,8 Ruma Srivastava, MD,9 Hani Al-
Saleh, MD,10 Sharon D. Dell, MD,11 Lisa R. Young, MD,12 and Robin R. Deterding, MD1

1Section of Pulmonology, Department of Pediatrics, University of Colorado School of Medicine

and Children’s Hospital Colorado, Aurora, CO; 2Department of Biostatistics and Informatics,
Colorado School of Public Health, University of Colorado, Aurora, CO; 3Department of
Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little
Rock, AR; 4 Division of Pulmonary Medicine, Department of Pediatrics, Boston Children’s
Hospital, Harvard Medical School, Boston, MA; 5Pulmonary Medicine, Cincinnati Children’s
Hospital and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati,
OH; 6Division of Pulmonology, Department of Pediatrics, University of Pittsburgh School of
Medicine, Pittsburgh, PA; 7Division of Pulmonology, Department of Pediatrics, University of
North Carolina at Chapel Hill, Chapel Hill, NC; 8Edward Mallinckrodt Department of Pediatrics,
Washington University School of Medicine, St. Louis, MO; 9Department of Pediatrics, Pulmonary
Medicine, Wayne State University and Children’s Hospital of Michigan, Detroit, MI; 10Farwaniya
Hospital, Sabah Al Nasser, Kuwait; 11Respiratory Medicine, Department of Pediatrics, The
Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; 12Division of
Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman
School of Medicine at the University of Pennsylvania, Philadelphia, PA

Corresponding Author:
Deborah R. Liptzin, M.D.
Address: Section of Pediatric Pulmonology, University of Colorado School of Medicine,
13123 East 16th Ave Box B-395, Aurora, CO 80045.
Email: [email protected]
Phone: 720 777-6181.
Fax: 720 777-7284

Author Contributions: DRL conceived and designed the study, collected, analyzed and
interpreted the data, wrote and revised the manuscript. RRD designed the study, interpreted
the data, revised the manuscript, and approved for submission. KP and JTB assisted in
designing the study, analyzed and interpreted the data, wrote and revised the manuscript, and
approved for submission. AA, MPF, AC, CTT, JBT, GK, JASH, JAW, RS, HA, SDD, and LRY
contributed to implementation of the study, collection and analysis of data, critically reviewed
and revised the manuscript, and approved for submission.

Sources of Support: This study was supported by grant UL1 TR001082 from the NIH/NCRR
Colorado CTSI, U01HL13475 (JAW), and NIH/NHLBI K24HL143281 (LRY).

Running Head: NEHI Clinical Score

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Descriptor Number: 14.6

Word Count: 1984

Key Words: infant, neuroendocrine cells, interstitial lung disease

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Abstract

Rationale: Neuroendocrine Cell Hyperplasia of Infancy (NEHI) is an important form of children’s

interstitial and diffuse lung disease (chILD) in which the diagnostic strategy has evolved. The

prevalence of comorbidities in NEHI that may influence treatment has not been previously

assessed.

Objectives: To evaluate a previously unpublished NEHI Clinical Score for assistance in diagnosis

of neuroendocrine cell hyperplasia of infancy (NEHI) and to assess comorbidities in NEHI.

Methods: We performed a retrospective chart review of 199 deidentified patients with NEHI

from eleven centers. Data were collected in a centralized REDCap registry, and we performed

descriptive statistics.

Results: The majority of patients with NEHI were male (66%) (Figure 1). The sensitivity of the

NEHI Clinical Score was 87% (95% CI 0.82, 0.91) for all patients from included centers; 93% (95%

CI 0.86, 0.97) for those with complete scores (e.g. no missing data). Findings were similar when

we limited the population to the 75 patients diagnosed by lung biopsy (87% with 95% CI 0.77,

0.93). Of those patients evaluated for comorbidities, 51% had gastroesophageal reflux, 35%

had aspiration or were at risk for aspiration, and 17% had evidence of immune system

abnormalities.

Conclusions: The NEHI Clinical Score is a sensitive tool for clinically evaluating NEHI; however,

its specificity has not yet been addressed. Clinicians should consider evaluating patients with

NEHI for comorbidities including gastroesophageal reflux, aspiration and immune system

abnormalities as these can contribute to the child’s clinical picture and may influence clinical

course and treatment.

