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Type B Niemann-Pick Disease: Findings at Chest Radiography, Thin-Section CT, and Pulmonary Function Testing¹

¹ From the Dept of Radiology (D.S.M., R.G., W.S.), Depts of Human Genetics and Pediatrics (M.P.W., R.J.D., M.M.M.), and Div of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine (G.S.), Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Laboratoire Fondation Gillet-Merieux, Centre Hospitalier Lyon-Sud, Lyon, France (M.V.), Clinica Pediatrica, Istituto per l'Infanzia Burlo Garofolo, Trieste, Italy (B.B.); Medical Genetics Service, Hospital de Clinical de Porto Alegre, Porto Alegre, Brazil (R.G.); Pediatric Clinic, Univ of Mainz, Mainz, Germany (E.M.); and Dept of Clinical Research, Genzyme, Cambridge, Mass (G.F.C.). Received Oct 3, 2004; revision requested Dec 7; revision received Jan 24, 2005; accepted Feb 24; final version accepted Apr 1. Supported by Genzyme Corporation. The U.S. patients were examined at the Mount Sinai General Clinical Research Center, which is supported by grant 5 MO1 RR00071 from the National Center for Research Resources. M.P.W. is the recipient of Mentored Patient-Oriented Research Career Development Award K23 RR16052-01 from the NIH. Address correspondence to D.S.M. (e-mail: david.mendelson{at}mountsinai.org).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Purpose: To evaluate findings at radiography, computed tomography (CT), and pulmonary function testing in patients with type B Niemann-Pick disease.

Materials and Methods: The study was approved by the institutional review board or ethics committee at each study site and was compliant with HIPAA at the U.S. site. Written informed consent was obtained from each patient or guardian and minor assent was obtained from all children before any study-related procedures. Pulmonary involvement in 53 patients (27 male and 26 female patients; age range, 7–65 years; mean age, 23.3 years) with type B Niemann-Pick disease was evaluated with imaging and pulmonary function tests. All patients underwent chest radiography and thin-section CT, and images were independently interpreted by one of two radiologists. Spirometry (forced vital capacity [FVC] and forced expiratory volume in 1 second [FEV₁]) was performed and diffusing capacity of lung for carbon monoxide (DLCO) was evaluated in all patients who could comply. A score for the degree of interstitial lung disease was derived at both radiography and CT, and the CT scores were then compared with results of pulmonary function testing and patient age by means of linear regression. CT scores were compared between the upper and lower lung zones by using the Wilcoxon signed rank test.

Results: Chest radiography and CT, respectively, revealed interstitial lung disease in 47 (90%) and 51 (98%) of the 52 patients who completed both imaging examinations. There was a basilar predominance of interstitial lung disease at CT. Six patients had pulmonary nodules, one of which was calcified at chest radiography. There were no statistically significant correlations between interstitial lung disease score at CT and age or percentage predicted FVC, FEV₁, or DLCO values.

Conclusion: Although pulmonary function test indexes may be abnormal, imaging findings do not necessarily correlate with pulmonary function in patients with type B Niemann-Pick disease.

© RSNA, 2005

	INTRODUCTION

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Types A and B Niemann-Pick disease are lysosomal storage disorders that result from deficient acid sphingomyelinase (ASM) activity and lead to the accumulation of sphingomyelin, primarily in tissues of the reticuloendothelial system (1,2). Type A disease is a severe neurodegenerative disorder that results in death early in childhood. Conversely, type B Niemann-Pick disease is a heterogeneous disorder, and most patients survive to adulthood with little or no neurologic disease. In childhood, the main disease manifestations are hepatosplenomegaly, excess bleeding and bruising, growth retardation, and recurrent respiratory infections. In some patients, progressive pulmonary disease can lead to oxygen dependence and/or reduced exercise tolerance. A specific diagnosis of type B Niemann-Pick disease can be made with the demonstration of reduced ASM activity in isolated leukocytes and/or cultured skin fibroblasts and the identification of two disease-causing ASM mutations (1).

