First booster dose uptake of COVID-19 vaccine and disease-related factors in chronic obstructive pulmonary disease—a cross-sectional survey in Hungary

Introduction

The coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is currently causing a pandemic (1). Slowing the spread of the global epidemic remains a paramount importance to everyone, with many segments of society working to reduce the number of new infections (2). The disease has mild to moderately severe symptoms in most infected individuals, where the recovery can happen without hospitalization (3). However, people with chronic diseases such as chronic obstructive pulmonary disease (COPD) and older people are at a higher risk of developing serious complications (4). Primary prevention, including basic and booster vaccination(s) against the virus, is paramount (5).

Studies have described that the COVID-19 booster vaccines uptake significantly reduce the transmission and severity of COVID-19 infection, while increasing the titer of antibodies against different types of coronavirus variants (6-8). Therefore, the Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and the European Medicines Agency (EMA) all unanimously recommend the inclusion of booster vaccine(s), especially for at-risk groups (6,7). CDC data show that those who have been vaccinated in time for the full series are 13 times less likely to die from COVID infection than those who have not been vaccinated, and three times less likely to die than those who have not received the first booster vaccine. In addition, the COVID-19 booster vaccines can be given at the same time as the seasonal annual flu inoculation, with no waiting period between vaccinations (8).

According to a CDC study, booster vaccines from Pfizer and Moderna’s COVID-19 inoculations are highly effective in preventing hospitalizations due to the Omicron variant (9). Booster vaccines can put a stop to the need for hospitalization after infection in 90% of cases and prevent the need for emergency department admission in 82% of patients who are infected and hospitalized (10). Data show that unvaccinated adults over the age of 65 who are infected with COVID-19 are 49 times more likely to be hospitalized than those who are vaccinated and have received the booster vaccine, too. The unvaccinated adults over the age of 50 years are 45 times more likely to be hospitalized than those who have been vaccinated and have received the booster dose, too (11-13).

Song et al.’s study found out that the actual uptake rate of COVID-19 vaccination was relatively low (39.0%) among COPD patients, although the majority of them would be willing to accept the COVID-19 vaccine (14). Surprisingly, nearly half of the patients who were not vaccinated against this disease were not recommended by their doctors to be even vaccinated against COVID-19, which was probably the main reason for the low vaccination rates among them. In addition, their data have shown that a significant proportion of them have a lack of the necessary knowledge about the inoculation and lack confidence in the efficiency and safety of COVID-19 vaccination, which also acts as a barrier to the uptake (14). Another Chinese study described the COVID-19 vaccination rate among postoperative breast cancer patients was only 36.0% and a significant proportion of patients believed that COVID-19 vaccination could have a negative impact on the chemotherapy they received, i.e., that their recovery would be set back by receiving the vaccine(s), and were also concerned about the side effects of the vaccine (15). The role of healthcare staff (doctors, nurses) is therefore indisputable in promoting any vaccination, including COVID-19, raising awareness, dispelling misinformation and providing patients with comprehensive information. Unfortunately, misconceptions and misinformation about vaccination remains a major barrier to the uptake and to achieve an optimal vaccination coverage as well as to herd immunity in Hungary for various vaccines, e.g., seasonal influenza, pneumococcal vaccines, COVID-19 vaccine (16). A recently published meta-analysis described an association between people’s gender, place of residence, sociodemographic characteristics and their willingness to be vaccinated against COVID-19 (17). This study showed that Chinese men are 1.48 times more likely to be vaccinated against COVID-19 than women are (17). No similar study specifically for COPD patients was found in the international and national literature, the uptake of the first booster vaccine COVID-19 among COPD patients in Hungary and its related factors have not been investigated yet. Therefore, the aim of our study was to assess the uptake rate among them and to describe the related factors of first booster vaccine uptake in relation to disease-related factors such as quality of life, presence of comorbidities, smoking status, gender, age, previous COVID-19 infection, number of hospital visits. We present the following article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1256/rc).

