Research ArticleClinical Studies
Open Access

The Long-term Lung and Respiratory Outcomes of Acid Sphingomyelinase Deficiency: A 10- and 20-year Follow-up Study

YU-NAN HUANG, SHANG-LUN CHIANG, JING-YANG HUANG, WEN-LI LU, DA-TIAN BAU, PEN-HUA SU and CHUNG-HSING WANG
In Vivo January 2024, 38 (1) 437-444; DOI: https://doi.org/10.21873/invivo.13457

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Abstract

Background/Aim: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder characterized by sphingomyelin accumulation causing progressive lung disease, respiratory failure, and death. Patients and Methods: This retrospective observational study used the TriNetX database of electronic health records for 15,108 patients with ASMD from 2000-2020. After exclusions, 8,980 individuals were followed for 10 or 20 years. Outcomes included incidence and prevalence of respiratory disorders. Associations of age, sex and race were assessed. Results: Nearly all respiratory outcomes increased significantly over 20 versus 10 years. Other respiratory disorders, specified respiratory disorders and secondary pulmonary hypertension exhibited the greatest increases, reflecting progressive lung damage in ASMD. While outcomes were poor overall, older age, male sex, and racial minority status associated with greater risks, indicating differences in disease progression or care. Conclusion: This study confirms the progressive nature of ASMD and need for close monitoring and treatment of pulmonary complications to reduce long-term morbidity and mortality. Genetic testing enabling diagnosis even for milder, adult-onset forms is critical to optimize outcomes.

Key Words:

Acid sphingomyelinase deficiency (ASMD), also known as Niemann-Pick disease types A and B, is a rare, genetic lysosomal storage disorder characterized by an accumulation of sphingomyelin due to deficient activity of the acid sphingomyelinase enzyme (1, 2). ASMD often manifests with systemic symptoms, including hepatosplenomegaly, progressive neurodegeneration, and notably, pulmonary complications (3, 4).

ASMD is caused by mutations in the SMPD1 gene which encodes acid sphingomyelinase, a lysosomal enzyme that breaks down sphingomyelin into ceramide and phosphocholine (2, 5, 6). In ASMD, lack of functional acid sphingomyelinase leads to sphingomyelin accumulation in cells throughout the body, including macrophages, hepatocytes, and lung epithelial and endothelial cells (2, 7-9).

In the lungs, excess sphingomyelin accumulation in alveolar macrophages impairs their normal function, causing a buildup of surfactant lipids and proteins in the alveoli known as pulmonary alveolar proteinosis (3, 10). The alveoli become filled with lipoproteinaceous material, impairing gas exchange and causing respiratory symptoms that can ultimately lead to respiratory failure if untreated due to impaired diffusion capacity and ventilation-perfusion mismatch (10-13).

Sphingomyelin accumulation in lung parenchymal and endothelial cells can also lead to non-specific interstitial pneumonia. This damages the alveolar epithelium and pulmonary capillaries, causing fibrosis and pulmonary hypertension over time. Some patients may develop chronic obstructive pulmonary disease (COPD)-like syndrome with emphysema and obstructive lung defects. Recurrent respiratory infections are common due to impaired mucociliary clearance and macrophage dysfunction.

The progressive lung damage and loss of function in ASMD is often irreversible, necessitating lung transplantation in some patients with end-stage respiratory disease. However, not all patients with ASMD experience severe or rapid progression of lung disease. Disease course can be variable, depending on the level of residual acid sphingomyelinase activity and other genetic/environmental modifiers. Regular monitoring of respiratory status and pulmonary function is important to help guide treatment interventions for these patients.

Previous studies have evaluated the spectrum of respiratory manifestations in ASMD, including alveolar proteinosis, interstitial lung disease, chronic obstructive pulmonary disease, respiratory infections, and respiratory failure. However, few studies have comprehensively analyzed longitudinal changes in the incidence of pulmonary complications over time. We aimed to address this gap by evaluating data on lung outcomes in ASMD from a large global cohort over a 20-year period. A multi-institutional collaboration was established to compile a database of 8,976 patients with confirmed ASMD diagnosis from January 1, 2000 to December 31, 2020.

Patients were stratified into two 10-year study periods: Period 1 from January 1, 2000 to December 31, 2010, and Period 2 from January 1, 2000 to December 31, 2020. The primary outcomes were incidence rates of key pulmonary complications including interstitial lung disease, chronic obstructive pulmonary disease, respiratory infections, respiratory failure, and lung transplantation. Secondary outcomes included prevalence of long-term oxygen use and overall mortality.

