The humanistic burden of Pompe disease: are there still unmet needs? A systematic review

Overall HRQoL burden was described in four studies; one in the absence of ERT [32], two among patients treated with ERT [26, 34], and one RCT in which patients were randomized to either placebo or ERT [31]. HRQoL was typically measured using the 36-item Short-Form Survey (SF-36) (Table 1).

Hagemans et al. [32] reported a cross-sectional analysis of the International Pompe Survey in 210 patients with LOPD, prior to approval of ERT. Patients presented with a wide range of disease severity, from the mildly affected to wheelchair- and ventilator-dependent, and reported significantly poorer HRQoL on the physical functioning, physical role functioning, general health, vitality, and social functioning subscales of the SF-36 than the general population (p < 0.001 on all scales). The difference was most profound for the physical functioning scale, with an adjusted mean score among patients of 29.3, compared with 83.1 (standard deviation [SD] not reported) in the general population. No significant differences were found for the bodily pain, emotional role functioning, or mental health scales, which, the authors speculated may have reflected the slow progression of limitations in daily activities, allowing patients to adapt over time to their situation and adjust their expectations. In a subset of 38 Dutch patients, the authors compared SF-36 scores at baseline and after 1 year; participants were asked on a 5-point scale whether their physical situation had improved a lot, improved a little, remained the same, deteriorated a little, or deteriorated a lot. Twenty-seven of the 38 participants reported deterioration in their physical situation, while none reported improvement. No significant differences were seen for any of the SF-36 subscales between the two time points. The authors suggested that either changes in the physical situation were not always accompanied by changes in QoL or that, as a generic QoL instrument, the SF-36 was insufficiently sensitive to capture such changes.

van der Ploeg et al. [31] reported data from the Late Onset Treatment Study (LOTS), an RCT of 90 LOPD patients aged 8 years or older, ambulatory, and free of invasive ventilation, who received ERT or placebo for 78 weeks. All patients had substantially diminished SF-36 physical component summary (PCS) scores at baseline (ERT-treated patients, 34.3 ± 8.9; placebo-treated patients, 34.9 ± 7.2), which were more than 1.5 SD below the norm for the US general population (50 ± 10). Importantly, despite treatment with ERT, the mean SF-36 PCS score did not increase significantly over the 78-week study ([35.1 ± 9.9], change [95% CI], 0.80 [−1.22 to 2.82]).

Boentert et al. [34] presented a cross-sectional analysis in which 60 of 65 German patients received ERT (mean ERT duration, 5 years), while Aslan et al. [26] described a prospective cohort study of nine Turkish LOPD patients receiving ERT, who participated in an inspiratory muscle training (IMT) program to improve QoL. Boentert et al. stated (without providing quantitative data) that despite ERT, LOPD patients had significantly lower HRQoL than the general population, based on the SF-36 subscales for physical functioning, physical role limitation, general health perception, vitality and social functioning. Aslan et al. also reported impaired HRQoL despite ERT, using the Nottingham Health Profile (NHP), which assesses subjective health status on a scale from 0 (good) to 100 (poor). At baseline, subscales of the NHP ranged from 15.7 for emotional reaction to 82.8 for physical ability. Following implementation of IMT, this study reported improvement in social isolation from 22.5 (interquartile range, 53.8–100.0) to 0.0 (0.0–16.9) (p = 0.02), but no other HRQoL subscale demonstrated a treatment response. This led the authors to speculate that participation in the IMT program and the associated weekly telephone contact may have been responsible for the improved social isolation scores.

This section describes patient-reported symptoms (PRS) that were reported alongside HRQoL, ADL, caregiver burden, treatment satisfaction and adherence. This is included because studies reporting on humanistic parameters frequently also describe common symptoms of Pompe disease (most notably pain, fatigue, and sleep disorders) with a considerable negative impact on humanistic burden. A systematic review of PRS was beyond the protocol-defined objectives of this review because PRS is typically classified under clinical burden.

Patient-reported symptoms were discussed in two publications in the absence of ERT [30, 32], and five publications in the presence of ERT [26, 34, 36, 38, 39]. In Hagemans et al. [32], where no ERT was available, excessive daytime sleepiness (EDS) was reported in approximately 25% of patients and sleep disturbances were reported in more than 40% of patients. In a later analysis of the same study, van der Meijden et al. [30] found that 78% of patients experienced fatigue (Fatigue Severity Scale [FSS] score ≥ 4), and 67% reported severe fatigue (FSS score ≥ 5).

