Abstract
Introduction
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogenous clinical manifestations, including interstitial lung disease (ILD). Respiratory manifestations are the leading causes of mortality in patients with ASMD type B and type A/B. In ILD, the percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO) is a common clinical endpoint; however, its clinical relevance in patients with ASMD remains unclear.
Methods
This post hoc analysis explored the relationship between DLCO and mortality risk in patients with ASMD type B and type A/B. Data from a prospective natural history study (NCT02004704) and a retrospective cohort study conducted in the United States were pooled based on the eligibility criteria. Percent predicted DLCO was imputed for 10 records (9/68 patients), assuming an annual 1% linear decrease in DLCO. A Cox proportional hazards model was fitted using percent predicted DLCO as a time-varying predictor at < 60% and ≥ 60%.
Results
A total of 68 patients (prospective study, n = 40; retrospective study, n = 28) diagnosed with ASMD type B or type A/B during childhood (aged 1–12 years) with ≥ 1 DLCO measurement were included in the analysis. A total of 12 deaths were recorded. The estimated hazard ratio (95% confidence interval) was 0.77 (0.22–2.67), indicating a potential trend toward an association of lower mortality risk with higher percent predicted DLCO (≥ 60%). However, the result was not statistically significant (p = 0.69) because of the limited sample size, thus warranting further prospective validation.
Conclusions
To our knowledge, this is the first analysis to explore the relationship between DLCO and mortality risk in patients with ASMD type B and type A/B. Overall, these findings underscore how DLCO affects the mortality risk in patients with ASMD.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12325-025-03481-4.
Keywords: Acid sphingomyelinase deficiency, Diffusing capacity of the lungs for carbon monoxide, Interstitial lung disease, Mortality, Overall survival, Post hoc analysis
Key Summary Points
| Why carry out this study? |
| Progressive interstitial lung disease (ILD) is a common manifestation and a major cause of death in patients with acid sphingomyelinase deficiency (ASMD). |
| Pulmonary function tests in patients presenting with ILD reflect a decreased diffusing capacity of the lungs for carbon monoxide (DLCO). |
| While several pulmonary function parameters may influence mortality risk in ILD, the clinical relevance of DLCO in ASMD remains unclear. |
| This post hoc analysis explored the relationship of DLCO and mortality risk in ASMD using pooled data from a prospective natural history study (NCT02004704) and a retrospective cohort study. |
| What was learned from the study? |
| The hazard ratio was estimated to be 0.77 (95% confidence interval, 0.22–2.67, p = 0.69) in a patient cohort diagnosed with ASMD during childhood (N = 68) using a Cox proportional hazards model to measure the association of mortality risk with DLCO as a time-varying predictor at two levels: < 60% and ≥ 60%. |
| DLCO < 60% was found to be associated with high number of respiratory events. |
| The mortality risk was high in patients with ASMD presenting with a low percent predicted DLCO; however, the results were not statistically significant, likely because of the small sample size. |
Introduction
Acid sphingomyelinase deficiency (ASMD), also termed Niemann–Pick disease types A, B, and A/B, is a rare lysosomal storage disorder [1, 2]. It is caused by pathogenic variants of the sphingomyelin phosphodiesterase 1 gene, leading to the accumulation of sphingomyelin in the body and resulting in multiple organ dysfunctions [3]. The estimated global prevalence of ASMD is approximately 0.4–0.6 per 100,000 live births [4]. ASMD is characterized by a broad clinical spectrum and is divided into three different phenotypes: ASMD type A (infantile neurovisceral form), ASMD type B (chronic visceral form), and ASMD type A/B (chronic neurovisceral form) [5, 6].
Patients with ASMD type B and type A/B present with diverse multisystemic manifestations, including splenomegaly, liver disease, and respiratory manifestations. Lung dysfunction and interstitial lung disease (ILD) are the most prominent respiratory clinical findings [3, 7]. Previous studies have shown that ASMD type B and type A/B account for considerable morbidity and mortality due to respiratory failure, neurodegeneration, and liver failure [8–10]. Hollack et al. reported that pulmonary disease was one of the most debilitating manifestations in patients with ASMD type B [11]. High severity of respiratory manifestations, including shortness of breath, chest pain, cough, and difficulty in breathing, have been reported in pediatric and adolescent patients with ASMD type B and type A/B [12, 13]. Patients with ASMD had compromised diffusing capacity of the lungs for carbon monoxide (DLCO), which correlated with symptom severity [14] and worsened over time [15]. While multiple pulmonary function parameters, including forced vital capacity (FVC) and DLCO, may affect patients with ILD, DLCO has emerged as one of the potentially important prognostic indicators [11]. Available evidence from natural history and observational studies of ASMD supports the use of DLCO as a clinically meaningful endpoint to assess the disease burden on patients with ASMD [11, 15–17].