Methods

Study design and population

A cross-sectional study was conducted in COPD patients from the eastern, western and central regions of Hungary from November 15, 2021. Patients were recruited from outpatient pulmonary clinics from community hospital, and their data were collected according to routine clinical practice. A total of 1,511 patients were included who were informed of the survey verbally and in writing before signing a consent statement. The exact dates of the COVID-19 vaccinations were obtained from the National eHealth Infrastructure (abbreviated EESZT). For one patient, the fact of revaccination could not be verified with certainty due to his employment abroad in the meantime, and he was excluded from the study, so 1,510 patients were included in the analysis. The study was approved by the Hungarian National Institute of Pharmacy and Nutrition (document No. IV/7743-1/2021/EKU) based on a positive review by the Hungarian National Research Ethics Committee (registration No. CHMED_2021/01), and the study complies with the Declaration of Helsinki (as revised in 2013). Inclusion criteria for the study were age over 35 years, patients with known COPD [forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) <70% after bronchodilator] (18), specialist diagnosis and inhalation therapy at least 1 year earlier. Exclusion criteria were the followings: if the patient did not meet any of the above expectations, or if the patient was unable to complete the portion of the questionnaire applicable to him/her. Anthropometric measurements, respiratory function test results, COVID infection history and post-COVID symptoms were recorded for the visiting patients. Our current study protocol and details of the conduct of the study were described in detail in our previous article (19).

Measurements

The uptake of the first booster dose (3rd vaccination) of COVID-19 vaccine was the outcome variable of the study. We have asked the participants if they had received a first booster dose of the vaccine, with the response options of yes/no. The gender was bivariate: male or female, and the place of residence was divided into three regions: Western, Eastern and Central Hungary. Our questionnaire asked about smoking habits: current heavy smoker, never smoked or quit smoking with response options. We also asked about co-morbidities, medications used for COPD, and the number of exacerbations (severe and moderate) in the past year. We also asked about the number of visits to healthcare facilities in the past year: visits to general practitioners (GPs), emergency departments, pulmonary departments and pulmonary outpatient services. When recording the COVID-19 vaccination history, we asked for vaccination status. Yes = vaccinated/no = not vaccinated. In the case of vaccinated patients, we also asked for the exact date of all three vaccinations and checked in EESZT, then recorded in the Excel spreadsheet of the survey. We asked whether the patient had SARS-CoV-2 infection, if so when, and whether he had required hospitalization for the acute COVID-19 infection. We also asked whether they had required pulmonary outpatient care for post-COVID symptoms, the response options were yes/no.

Examination of respiratory function

All patients underwent respiratory function testing with an automated computerized spirometer. Dynamic lung volume is defined as FEV₁, the degree of airway obstruction (ratio of FEV1/FVC) and the inspiratory vital capacity (IVC). Global Lung Function Initiative (GLI)—defined normal spirometry stratifies patients into Global Initiative for Chronic Obstructive Lung Disease (GOLD) A–D stages based on current and future risk parameters such as associated symptoms, quality of life [COPD Assessment Test (CAT)/modified Medical Research Council (mMRC)] and exacerbation numbers (20).

Quality of life examination

The CAT is used to measure quality of life. Patients answered eight questions and rated symptoms on a scale from 0 to 5, with 0 being healthy and 5 being severe symptoms. Subjective assessments of cough, sputum production, hyperinflation, resilience and energy levels while climbing stairs, and whether the patient dared to leave the house or whether the illness interfered with sleep (21).

mMRC dyspnea questionnaire

The mMRC questionnaire stratifies the severity of dyspnea and consists of five items; it almost completely covers the entire spectrum of shortness of breath, from no problems (grade 0) to complete respiratory failure (grade 5). Patient-rated on a scale of 0–5, all questions are relevant to daily activities and easy for the patient to understand. A score can be calculated in seconds and is the number that best matches the patient’s condition (22).

Definition of exacerbation

COPD exacerbations were defined according to the current GOLD definition. Moderate exacerbations require a prescription for antibiotics or systemic corticosteroids, whereas severe exacerbations require admission to the emergency department or hospital (18,20).

Definition of COVID-19 infection

Any subject, who was asymptomatic or developed at least one of the following symptoms during the study period: cough, increased body temperature, fever, dyspnea, sudden loss of smell, loss of taste, or dysgeusia, and had detectable SARS-CoV-2 nucleic acid or antigen.

Body mass index (BMI)

BMI (kg/m²) is calculated by dividing weight in kilograms (kg) by the square of height in meters (m²).