Patients receiving ERT also had poor sleep quality, as assessed by Aslan et al. [26] using the Pittsburgh Sleep Quality Index (PSQI) to measure the quality and patterns of sleep during the previous four weeks. Among these patients, there was a median (interquartile range) total score of 5.0 (2.0–10.5; a cut off score of 5 or more distinguishes ‘bad sleepers’). Introduction of IMT did not improve sleep quality. Boentert et al. [34] also reported sleep symptoms, noting that 45.2% of patients were bad sleepers according to the PSQI (mean PSQI global score, 6.2 ± 3.7). Scores for sleep disturbances, sleep quality impairment and reduced daytime performance were the highest of the PSQI component scales. EDS was reported by 24.6% of patients (mean ESS, 6.9 ± 4.3).

In addition, Boentert et al. also presented respiratory symptoms, reporting that morning headache was reported by 40.0% of patients (‘occasional’ 35.4%; ‘often’ 4.6%) [34]. Nocturnal dyspnea was specified as ‘occasional’ by 18.5% of patients and as ‘often’ by 6.2%. Orthopnea was reported by 60.0% of patients, resting dyspnea in the upright position by 4.6%, and exertional dyspnea by 93.8% of patients. Dyspnea was reported in 29.2%, 40.0% and 24.6% of patients on mild, moderate and heavy exercise, respectively.

A cross-sectional study in 57 German adult LOPD patients (84% on ERT) and 57 controls reported the impact of urge incontinence and gastrointestinal symptoms [39]. In this study, stool urgency, diarrhea, and urinary urge incontinence were reported significantly more frequently in patients compared with the age- and gender-matched controls (55%, 56%, 33% vs. 20%, 18%, 7%).

In a cross-sectional analysis from Germany and the Netherlands from the International Pompe Survey, Güngör et al. [36] assessed the presence and severity of pain in 124 adult LOPD patients, 101 of whom were receiving ERT (median ERT duration, 4 years). They noted that a significantly greater proportion of ERT-treated LOPD patients reported pain compared with unaffected controls (45% vs. 27%, respectively; p = 0.004) on the Brief Pain Inventory (BPI) (Short-Form). In this study, the median pain severity score (PSS) – calculated from the BPI (Table 1) – was higher (worse) among patients than controls reporting pain in the previous 24 h (median PSS 3.1 [range 0.75–8] vs. 2.6, [range 0.75–5.25], respectively; p = 0.06). Similarly, the pain interference score (PIS; also calculated from BPI), was significantly higher (worse) in patients than controls (median PIS 3.3 [range 0–8.4] vs. 1.3 [range 0–4.4] respectively; p = 0.001). Pain particularly interfered (PIS score ≥ 4) with patients’ general activities, walking, and normal work, and showed a mild interference (PIS score ≥ 3) with mood, sleep, and enjoyment of life. For each of the seven domains of daily life, PIS scores were significantly worse in LOPD patients than controls, except for interference with sleep. The authors concluded that while pain is not the most prominent symptom of Pompe disease, it is a common and debilitating aspect of the disease that merits identification and management in this population.

In a follow-up to this study, the same group surveyed 25 patients from the UK using the long-form of BPI, which assesses pain over the previous 7 days [38]. This study reported that 88% of patients reported pain in the last week, a considerably higher proportion than the 45% reporting current pain in Güngör et al. [36]. Median PSS (3.9 [0.5–7.5] vs 3.1 [0.75–8.0]) and median PIS (3.9 [0–7.5] vs 3.3 [0–8.4]) were only slightly higher (worse) in this paper than in the publication by Güngör et al. [36, 38]. These data reinforce the troublesome nature of pain in LOPD.

