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* From Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH.
Correspondence to: Patricia Joseph, MD, FCCP, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0564; e-mail: patricia.joseph{at}uc.edu
Abstract
Background: Childhood interstitial lung disease (ILD) is a spectrum of diseases including many different rare lung conditions. We present a family with an unusual presentation of ILD in association with rheumatologic and immunologic abnormalities.
Methods: Eight children with a common father were evaluated for evidence of lung disease in association with rheumatologic findings. All underwent routine history and physical examination, hematologic evaluation, and chest radiography and/or CT scan of the chest. Seven children underwent a more extensive immunologic evaluation. Those who were able underwent pulmonary function testing, and four children underwent lung biopsy.
Results: Six of eight children with a common father were found to have radiographic findings consistent with ILD. These children also had evidence of autoimmune disease with joint symptoms, alopecia, rheumatoid factor production, and hypergammaglobulinemia. Open-lung biopsy in four children revealed a spectrum of pulmonary lymphoid proliferations ranging from reactive lymphoid hyperplasia to lymphoid interstitial pneumonia.
Conclusion: The findings of ILD and autoimmunity in a kindred of children suggest a novel genetic disorder of autosomal dominant pattern and variable penetrance. Although the precise pathogenesis remains unclear, these cases provide valuable insight into childhood ILD.
Key Words: autoimmune diseases • interstitial lung disease • pediatrics • pulmonary fibrosis
Childhood interstitial lung disease (ILD) is a broad category that includes many rare lung conditions. Rather than a discrete entity, perhaps it should be considered a clinical syndrome "characterized by tachypnea, crackles, hypoxemia and/or diffuse infiltrates."1 With an estimated prevalence of 3.6 cases per million, ILD in children is extremely rare, and disease pathogenesis and natural history are poorly understood.2
The international consensus statement defining pathologic, radiologic, and clinical manifestations of idiopathic interstitial pneumonias in adults is largely not applicable to children.34 While the majority of cases of ILD are idiopathic, ILD can occur in association with other systemic disorders. ILD associated with rheumatologic diseases and environmental exposures, such as hypersensitivity pneumonitis, can overlap between adults and children. More than 50% of adults with systemic lupus erythematosus, approximately 50% with rheumatoid arthritis, 70% with scleroderma, and 5 to 40% with polymyositis-dermatomyositis have pulmonary involvement at diagnosis.56 Most of the information about the prevalence of ILD in association with rheumatologic diseases in children is derived from case reports.789
Certain forms of ILD are heritable, including those that occur in conjunction with known Mendelian disorders (ie, Hermansky-Pudlak syndrome, tuberous sclerosis, Niemann-Pick disease).10 Recently, specific mutations in genes for surfactant protein B (SFTPB) and surfactant protein C (SFTPC) and adenosine triphosphate-binding cassette A-3 (ABCA3) gene have been described. These defects cause a disease spectrum from early neonatal death (SFTPB) to a highly variable presentation in adults and children (SFTPC).111213 "Hereditary" idiopathic pulmonary fibrosis has been identified in family cohorts, in whom a genetic basis has yet to be identified.1415 We present a kindred of children with lung disease associated with rheumatologic and immunologic abnormalities. Because of the heritable pattern, this family provides opportunity for insights into mechanisms of ILD pathogenesis.
Materials and Methods
Identification of Patients
The proband, a 10-year-old, African-American girl (patient C), presented to rheumatology clinic with alopecia, joint pain, and eczema. Symptoms of dyspnea with minimal exertion, chest tightness, and intermittent cough prompted a chest CT scan and then pulmonary consultation. Case histories are outlined in the Appendix with patients labeled A through H. Two family members (patients D and G) were subsequently evaluated for similar symptoms. The remaining siblings were later evaluated, although symptoms were mild or absent. All studies were performed as part of clinical care so institutional board approval was not obtained.
Pulmonary Function Testing
Patients, if able, performed spirometry and plethysmography. Results were expressed as a percentage of predicted normal values derived from American Thoracic Society recommendations.1617
Bronchoscopy
Four patients (patients A, C, D, and G) underwent flexible bronchoscopy with BAL under general anesthesia. Samples were submitted for microbiology and cytologic evaluation.