DLCO has been utilized as a key clinical outcome measure in patients with ASMD treated with olipudase alfa, a recombinant human acid sphingomyelinase enzyme replacement therapy [18–20]. Olipudase alfa improved lung function and increased the mean percent predicted DLCO by 46.6% during 2 years of treatment in pediatric patients with ASMD (NCT02004704) [18] and by 28.5% in adult patients (NCT02004691) [20] during 2 years of treatment with olipudase alfa.
Reduced DLCO is associated with an increased risk of mortality in patients with ILD [17]. However, limited evidence is available on the clinical relevance of DLCO in patients with ASMD. Therefore, we conducted a post hoc analysis to understand the relationship between DLCO and mortality risk in patients with ASMD type B and type A/B using pooled data from a prospective natural history study and a retrospective cohort study [15, 21].
Methods
Study Design and Participants
This post hoc analysis was conducted using the pooled medical records of patients with chronic ASMD (type B or type A/B) from two studies [15, 21]. The first was a prospective, multicenter longitudinal natural history study (NCT02004704) designed to characterize the clinical manifestations and disease progression in patients with chronic ASMD over a period of approximately 11 years [15]. The second was an observational, multicenter, retrospective cohort study that evaluated the disease burden and survival in patients with ASMD in the United States (US) [21]. The prospective study included patients from five countries (Brazil, Germany, France, Italy, and the US) who were enrolled between May 5, 2001, and June 17, 2002 [15]. The retrospective study was conducted using medical records of patients with ASMD (either alive or deceased) in the US between January 1, 1990, and February 28, 2021 [21]. The current analysis included patients who were diagnosed with ASMD during childhood (aged 1–12 years) with ≥ 1 DLCO measurement [15, 21]. The analysis assumed that patients with disease onset within a specific age group would result in a coherent sample pool with similar disease progression. Patients who were ineligible for overall survival (OS) analysis, patients with completely missing DLCO and those with age of diagnosis not between 1–12 years were excluded from the analysis. Data with an outlier DLCO were not included in the analysis.
This article is a post hoc analysis on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Data Collection
Data on patient demographics and OS were pooled from the included studies [15, 21]. Percent predicted DLCO data were recorded at the baseline, 12-month follow-up, and final visit for each patient in the prospective study, whereas these data were reported at the first symptom presentation, diagnosis, and last follow-up in the retrospective study. Analysis was conducted using longitudinal data collected from both studies; that is, a patient could have multiple records denoting different DLCO measurements and a record at the last follow-up or death. Data on the percent predicted DLCO (adjusted for hemoglobin) were collected; however, for the majority of the patients included in the retrospective study, data on the percent predicted DLCO (adjusted for hemoglobin) were not reported. In such cases, unadjusted percent predicted DLCO data were used for analysis. Percent predicted DLCO was categorized using two levels: < 60% and ≥ 60%. Percent predicted DLCO < 60% was used as a reference category as symptomatic presentations of respiratory manifestations were prominent at DLCO < 60% [22].
Statistical Methods
Patient demographics are summarized using descriptive statistics. Continuous variables were presented as mean and standard deviation or median and interquartile range. Categorical variables were expressed as numbers and percentages. The number and percentage of patients with respiratory events are presented per DLCO category, with no imputations. Mortality outcomes were previously estimated in both studies using Kaplan–Meier survival analysis [15, 21]. A Cox proportional hazards model was used to determine the relationship between mortality risk and percent predicted DLCO as a time-varying predictor at two levels: < 60% and ≥ 60%. The missing values of percent predicted DLCO were imputed using the nearest available record (in terms of time) for the DLCO values, assuming an annual 1% linear decrease in DLCO based on the findings from the prospective study [15]. Statistical analyses were conducted using “stcox” in STATA 17 (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX, USA: StataCorp LLC). Moreover, the association between percent predicted DLCO categories (< 60% and > 60%) versus onset of respiratory events was examined. Respiratory events included in this analysis were validated through clinical review.
Results
Study Participants
Of the 169 patients with chronic ASMD pooled from the two studies [15, 21], 68 (prospective: n = 40/59; retrospective: n = 28/110) were included in this post hoc analysis based on the eligibility criteria (Fig. 1).
Fig. 1.
Disposition of patients with ASMD type B or type A/B. *Pooled data were collected from a prospective study conducted across five different countries [n = 59; Brazil (n = 13), Germany (n = 5), France (n = 7), Italy (n = 8, and the US (n = 26)], and a retrospective study conducted in the US alone (n = 110). **Patients with incomplete survival data (only the date of the last follow-up was available). ASMD acid sphingomyelinase deficiency, DLCO diffusing capacity of the lungs for carbon monoxide, N total number of patients, n number of patients, OS overall survival
The median age of the included patients at diagnosis was 4.0 years in the prospective study and 3.5 years in the retrospective study. Patient demographics are presented in Table 1.