In this study, we analyzed changes in the epidemiology of pulmonary disease in ASMD over time. The rarity and variability in the progression of this disorder warrants continued close monitoring and analysis to guide future management recommendations. This study addresses this need by providing a comprehensive and longitudinal overview of lung outcomes in a large patient cohort with ASMD.

Patients and Methods

We conducted a retrospective observational cohort study using the TriNetX research database. This global federated database comprises real-time electronic medical records of approximately 140 million patients across 110 healthcare organizations, primarily the United States. The database also includes data from healthcare centers in Australia, Germany, UK, Italy, Singapore, Israel, and Taiwan. Topaloglu et al. (14) provide a detailed description of the database.

The TriNetX research network database includes anonymized electronic medical records from patients across 110 participating healthcare organizations, providing real-world data on demographics, diagnoses, medications, procedures, and tests. We identified all patients diagnosed with ASMD through June 25, 2023 in TriNetX using the International Classification of Diseases, Tenth Revision (ICD-10) code E75.24. Patients were included based on documented phenotypic subtype, defined by ICD-10 code E75.24 in combination with D50-D53, D55-D59, D61, D62, D63, D64, D64.9, D69.5, D69.6, E88.02, F80.9, G10, G11.4, G25.2, G71.9, G72.9, G93.9, H50.9, J69.0, J84.9, M79.1, M81.0, M84.4, M85.9, M87.0, M88, M89, M89.5, M89.9, R10, R16, R16.0, R16.1, R16.2, R27.0, R47.1, R53, and R62.51. Searches were conducted June 20 through June 25, 2023. At search, 110 organizations contributed data. TriNetX provides only de-identified data, precluding the need for ethical approval. TriNetX and contributing networks comply with the Health Insurance Portability and Accountability Act (HIPAA) to protect healthcare data privacy and security. Aggregate or patient-level data from TriNetX contain only de-identified information per HIPAA §164.514(a). Extensive data quality assessments ensure adherence to institutional review board requirements as well as data completeness, plausibility and conformance (14, 15). We conducted this study according to the Declaration of Helsinki.

Study outcomes. We aimed to assess long-term respiratory outcomes of ASMD over 10- and 20-year follow-up periods. Outcomes included incidence and prevalence of pneumonia (PNEU), COPD, acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF), respiratory failure (RF), other lung disorders (OLD), other specified respiratory disorders (OSRD), pulmonary hypertension, categorized as primary or secondary (PH), pulmonary heart disease (PHD), other chronic obstructive pulmonary disease (OCOPD), other respiratory disorders (ORD), pulmonary embolism (PE), other pulmonary heart diseases (OPHD), hemorrhage from respiratory passages (HRP), other secondary pulmonary hypertension (OSPH), restrictive lung disease (RLD), and pulmonary hypertension unspecified (PHU). Incidence rates were calculated per 100,000 person-years.

These conditions commonly afflict ASMD patients, reflecting pathological metabolite accumulation, inflammation, and fibrosis in the lungs and pulmonary vasculature. We sought to characterize disease progression and changes in risk profiles as patients age.

Stratified analyses. To assess respiratory disease risk factors and the impact of patient characteristics on outcomes, we conducted stratified analyses of demographic and clinical variables. Specifically, patients were separated into age strata spanning 5-10 years, with narrower increments of 0-4, 5-9, and 10-14 years to closely analyze younger groups at and shortly following initial diagnosis. Male and female patients were analyzed separately to evaluate sex differences. Patients were also categorized into broad racial groups: White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and unknown race. Racial categories were broadly defined given variability in classifications across contributing sources. However, the White subgroup likely includes those of Ashkenazi Jewish descent, among whom ASMD incidence is elevated, though numbers of Ashkenazi Jews actually captured is unknown. These stratified analyses aimed to determine how key patient attributes influence respiratory disease risks and outcomes over both 10- and 20- year follow-up to identify factors contributing to health disparities and shape targeted interventions. Results revealed significant differences in nearly all respiratory outcomes across age, sex, and racial strata.

Statistical analyses. We conducted a descriptive analysis of the data. Incidence rates of pulmonary and respiratory conditions of interest were calculated as the number of patients with events occurring during patient follow-up time at risk, divided by the total follow-up time in person-years (P-Y). Incidence rates are reported per 1,000 P-Y. ASMD patients who commenced with phenotype after the index date contributed person-time to both 10-years and 20-years cohorts. Patients with pulmonary and respiratory conditions were censored at the point at which they included.