Chest CT Scan
High-resolution imaging was performed during inspiration and expiration. Older patients (patients A, B, C, D, and E) underwent imaging during voluntary breath holding, and younger patients (patient F, G, and H) with a controlled ventilation technique.18
Laboratory Studies
Studies were performed in the clinical laboratory at Cincinnati Children’s Hospital Medical Center. The lymphocyte subpopulation analysis used an automated flow analysis methodology.
Lung Biopsy
Lung biopsy was performed in four patients using a minimally invasive thoracoscopic technique under general anesthesia without need for single-lung ventilation, as previously described.1920 Tissue specimens were processed according to a consensus protocol for handling lung biopsy tissue.21
Results
The patients studied share a complex family grouping (Fig 1 ). Details of the case histories are outlined in the Appendix and summarized in Table 1 . Patient C is the proband. All three mothers are asymptomatic. The father has declined evaluation but has overlapping symptoms including alopecia, eczema, and possible exercise limitation. His eight children have varying clinical presentations. Five children (patients A, B, E, F, and H) were evaluated for lung disease due to the findings in their siblings. Evaluation of patient H was limited due to his young age and lack of symptoms. Four children (patients A, C, D, and G) were symptomatic at their initial evaluation. Six children had decreased weight for height ratio (patients A, B, C, D, E, and G). Two were hospitalized as infants for failure to thrive (patients C and G) and had tachypnea, hypoxemia, and crackles on initial pulmonary evaluation. None had significant environmental exposures or travel.
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Lymphocyte subpopulation analysis revealed expanded B-cell percentages in all except patient F, who was unaffected (Table 3). In addition, all affected children except patients A and G had low CD8 percentages as well. By 2 years of age, however, the latter child (patient G) had acquired a low CD8 percentage also (10%, not shown). Patients A, C, D, and G had normal T-cell proliferation to mitogens. Patients A and G underwent natural killer (NK) cell function testing that was normal.
The four oldest children (patients A, B, C, and D) underwent pulmonary function tests (PFTs). Patients C and D had obstructive ventilatory defects, while patients A and B had no obstruction or restriction. All four children had a significant diffusion defect (Table 4 ). CT scan abnormalities varied. Five had diffuse ground-glass opacities (patients B, C, D, E, and G), four had cystic changes (patients B, C, D, and G), and two had tree-in-bud changes (patients B and C). Patient A had multiple noncalcified nodules without ground-glass opacities, tree-in-bud changes or cystic changes (Fig 2 ). Two children (patients F and H) had normal chest CT scans. Results of SFTPB, SFTPC, and ABCA3 mutational analyses were negative in patients C and G.
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We have identified a family with a common father and symptoms of alopecia, eczema, and joint pain in association with ILD. The severity of lung disease was variable and independent of age. The affected children have CT scan evidence of ILD and diffusion defect on PFTs (if able). Surfactant studies and lung histology do not suggest SFTPB, SFTPC, or ABCA3 genes mutations as an etiology in this family. Immunologic evaluation revealed evidence of B-cell dysregulation characterized by expanded numbers of B-cells, hypergammaglobulinemia, and significant auto-antibody production.
It is important to note that the proband presented with rheumatologic and pulmonary symptoms, but many siblings had evidence of ILD in the absence of overt pulmonary symptoms. This illustrates the need for careful evaluation for pulmonary disorders in children with rheumatologic diseases. In such patients, pulmonary symptoms may be masked by overlapping rheumatologic symptoms such as exercise limitations secondary to joint inflammation.
