Abstract
Background
Asthma causes various clinical symptoms, including unpredictable severe exacerbations, and even though most patients can achieve a reasonable disease control due to adequate treatment, some patients do not. This study seeks to describe healthcare resource utilization (HCRU) and treatment of asthma and severe asthma patients in Germany.
Method
A retrospective claims data analysis has been conducted on adult asthma patients and a subset of patients with severe asthma, identified during July 2017 – June 2018. A proxy was used to identify severe asthma patients based on therapy options recommended within the German treatment guideline for treating these patients. These include (i) biologics, (ii) medium/high-dose inhaled corticosteroids (ICS) in conjunction with LABA/montelukast and antibiotics/oral corticosteroids (OCS), and (iii) long-term OCS therapy. HCRU and treatment of patients were observed during a 1-year follow-up period (July 2018 – June 2019).
Results
The study included 388 932 adult asthma patients (prevalence: 7.90%), with 2.51%-12.88% affected by severe asthma (depending on the definition). 22.60% of all asthma patients experienced hospitalizations (severe asthma: 36.11%). Furthermore, 13.59% received OCS (severe asthma: 39.91%), but only 0.18% (severe asthma: 1.25%) received biologics. Only 23.95% (severe asthma: 41.17%) visited a pulmonologist.
Conclusions
A considerable proportion of severe asthma patients receive long-term OCS therapy. However, less than 50% have seen a pulmonologist who would typically seek a change in treatment to avoid the long-term consequences of OCS. To optimize the treatment of severe asthma in Germany, better referral of these patients to specialists is needed and considering potential treatment alternatives.
Background
Bronchial asthma (asthma) is a chronic inflammatory disease of the airways that affected about 262 million people worldwide in 2019 and is, therefore, one of the most common chronic diseases (Citation1). It is a heterogeneous disease, and due to its complexity, several endotypes and phenotypes with variable clinical presentation need to be distinguished (Citation2,Citation3). Asthma causes respiratory symptoms such as wheezing, dyspnea, cough, and chest tightness (Citation4–7). Moreover, unpredictable exacerbations (also called flare-ups) can lead to emergency room (ER) visits and hospitalizations; in some cases they even can be fatal (Citation8). To prevent such exacerbations and to reduce the burden of symptoms caused by asthma, appropriate medical care of patients is important to achieve optimal asthma control. However, different phenotypes are driven by different mechanistic pathways, as for example eosinophilic and noneosinophilic asthma with different airway or peripheral blood cellular profiles. Therefore effective management of asthma must take into account phenotype and disease severity (Citation4,Citation9).
In the Global Initiative for Asthma (GINA) guidelines, asthma severity is classified into four groups based on a patient’s clinical manifestation of the disease prior to treatment, the daily medication regimen applied, and response to treatment: (1) intermittent, (2) mild persistent, (3) moderate persistent, and (4) severe persistent asthma (Citation10,Citation11). According to GINA and the German treatment guideline for asthma, a stepwise adjustment of on-demand and long-term medication is recommended if asthma control (defined as minimal chronic symptoms, infrequent exacerbations, no ER visits, and no limitations on activities) cannot be achieved under therapy with the current medication (Citation11,Citation12).
Even though the choice of adequate treatment enables the majority of patients to achieve good asthma control, some patients remain inadequately controlled, despite administration of optimized high-dose inhaled corticosteroid (ICS) with a second controller (i.e. long-acting β2-agonist (LABA) or montelukast) (Citation10). For optimized management of these severe asthma patients, the disease phenotype should be considered to select appropriate add-on treatments. These include for example long-acting muscarinic antagonists (LAMA), leukotriene receptor antagonists (LTRA), and biologic agents, including mepolizumab, omalizumab, reslizumab, benralizumab, dupilumab and tezepelumabFootnote1 (Citation10,Citation13–17). Furthermore, research is also being conducted on other potentially useful add-on therapies such as low dose azithromycin for the use in non-eosinophilic asthma, which is known for its poor response to standard asthma treatments (Citation7,Citation18). Oral corticosteroids (OCS) can additionally be used as an alternative treatment for patients with severe asthma. The side-effects of long-term OCS use are severe and include various infections (e.g. pneumonia, herpes zoster and urinary tract infections), bone and muscle disease (e.g. osteoporosis, avascular necrosis and muscle weakness), atrial fibrillation, hypertension, and dyslipidemia (Citation19). Thus, maintenance use of OCS should be avoided and other treatment options should be favored (Citation7,Citation19–23).