To our knowledge, the pulmonary radiologic findings in type B Niemann-Pick disease have been described only in single case reports or small series of patients (3–8). Thus, the purpose of our study was to evaluate the findings at radiography, computed tomography (CT), and pulmonary function testing in patients with type B Niemann-Pick disease.

	MATERIALS AND METHODS

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This study was sponsored by Genzyme (Cambridge, Mass) and conducted according to good clinical practice guidelines (9). Those authors who are not employees of or consultants for Genzyme had control of inclusion of any data and information that might present a conflict of interest for those authors who are employees of or consultants for Genzyme.

Study Population
Fifty-three patients with type B Niemann-Pick disease (27 male and 26 female patients; age range, 7–65 years; mean age, 23.3 years) underwent both imaging and pulmonary function testing as part of a prospective survey study at one of four sites (United States, Brazil, Italy, and France). The patients were consecutively enrolled in the study between May 2001 and June 2002. Twenty-five patients were in the pediatric age group (younger than 18 years of age; age range, 7.3–17.6 years; mean age, 12.6 years; 16 boys and nine girls) and 28 were adults (at least 18 years of age; age range, 18.0–64.6; mean age, 32.9 years; 11 men and 17 women). The diagnosis of type B Niemann-Pick disease was confirmed in each patient with the demonstration of reduced ASM activity in isolated leukocytes and/or cultured skin fibroblasts and the identification of two disease-causing ASM mutations (1).

The study was approved by the institutional review board or ethics committee at each site. The Health Insurance Portability and Accountability Act, or HIPAA, was passed subsequent to the collection of the clinical data; however, data obtained at the U.S. site after HIPAA was passed have been treated in a HIPAA-compliant fashion. Voluntary written informed consent was obtained from each patient or guardian and minor assent was obtained from all children before any study-related procedures were performed.

Imaging Studies and Interpretation
All patients underwent posteroanterior and lateral chest radiography. Radiographs were obtained by using the standard technique employed at each institution. No technique was specified. The radiographs were scored by assessing each lung separately for any stigmata of interstitial disease, including reticular, nodular, and prominent bronchovascular changes. An integer scale score of 0–3 was used to quantify the overall degree of interstitial lung disease present in each lung zone as follows: A score of 0 indicated no interstitial lung disease; a score of 1, mild interstitial lung disease (affecting 0%–25% of the lung volume); a score of 2, moderate interstitial lung disease (affecting 26%–50% of the lung volume); and a score of 3, severe interstitial lung disease (affecting 51%–100% of the lung volume). An overall score for each patient was obtained by averaging the scores for both lungs. Lung volumes were also assessed as normal, diminished, or increased. The presence of pulmonary nodules and whether they appeared to be calcified was recorded.

CT scans were obtained with one of three scanners (9800 CT/I or Pro-Speed S, GE Medical Systems, Milwaukee, Wis; or Somatom Plus 4, Siemens, Erlangen, Germany) in 52 of the 53 patients. The CT examination could not be completed in one patient. Technical factors were adjusted at each study site according to local practice. For thin-section CT, 1-mm-thick images reconstructed with a high-spatial-frequency algorithm were obtained at four different levels that corresponded to the aortic arch (upper lung zone, level 1), carina (midlung zone, level 2), midway between the carina and the higher hemidiaphragm (lower lung zone, level 3), and 1 cm above the higher hemidiaphragm (lower lung zone, level 4). The lower lung zone was divided into two levels to reflect the fact that some diseases manifest with progressively more severe changes as they approach the diaphragm.