Standard radiographic and pulmonary function studies may not yield classic findings of ILD. In our cohort, no restrictive lung defect was noted, but two children (patients C and D) had an obstructive ventilatory defect, and two children (patients A and B) had normal spirometry. All four children had a diffusion defect (adjusted diffusion capacity of the lung for carbon monoxide < 80%). Adults at presentation with rheumatoid arthritis showed 37% with an obstructive defect, 8.6% with a restrictive defect, and 6.5% with a mixed defect.22 Copley et al23 reported that ILD was identified on CT scan 66% of the time vs only 45% on chest radiography (p < 0.025). Therefore, it may be more appropriate to consider a chest CT scan early in children with suspected ILD. With the exception of genetic mutations of surfactant metabolism, lung biopsy remains the "gold standard" for laboratory confirmation of ILD in children.24 VATS is the preferred approach because it provides decreased morbidity with adequate tissue samples.192025
In our patients, lung biopsies revealed a spectrum of reactive lymphoid hyperplasia in the lung with overlapping histologic patterns, including follicular bronchiolitis and lymphocytic interstitial pneumonia (LIP).26 Chest CT scans that show areas of ground-glass attenuation, poorly defined centrilobular nodules, and subpleural small nodules support these diagnoses.27 Patterns of follicular bronchiolitis and LIP are suggestive of several etiologies including, but not limited to viruses (ie, EBV, HIV, and HHV-6), autoimmune diseases, and congenital immunodeficiency.28 In our cohort, the children who underwent lung biopsy were HIV negative, and findings for EBV in the lung were negative in biopsies in three patients. All but one child had serologic evidence of remote EBV without evidence of a symptomatic illness. One child (patient A) had a positive EBV and HHV-6 PCR in his lung biopsy, and another (patient D) had parainfluenza type 1. Because these biopsies were performed at a time when the patients were at their clinical baseline without evidence of acute infection, the significance of these findings is unknown.
LIP has been described in a variety of autoimmune disorders, primarily in adults.29 Although clinical findings such as elevated RF levels and variable ANA suggest an autoimmune etiology in this family, the clinical symptoms of these patients are not consistent with Sjogren syndrome, Hashimoto disease, myasthenia gravis, or systemic lupus erythematosus, and specific autoantibodies for these diseases are negative. Two children have joint symptoms of arthralgia and one has arthritis, but the remainder have no evidence for juvenile rheumatoid arthritis.
There is also no evidence for primary immune deficiency such as common variable immune deficiency, which can be associated with LIP, since B-cell, T-cell, and NK-cell function is intact and there is no history of recurrent infections other than "pneumonia" in the affected children. In our kindred, B-cell percentages were expanded in all affected children except patient F, who appears unaffected. This suggests a correlation between B-cell expansion and lung disease. In the youngest child, B-cell expansion preceded the appearance of elevated IgG and RF. Expanded B-cell numbers preceding hypergammaglobulinemia suggests that B-cell activation is a precursor for abnormal plasma cell activity. The mechanism for chronic B-cell expansion/activation is unclear, but possibilities include the following: (1) ongoing stimulation from activated T-cells and/or persistent antigenic stimulus, as may occur in genetic disorders of NK or T-cell deficiency, chronic viral infections such as HIV, or autoimmune disorders; (2) autonomous B-cell activation and differentiation in the absence of typical T-cell or antigen stimulation; or (3) failure of appropriate B-cell death following removal of antigenic stimulus, such as occurs in disorders of apoptosis as described below.
In one case series of individuals with LIP, 80% of cases were found to have polyclonal hypergammaglobulinemia.30 Hypergammaglobulinemia is noted in many immune system disorders including viral infections such as HIV and autoimmune diseases such as Sjogren syndrome, juvenile rheumatoid arthritis, and autoimmune hepatitis, all of which are associated with abnormal B-cell activation and/or differentiation.31323334 It is also reported in cases of lymphoproliferative diseases such as autoimmune lymphoproliferative syndrome, a defect of lymphocyte apoptosis caused by gene defects in the Fas gene.35 Other atypical cellular proliferative disorders such as Rosai Dorfman and Castleman disease present with hypergammaglobulinemia.36 Histologic features similar to LIP are described in multicentric Castleman disease, with or without association to viral infections such as HIV.3738 Importantly, the clinical, histologic, and laboratory features of these children do not meet criteria for any of these specific disorders of cellular proliferation.