Table 1.
Demographics of patients with ASMD type B or type A/B
| Characteristic | Pooled analysis (N = 68) | Prospective study (N = 40) | Retrospective study (N = 28) |
|---|---|---|---|
| Country, n (%) | |||
| Brazil | 9 (13.2) | 9 (22.5) | NA |
| Germany | 3 (4.4) | 3 (7.5) | NA |
| France | 4 (5.9) | 4 (10.0) | NA |
| Italy | 5 (7.4) | 5 (12.5) | NA |
| US | 47 (69.1) | 19 (47.5) | 28 (100.0)a |
| Sex, n (%) | |||
| Female | 33 (48.5) | 19 (47.5) | 14 (50.0) |
| Male | 35 (51.5) | 21 (52.5) | 14 (50.0) |
| Age at index date (years) | |||
| Mean (SD) | 12.9 (10.5) | 18.7 (9.9)b | 4.7 (3.6)c |
| Median (IQR) | 11 (5.0–17.7) | 16.3 (12.1–21.1) | 3.4 (1.9–6.0) |
| Age at diagnosis (years) | |||
| Mean (SD) | 5.2 (3.4) | 5.3 (3.3) | 5.0 (3.5) |
| Median (IQR) | 4.0 (2.4–7.9) | 4.0 (2.5–8.3) | 3.5 (2.0–6.4) |
ASMD acid sphingomyelinase deficiency, IQR interquartile range, N total number of patients, n number of patients, NA not applicable, SD standard deviation, US United States
aThe retrospective study was conducted in the US only
bFor the prospective study, age at index date refers to the age at baseline
cFor the retrospective study, age at index date refers to the age at first presentation or diagnosis, whichever occurred first
Association between Mortality Risk and Percent Predicted DLCO
Percent predicted DLCO was imputed for 10 records (9/68 patients), considering a linear increase or decrease from the nearest age with available DLCO values. For patients with a percent predicted DLCO ≥ 60%, 37 patients with 60 records were included, and 4 deaths were reported. For patients with a percent predicted DLCO < 60%, 44 patients with 73 records were included, and 8 deaths were reported. The estimated hazard ratio (95% confidence interval) was 0.77 (0.22–2.67) (Table 2; Fig. S1). A lower mortality risk was computed with a higher percent predicted DLCO category [DLCO ≥ 60% (less severe)] than with a lower percent predicted DLCO category [DLCO < 60% (more severe)]. However, the result was not statistically significant (p = 0.69), likely because of the small sample size.
Table 2.
Cox model findings with DLCO as a time-varying predictor in patients with ASMD type B or type A/B
| HR | SE | p value | 95% CI | Patients | Records | Deaths | |
|---|---|---|---|---|---|---|---|
| DLCO < 60 (reference) | – | – | – | – | 44 | 73 | 8 |
| DLCO ≥ 60 | 0.77 | 0.49 | 0.69 | 0.22–2.67 | 37 | 60 | 4 |
ASMD acid sphingomyelinase deficiency, CI confidence interval, DLCO diffusing capacity of the lungs for carbon monoxide, HR hazard ratio, SE standard error
Distribution of Respiratory Events
Respiratory events considered for all patients in the prospective study primarily were bronchospasm, bronchitis, fibrosis/ILD, need for supplemental oxygen, pneumonia, pneumothorax, and pulmonary infections. Major ones considered for all patients in the retrospective study were ILD, alveolar infiltrates, respiratory distress, and lower respiratory infection with severity grading. The respiratory events from the prospective study that aligned with the events recorded from the retrospective study were included in the current analysis. Data related to respiratory symptoms were excluded from the analysis. From the prospective study, only ongoing respiratory events at each visit were considered; respiratory events that had occurred in the past were excluded. In both studies, the highest number of respiratory events was reported for patients with a percent predicted DLCO < 60% (Table S1).
Discussion
The current post hoc analysis explored the relationship between DLCO and mortality risk in patients diagnosed with ASMD during childhood (1–12 years). This age range is particularly important because a substantial disease burden and risk of early death have been observed in patients with the onset of symptoms or ASMD diagnosis during childhood [8, 9]. While previous studies conducted by McGovern et al. [15] and Pulikottil-Jacob et al. [21] provided information on clinical features, disease burden, and survival probability, the present analysis bridges the evidence gap in the clinical relevance of DLCO in ASMD.
