The impact of COVID-19 infection, the pandemic and its associated control measures on patients with Pompe disease

This one-time, cross-sectional, questionnaire survey was designed to assess the impact of COVID-19 infection(s), as well as the pandemic and its associated control measures on patients with Pompe disease worldwide. An online questionnaire was created as a collaboration between the Center for Lysosomal and Metabolic Diseases (CLMD) of the Erasmus MC University Medical Center, and the International Pompe Association (IPA), as on request of the IPA. Patients were eligible to participate in this study if they had a diagnosis of Pompe disease, were over 16 years of age and were able to speak one of the eight languages in which the questionnaire was available. All of the outcomes used in this study are patient-reported.

The study design was submitted for approval by the Medical Ethics Committee of the Erasmus MC University Medical Center. It was labeled as not subject to Medical Research Involving Human Subjects Act (WMO) on the June 28, 2022 (MEC-2022-0411). All patients provided online informed consent by checking the consent question in the online survey.

From September 20, 2022, patients were invited to participate in this study by their national patient organization (Australia, Canada, China, France, Germany, Italy, the Netherlands, New Zealand, Portugal, Spain, UK and USA) or were individually approached by representatives of the IPA. Reminders were sent in several countries, e.g., when the number of responses received was lower than expected. In addition, the survey was advertised on social media, asking the patient to contact designated representatives. The questionnaire was officially closed on November 7, 2022. The time period in which the survey was available is visualized in Fig. 1.

The questionnaire was designed using SurveyMonkey and contained 87 questions. The full questionnaire can be found in Supplementary File 1. It did not ask for any identifiable information except sex, country, month and year of birth, age of onset symptoms and age of diagnosis (for Pompe disease). The content of the questionnaire was based on patient experiences reported by representatives of the IPA and recently published literature regarding COVID-19 and its overall impact on physical and mental health in the general population and in patients with NMDs. Questions were mostly asked in the form of multiple-choice questions and using various formats of a Likert scale, but also yes/no questions and a few open questions were included. The questionnaire was divided into three parts. Part A was designed to collect data regarding the patients’ overall health with respect to Pompe disease. This was based on core elements of the Pompe-specific questionnaire developed for the ongoing annual Pompe survey [36]. Part B was used to assess COVID-19 specific topics, such as vaccination status, precautions taken, the patients’ history of COVID-19 infection(s), the severity of the infection(s) and the effect this had on their mobility and overall and respiratory condition. Lastly, part C was designed to assess the effects of the COVID-19 pandemic on patients’ general health with respect to Pompe disease, their lifestyle, treatment and mental health. The questionnaire was translated into eight different languages (Chinese, Dutch, English, French, German, Italian, Portuguese and Spanish). This was done by the process of forward translation and consensus by two independent IPA associates who have high proficiency in the language of interest.

Patients were excluded if they did not answer any COVID-19-related questions. Data cleaning involved fixing and/or removing incorrect and duplicate data. Alleged duplicates were identified by birth year, birth month, sex, country of origin, age of onset symptoms and age of diagnosis. If potential duplicates responded differently on many of the questions in sections A, B and C, or if there were essential differences between them, both responses were retained. Essential differences were defined as differences in certain abilities (e.g., walking, breathing), use of aids, specific years and answers that were on two different ends of a spectrum (e.g., not feeling concerned about the pandemic and feeling very anxious). A consensus meeting (M.T.M.T., R.M.v.d.E. and N.A.M.E.v.d.B.) was held on November 9, 2022, to reach agreement about removing or retaining alleged duplicates. When consensus was met, the response that contained the most answered questions was retained. Both fully and partially completed questionnaires, given that at least one COVID-19-related question was answered, were analyzed in this study. With regard to open questions, consensus meetings (M.T.M.T., R.M.v.d.E. and N.A.M.E.v.d.B.) were held to discuss the correct interpretation of the answers. Some open answers were considered to match an already pre-specified answer and were interpreted accordingly.