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Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of children’s interstitial and diffuse

lung disease (chILD). It was initially named Persistent Tachypnea of Infancy (1) and

subsequently NEHI once biopsy findings of increased numbers of neuroendocrine cells in the

airways were described (2). NEHI is a distinct entity with characteristic clinical features, infant

pulmonary function testing, and high resolution (inspiratory and expiratory) chest computed

tomography (HRCT) findings. The pathophysiology of NEHI is poorly understood. Patients with

NEHI exhibit tachypnea, retractions, crackles, and hypoxemia. Clubbing is absent, as are cough

or wheeze at well baseline (2). Non-pulmonary manifestations of NEHI include failure to thrive

and developmental delays (3). Infant pulmonary function tests reveal tachypnea, air trapping,

and variable degrees of airflow obstruction (4). Characteristic HRCT findings include air

trapping and ground glass opacities predominantly in the right middle lobe, lingula, and/or

perihilar regions (5). NEHI can be diagnosed clinically by HRCT scan in the appropriate clinical

context.(6) Pathologic findings of NEHI are notable for an increased percentage of airway

neuroendocrine cells(2). Currently, lung biopsies are typically performed in children with

atypical presentations and/or at centers less familiar with chILD. Anecdotally, some patients

with NEHI have been found to have a variety of comorbidities, including immunologic

abnormalities and aspiration/gastroesophageal reflux, but this has not been formally evaluated

or reported.

Leland Fan, M.D., initially proposed a clinical score for NEHI that includes 10 prototypical

clinical features. We utilized the largest prospective multicenter cohort of clinician defined

NEHI cases to date to test the hypothesis that the NEHI Clinical Score is a sensitive test for NEHI.

We also evaluated the frequency of comorbidities in this large cohort of patients with NEHI.

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Methods

Patients were enrolled through eleven North American centers within the chILD Research

Network: Arkansas Children’s Hospital/University of Arkansas Medical School, Boston Children’s

Hospital/Harvard Medical School, Children’s Hospital Colorado/University of Colorado School of

Medicine, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center,

Children’s Mercy Kansas City/University of Missouri-Kansas City, Cincinnati Children’s Hospital

Medical Center, St. Louis Children’s Hospital/Washington University School of Medicine, Rady

Children’s Hospital/University of California San Diego, Children’s Hospital of Michigan/Wayne

State University, Vanderbilt University Medical Center, and Hospital for Sick Children. Centers

entered as few as two patients to as many as 114 patients (Figure 1). The institutional review

board of each participating institution approved this study and informed consent was waived.

The NEHI clinical score consists of the following ten items: symptom onset before 12

months of age, failure to thrive, absence of clubbing, absence of cough when well, absence of

wheeze when well, abnormal chest wall (barrel chest or pectus excavatum), crackles,

hypoxemia, tachypnea, and retractions. Each of the ten items are assigned a value of zero

(no/not present) or one (yes/present), and the score is the sum of these values, with a

maximum score of ten (e.g. patient with symptom onset at 5 months of age, failure to thrive,

no clubbing, no cough when well, no wheeze when well, barrel chest, crackles, hypoxemia,

tachypnea, and retractions). A score of 7 or higher is considered consistent with NEHI based on

our clinical experience.

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Data were entered retrospectively by the site clinician into a standardized data

collection form in REDCap (Research Electronic Data Capture), a secure, web-based application

designed to support data capture for research studies (7). Identification of patients was unique

to each center: there was no unifying electronic health record search for patients. Diagnosis of

NEHI was determined by the entering clinician who noted if the patient was diagnosed by lung

biopsy or by HRCT and consistent clinical course. Data collection included information on chILD

center location, sex, race, ethnicity, mode of diagnosis (lung biopsy or by HRCT and consistent

clinical course), age at symptom onset, clinical findings, and comorbidities. Failure to thrive

was defined as body mass index or weight for length less than the 25th percentile or if “failure

to thrive” was documented in the medical record. Hypoxemia, tachypnea, chest wall

abnormalities, and retractions were determined at the discretion of the clinician entering data.

Database fields for comorbidities included reflux testing: abnormal/normal/not done, swallow

study: frank aspiration/abnormal without frank aspiration/normal/not done, and immune

testing: abnormal/normal/not done.

Data elements that were not entered were considered missing data. Descriptive

statistics were calculated and summarized. Not all data were available for each data element.

The available number (N=) is presented in the tables with the variable. Sensitivity was

calculated for a cutoff NEHI Clinical Score of 7 or greater compared to clinician diagnosis of

NEHI based on lung biopsy and/or diagnosed clinically. Proportions were presented with 95%

Wilson confidence intervals.

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Results

Demographic data are presented in Table 1. The patients were predominantly male (66%),

Caucasian (69%), non-Hispanic (68%), and born at full term (88%). The rate of preterm births

(<37 weeks) was 11% (95% CI 7.55,16.73). Median age at symptom onset was 4 months (IQR 2-

6 months). A majority (62%) of patients were diagnosed by clinical and radiographic features

rather than by lung biopsy (38%).