Statistical analysis

All statistical analyses were conducted in SPSS 28.0.0. Non-parametric statistical techniques were utilized because the majority of the continuous data did not conform to the normal distribution, as demonstrated by the Shapiro-Wilk test. Medians and interquartile ranges (IQRs) were used to interpret and represent continuous variables. Case numbers and ratios were used to present categorical data. Continuous variables were compared between the two groups using Mann-Whitney tests; Kruskal-Wallis tests were used when there were more than two groups. Fisher’s exact test was used to investigate categorical variable frequency differences. The data were described using multiple logistic regression analysis to explain the relationship between various variables and unvaccinated and triple-vaccinated patients. Odds ratios (ORs) are presented with 95% confidence intervals (95% CIs), the significance level was P<0.05. In the logistic regression analysis, ORs are presented for sex (female/male), age, region of living (central/eastern/western), number of moderate/severe exacerbations (<1/≥1), GP care and emergency/pulmonary hospitalization (yes/no), CAT score, mMRC score, GOLD stage (CD/AB), currently smoking status (yes/no), number of comorbidities (<2/≥2), previous history of COVID-19 infection (yes/no), and participation in COVID-19 rehabilitation (yes/no). All statistical tests were two-sided, took into account a 95% CI, and the significance level was set at P<0.05.

Results

Sociodemographic and functional features

A total of 1,510 COPD patients took part in the study, 52.05% of whom were female and 47.95% male. The observed patients had been smoking an average of 17.5 cigarettes a day for 35.5 years. Almost half of the patients (46.49%) (n=702) were still active smokers, while 14.7% of patients (n=222) had never smoked. Demographic and anthropometric characteristics of the patients are presented in Table 1.

Overall, 943 (62.45%) participants received a booster dose of COVID-19 vaccine. The median age of the patients was 67 [61–72] years, older age can be associated with a higher proportion of COVID-19 booster vaccine administration 68 [63–73] vs. 64 [57–70], P<0.001. The booster dose was used significantly more in the western regions of the country (42.42%) than in the eastern (30.54%) or central (27.04%) regions. Significantly more men (51.64%) received the booster dose than women (48.36%). Patients who quit smoking and those who never smoked were significantly more likely to take the first booster dose of COVID-19 vaccine (P<0.001) (Table 1).

Co-morbidities, quality of life, acute SARS-CoV-2 infection and post-COVID symptoms

Among the comorbidities the presence of hypertension (P=0.04) and acute myocardial infarction (MI) (P=0.008) were significantly associated with first booster vaccine uptake (Table 2). The quality of life: CAT: 16 [11–21] vs. 14 [10–19], P <0.001, mMRC dyspnoea scale points: 2 [2–2] vs. 2 [1–2], P=0.01, the severity of the disease (GOLD stage) and the number of moderate exacerbations in the previous year: 1 [0–1] vs. 0 [0–1], P=0.04 were also significantly associated with the uptake of the 3rd COVID-19 vaccination (Table 1). None of the three vaccine recipients had developed COVID-19 acute infection, while 11.46% of those who did not receive the first booster vaccination developed one (P<0.001). One-fifth (n=16) also required hospitalization for acute SARS-CoV-2 infection, and almost the same proportion (n=14) required pulmonary outpatient rehabilitation for post-COVID symptoms (Table 1).

Patients’ inhaled medication use and number of hospital visits

Table 3 presents the medications used by our patients, showing that those who took the third vaccination (first booster), required significantly fewer short-acting beta-agonists (SABAs) (P<0.001), so there were fewer exacerbations during the study period. Significantly, fewer used a combination of inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) (P=0.01), and a combination of LABA, long-acting muscarinic antagonist (LAMA) and ICS or “triple therapy” (P=0.04). Patients who received three vaccinations used LAMA significantly more, than those who did not receive the third vaccination (P=0.04). No significant difference was found for the other combinations. The number of visits to healthcare facilities by COPD patients in the past year can be seen in Table 4. Patients receiving the COVID-19 first booster dose had a significantly lower rate of emergency department visits, which is associated with disease severity: 0 [0–0] vs. 0 [0–0], P=0.01.

Multiple logistic regression analysis

Multiple logistic regression analysis showed that male gender (OR: 0.74; 95% CI: 0.57–0.96; P=0.02), older age (OR: 1.06; 95% CI: 1.04–1.08; P<0.001), absence of previous COVID-19 infection (OR: 0.34; 95% CI: 0.23–0.51; P<0.001) significantly influenced the uptake of first booster vaccination and were predictive factors for uptake of the third COVID-19 vaccine. Those who had sought emergency care in the past year were less likely to receive a third vaccination (OR: 0.54; 95% CI: 0.37–0.79; P=0.002) (Table 5).