Each image received three independent scores that categorized (a) the overall presence of interstitial lung disease, (b) the presence of thickened interlobular septa and intralobular lines, and (c) the presence of regions of ground-glass opacity on both the right and the left sides (scored by using an integer scale of 0–3 as follows: a score of 0 indicated no disease; a score of 1, 0%–25% lung involvement; a score of 2, 26%–50% lung involvement; and a score of 3, more than 50% lung involvement). The four levels in each lung were individually scored, for a total of eight values for each patient. The values for levels 3 and 4 were averaged to arrive at a score for the lower lung zone. Mild lung disease was diagnosed if the overall average score was less than or equal to 1, moderate disease was diagnosed if the overall average score was more than 1 and less than or equal to 2, and severe disease was diagnosed if the overall average score was more than 2 (Figs 1–4). Given that these CT examinations were limited to four select levels, we did not attempt to assess lymphadenopathy, pleural disease, lobar distribution, or other changes that would have necessitated imaging of the entire thorax. If a focal change that could be classified into one of these categories was observed, it was recorded as miscellaneous information. Hence, such changes were not scored.

View larger version (154K): [in this window] [in a new window] [Download PPT slide]   Figure 1: Representative unenhanced transverse CT scan of midlung zones in 16-year-old boy shows severe interstitial changes. Note the presence of ground-glass opacities and the intermixed thickened interlobular septa and intralobular lines in some areas; these findings are suggestive of the "crazy paving" sign. Results of pulmonary function testing were normal, which demonstrates that the radiographic findings do not always correspond to the clinical state.

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 2: Unenhanced transverse CT scan of lower lung zones in 12-year-old boy shows severe thickening of the interlobular septa and intralobular interstitium.

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Unenhanced transverse CT scan in 48-year-old man shows moderate changes in the midlung zone. Note that some areas of ground-glass opacity (arrows) are intermixed with areas of predominantly interlobular septal thickening.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 4: Unenhanced transverse CT scan in 28-year-old woman. Mild ground-glass opacity (arrows) is seen relatively anteriorly in the upper lung zones. In general, the changes in the upper lung zones were milder in degree than those in the middle and lower lung zones.

Pulmonary Function Tests
Spirometry to assess forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) was performed and diffusing capacity of lung for carbon monoxide (DLCO) was evaluated in accordance with American Thoracic Society standards (10–12) in all patients who were able to comply. For spirometry, we used the predicted values obtained by Polgar and Promadhat (13) for patients younger than 8 years. The predicted values obtained by Hankinson et al (14) were used for all other patients. Any patients with a race or ethnicity other than white, African-American, or Mexican-American (ie, Cherokee Indian, white and Asian, Jewish, and Hispanic) were classified as white. A restrictive ventilatory defect was suggested when the FVC was less than 80% of the predicted value and the FEV₁/FVC ratio was more than 0.70. Airway obstruction was defined as a situation in which the FEV₁/FVC ratio was less than or equal to 0.70 and the FEV₁ was less than 80% of the predicted value (15). For DLCO, the predicted values used by Polgar and Promadhat (13) and Van Ganse et al (16) were used for children and adults, respectively. DLCO was adjusted for hemoglobin level and was considered abnormal if it was less than 70% of the predicted value.

Statistical Analysis
Statistical analysis was performed by using software (SAS, version 8.0; SAS Institute, Cary, NC), and data were summarized by using descriptive statistics. To determine whether there was a relationship between radiologic evidence of lung disease and functional impairment in patients with type B Niemann-Pick disease, the interstitial lung disease score determined with CT, pulmonary function test results (ie, percentage of predicted FVC, FEV₁, and DLCO), and patient age were evaluated with correlation analysis by using the Spearman rank correlation coefficient. The Wilcoxon signed rank test was used to compare the CT scores between the upper and lower lung zones. P values of less than .05 were considered to indicate statistically significant differences.