The International Pompe Survey is the primary source of data on ADL burden [33]. This cross-sectional analysis was conducted in 257 patients with treatment-naïve LOPD (across a broad range of severity) with a median age of onset of 38 years. The impact of LOPD on participation in ADL was assessed using the Rotterdam Handicap Scale (RHS). The mean RHS score among patients in this study was 25.9 ± 6.5 (median, 27), compared with a maximum of 36, which would be scored by a healthy person. Mean RHS scores ranged from 25.5 in Germany to 27.7 in France, but the differences between countries were not statistically significant. Highest scores (reflecting least restrictions) were found for ‘mobility indoors’ and ‘leisure activities indoors’, while the lowest scores were found for ‘domestic tasks indoors’, ‘domestic tasks outdoors’, and ‘work/study’. The authors suggested that their findings demonstrate the considerable impact of Pompe disease on patients’ everyday life experiences.

One publication so far examined caregiver burden in LOPD [37]. This Dutch study was conducted among 67 patients with LOPD and their caregivers. Caregivers were most often partners (92%), while for children, parents were generally the primary caregivers (94%). Fifty-nine of the 67 patients were receiving ERT.

Caregivers provided about 17.7 h per week of informal care, with some variation (SD 27.5) [37]. Adults primarily received maintenance for household activities (48% of time) and only limited for personal care (18%). In pediatric patients, informal care given as personal care (32% of time) and social activities (36%) was most significant. No caregiver time was spent on specific nursing activities in both age groups. Informal care was provided at the expense of the caregiver’s leisure or work time. The majority (97%) of caregivers gained ‘some satisfaction’, while up to 60% gained a ‘lot of fulfillment’ for providing care. 50% of caregivers reported mental health problems, while 40% had physical health problems. The average burden for caregivers was 3.2 (range, 0.0 to 8.9), measured on a self-rated Visual Analog Scale (VAS, ranging from 0 [not at all straining] to 10 [too much straining]). The mean burden of caregiving for patients below the age of 18 years was higher than for adults (4.1 versus 2.9 respectively; p = 0.075). Caregiver burden for patients with LOPD was relatively mild and well-being was not far below the population norms.

In Boentert et al. [34], fatigue among ERT-treated LOPD patients was assessed using the FSS and sleep quality was measured using the PSQI. In this analysis, the PCS and MCS of the SF-36 were both inversely correlated with the FSS score (PCS, r = −0.46, p < 0.001; MCS, r = −0.44, p < 0.01) and the PSQI global score (PCS, r = −0.38, p < 0.001; MCS, −0.47, p < 0.001). In terms of the impact of pain on HRQoL, Güngör et al. [36] reported that ERT-treated patients with pain had significantly lower physical (median PCS score 30 [range, 11–45] vs. 35 [range, 17–58], respectively; p < 0.001) and mental HRQoL (median MCS scores 54 [range, 29–74] vs. 58 [range, 29–71], respectively; p = 0.049) than those without pain.

The relationship between the RHS and the SF-36 was investigated in the absence of ERT by Hagemans et al. [33]. The RHS correlated significantly with all SF-36 subscales except for the mental health domain. The largest positive correlation of RHS (r = 0.83, p < 0.001) was found with the physical functioning subscale of SF-36.

Kanters et al. [37] reported a significant, inverse correlation between patient HRQoL and both caregiver burden and the volume of care provided (rho = −0.430 and rho = −0.465, respectively; p < 0.001 in both cases) in ERT-treated patients. Patients with the lowest HRQoL (lowest quartile) received 35.1 h of care per week, with a caregiver burden of 5.3 on the self-rated burden scale, whereas patients with HRQoL in the highest quartile received only 3.9 h of care per week, with a lower caregiver burden of 2.3 on the self-rated scale.

Boentert et al. [34] found that the functional ability of ERT-treated patients (measured using RHS) was inversely correlated with fatigue (FSS, r = −0.40, p < 0.01) and sleep disturbance, (PSQI, r = −0.46, p < 0.001). Similarly, Güngör et al. [36] reported that ERT-treated patients with pain had lower functional abilities based on median RHS scores than those without pain (26 [range, 15–36] vs. 28 [range, 16–36], respectively; p = 0.02).

Boentert et al. [34] reported, unsurprisingly, that PSQI global score was positively correlated with FSS score (r = 0.33, p = 0.01) in the presence of ERT, indicating that fatigue increased with greater sleep disturbance.