Discussion

The aim of our study was to investigate the uptake rate of the first booster vaccine against COVID-19 and to identify predictors of vaccine uptake. Our results suggest that the coverage of COVID-19 first booster vaccination among patients is suboptimal (62.45%), i.e., lower than the target. Patients vaccinated three times compared to those who did not receive a third vaccination, the difference between their quality of life (CAT), severity of dyspnea (mMRC) and the number of moderate exacerbations were all significant. In terms of post-COVID symptoms, there were significantly fewer outpatient hospital admissions among patients who had been vaccinated three times. The factors that were most associated with higher COVID-19 vaccine booster dose uptake were the following: older age, male sex, place of residence (western regions of Hungary), quality of life (CAT, mMRC), absence of previous COVID-19 infection and lower rates of exacerbations and emergency hospital visits.

In Hungary, large quantities of vaccines of all types are available, but unfortunately, the vaccination coverage rate is very low, with just over one third of people having received the first booster vaccine (39.7%) (23). The WHO target is at least 70% and 100% for elderly, vulnerable people and health workers (24). In Hungary, there has been strong social and health action to increase the vaccination coverage rate, with a target of at least 80%. Governmental measures to protect the population are also very strong, e.g., formal, valid proof of COVID immunity or a recent negative COVID-19 antigen test/negative PCR result is required in public enclosed spaces that are visited daily (e.g., health care facilities) and there was a 10-day official quarantine during the study period in case of COVID-19 infection (19). In the present study, the vaccination coverage of COPD patients is below the desired target but better than the Hungarian average population (62.45% vs. 39.70%). Those who have not yet received a first booster vaccine should definitely consider receiving one, as this new vaccine offers hope of mitigating the effects of future potential new waves of COVID-19 (25). New generation vaccines are already available, in the hope that these will not only increase the number of antibodies more potently, thus providing stronger protection, but hopefully this protection will also be longer and more durable, so that fewer booster vaccines will be needed in the future. Vaccines are also the best way to prevent serious infections, hospitalizations and death (26,27). It is therefore a priority for health workers to promote vaccination, raise awareness about the efficacy and safety of vaccines, and highlight the importance of taking booster vaccine(s), especially for at-risk groups e.g., elderly, chronically ill, health workers at risk, but all in all for the general public.

The presence of COPD does not necessarily mean a higher risk of developing COVID-19, but patients treated with multiple drugs, some of which affect the immune system, such as high-dose systemic steroids given in exacerbation, have a more severe outcome. COVID-19 affects the respiratory system, so COPD increases the chance of developing more serious complications. In COPD, on the one hand, the body’s defence system does not function properly and on the other hand, the respiratory surface area is reduced, as well as the respiratory reserve, which in the case of pneumonia, quickly leads to respiratory failure (28). Some patients already need oxygen therapy on a daily basis, and for them, coronavirus infection can be particularly dangerous. Active smokers and patients with COPD have increased expression of the angiotensin converting enzyme-2 (ACE-2) receptor in the lower airways, which may partly explain why COVID-19 poses an increased risk among them (29). In the case of other respiratory viruses, such as respiratory syncytial virus, inhaled tobacco smoke has been described to increase both the speed and severity of transmission of viral respiratory infection (30). However, the specific mechanisms by which COVID-19 infection increases COPD severity and mortality through specific pathomechanisms are not yet known.

COPD exacerbation is a very important event in the natural course of the disease, which is associated with worsening of symptoms, often resulting in hospitalization and a rather poor prognosis. Causes include various bacteria, other pathogenic factors such as increased air pollution, stress, etc., but viral infections, including coronaviruses, remain the main trigger (31). The reduction in the number of potentially fatal exacerbations also justifies effective preventive measures, including vaccination, to reduce the risk of COVID-19 infection in COPD patients and current smokers. There are gender differences in vaccine uptake in COPD patients, e.g., lower uptake of influenza vaccine among women (32) and lower uptake of COVID-19 vaccine, than men (33). This is confirmed by our present study. Studies have also described that vaccine uptake increases with age, which also correlates positively with our study (33-36).