Patients were divided into four categories with regard to the severity of Pompe disease. The first category consisted of mildly affected patients, defined as those reporting to use neither breathing aids nor walking aids nor a wheelchair/mobility scooter. Patients who did not use breathing aids, but did use walking aids (or reported not to use walking aids but needing to use one according to their physician) and/or were partially wheelchair-/mobility scooter-dependent, were in the second category and were classified as moderately affected. The third category consisted of severely affected patients, meaning (1) patients using breathing aids solely during the nighttime (or reporting not to use them but needing them according to their physician) or (2) being fully wheelchair-/mobility scooter-dependent. Finally, the last category consisted of very severely affected patients, meaning those reporting (1) using both breathing aids during the nighttime and being fully wheelchair-/mobility scooter-dependent or (2) using breathing aids during the daytime or both day- and nighttime (irrespective of their wheelchair use) or (3) having invasive ventilation (irrespective of their wheelchair use). With regard to age, patients were divided into four age groups: 16–35, 35–50, 50–65 and over 65 years of age.

Descriptive analyses, based on the total number of patients who filled in the question of interest, were performed using IBM Statistical Package for the Social Sciences (SPSS) version 28. The median (interquartile range) was reported for numerical data and the absolute number (%) for categorical data.

A total of 366 responses were assessed for eligibility. Due to the use of multiple platforms to distribute the questionnaire, it was not possible to calculate the average response rate. We excluded 17 patients (no answers to any outcome measures) and removed 7 duplicates (Fig. 2). The final study population consisted of 342 patients. A little over half of patients identified as female (56.7%), the median age was 51 years (IQR 38.0–61.0) and the median disease duration was 22 years (IQR 13.0–31.0) (Table 1). Patients originated from 25 different countries (Fig. 3), the highest number coming from the Netherlands, the USA and Germany. Most patients (n = 297) reported being currently treated with ERT. One patient reported to have been treated with gene therapy. Of the 342 patients, 97 were mildly affected by Pompe disease, 46 patients were moderately affected, 121 patients were severely affected and 78 patients were defined to be very severely affected. Two patients reported to need breathing aids according to their physician, but to not have access to them. One of them also needed walking aids according to their physician, but did not have access to them. Both patients originated from Brazil.

Almost half of the patients (159/334 [47.6%]) reported to have had a confirmed COVID-19 infection (Table 2). Most patients (108/155 [69.7%]) recovered within 4 weeks, while 23.9% (37/155) took longer to recover. Ten patients (10/155 [6.5%]) indicated they were not fully recovered of whom six had a COVID-19 infection within 4 months prior to completing the questionnaire. Of the patients who needed longer than 4 weeks to recover, tiredness and pain were the most common residual complaints.

Eight patients (8/155 [5.1%]) were hospitalized due to their first COVID infection, six of whom were female, seven were severely or very severely affected (by Pompe disease) and five were between 35 and 50 years. All hospitalized patients were vaccinated. No hospitalized patients needed to be admitted to the intensive care unit, although two needed temporarily respiratory support (both female, severely affected and over 50 years of age).

Of the patients who had gone through a COVID-19 infection, one in three indicated that the infection worsened their overall condition (53/155 [34.2%]), one in four their mobility status (38/154 [24.6%]) and one in five their respiratory status (34/155 [21.9%]). Over half of patients (89/154 [57.8%]) did not indicate worsening of any of these three domains. Worsening was more commonly reported in patients over 65 years of age and in very severely affected patients (Fig. 4). Similar proportions were observed between sexes (overall condition 34.1% females and 34.3% males; respiratory status 20.0% females and 24.3% males; and mobility status 22.6% females and 27.1% males). Due to their COVID-19 infection, four patients reported needing more hours of ventilator support per day (two of whom reported this was permanent), two patients started using breathing aids (one of whom needed it permanently) and one patient needed the settings of his breathing aids adjusted.

Most patients received one or more COVID-19 vaccination(s) (326/342 [95.3%]), of whom 309 indicated to have received all recommended doses. This proportion was similar among sexes (95.9% female, 94.6% male). A bigger proportion of mildly affected patients (8.2% mild, 2.2% moderate, 3.3% severe and 3.8% very severe) and patients under 50 years of age (7.9% under 50 and 2.1% above 50) were not vaccinated. Most patients (285/318 [89.6%]) reported also to have received one or more booster doses.

At the start of the pandemic, the majority of patients (224/333 [67.3%]) reported they were in quarantine and only met with essential contacts. This precaution was taken by a larger proportion of the severely and very severely affected patients (48.4% mild, 63.0% moderate, 74.6% severe and 82.4% very severe) (Fig. 5). Numerous patients also took more general precautions, e.g., wearing a facemask (237/333 [71.2%]) and keeping 1.5 m distance (236/333 [70.9%]). Among patients who reported to take other precautions, disinfecting hands or objects was most commonly reported. Only six patients (1.8%) reported to take no precautions at the beginning of the pandemic.