	RESULTS

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Imaging Abnormalities
Among the 52 patients who completed both imaging examinations, interstitial lung disease was detected with radiography in 47 (90%) and with CT in 51 (98%). The mean interstitial lung disease scores for radiography and CT were 2.04 ± 1.06 (standard deviation) and 1.79 ± 0.90, respectively. The spectrum of CT changes is illustrated in Figures 1–4. Figure 5 summarizes the CT interstitial lung disease score versus age for all patients. Thirty-eight patients (73%) had moderate (n = 17) or severe (n = 21) interstitial lung disease. Notably, chest imaging abnormalities were detected in all evaluated age groups, and there was no significant linear trend in the CT interstitial lung disease score with age (r = –0.055, P = .696). Further analysis of the CT scans for the presence of thickened interlobular septa and intralobular lines and ground-glass opacity yielded similar mean scores: 1.49 ± 0.96 for thickened interlobular septa and intralobular lines and 1.47 ± 0.80 for ground-glass opacity. The linear and ground-glass opacities intermittently overlapped in a manner that could be characterized as crazy paving (17). This, however, was not usually the dominant pattern, and many patients had separate intermixed areas of both types of changes.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 5: Graph shows relationship between interstitial lung disease (ILD) score at thin-section CT (HRCT) and age. The correlation between interstitial lung disease score and age was not significant (r = –0.055, P = .696).

Chest radiography also revealed the presence of focal pulmonary nodules in six patients, with one nodule appearing to be calcified. Twenty patients had radiographic evidence of diminished lung volume, although it is not clear whether this was caused by pulmonary disease, abdominal organomegaly, or both.

Pulmonary Function Tests
Fifty of the 53 patients (94%) were able to successfully complete spirometry, and 43 (81%) were able to complete the assessment of DLCO. All but one of the patients who had incomplete or absent pulmonary function test data were in the pediatric age group and were unable to comply with the testing regimen. The mean percentage of predicted values for FVC, FEV₁, and DLCO were 82.4%, 79.8%, and 60.4%, respectively, and the mean FEV₁/FVC ratio was 0.84. Of the 43 patients in whom DLCO was evaluated, 30 (70%) had an abnormal DLCO (<70% of predicted value).

Correlation of Imaging Findings and Pulmonary Function
There was not a strong correlation between CT interstitial lung disease score and percentage of predicted FVC (r = –0.349, P = .013) or FEV₁ (r = –0.367, P = .009). Similarly, although there was a trend for the percentage of predicted DLCO to decrease as the CT interstitial lung disease score increased (Fig 6), the correlation between the two measures was not strong (r = –0.385, P = .011). For example, four patients (Fig 1) had severe CT interstitial lung disease (score, >2.0) and normal gas transfer (DLCO, 70% of predicted value) and three patients had a moderate (DLCO, <60% of predicted value) to severe (DLCO, <50% of predicted value) gas transfer defect and mild interstitial lung disease (score, 1.0).

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 6: Graph shows relationship between interstitial lung disease (ILD) score at thin-section CT (HRCT) and percentage of predicted DLCO. Although there was a trend toward a diminishment in the percentage of predicted DLCO as the interstitial lung disease score increased, the correlation between these two measures was not strong (r = –0.385, P = .011). Several patients had disparate results.

	DISCUSSION

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Our findings are consistent with those in previous case reports of patients with type B Niemann-Pick disease who were noted to have chest radiographic features that were out of proportion to the degree of pulmonary impairment (3). Review of the literature, however, is limited by the fact that some previous reports have included patients with type C Niemann-Pick disease (6), which does not result from ASM deficiency, and patients in whom the diagnosis was not confirmed either enzymatically or with demonstration of the presence of mutations in the ASM gene (6)—patients who may have been affected by another of the lipid storage disorders. Conversely, in our series, results of genotyping studies confirmed the presence of two deleterious mutations in the ASM gene, which helped firmly establish the diagnosis of type B Niemann-Pick disease.

The morphologic changes at CT included thickened interlobular septa, intralobular lines, and ground-glass opacities. Although these regions were often separate from one another, they were occasionally intermixed. The intermixed regions could be characterized as showing crazy paving, and, although this was not the predominant pattern, type B Niemann-Pick disease should be added to the list of entities that can demonstrate crazy paving.