It has been estimated that around 5% to 10% of asthma patients suffer from severe asthma, with a wide prevalence range of 1.8–38% (Citation24–26). Although severe uncontrolled asthma affects only a subpopulation of asthma patients it contributes seriously to the overall burden of asthma for patients and healthcare systems (Citation27,Citation28). Most recent data in this respect as well as evidence regarding the treatment of severe asthma patients in the real world are lacking for Germany. Therefore, the aim of this retrospective claims data analysis was to assess the epidemiology of asthma and severe asthma in Germany, to outline respective patient characteristics and to describe the healthcare resource utilization including drug treatments of patients with severe asthma.
Materials and methods
Data and study population
This study describes a retrospective, non-interventional cohort analysis of asthma patients and a subset of patients with a severe form of asthma. It is based on anonymized routine health insurance data from two German sickness funds (AOK PLUS and AOK BW) that include approximately 5 million individuals (i.e. 6% of the total German population) that were continuously insured in their respective sickness fund from 1 January 2014 until 30 June 2019 (death as an exception). Anonymized patient-level data was provided on inpatient and outpatient visits, along with information on diagnoses, pharmaceutical and non-pharmaceutical interventions i.e. prescriptions and related healthcare costs. Since the data were available in anonymized form, no approval of the research project by an ethics committee was required. However, the data owners (AOK PLUS and AOK BW) gave their permission to use the data on the basis of the study protocol and, together with clinical experts and the sponsor (GSK), were part of a Scientific Steering Committee that led the study.
The selection of the study population was based on diagnoses codes, documented according to the International Statistical Classification of Diseases and Related Health Problems 10. Revision, German Modification ICD-10-GM, and outpatient medication prescriptions recorded based upon the Pharmaceutical Central Number (PZN) and the Anatomical Therapeutic Chemical Classification System (ATC) for active substances. Asthma patients were included into the study if they had one of the following between 1 January 2014 and 30 June 2018:
at least one primary inpatient diagnosis of asthma (ICD-10-GM J45/J46) and/or,
at least two confirmed outpatient diagnoses (from any physician) within one year, and/or
at least one secondary inpatient diagnosis in addition to at least one confirmed outpatient diagnosis (from any physician) within one year
Furthermore, patients had to be alive and at least 18 years of age on 1 July 2018. Patients were observed during a 1-year baseline period (July 2017 – June 2018) and during a 1-year follow-up period (July 2018 – June 2019).
Due to the lack of clinical/laboratory information and as there is no ICD-10 code that identifies asthma severity and as there is no link between diagnosis and drug prescription, a proxy was used to group patients into mild/moderate and severe asthma in the baseline year. The proxy was developed by experienced clinicians, based on the definition for severe asthma stated in the GINA guideline and the German treatment guideline (i.e. based upon treatments recommended for step 4 and step 5 in the GINA guideline) and considering available information in the dataset. Thus, asthma patients must have met at least one of the following criteria during the baseline period, in order to be classified as a severe asthma patient:
At least one prescription for IgE- or IL-5 antibody approved for the use in severe asthma patients at the respective time (including: mepolizumab, reslizumab, benralizumab, omalizumab)Footnote2;
at least one prescription of a medium or high-doseFootnote3 ICS in combination with LABA or montelukast together with either (i) at least one prescription of an antibiotic or (ii) at least one prescription of short-term OCS (defined as available medication for less than 30 days);
long-term therapy with OCS (defined as available medication for at least 30 days).
A combination therapy was defined as either a fixed-dose combination or separate prescriptions of the agents within 60 days of each other.
In a sensitivity analysis a narrower definition of severe asthma was applied, considering only patients with either criterion I (biologics) or II (ICS with LABA/montelukast and with OCS or antibiotics). All patients who did not fulfill the criteria were grouped into a cohort of mild to moderate asthma patients.