Figure 2 demonstrates the NEHI Clinical Score for the population of 199 patients. The

sensitivity of the NEHI Clinical Score was 87% (95% CI 0.82, 0.91) for all patients from included

centers. When only patients with complete data (the clinician entered yes or no for all 10

components) were included, 93% of 91 patients (95% CI 0.86, 0.97) had a NEHI Clinical Score of

7 or greater. The breakdown for each component of the NEHI Clinical Score is presented in

Figure 3; the most common missing data were chest wall abnormalities (81 patients) and failure

to thrive (54 patients). When only the 75 patients who were diagnosed by biopsy were

included, 65 had NEHI Clinical Scores suggestive of a diagnosis of NEHI (i.e. 7 or greater)

resulting in a sensitivity of 87% (95% CI .77, .93). When only those diagnosed by biopsy with no

missing data are evaluated (24 patients), all had a NEHI Clinical Score suggestive of NEHI (i.e. 7

or greater), resulting in a sensitivity of 100%.

Table 2 demonstrates the comorbidities assessed. Of the 98 who were tested for

gastroesophageal reflux, half had abnormal results. Of the 103 who were evaluated for

aspiration, one-third had abnormal results. Sixty two percent (117/189) of patients underwent

some type of immunologic evaluation and 17% of those (20/117) had abnormalities. Immune

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system abnormalities included seven patients with low IgG, one with elevated IgG, two with

elevated IgM, and one each with elevated IgA, elevated IgE, low IgA, low C3, and cyclic

neutropenia of infancy. Seven patients had unspecified abnormalities of the immune system.

Several patients had more than one abnormality noted. Those who had low IgG levels were

evaluated from 4 months of age to 27 months of age. Several patients were tested on more

than one occasion and were included as having immune system abnormalities if they were

abnormally low ever. IgG ranges were adjusted by age.

Discussion

Establishing the diagnosis of NEHI can be challenging if the HRCT findings are atypical. With a

sensitivity of 87% (all 199 patients, all patients with biopsies) to 93% (patients with complete

data) to 100% (patients with biopsies and complete data), the NEHI Clinical Score may be a

helpful tool in recognition of NEHI. Some centers have been using this score informally. When

evaluated serially, the score decreases with age as symptoms like failure to thrive, crackles,

hypoxemia, tachypnea, and retractions improve over time in children with NEHI. Parts of the

score such as symptom onset before 12 months of age will persist over time. Including patients

who were diagnosed clinically raises the question of whether these patients truly had NEHI.

The literature suggests that biopsy is unnecessary to diagnose NEHI.(6) Additionally, we

evaluated the subset of patients who were diagnosed by biopsy, and the NEHI clinical score was

similarly sensitive. This study was limited by its retrospective design, missing data elements,

and lack of a control group. Prospective studies such as those being performed through the

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chILD Research Network will permit further analysis of the NEHI Clinical Score as a clinical

prediction score in combination with HRCT for diagnosis and to assess disease trajectory (8, 9).

In this cohort, we found a male predominance, which has been previously reported (2,

4, 6, 10, 11), but not consistently in all NEHI cohorts (3, 12, 13) and not consistently in all

included centers (Figure 1). The etiology of this sex difference in NEHI is poorly understood.

There is a known male predominance in respiratory diseases among infants and young children

in general, though this also is not well understood (14). Most NEHI patients were born full term,

and the rate of preterm births was not significantly different than the national preterm birth

rate of 9.62% (15).

Clinicians should consider evaluating patients with NEHI for comorbidities including

sleep disordered breathing (16), gastroesophageal reflux, aspiration, and

hypogammaglobulinemia. Except for sleep disordered breathing (16), these comorbidities have

not previously been described and may significantly influence treatment in an individual

patient. It is unknown whether some of these comorbidities contribute to the clinical picture of

NEHI and/or are exacerbated by NEHI.

The etiology of gastroesophageal reflux in patients with NEHI may be explained by

hyperinflation leading to increased elastic recoil of the lung which in turn leads to more

negative intrapleural pressure. More negative intrapleural pressure leads to a pressure

gradient from the stomach to the intrathoracic esophagus, leading to more reflux.

Gastroesophageal reflux has been described in other forms of obstructive lung disease such as

cystic fibrosis and chronic obstructive pulmonary disease (17-19). Aspiration may be more

common among NEHI patients because of the tachypnea and increased work of breathing

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making coordination of swallowing more difficult. Aspiration in the setting of tachypnea and

increased work of breathing has been described in infants with bronchiolitis (20).

Immunologic evaluation is not universally performed in patients with NEHI. The

mechanism leading to hypogammaglobulinemia in the eight patients with NEHI in this cohort is

unknown. It is possible that patients have transient hypogammaglobulinemia of infancy (21).