The lack of correlation between functional pulmonary impairment and the findings at radiography and thin-section CT may be due to the pathologic basis of the lung abnormalities in type B Niemann-Pick disease. Pathologic pulmonary findings have been reported for a small number of patients (7,18); such reports have revealed that foam cells are consistently present in either the alveoli and/or the interstitium, whereas fibrosis is generally not present or is mild. Therefore, it is possible that the interstitial disease detected at radiography and CT is due to the infiltration of these histiocytes, which manifests in a pattern that is typically associated with fibrosis. Conversely, a significant correlation between thin-section CT findings and pulmonary function measurements—including spirometric findings and DLCO—has been demonstrated in patients with idiopathic pulmonary fibrosis (19). Furthermore, most of the patients in the present study had some degree of hepatosplenomegaly, and the degree to which this contributes to abnormal pulmonary function test values in some patients is not well defined. Thus, a full understanding of the pulmonary function test abnormalities is confounded by the presence of multiple anatomic abnormalities; we are analyzing the pulmonary function test abnormalities separately from the radiologic findings.

We have also noted that pulmonary nodules can be seen in type B Niemann-Pick disease. Notably, these were not detected with thin-section CT when a limited number of CT sections were obtained, and many were obscured on radiographs by the superimposed interstitial disease. The presence of calcified pulmonary nodules and calcifications in other organs has previously been described in one case series (8). The pulmonary nodules may represent another manifestation of this storage disorder.

Limitations of this study included the lack of pathologic confirmation and correlation with regard to the pulmonary findings. Our patients did not undergo any lung biopsy procedure with regard to their pulmonary disease. Another limitation is that one radiologist (either D.S.M. or R.G.) performed the radiologic interpretations, and, thus, none of the observations were designed for assessment of interobserver and intraobserver variations in interpretation. In addition, although we believe that the quality of the limited CT examinations was acceptable, they were performed with several different CT scanners by using varying techniques. The section thickness, however, was consistently maintained at 1 mm. Furthermore, although the four selected levels for CT provided information with regard to the distribution of interstitial changes in the different lung zones, it is possible that other changes, including lymphadenopathy, pleural disease, and focal lung disease, were not detected.

In summary, interstitial lung disease and resting pulmonary function abnormalities are common features of type B Niemann-Pick disease. Our finding that imaging features do not necessarily correlate with the degree of pulmonary function impairment may be a reflection of the nature of interstitial lung disease, which is not typically characterized by fibrosis. Therefore, findings at radiography and thin-section CT must be interpreted in concert with functional data and the clinical status of the patient. Radiologic features alone should not form the basis for performing more invasive diagnostic tests such as biopsy because little additional information of clinical usefulness is likely to be obtained, particularly in patients with no pulmonary symptoms. Finally, longitudinal studies to determine whether imaging in individual patients is predictive of the rate of clinical pulmonary disease progression are needed to assess the usefulness of imaging studies in the clinical management of pulmonary disease in patients with type B Niemann-Pick disease.

	ACKNOWLEDGMENTS

 
We thank Noriko Kuriyama, MA, for her assistance in preparing the statistical analysis.

	FOOTNOTES

 

Abbreviations: ASM = acid sphingomyelinase • DLCO = diffusing capacity of lung for carbon monoxide • FEV₁ = forced expiratory volume in 1 second • FVC = forced vital capacity

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, D.S.M., G.F.C., M.M.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, D.S.M., R.J.D., R.G., G.S., E.M., G.F.C.; clinical studies, all authors; statistical analysis, D.S.M., G.F.C.; and manuscript editing, D.S.M., M.P.W., R.J.D., R.G., W.S., G.S., R.G., G.F.C.

	References

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 

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This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2381041696v1 238/1/339    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mendelson, D. S. Articles by McGovern, M. M. Search for Related Content PubMed PubMed Citation Articles by Mendelson, D. S. Articles by McGovern, M. M.