In review of the literature, we identified three similar reports of families with pediatric ILD. Childhood onset of pulmonary fibrosis associated with LIP is reported in two siblings but without associated evidence of collagen vascular disease.39 One sibling had progressive fibrosis and death within 4 years of diagnosis; the second has survived > 10 years with minimal symptoms. In a second family, six children with one father presented with pulmonary fibrosis.7 The father and several children of this cohort also had arthritis and autoantibodies. In a third kindred, multiple family members presented with autoimmune features, arthritis, and pulmonary fibrosis.8 The proband was a school-age child with arthritis, hypergammaglobulinemia, and evidence of B-cell activation similar to the features described here.
In our cohort, the pattern of inheritance appears autosomal dominant, with variable severity of disease between the children, suggesting incomplete penetrance. Specifically, the lung disease in patient G is far more severe than his elder siblings based on CT evidence, hypoxemia, and exercise limitation. Potential explanations include the following: (1) disease progression halts at some time point; (2) different family members have milder disease at onset; (3) differences reflect variable genetic penetrance; (4) modifier genes may influence disease severity; or (5) confounding factors, (eg, malnutrition, aspiration, infection, or environmental exposures) may influence disease severity. Further efforts are underway to identify the genetic defect. The progression of disease is undetermined. The periodic evaluation of the children by immune, radiographic, and pulmonary function measures will provide a unique opportunity to follow disease progression.
In summary, we present a family with apparent autosomal dominant pattern of ILD associated with rheumatologic symptoms of alopecia, joint symptoms, and eczema, and evidence of B-cell activation. This family highlights the importance of careful evaluation for subclinical pulmonary disease in children with rheumatologic disorders. Further investigation into the genetic etiology underlying the lung disease in this family may yield insights into the pathogenesis of pediatric ILD and disorders of lymphocyte proliferation.
Appendix
None of the parents have been formally evaluated. All three mothers deny respiratory or rheumatologic symptoms. The father, who has declined formal medical evaluation, only admits alopecia and eczema. He denies overt rheumatologic or respiratory symptoms, but family members suggest that he has limited exercise tolerance with dyspnea on exertion. All of his known children have been evaluated and are presented here (Fig 1). Case studies are presented by age, with patient C being the proband. None of the patients report significant environmental exposures or travel.
Patient A
Patient A, a 15.5-year-old, African-American boy with no significant medical history came to medical attention due to his half-siblings’ illness. He reported alopecia totalis, eczema, conjunctivitis, and dyspnea with minimal exertion but denied joint pain. On examination, he was not tachypneic (20 breaths/min) or hypoxic (oxygen saturation 98% on room air). Weight was 44.7 kg (10th percentile), and height was 162.1 cm (25th percentile). Physical examination revealed bald patches on his head and an eczematous rash on his elbows. His conjunctiva were erythematous and inflamed with a blue rim around the iris. His lungs were clear to auscultation bilaterally without crackles, wheezes, or rhonchi.
PFTs revealed normal spirometry and lung volumes with a mild diffusion defect (Table 4). Chest CT scan showing multiple noncalcified nodules in every lobe of the lung without interstitial changes (Fig 2) was unchanged 6 months later. ESR, IgG, and IgE were elevated, but RF was within normal limits (Table 2). Lymphocyte subpopulation analysis revealed an expanded B-cell line (Table 3). Flexible bronchoscopy revealed normal anatomy and negative bacterial, viral, and fungal culture results. The patient underwent VATS lung biopsy. Pathology examination revealed chronic bronchiolitis with follicular hyperplasia (Fig 3). PCR findings on the lung biopsy for EBV and HHV-6 were positive.
Patient B
Patient B, a 10-year-old, African-American girl with no significant previous medical history came to medical attention due to her half-siblings’ illness. Her history was significant for alopecia, eczema, and conjunctivitis. She had dyspnea with maximal exertion but was not tachypneic (24 breaths/min) or hypoxic (oxygen saturation 98% on room air). Weight was 32.9 kg (50th percentile), and height was 147.4 cm (97th percentile). Her conjunctiva were erythematous bilaterally. Her lungs were clear to auscultation bilaterally without crackles, wheezes, or rhonchi.