Güngör et al. [36] found that ERT-treated patients with pain had significantly higher levels of depression and anxiety than those without pain. Anxiety and depression were measured using the median Hospital Anxiety and Depression Scale (HADS), with higher scores indicating greater anxiety or depression. HADS anxiety score among patients reporting pain was 5 (range, 0–15) compared with 3 (range, 0–12) among patients with no pain (p = 0.003), while the HADS depression score was 5 (range, 0–13) and 3 (range, 0–12) for patients with and without pain, respectively (p = 0.005).

Hagemans et al. [32] found that wheelchair use is associated with lower HRQoL and ADL scores. In their 2004 study, untreated patients who used a wheelchair scored on average 23.6 points lower on the physical functioning scale and 15.1 points lower on the social functioning scale of the SF-36 than patients who did not need a wheelchair (regression coefficient (B) = −23.6 and −15.1, p < 0.001) [32]. In their 2007 study, Hagemans et al. [33] reported significantly lower mean RHS scores in patients who used a wheelchair than those who did not (20.9 vs. 29.5, respectively; p < 0.001).

Kanters et al. [37] reported that ERT-treated wheelchair users received significantly more hours of informal care than patients who were not wheelchair-dependent (25.6 h vs. 14.0 h, respectively; p < 0.001). As such, caregiver burden was significantly higher (self-rated scale, 5.1 vs. 2.4, respectively; p = 0.002) and caregiver well-being was significantly lower (CarerQoL-VAS, 6.4 vs. 7.5, respectively; p = 0.024) for patients who used a wheelchair than those who did not.

An association between increased respiratory symptoms and poorer HRQoL (both physical and mental components) among ERT-treated patients was reported by Boentert et al. [34]. Respiratory symptoms were quantified using the respiratory symptoms questionnaire (RSQ), in which a low score indicates less frequent respiratory symptoms. Both the PCS score and the MCS score were negatively correlated with the RSQ score (PCS, r = −0.25, p < 0.05; MCS, r = −0.46, p < 0.001). This finding is consistent with data from untreated patients reported by Hagemans et al. [32], in which reduced respiratory distress was significantly associated with higher HRQoL.

Boentert et al. [34] also found that higher levels of respiratory distress were associated with greater sleep disturbance, as demonstrated by a positive correlation between PSQI and RSQ scores (r = 0.43, p < 0.0001). Fatigue, measured using the FSS, was also positively associated with respiratory distress, assessed using the RSQ (r = 0.58, p < 0.0001), while respiratory distress and functional ability were inversely related, with RHS scores strongly associated with both upright and supine forced vital capacity (FVC) (r = 0.62 and r = 0.69, respectively, p < 0.001). Similar findings were observed in the absence of ERT, with Hagemans et al. [32] reporting that the need for home ventilatory support was associated with lower physical functioning scores (B = −8.4, p = 0.004), and that mean RHS scores were significantly lower in patients receiving respiratory support than those without it (22.9 vs. 28.5, p < 0.001). Among the patients who used respiratory support, the correlation between the number of hours of ventilation and the RHS score was −0.59 (p < 0.001), suggesting a reduction in functional ability with increasing use of ventilation. Consistent with this, in this study, almost all patients requiring more than 12 h of ventilation per day required a wheelchair.

Boentert et al. [34] assessed the relationship between fatigue and “cardiopulmonary distress” in patients receiving ERT, as measured using the 6MWT and FVC. It should be noted that 6MWT and FVC are not direct measures of cardiopulmonary distress; the 6MWT in particular reflects various aspects of physical functioning and may be influenced by cardiac function, walking ability, and respiratory muscle strength. The FSS score was inversely correlated with the 6MWT (r = −0.35, p < 0.01) (meaning that patients with more severe fatigue performed less well on the 6MWT), but surprisingly, this negative correlation was only apparent in the male subgroup (r = −0.53, p < 0.01), indicating that fatigue in female patients may be independent of motor performance.

Seven articles describe the impact of ERT on HRQoL in LOPD (Table 2) [25, 27‐29, 31, 35, 39]: van der Ploeg et al. (2010) reported results from LOTS [31] (discussed above); Güngör et al. [29] evaluated 174 untreated patients who transitioned to ERT during the study; Angelini et al. [25] describe clinical response and changes in functional ability in a prospective cohort study of 11 adult patients; Strothotte et al. [28] and Regnery et al. [27] report data from an open-label observational trial in 44 and 38 adult patients, respectively, in Germany over periods of 12 and 36 months Freedman et al. [35] present a cross-sectional analysis of seven families of young patients (age not specified) with LOPD in Australia, using semi-structured interviews; and van Capelle [41] reports a case series of two children and one adult with LOPD treated with ERT in the Netherlands.