However, vaccine hesitancy and misinformation remains a major barrier to achieving optimal vaccination coverage around the world, including Hungary. Previous studies have described that the willingness to receive booster doses of COVID-19 vaccine is based primarily on the benefits of information and communication (37,38). While the National Immunisation Programme in Hungary—thanks to the National Immunisation Programme—is an example of an almost 100% vaccination rate in children, the adult immunisation programme is still on hold. The benefits, both social and economic, of launching an effective lifelong vaccination programme for adulthood could bring very significant results. On the one hand, it is an effective protection against serious infectious diseases and, on the other hand, the widespread use of vaccination can indirectly reduce the use of antibiotics, thus contributing to the reduction of antibiotic resistance (39).

In Hungary, people received the vaccination card after the second COVID vaccination, so they were not forced to take the first booster vaccination, except the workers in high-risk jobs, e.g., people working in health care and higher education institutions. Therefore, the uptake rate of the 3rd vaccination is much lower, than that of the second COVID-19 vaccination (63.2% vs. 39.7%) (23). Studies have described that the uptake rate of COVID-19 booster dose increased as the educational attainment increased (40,41). Comorbidities such as respiratory diseases (for example asthma, COPD), hypertension, diabetes mellitus, tumour and immunodeficiency diseases showed positive correlations with participation in booster vaccination (42). Our current research has reached a similar conclusion. Several studies have described younger age, female sex, lower education and lower income as being associated with lower vaccine uptake (43-45). In addition, the recommendation of doctors and health care staff is the primary factor driving vaccine uptake (46), which is also true for patients with chronic diseases (47). Doctor recommendation is also a well-known motivating factor for uptake of other infectious disease vaccines (48,49). A cross-sectional study made in Beijing (14) revealed that the actual uptake rate of the vaccine was relatively low (39.0%), although their research predicted that the majority of their patients would be willing to accept the COVID-19 vaccine. To their surprise, only 16.2% of patients (n=161) who had not received COVID-19 vaccination reported that clinicians had recommended the uptake, while 23.5% were unaware of the inoculation, probably the main reason for the low uptake rates among these patients. Educating patients that the benefits of vaccination outweigh the potential risks should be a very important task for healthcare workers. Revaccination, i.e., receiving three vaccines, provides long-lasting protection not only against acute COVID-19 infection, but also against respiratory failure, the development of post-COVID syndrome and death. These are very important because COPD patients are at higher risk of developing serious complications from COVID-19 (19).

There is currently no data available on the effectiveness of COVID-19 vaccines specifically for people with COPD. However, all approved vaccines show fully reliable and promising levels of efficacy (50). The humoral and cellular immune responses of COPD patients to COVID-19 vaccination were similar to those of healthy controls, ensuring that current vaccines elicit the desired immune response in COPD despite the presence of immune dysregulation (51). A preprint 2021 study suggests that those who receive the full vaccine series (i.e., 3 vaccines) are three times less likely to acquire a new COVID-19 infection (52). Our present research also supports the protection of vaccinated patients. For all these reasons, we would like to recommend that health organizations, the government and other authorities develop strategies to increase public knowledge and awareness in order to dispel myths and disinformation about the booster dose of COVID-19 vaccine as well as to achieve full vaccination coverage and herd immunity.

Limitation

Our cross-sectional survey is an observational study that should be interpreted with caution. First and foremost, a potential bias may be the fact that vaccinated patients are more likely to have access to health care, be more motivated to seek treatment and take other protective measures for themselves such as adherence to medication, avoiding tobacco smoke and people with active respiratory infections, using masks and washing hands regularly. Second, our patients were not longitudinally followed up over time; therefore, we do not know whether they subsequently received booster (third and fourth) vaccinations. Thirdly, our questionnaires, e.g., CAT, mMRC, might be validated, but they are subjective and symptom-based, as is the experience of moderate exacerbation. The symptoms were based on patient self-reported data, potentially leading to misclassification, and we did not ask about patients’ attitudes, fears and knowledge about vaccines. Fourthly, and last, those who have taken the full series of vaccinations are more likely to be health conscious and in addition more cooperative with their doctor, which has a long-term impact on their quality of life.