Outcomes and statistical analysis
For the defined asthma cohorts baseline characteristics were described during the baseline period from 1 July 2017 to 30 June 2018, and compared between severe asthma patients and mild/moderate asthma patients. Furthermore, relevant comorbidities (related to asthma or related to medications used to treat asthma) were observed during the baseline period. Moreover, healthcare resource utilization and treatment of severe asthma patients were described for the one-year follow-up period after cohort identification. The number of patients with at least one prescription, number of prescriptions, and the average dosage a patient received were calculated for pre-selected (asthma) medications such as ICS, LABA, leukotriene receptor antagonists (LTRA), OCS, and others. Each patient’s total prescription supply (measured in days) was calculated based on the number of packages received by patients, each package’s size (e.g. number of tablets, capsules, or single doses), the concentration of the active substance in each package, and the defined daily doses (DDD) for medications, according to the World Health Organization (WHO); all numbers were reported per observed patient year (PPY). In addition, combination therapies have been observed and defined as either a prescription of a fixed-dose combination or at least one prescription of each agent class of the specified combinations prescribed within 60 days. Furthermore, within the German system, patients receive various diagnoses during their inpatient stays, recorded via ICD-10 codes. The most important of these is the main diagnosis, which provides the basis for billing/reimbursement, and generally encompasses the underlying reason for the hospitalization. In addition to this main code, a range of other primary and secondary codes are also logged, which may cover a diverse array of symptoms, infections, and conditions that were detected and treated during the inpatient stay. In this study, only hospitalizations related to asthma as the main diagnosis were observed separately from patients with hospitalizations related to other conditions.
All reported p values in case of comparisons were two-sided, and all analyses were carried out using Microsoft SQL Server 2019, Microsoft Excel 2019 (Microsoft Corporation, Redmond, WA), and Stata version 16.1 software (Stata Statistical Software: Release 14, StataCorp, College Station, TX).
Results
Study sample
In total, 388 932 asthma patients were identified, which corresponds to a proportion of 7.90% within the combined AOK PLUS and AOK BW databases; 12 909 patients (3.32%) were newly diagnosed in the baseline year. The asthma prevalence was higher among females (9.51%) compared to males (6.33%).
Of the 388 932 identified asthma patients, 338 851 (87.12%) were classified as mild to moderate asthma patients and 50 081 (12.88%) as patients with severe asthma. 552 (1.1%) of these were assigned to the cohort of severe asthma patients because they received biologics during the baseline year, whereas most patients were assigned to this cohort due to long-term use of OCS [44 618 (89.1%) patients]. Furthermore, 4911 (9.8%) patients were assigned to this cohort because of prescriptions with medium to high dose ICS with LABA or montelukast (in addition to antibiotics or OCS). Within the sensitivity analysis, 9773 patients (2.51%) were identified as severe asthma patients. The mean age in the general asthma cohort was 54.82 years (median 56 years), 59.47% of the patients were female (). Severe asthma patients were notably older than patients with mild to moderate asthma (62.71 vs. 53.65 years; p < 0.001), and the proportion of females was significantly higher (61.76% vs. 59.13%; p < 0.001). Similar results emerged when comparing the sensitivity cohorts. In total, 8167 asthma patients (2.10%) died within the one year of follow-up, and a significant difference (p < 0.001) between deaths was observed between severe asthma patients (2497 deceased; 4.99%) and patients with mild to moderate asthma (5670 deceased; 1.67%).
Within all observed cohorts, rhinitis/sinusitis (J30.-; J31.0; J32.-) was the most common comorbidity, with 32.12% of all asthma patients, 31.96% of mild to moderate asthma patients, and 33.32% of severe asthma patients being affected. Moreover, 5374 (10.73%) of patients with severe asthma versus 28 355 (8.37%) with mild to moderate asthma suffered from either urticaria or atopic dermatitis. Other comorbidities generally more common in the severe versus the mild to moderate asthma cohorts were osteoporosis (19.94% vs. 8.57%), nasal polyps (2.18% vs. 0.91%), polyarteritis with lung involvement (7.77% vs. 4.37%) and cataract (18.44% vs. 13.25%) ().
Treatment patterns of severe asthma patients
During the one-year follow-up period, the majority of the severe asthma patients (83.05%) received at least one drug prescription related to the respiratory system (any prescription with ATC R03) and/or an oral corticosteroid (H02) (). The percentage was even higher for the sensitivity cohort of severe asthma patients (92.70%).