When filling in the questionnaire (September–November 2022), a minority of patients (30/333 [9.0%]) still reported to be in quarantine and to only meet with essential contacts. As before, this consisted of a bigger proportion of very severely affected patients compared to other severity groups (3.2% mild, 2.2% moderate, 9.3% severe and 20.3% very severe). Compared to the start of the pandemic, less patients took more general precautions, with wearing a mask when out in public or around those not in their household being the most applied (151/333 [45.3%]). Among patients who reported to take other precautions, disinfecting hands or other objects and avoiding crowds and large groups of people was most commonly reported. In contrast to the start of the pandemic, more patients (123/333 [36.9%]) took no precautions, especially among mildly affected patients (50.1% mild, 37.0% moderate, 33.9% severe and 24.3% very severe) (Fig. 5).

A change in medical appointments due to the pandemic, including less appointments and online consultations, was reported by 56% of patients (182/325). A larger proportion of severely and very severely affected patients reported a change in medical appointments (46.7% mild, 50.0% moderate, 61.7% severe and 62.5% very severe), as well as a bigger proportion of patients from the USA (35/49 [71.4%]) and Italy (21/28 [75.0%]) (Fig. 6). Physical therapy was reported to have been paused once or more than once as a consequence of the pandemic by 52.6% of patients (141/268). The duration of this cessation ranged from 2 weeks to 24 months in total (median 3 months (IQR 1.8–11.0)). Multiple patients reported to receive caregiver help (80/324 [24.7%]), of whom 23 patients experienced reduced visits as a result of the pandemic (28.7%). This change was reported by all 6 patients from Brazil with caregiver help (Fig. 6). The most reported consequence of reduced visits was increased loneliness and/or social isolation.

Overall health with respect to Pompe disease Compared to the start of the pandemic, 43.1% of patients (140/325) reported that their overall health with respect to Pompe disease had worsened, of whom 90 (64.3%, 27.7% of total) believed this was due to the pandemic and/or lockdown (Fig. 7a). A smaller proportion of milder affected patients (17.8% mild, 16.7% moderate, 40.0% severe and 25.6% very severe) and a larger proportion of woman (61.1% females and 38.9% males) indicated worsening of their disease due to the pandemic. Of the patients indicating worsening of their disease because of the pandemic, 42.2% experienced a COVID-19 infection. The most commonly reported lifestyle changes as a result of the pandemic were: less exercise (139/324 [42.9%]), being more aware of food habits (82/321 [25.5%]), both more and less snacking (58/320 [18.1%] and 54/320 [16.9%]) and a decrease in hours of sleep (52/324 [16.0%]) (Fig. 7b) (see Supplementary File 1 for all possible answer options).

Mental health Many patients reported to be mentally affected by the pandemic (179/323 [55.4%]), e.g., experiencing possible symptoms of anxiety or depression or experiencing problems with concentrating or sleeping. A bigger proportion of female patients (60.9% females and 48.6% males) and mildly affected patients (61.5% mild, 47.8% moderate, 56.5% severe and 50.7% very severe) reported that their mental health was affected by the pandemic (Fig. 7c). Feeling nervous, restless or tense was the most common complaint (113/323 [35.0%]) and talking to friends and/or family was the most common reported coping mechanism (248/323 [76.8%]) (Fig. 7d) (see Supplementary File 1 for all possible answer options).

Moreover, a considerable number of patients were reported to have experienced an increased feeling of loneliness and/or social isolation as a result of the pandemic and/or lockdown (139/320 [43.4%]). The proportion of patients experiencing loneliness and/or social isolation was bigger in females (46.4% females and 39.7% males) (Fig. 7e) and smallest in patients over 65 years of age (44.4% 16–35, 52.0% 35–50, 43.1% 50–65 and 32.2% 65 +). Most patients (98/139 [70.5%]) experiencing loneliness and/or social isolation were still taking one or more precautions when filling in the survey. The most often reported coping mechanism was an increase in time spent on entertainment (e.g., reading, watching television, etc.) (102/320 [31.9%]) (Fig. 7f) (see Supplementary File 1 for all possible answer options). In total, 2 in 3 patients (183/278 [65.8%]) indicated to be affected mentally and/or experiencing an increased feeling of loneliness and/or social isolation as a result of the pandemic.