PFTs revealed normal spirometry and lung volumes with borderline diffusion abnormality initially (Table 4) and were not changed at 6 months. Her chest CT scan showed ground-glass opacities, blebs, and tree-in-bud opacities (Fig 2) and remained unchanged at 6 months. ESR, IgG, IgA, and RF were elevated (Table 2). Her lymphocyte subpopulation analysis revealed an expanded B-cell line (Table 3).
Patient C
The proband, a 10-year-old, African-American girl with a medical history significant for "asthma" and failure to thrive as an infant presented to rheumatology clinic at 8 years of age with joint pain, hair loss, and eczema. She was thought clinically to have juvenile rheumatoid arthritis. However, her dramatically elevated RF (Table 2) and chest CT scan findings (Fig 2) were not consistent with typical juvenile rheumatoid arthritis. Chest CT scan showed ground-glass opacities with subpleural cystic changes (Fig 2; the first study used helical techniques with 5-mm contiguous images and inspiratory high-resolution images).
She was referred for pulmonary evaluation, where she reported dyspnea on exertion, chest tightness, and intermittent cough. She was tachypneic (44 breaths/min) and mildly hypoxic (oxygen saturation 94% on room air). Her weight of 22.6 kg (10th percentile) was low in comparison to her height (130 cm, 50th percentile). Pertinent findings on physical examination included low lung volumes to percussion, bibasilar crackles, 3+ clubbing, hair loss, and an eczematous rash. A PFT revealed a nonspecific ventilatory defect with a moderate diffusion defect (Table 4). Chest CT scan showed diffuse subpleural cystic lesions and tree-in-bud changes (Fig 2). Initial laboratory evaluation (electrolytes, liver function tests, CBC with differential) was normal. Her ESR and C-reactive protein were elevated, as were Igs (Table 2). Her B-cell line was hyperexpanded (Table 3). Flexible bronchoscopy revealed normal bronchial anatomy and negative culture findings (bacterial, viral, and fungal). There were 40% lipid-laden macrophages present in BAL fluid, but there was no significant gastroesophageal reflux by pH probe. Echocardiogram was normal. Tissue from VATS lung biopsy was consistent with LIP (Fig 3). Treatment with oral steroids improved the extrapulmonary symptoms (ie, joint pain) and the PFT results improved mildly (Table 4), but the chest CT scan showed progression of disease.
Patient D
Patient D, 9-year-old, African-American boy with no significant medical history came to medical attention for symptoms similar to his older sibling: alopecia, eczema, joint pain, and dyspnea with activity. He was not tachypneic (22 breaths/min) or hypoxic (oxygen saturation 96% on room air). He was reportedly always small and thin, but weight was 24.1 kg (50th percentile) and height was 129.5 cm (75th percentile). Physical findings included complete loss of hair including eyebrows, an eczematous rash, and mild clubbing. A lung examination was normal.
PFTs revealed a mild obstructive defect (Table 4). Chest CT scan showed cystic changes with ground-glass opacities (Fig 2). Laboratory evaluation revealed a microcytic anemia, elevated RF, and elevated IgG and IgA (Table 2). Lymphocyte subpopulation analysis revealed an expanded B-cell line with suppressed T-suppressor cells (Table 3).
One year after initial evaluation, a dry cough and dyspnea with activity developed. His weight had only increased by 1 lb. He had new crackles on physical examination. PFTs showed a mild obstructive defect with a mild diffusion abnormality (Table 4). Repeat chest CT scan showed no radiographic evidence of disease progression. Flexible bronchoscopy revealed normal anatomy and negative bacterial, viral, and fungal culture results. VATS lung biopsy demonstrated a chronic bronchiolitis with follicular hyperplasia (Fig 3). Results by PCR on the lung tissue were positive for parainfluenza 1.
Patient E
Patient E, a 6-year-old, African-American girl with no significant medical history came to medical attention due to her siblings’ illness. She had alopecia and eczema without joint pain. She was not tachypneic (28 breaths/min) or hypoxic (oxygen saturation 100% on room air). Weight was 18.3 kg (50th percentile), and height was 115.8 cm (75th percentile). Pertinent physical findings included patchy hair loss on her temples and an eczematous rash. Lung examination was normal.