The current analysis showed a high disease burden with respect to respiratory events from the included studies [15, 21]. In a separate retrospective analysis conducted by Mengel et al., 77.4% of patients reported ≥ 1 respiratory clinical finding; ILD was reported in 100.0% of patients with ASMD type A/B and 66.7% of patients with ASMD type B [10]. Pokrzywinski et al. reported respiratory events as a major disease manifestation in all patients, including 12 pediatric and adolescent patients with ASMD [13]. In another retrospective analysis of 10 patients, all patients showed with signs of ILD [23].
In a retrospective chart review by Cox et al., respiratory events, including pneumonia and ILD, were commonly reported in patients with ASMD, with respiratory failure and pneumonia being the major causes of mortality in pediatric patients [9]. Previous studies have reported pneumonia/respiratory failure as a primary cause of mortality in the pediatric population [8, 24].
For the population included in the analysis, a total of 12 deaths were recorded (prospective study: n = 6; retrospective study: n = 6) [15, 21]. DLCO < 60% was used as a reference category as the symptomatic presentations of respiratory manifestations are prominent at DLCO < 60% [22]. Our analysis showed a potential trend of high mortality risk association with a low percent predicted DLCO (< 60%), although the results were not statistically significant. DLCO is considered a strong predictor of mortality in patients with respiratory issues, such as obstructive lung disease and ILD, with low DLCO measurements indicating an increased risk of mortality [22]. Recommendations for the clinical monitoring of patients with ASMD have indicated periodic assessments for respiratory diseases by measuring DLCO values and oxygen saturation, as respiratory involvement is a primary feature of the multisystem manifestation in ASMD [25].
The current analysis had certain limitations. This post hoc analysis was exploratory in nature. The small sample size warrants future analysis to validate the outcomes. The data were collected from prospective and retrospective studies; therefore, the study design heterogeneity might have impacted the outcomes. Given the small number of overall survival events (12 deaths in total), it was not feasible to fit models with multiple predictors without risking overfitting and generating potentially misleading results. Moreover, as missing DLCO values were imputed in this study, the results should be interpreted with caution. Future research with assessments adjusted for Hb levels can provide critical insights into the robustness of these findings.
Conclusion
To our knowledge, this is the first analysis to explore the relationship between DLCO and mortality risk in patients with ASMD type B and type A/B. Patients with ASMD presenting with a lower percent predicted DLCO (< 60%) showed a trend toward higher mortality risk than those with a higher percent predicted DLCO. This suggests that DLCO can affect the survival of patients with ASMD; however, future research with a larger sample size is warranted to further assess the relationship between mortality risk in ASMD and DLCO. The present findings can be used as a basis for further clinical evaluation to bridge the knowledge gap and improve patient-related outcomes through timely diagnosis and management.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank all the participants of this study for their time, commitment, and valuable contribution to this research.
Medical Writing/Editorial Assistance
Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Bushra Nabi and Mau Sinha of Sanofi, in accordance with Good Publication Practice guidelines.
Author Contributions
Conceptualization and design: Maja Gasparic and Ruth Pulikottil-Jacob. Formal analysis: Venediktos Kapetanakis and Pragya Shukla. Data interpretation and validation: All authors. Supervision: Maja Gasparic, Marie Fournier, and Ruth Pulikottil-Jacob. Drafting of the manuscript and critical revision: Wim A. Wuyts, Francesco Bonella, Maurizio Scarpa, Venediktos Kapetanakis, Pragya Shukla, Marie Fournier, Maja Gasparic, and Ruth Pulikottil-Jacob.
Funding
The study was funded by Sanofi. The journals Rapid Service and Open Access fees were funded by Sanofi.
Data Availability
All data generated or analyzed during this study are included in Table S1 under electronic supplementary material. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of the participants.
Declarations
Conflicts of Interest
Wim A. Wuyts received funds for advisory boards from Sanofi, Boehringer Ingelheim, Alentis, and Roche. Francesco Bonella received speaker and advisor honoraria, and travel cost refunds from Sanofi, Boehringer Ingelheim and Savara Pharma. Maurizio Scarpa received research funding and honoraria from Sanofi, Takeda, Chiesi, Ultragenyx, Amicus, Azafaros, BioMarin, and Orchard. Venediktos Kapetanakis and Pragya Shukla are employees of Evidera, a part of Thermo Fisher Scientific, which received fees from Sanofi for the conduct of statistical analyses. Maja Gasparic and Marie Fournier are employees of Sanofi and may hold stocks and/or stock options in the company. Ruth Pulikottil-Jacob was an employee of Sanofi at the time of study conduct and may hold stocks and/or stock options in the company.
Ethical Approval
This article is a post hoc analysis on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data generated or analyzed during this study are included in Table S1 under electronic supplementary material. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of the participants.