Results

Baseline characteristics. A patient selection flowchart is shown in Figure 1. In total, 15,108 patients with ASMD were identified in the TriNetX database: 8,980 ASMD patients at baseline and during follow-up. Follow-up duration was 10 years (2000 to 2010) or 20 years (2000 to 2020). Geographic distribution included 99% from US Regions [56% Northeast (N=5,038), 8% Midwest (N=692), 22% South (N=2,010), 13% West (N=1,175)] and <1% Ex-US Regions (N=65).

Figure 1.
Figure 1.

Flow diagram of acid sphingomyelinase deficiency (ASMD) patients’ selection from the TriNetX database.

Baseline characteristics are presented in Table I. The cohort included 8,628 individuals with ASMD. A total of 352 were excluded for meeting event criteria >20 years ago. Most were female (N=5,445, 63%) and white (N=5,913, 69%). Mean age was 55±18.9 years. Mean BMI was 28.6±6.9 kg/m2, overweight. Blood pressure was available for 27% (mean systolic 125±19.3 mmHg, diastolic 74±11.1 mmHg), within normal limits. Mean creatinine was 1.02±3.29 mg/dl, normal (0.5-1.50 mg/dl). Mean calcium was 9.36±0.513 mg/dl, below normal (8.5-10.50 mg/dl), reflecting possible bone disease. Mean cholesterol was 195±49.8 mg/dl, comparable to general population. Mean glucose was 106±43.8 mg/dl, indicating good control. Mean hemoglobin was 13.5±1.72 g/dl. Liver enzymes were normal. Complete blood counts were available for 60-61% (erythrocytes 4.47±0.551×106/μl, leukocytes 12.8±157×106/μl, platelets 245±73.9×103/μl), within reference ranges.

View this table:
Table I.

Baseline characteristics of acid sphingomyelinase deficiency (ASMD) patients.

Mean iron was 80±42.2 μg/dl, below normal (males 65-175 μg/dl, females 50-170 μg/dl), indicating possible iron deficiency from intestinal bleeding or transport defects in ASMD. Mean ferritin was elevated at 175±446 ng/ml compared to normal (men 22-322 ng/ml, women 11-307 ng/ml). Hyperferritinemia indicates ASMD severity and inflammation.

In summary, this ASMD cohort was predominantly female and white, middle-aged, overweight, and otherwise had normal metabolic parameters. Calcium and iron levels were below normal, possibly reflecting bone and iron involvement common in ASMD. Elevated ferritin likely signifies disease severity and chronic inflammation, a hallmark of lysosomal disorders like ASMD.

Incidence and prevalence of pulmonary and respiratory results in ASMD patients tracked for 10- and 20-years. The incidence and prevalence of nearly all measured respiratory outcomes increased significantly from 10- to 20-years of follow-up. The incidence proportion, and prevalence proportion of numerous pulmonary and respiratory outcomes rose substantially over 20 versus 10 years of follow-up (Figure 2 and Figure 3).

Figure 2.
Figure 2.

Incidence of pulmonary and respiratory conditions in acid sphingomyelinase deficiency (ASMD) for 10-years and 20-years follow-up.

Figure 3.
Figure 3.

Prevalence of pulmonary and respiratory conditions in acid sphingomyelinase deficiency (ASMD) during 10-years and 20-years follow-up.

For pneumonia (PNEU), the incidence proportion increased from 2.53% to 10.51%, prevalence proportion from 2.53% to 10.51%, and incidence rate from 0.0000895 to 0.000021305 per 1,000 person-years. Significant rises in other outcomes were observed for COPD, ARDS, PF, RF, OLD, OSRD, OPHD, PHD, primary pulmonary hypertension (PPH), OCOPD, ORD, HOR, PE, HRP, OSPH, and PHU (Figure 2 and Figure 3).

The most substantial increases were in ORD, OSRD, and OSPH, with 16-, 40-, and 6-fold rises in incidence proportion; 17-, 40-, and 6-fold rises in prevalence proportion; and 4.6-, 22-, and 3.3-fold rises in incidence rate, respectively, over 20 versus 10 years. ARDS, IPD, and HOR emerged over 20-year follow-up but were absent over 10-years (Figure 2 and Figure 3).

These significant rises in respiratory disease burden over long-term follow-up highlight the progressive nature of ASMD and need for close monitoring and optimal treatment of respiratory complications to reduce morbidity and mortality.