She was unable to perform PFTs. Chest CT scan showed diffuse ground-glass opacities without cystic changes (Fig 2). Laboratory evaluation revealed a microcytic anemia, elevated ESR, and elevated IgA. RF was within normal limits (Table 2). Lymphocyte subpopulation analysis revealed an expanded B-cell line with a suppressed T-suppressor cell line (Table 3). She remains asymptomatic and unable to perform PFTs.
Patient F
Patient F, a 4-year-old, African American girl with no significant medical history came to medical attention due to her siblings’ illness. She denied alopecia, eczema, joint pain, dyspnea, cough, or wheeze. She was not tachypneic (20 breaths/min) or hypoxic (oxygen saturation 100% on room air). Weight was 14.6 kg (50th percentile), and height was 96.3 cm (75th percentile). Physical examination was normal. She was unable to perform PFTs. Her chest CT scan was normal. Laboratory evaluation revealed an elevated ESR. Her RF and lymphocyte subpopulation analysis were within normal limits (Tables 2, 3).
Patient G
Patient G is a 16-month-old, African-American boy with a history of failure to thrive and recurrent pneumonia. He was hospitalized three times for "bronchiolitis/pneumonia" in the first 6 months of life. He had mild alopecia and eczema without joint symptoms. His persistent symptoms and his siblings’ illness prompted pulmonary evaluation. He was tachypneic (56 breaths/min) and hypoxic (oxygen saturation 93% on room air). Weight was 6.58 kg (< 3rd percentile), and height was 67.5 cm (50th percentile). Physical examination demonstrated mild clubbing, an eczematous rash, and hair loss on his scalp. He had subcostal and substernal retractions. His lungs were coarse to auscultation with poor aeration at the bases.
Infant PFTs showed a ventilatory defect based on forced flows from tidal breathing (maximal flow at functional residual capacity, 50%; tidal volume, 77%). Forced flows were not obtained due to tachypnea. Chest radiography showed minimal changes, but CT scan showed ground-glass opacities with cystic changes more prominent in the lower lobes (Fig 2; the first study used helical techniques during quiet respirations in both decubitus positions, 1.25-mm sections at 15-mm intervals). Laboratory evaluation revealed elevated ESR, IgG, IgM, and RF (Table 2). Lymphocyte subpopulation analysis revealed an expanded B-cell line (Table 3). Flexible bronchoscopy was unremarkable, and culture findings were negative. A pH probe showed no significant reflux. Due to the severity of disease and lack of diagnosis, the patient underwent VATS lung biopsy. The pathologic diagnosis revealed severe follicular bronchiolitis with extension into the interstitium in a LIP-like pattern. Approximately 1 year after presentation, the patient had inadequate weight gain and remained tachypneic and hypoxic. He underwent a 6-week trial of azithromycin without improvement. Subsequent chest CT scan showed worsening disease.
Patient H
Patient H is a 3-month-old, African American boy who was born during the evaluation of his siblings. He did not have alopecia, eczema, or joint pain. He had appropriate weight gain. Physical examination was unremarkable. The mother reports no symptoms in him similar to her affected children. His chest CT scan showed no evidence of ILD. Because of his young age and normal clinical examination, extensive laboratory evaluation has not yet been performed.
Footnotes
Abbreviations: ABCA3 = adenosine triphosphate-binding cassette A-3; ANA = anti-nuclear antibody; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; HHV = human herpes virus; ILD = interstitial lung disease; LIP = lymphocytic interstitial pneumonia; NK = natural killer; PCR = polymerase chain reaction; PFT = pulmonary function test; RF = rheumatoid factor; SFTPB = surfactant protein B; SFTPC = surfactant protein C; VATS = video-assisted thorascopic surgery
This work was performed at Cincinnati Children’s Hospital Medical Center.
The authors have no actual or potential conflict of interests to disclose.
Received for publication October 11, 2006. Accepted for publication March 26, 2007.
References
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