As reported earlier, van der Ploeg et al. found that untreated patients with LOPD had lower SF-36 scores at baseline, which did not improve significantly over 78 weeks’ treatment with ERT [31]. Similarly, Güngör et al. [29], evaluated PCS and MCS components of the SF-36 during three time periods: pre-ERT, first 2 years of ERT, and after more than 2 years of ERT. Before ERT, the PCS decreased significantly by 0.73 score points per year (sp/y). This was followed in the first 2 years after treatment by a significant increase of 1.49 sp./y, and by stabilization thereafter. The MCS was generally stable during the entire follow-up period. Throughout treatment follow-up, the physical functioning, physical role, general health and vitality domains improved, with particularly large increases during the first 2 years of ERT in physical role (9 sp./y), general health (5 sp./y) and vitality (4 sp./y), and a renewed decline thereafter. Mental health domain scores increased in the first 2 years of ERT (2 sp./y), and then declined, while social functioning and emotional role did not improve with treatment. The authors noted that the initiation of ERT halted the progressive decline in physical health status observed in the pre-treatment period, and argued that improvements in the physical functioning and physical role domains may be attributed to the positive effect of ERT on muscle function and strength reported in other studies.

A small prospective Italian study [25], described the clinical response and changes in functional ability in 11 adult patients (age at onset 15–42 years), although results of SF-36 testing are reported in only three patients: one had a mild improvement of mental health but not of bodily pain; the second had no improvement in mental health or role physical; and no HRQoL data are available for the third patient who stopped treatment after 3 months following ERT-related adverse events. These limited data are consistent with the open-label observational study of adult patients (mean age at onset 36 years) in Germany [27, 28]. Here, patients showed no significant longitudinal changes in HRQoL over the course of either 12 or 36 months of ERT treatment [27, 28]. The authors concluded that ERT stabilizes the chronic progressive natural disease course of LOPD in some patients, although motor performance and lung function still appear to decline in up to a third [27, 28].

Freedman et al. [35] reported on a cross-sectional study that used qualitative interviews to assess ERT response. They concluded that improved physical health resulted in increased psychosocial well-being. A benefit of ERT was also found by van Capelle et al. [41] in SF-36 sub-domains for two of three patients for whom these data were reported: one patient showed improvements on the physical health and, to a lesser extent, on the mental health domains, while the other showed particular improvements on the bodily pain and general health domains (no further details provided). The methodology of these studies (e.g., small sample size and reliance on qualitative interviews) limits interpretation and generalizability of their results.

Data on the impact of ERT on fatigue and pain were identified from the following four publications on humanistic burden, as described above [25, 29, 30, 41].

The impact of ERT on patients’ ability to perform ADL was reported in three studies, including Güngör et al. [29] and van Capelle et al. [41] described previously. In addition, information is taken from a Japanese case series of five long-term, ventilator-dependent patients with advanced LOPD (mean age of onset, 22 years), which examined the efficacy of ERT over a 2-year period [40].

In the International Pompe Survey [29], RHS scores decreased significantly by a mean of 0.49 sp./y (95% CI, −0.63 to −0.34) before ERT initiation and stabilized during ERT treatment (−0.02 sp./y; 95% CI, −0.17 to 0.13). No formal statistical comparisons between the two time periods were provided for ADL. Subgroup analyses showed that overall, RHS scores were better in less severely affected than in more severely affected patients, but the effects of ERT on the ADL of these subgroups did not differ. Van Capelle et al. [41] reported improved RHS scores over time for two of three adults receiving ERT (from 16 and 18 after 3 years of ERT to 25 and 20, respectively, after 8 years). Finally, Furusawa et al. [40] assessed the impact of ERT on patient ADL through interviews with patients and their families. Qualitatively, the authors reported that all patients showed some improvements in ADL and in muscle function, while they also argued that ERT elicited improvements in walking distance and stabilization of pulmonary function. The authors speculated that the improved muscle strength resulted in the better ADL and HRQoL during the follow-up period; however, no quantitative analysis was provided to support this.