Incidence rates of 10-years and 20-years follow-up in ASMD patients. The study followed 8,976 ASMD patients for 10- and 20-years. Over 10 years of follow-up, incidence rates per 1,000 person-years were 0.0092 for PPH, 0.0166 for OSPH, 0.0012 for PH, 0.0232 for PHD, 0.0061 for ILD, 0.0523 for OLD, 0.0341 for RLD, 0.0253 for PHR, and 0.0120 for PE (Figure 4).

Figure 4.
Figure 4.

Incidence rate of pulmonary and respiratory conditions in acid sphingomyelinase deficiency (ASMD) for 10-years and 20-years follow-up. Pneumonia (PNEU), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF), respiratory failure (RF), other lung disorders (OLD), other specified respiratory disorders (OSRD), pulmonary hypertension, categorized as primary or secondary (PH), pulmonary heart disease (PHD), other chronic obstructive pulmonary disease (OCOPD), other respiratory disorders (ORD), pulmonary embolism (PE), other pulmonary heart diseases (OPHD), hemorrhage from respiratory passages (HRP), other secondary pulmonary hypertension (OSPH), restrictive lung disease (RLD), and pulmonary hypertension unspecified (PHU).

Over 20 years of follow-up, incidence rates per 1,000 person-years rose to 0.0092 for PPH, 0.0288 for OSPH, 0.0148 for PH, 0.0336 for PHD, 0.0122 for ILD, 0.0519 for OLD, 0.0488 for RLD, 0.0528 for PHR, and 0.0188 for PE. Except for PPH and OLD, significant increases were observed in all other pulmonary and respiratory conditions from 10 to 20 years (Figure 4).

Stratified analyses. To investigate respiratory disease outcomes in ASMD across patient subgroups, we conducted stratified analyses of a global cohort spanning 10- and 20-year follow-up periods. The study population originally included 15,108 patients and after applying inclusion criteria, 8,980 individuals remained for long-term follow-up analysis (Figure 1).

Patients were first stratified by age into groups separated by 5- to 10-year increments, including narrower strata for younger patients, to analyze how risks may change over the disease course. Older groups, especially ages 65 and over, exhibited significantly higher incidence and prevalence of nearly all pulmonary and respiratory outcomes versus younger strata, likely reflecting progressive respiratory decline, increasing infection susceptibility with age, and aging-related comorbidities.

We then examined potential differences between male and female patients. Overall, males showed slightly higher incidence and prevalence of respiratory disease versus females, possibly indicating faster disease progression, though differences were modest, and both sexes remain at high long-term risk. Finally, we explored how race may impact outcomes by stratifying patients into White, Black or African American, Asian, American Indian or Alaskan Native, Native Hawaiian or Other Pacific Islander, and unknown race groups. Racial minorities, particularly Black or African American and Asian patients, displayed higher respiratory disease incidence and prevalence than White patients, potentially due to healthcare access disparities and suboptimal disease management. However, the White group may contain a sizeable Ashkenazi Jewish subset with comparatively better outcomes from genetic counseling and treatment. This finding highlights the need to understand how race and ethnicity influence disease progression and care access in ASMD.

In summary, stratified analyses revealed significant respiratory disease risk differences across age, sex, and race in ASMD. Ongoing research should aim to determine factors underlying these associations and implement interventions promoting health equity. Long-term follow-up, early treatment, and comorbidity management are critical for all patients to minimize respiratory morbidity and mortality, regardless of demographic background. Overall, age appears to drive substantial respiratory decline, though outcomes remain poor across groups, underscoring the progressive, pervasive nature of lung disease in ASMD.

Discussion

This large longitudinal study provides crucial insights into the lung and respiratory outcomes of patients with ASMD. The results confirm the progressive nature of this rare lysosomal storage disease and highlight the need for close monitoring and optimal treatment of pulmonary complications to reduce morbidity and mortality, especially over the long term.

The study followed 8,980 ASMD patients for up to 20 years, during which time the incidence and prevalence of nearly all measured lung and respiratory outcomes rose significantly, particularly other respiratory disorders, other specified respiratory disorders, and other secondary pulmonary hypertension. The manifold increase in these complications likely reflects the ongoing cellular damage and pulmonary vascular injury that characterize ASMD. While outcomes were poor overall, older age, male, and racial minority status were associated with greater risks, suggesting differences in disease progression rates, access to healthcare, and quality of management. Targeted interventions may help address these disparities, though continued follow-up and treatment remain critical for all patients given the severe respiratory morbidity and mortality observed across groups.