28 666 severe asthma patients (57.24%) received combination therapies of ICS, LABA and/or LTRA; the majority of these were LABA + ICS combinations (single agent or fixed-dose prescriptions), which were prescribed in 28 606 (57.12%) of all severe asthma patients. The most often prescribed agents in the severe asthma cohort were Glucocorticoids (51.65% of patients, mean number of prescriptions: 1.54), followed by a fixed-dose combination of LABA + ICS (50.27% of patients, mean number of prescriptions: 1.57 per patient). Furthermore, OCS were prescribed to almost half of severe asthma patients (47.66% of patients, mean number of prescriptions: 1.42). Those severe asthma patients who received at least one prescription of OCS received on average 170 days of supply, based on the DDD (according to the WHO). Within the sensitivity analysis, OCS was prescribed about 8% less often (39.91% of patients, mean number of prescriptions: 1.10). In total, 624 of the severe asthma population (1.25%) received at least one biologic agent.
Healthcare resource utilization
18 083 (36.11%) severe asthma patients were hospitalized during the one-year follow-up period, with on average 6.62 days of stay PPY. Among them, 4983 patients (38.74%) were hospitalized due to diseases of the respiratory system, whereas 455 severe asthma patients (0.91%) were hospitalized with asthma as the main diagnosis. 2374 severe asthma patients (4.74%) had at least one rehabilitation stay; only 122 of these (0.22%) were directly associated with asthma.
The number of severe asthma patients with at least one outpatient visit related to asthma was generally high. Within one year, 34 176 severe asthma patients (68.24%) visited a general practitioner at least once due to asthma. Furthermore, 18 860 of severe asthma patients (37.66%) visited a pulmonologist during the follow-up year; this number was higher in the sensitivity analysis, with 51.47% of severe asthma patients visiting a pulmonologist. summarizes the HCRU findings.
Discussion
The aim of this study was to describe the epidemiological characteristics of severe asthma patients in Germany as well as to describe the pharmacological treatment and the HCRU associated with the treatment of these patients.
The study included 388 932 patients diagnosed with asthma from two sickness funds, which equals a prevalence of 7.90% (females: 9.51%/males: 6.33%). Our identified prevalence as well as the demographic characteristics of asthma patients, are well in line with previous studies (Citation4,Citation5,Citation29,Citation30). Among all observed patients, we classified 50 081 patients affected by severe asthma, which equals a proportion of 12.88% of all asthma patients. Within a sensitivity analysis, this proportion was notably lower, with only 2.51% of patients that matched the severe asthma inclusion criteria. The difference could mainly be explained by asthma patients who received a long-term OCS therapy (44 618 patients) and who were considered to be affected by severe asthma in the base but not in the sensitivity analysis. We included the long-term OCS use as a criterion indicating severe asthma, as this is in line with the GINA guidelines and has been used to identify severe asthma in previous studies (Citation29,Citation31,Citation32). While long-term use of OCS is generally avoided in the treatment of patients with other associated diseases (included in ), we cannot rule out the possibility that some patients received long-term OCS for treatment of other diseases within our analysis of real-world data. Yet, due to the substantial number of patients with OCS use, we conclude that most long-term OCS users with asthma demonstrate existing unmet needs, given well-known toxicity risks associated with long-term OCS use.
As was observed in previous studies, patients with severe asthma were significantly (p < 0.001) older than mild to moderate asthma patients in our study (62.71 vs. 53.65 years); differences in age and asthma severity contributed to a threefold higher mortality rate in patients with severe asthma (as compared to patients with mild to moderate asthma) and a higher comorbidity burden (Citation33–35). Previous studies showed similar results in terms of comorbidities and consistently reported higher proportions in severe asthma patients compared to mild to moderate asthma patients (Citation33,Citation34,Citation36). Moreover, rhinitis was found to be the most common disease among all asthma patients (32.12%), which is also in line with previous investigations (Citation13,Citation26,Citation35).