We suggest evaluating for hypogammaglobulinemia among NEHI patients since this may lead to

specific therapy, e.g. prophylactic antibiotic therapy and/or intravenous immunoglobulin, given

the higher morbidity of respiratory infections in patients with underlying lung disease. Some

patients were noted to have other immunologic abnormalities, such as elevated IgA, elevated

IgE, elevated IgG, low IgA, low C3, and elevated IgM. Assessing for immunologic abnormalities

in future prospective studies would be helpful to better define the spectrum of immunologic

abnormalities in NEHI.

The pathophysiology of NEHI is not well understood, but the constellation of symptoms

and laboratory findings reinforce that NEHI is a clinical entity with a unique combination of

physiologic changes, HRCT findings, symptoms, and lung biopsy findings (2, 4-6). Chest wall

shape was not consistently evaluated in all centers and would be useful to assess in future

prospective studies. NEHI patients have significant elevated residual volumes and air trapping

(4) and HRCT scans have demonstrated that patients with NEHI have altered chest wall shape

with increased anterior-posterior diameter (22). Having physicians closely evaluate chest shape

during the physical exam is a useful assessment that may turn out to reflect underlying

physiology and anatomy. Future radiologic evaluations may allow for more objective

evaluation of chest wall shape.

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We propose the NEHI clinical score as a sensitive tool for clinicians to identify patients

for whom further evaluation for NEHI should be considered (e.g. HRCT scan, infant pulmonary

function tests). In future studies, we hope to compare the NEHI score in this cohort to disease

control groups such as asthma, cystic fibrosis, or in other forms of chILD in the chILDRN

prospective database. We highlight several comorbidities that should be evaluated for and

addressed in patients with NEHI since appropriate treatments may modify disease course.

Prospective studies in infants with suspected NEHI could evaluate the predictive characteristics

of the NEHI Clinical Score, and a longitudinal study could evaluate the NEHI Clinical Score’s

variation over time.

Acknowledgements

We would like to thank Leland Fan, MD for inspiring the current project as well as the research

coordinators who entered data and/or managed the database, including Pamela Morel, Emily

Trefethen, Elizabeth Carpino, and Heidi Luckey Zahller.

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References

1. Deterding RR, Fan LL, Morton R, Hay TC, Langston C. Persistent tachypnea of infancy (PTI)--a
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neuroendocrine cell hyperplasia. Pediatr Pulmonol 2005; 40: 157-165.
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14. Liptzin DR, Landau LI, Taussig LM. Sex and the lung: Observations, hypotheses, and future
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Table 1. Demographics of subjects diagnosed with Neuroendocrine Cell Hyperplasia of Infancy

(NEHI) (N = 199)

N (%) or
Median [Inner Quartile, Outer Quartile]
Sex (N=195)
Male 129 (66)
Female 66 (34)
Gestational age at birth (N=185)
Full term (>37 weeks) 164 (89)
>32-36 weeks 17 (9)
28-32 weeks 4 (2)
<28 weeks NA
Race (N=173)
White 120 (69)
African American 4 (2)
American Indian NA (NA)
Hawaiian NA (NA)
Pacific Islander NA (NA)
Asian 2 (1)
Other 21 (12)
Ethnicity (N=164)
Hispanic 20 (12)
Non-Hispanic 112 (68)
Refused or Unknown 32 (20)
Age of symptom onset (in months) 4 [2, 6]
Mode of diagnosis (N=198)
Lung biopsy 75 (38)
No biopsy 123 (62)

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Table 2. Evaluation of comorbidities in 199 patients with Neuroendocrine Cell Hyperplasia of

Infancy (NEHI)

N (%)
Gastroesophageal reflux testing (N=185)
Abnormal 50 (27)
Normal 48 (26)
Not Done 87 (47)
Swallow study (N=189)
Frank Aspiration 8 (4)
Abnormal without Frank Aspiration 28 (15)
Normal 67 (35)
Not Done 86 (46)

Immune system evaluation (N=189)

Abnormal 20 (11)
Normal 97 (51)
Not Done 72 (38)
Specific immune abnormalities (N = 12)
Low Immunoglobulin G 7 (58)
Other 5 (42)

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Figure Legends

Figure 1. Distribution of patients by center and by sex.

Figure 2. Distribution of the NEHI clinical score in 199 patients. The shaded area indicates those

with scores above 7 and consistent with NEHI.

Figure 3. Each component of the NEHI Clinical Score in 199 patients with NEHI. Each

component of the score is yes (blue), no (red), or missing (gray). Components are presented as

percentages of all included patients.

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Figure 1. Distribution of patients by center and by sex.

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Figure 2. Distribution of the NEHI clinical score in 199 patients. The shaded area indicates those with scores
above 7 and consistent with NEHI.

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Figure 3. Each component of the NEHI Clinical Score in 199 patients with NEHI. Each component of the
score is yes (blue), no (red), or missing (gray). Components are presented as percentages of all included
patients.

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