Conclusions

Among COPD patients in Hungary, uptake of the COVID-19 booster vaccine is lower than the targeted value. The factors that were most associated with higher COVID-19 vaccine booster dose uptake were the following: older age, male sex, region of residence (western regions of Hungary), better quality of life, lower number of exacerbations and emergency hospital visits, and absence of prior COVID-19 infection. Health personnel should make it a priority to promote vaccination, to raise awareness of the efficacy and safety of them, to educate patients as well as to highlight the importance of taking booster vaccine(s).

Acknowledgments

The authors would like to thank all clinicians partaking in the collection of clinical data: Alb Krisztina Éva, Alföldi Ibolya, Bánvölgyi Aranka, Bárány Magdolna, Bártfai Zoltán, Bartha Anna, Beke Márta, Bencze Ágota, Bende Zoltán Gyula, Bérdi Eszter, Berzai Eszter Júlia, Bitay Zsuzsanna, Bolya Zsuzsanna, Borota Mirela, Böszörményi Katalin, Breining Ildikó, Búrzuk Valéria, Czompó Márta, Csajbók Valéria, Csicsári Katalin, Csollák Mária, Csontos Éva, Diós Edit, Donka Tünde, Draskóczy Andrea, Ferencz Barbara Aranka, Filkorn Rózsa, Frank Emil, Füleki Margit, Füzesi Edit, Füzesi Katalin, Gönczi Mariann, Hajdu Krisztina, Hangonyi Csilla Mária, Horváth Gabriella, Huszár Hermina Eveline, Igyártó Rozália, Jakab Zoltán, Jancsikin Ljubomir, Juhász Erzsébet, Juhász Tibor, Kalmár Éva, Kaposi Katalin, Kató Ernő, Kecskés Teréz, Kerényi Ildikó Zsuzsanna, Kis Sándor, Kiss Gabriella, Kollár Erzsébet, Kondora Zsanett, Kontz Katalin, Kónya Melinda, Körmendy Szabolcs Dénes, Kuberka Zoltán, Kuczkó Éva Mária, Kukuly Alla, Kukuly Miklós, Kurucz Anikó, Kurucz Edina, Lukács Zsuzsanna Éva, Madai Ildikó Zsuzsanna, Maha Jakoob, Major Katalin, Makk László, Medek Lívia, Mészáros Imre, Mózes Imre István, Nádudvary Ildikó, Nagy Andrea, Nagy Emília, Osvai László, Papp Márta, Pappné Dr. Ferenczy Nóra, Poncsák Mária, Puskás Emese, Radeczky Éva, Radu Simona, Schlezák Judit, Selypes Ágnes Erzsébet, Simorjay Zsuzsanna, Sipos Anikó, Sipos Valéria, Somogyi István, Steierlein Mária, Süveges Tibor, Szabó Csilla, Szabó Éva Teréz, Szabó Gyöngyi, Szabó Marianna, Szabó Márta, Szakács Éva, Száraz Éva, Szarka Ildikó, Szeleczki Róza, Szenes Éva Julianna, Szereday Ildikó, Szigeti Ilona, Szilas Gábor, Szkunzjak Viktória, Szolnoki Erzsébet, Tamás Gabriella, Tankó Magda, Tehenes Sándor, Tóth Sándor, Tóth Tivadar, Tóth Zsuzsanna, Unger Erika, Varga Ágnes, Várnai Beáta, Vecsey Erika, Vidák Zsolt, Vincze Árpád, Vinkler Ilona, Vitus Ernő, Walcz Erzsébet, Zagyva Tamás.

Funding: The research was funded by Chiesi Hungary Ltd. MF was supported by project No. TKP2021-NKTA-47, which has been implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-NKTA funding scheme.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1256/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1256/dss

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1256/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1256/coif). All authors report that the research was funded by Chiesi Hungary Ltd. AH, BS, and GT are employees of Chiesi Hungary Ltd. MF was supported by project No. TKP2021-NKTA-47, which has been implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-NKTA funding scheme.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study protocol was approved by the Hungarian National Institute of Pharmacy and Nutrition (docket No. IV/7743-1/2021/EKU) based on the positive assessment by the National Scientific and Research Ethics Committee of Hungary (registration No. CHMED_2021/01), and it complies with the Helsinki Declaration (as revised in 2013). Patients were given oral and written information prior to the assessment, and then they signed a statement of consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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