Lysosomal storage disorders (LSDs) are a group of genetic diseases caused by mutations affecting lysosomal enzyme function (16). ASMD and other LSDs with pulmonary involvement like Gaucher disease and Fabry disease are multisystemic, complex and clinically heterogeneous. While respiratory complications significantly impact morbidity and mortality, they are not always recognized as a primary feature. For ASMD and Gaucher disease, analysis of bronchoalveolar lavage fluid and lung biopsies may show characteristic foamy macrophages. Interstitial lung disease occurs frequently in ASMD and can lead to respiratory failure if untreated. Enzyme replacement therapy (ERT) has improved outcomes for some LSDs when initiated early, though its effects on lung health and the ideal timing of treatment remain unclear for certain diseases including ASMD (17-19).

Historically, LSDs have been considered pediatric conditions detected through newborn screening. However, improved molecular testing enables diagnosis of milder, later-onset forms in adults. Early diagnosis and treatment are crucial to optimize outcomes, as evidenced by studies like our analysis of long-term respiratory outcomes in ASMD. Next-generation sequencing has made genetic testing more accessible, allowing expansion of newborn screening and facilitating diagnosis of LSDs in patients of all ages (20, 21). Testing provides a definitive diagnosis even for milder cases that remain difficult to recognize based on symptoms given their rarity and heterogeneity. For some LSDs, therapies like enzyme replacement can help slow disease progression when started early. Without diagnosis, irreversible organ damage may occur before treatment. While newborn screening remains important, expanding genetic testing in adults with appropriate indications is critical to promote timely diagnosis and care across the lifespan (22). Improving access addresses major unmet needs, optimizing outcomes for all with these diseases. For ASMD, this longitudinal study highlights the significance of diagnosis and treatment by showing significantly rising risks of respiratory disorders, specified respiratory disorders and pulmonary hypertension over 20 years of follow-up. These findings probably reflect progressive lung damage from sphingomyelin accumulation, though the effects of available treatments remain unclear.

A major strength of this study is its large, global cohort and extended follow-up, providing a comprehensive overview of long-term respiratory outcomes in ASMD. The results align with and add to previous research showing variable but typically poor pulmonary prognosis, with most patients experiencing progressive decline (13, 17, 18, 23, 24). While the cohort findings align with previous research, several limitations warrant consideration. As an observational study, causal conclusions cannot be drawn. Data were derived from electronic medical records which rely on accurate clinical documentation, and we lacked information on patient compliance, lifestyle factors, environmental exposures, and other potential confounders. The generalizability of these findings may be limited given the predominantly North American and white study population. In addition, this was an observational study, so results could have been impacted by uncontrolled confounding factors despite adjustments. The broad racial categories used could mask differences between specific ethnic populations. Despite these limitations, the results offer valuable information on long-term respiratory risks that can help guide screening, management, and health policy for ASMD.

In summary, this study highlights the substantial respiratory burden of ASMD. While outcomes remain poor overall, targeted strategies may help address disparities in certain groups. Ongoing research is urgently needed to better understand disease modifiers, improve treatments, and promote health equity to maximize respiratory health for all patients with this progressive disorder. Overall, early, aggressive management of pulmonary complications is critical, especially given the significant morbidity and mortality observed over the long term.

Footnotes

  • Authors’ Contributions

    Manuscript writing: YNH, SLC, and CHW; conceptualization and experimental design: JYH, WLL, DTB, and PHS; data analysis: YNH, SLC, and JYH; contribution of reagents/materials/analysis tools: PHS and CHW.

  • Funding

    This research was generously funded by the Department of Medical Research at both China Medical University Hospital and Chung Shan Medical University. At China Medical University Hospital, grant numbers DMR-108-048, DMR-109-052, DMR-109-180, DMR-110-063, and DMR-110-066 were awarded to CHW, providing substantial support for the work. Chung Shan Medical University extended their support through grant number CSH-2021-C-033, awarded to PHS.

  • Conflicts of Interest

    The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

  • Received August 16, 2023.
  • Revision received September 17, 2023.
  • Accepted September 18, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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The Long-term Lung and Respiratory Outcomes of Acid Sphingomyelinase Deficiency: A 10- and 20-year Follow-up Study
YU-NAN HUANG, SHANG-LUN CHIANG, JING-YANG HUANG, WEN-LI LU, DA-TIAN BAU, PEN-HUA SU, CHUNG-HSING WANG
In Vivo Jan 2024, 38 (1) 437-444; DOI: 10.21873/invivo.13457
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