More than one-third of all patients with severe asthma experienced at least one hospitalization within one year of observation (36.11%). However, only 0.91% of the patients experienced at least one asthma-related hospitalization. As the latter can be considered a proxy of severe exacerbations (Citation11), this could be considered as an indicator for a good asthma control. However, this contrasts with the high proportion of patients with OCS prescriptions, which in turn suggests non-optimal asthma control within our population of severe asthma patients. A higher hospitalization rate due to asthma were observed in a national health interview survey in Germany where 9.0% of participants reported hospitalization due to asthma (Citation37). This difference may be related to the identification of asthma-related hospitalizations, as only patients who had at least one overnight stay were reported within our study. In addition, differences in codes logged in the inpatient setting might have resulted in the under-detection of asthma-related hospitalizations, as only main diagnoses were considered. Future studies should compare the number of patients admitted to the hospital with a main, primary or secondary asthma code, versus the number admitted via a main code only. Furthermore, about 4.74% of severe asthma patients had at least one (inpatient) rehabilitation, but only the minority of rehabilitations were associated with an asthma diagnosis (0.22%). This aligns with previous studies, which also reported a low number of rehabilitation stays due to asthma (Citation39,Citation40).
Generally, we observed a decline in HCRU between the baseline and follow-up periods in our severe asthma population. However, this is mainly related to our patient inclusion criteria, as we observed asthma patients diagnosed with the severe form of the disease in a baseline period and then followed-up for 12 months, without including those patients newly diagnosed with severe asthma in the follow-up period. It can be assumed that as at least a substantial percentage of patients diagnosed with severe asthma received a respective drug treatment (including OCS), a certain level of asthma control was achieved and, consequently, a decrease in hospitalizations due to respiratory reasons in these patients could be observed.
About 50% of severe asthma patients received ICS + LABA combination therapy prescriptions; the relatively high amount was partly related to the sample definition of severe asthma patients, as they had to be prescribed medium to high dose ICS + LABA or montelukast as combination therapy during the baseline year. A high intake of ICS and LABA, either as monotherapy or ICS/LABA combination therapy, is in line with previous studies (Citation41,Citation42). Furthermore, a high OCS intake in severe asthma patients was observed, with about 50% receiving at least one OCS prescription (Citation26,Citation29,Citation41). In addition, only 1.25% of severe asthma patients received biologic agents (Mepolizumab, Omalizumab, Reslizumab, Benralizumab) within a one-year period. This stands absolutely in contrast with the GINA recommendations, which suggest biologic agents for the treatment of severe asthma, while OCS should be avoided as maintenance treatment because of its severe side effects as outlined in the introduction (Citation7). Furthermore, it was found that about 20% and 18% of respective patients with severe asthma had osteoporosis or a cataract, which both constitute adverse events of long-term use of OCS. Although it cannot be determined whether the use of OCS caused these events, some impact remains likely given the much higher prevalence of these conditions within our patient population, as compared to reported rates in the German population [osteoporosis: 5.00% (Citation43); cataract: 7.60% (Citation44)]. Previous real-world studies came to similar conclusions regarding high rates of long-term OCS use and lower use of biologics (Citation41,Citation45–47). Poor asthma management is furthermore indicated by the fact that only 37–50% of the severe asthma patients visited a pulmonologist at least once during the observational period, as these specialists typically would induce a treatment switch from long-term OCS to more appropriate treatments. Thus, the care of severe asthma patients clearly needs to be improved in Germany. This should include pulmonologist specialist care and potential treatment with biologic agents.
Limitations
The main strength of this claims data study is the analysis of a large database, representing 6% of the overall German population and covering all relevant inpatient and outpatient care. Due to the nature of our study, our results were not affected by any selection bias and were generally less susceptible to missing data since German claims data typically include information on all filled prescriptions/refills at the patient level, irrespective of the prescribing physician. Nevertheless, we acknowledge some limitations of our analysis.
First, all data used in this study were based on inpatient and outpatient claims from an administrative claims database, and no clinical data were available to confirm the asthma group assignment. So, the study relied on documented ICD-10-GM codes J45 and J46 to identify asthma. Since German claims databases contain data from routine practice, data may be missing or subject to coding errors regarding outpatient diagnoses. However, the coding of the database is generally considered to be of high quality (Citation48,Citation49). Second, the difference between the number of severe asthma patients in the main analysis and sensitivity analysis suggests that clinical confirmation might have been helpful in identifying severe asthma patients. However, only minor differences in treatment patterns and HCRU were found in the severe asthma cohort and sensitivity cohort results, indicating that severe asthma patients were defined correctly. In addition, as discussed above, long-term OCS use associated with asthma is a strong signal for a severe form of asthma. In addition, as the administration of antibiotics is also indicated for other diseases, the criterion moderate- to high-dose ICS + LABA or montelukast in combination with antibiotic (and/or OCS) may be somewhat lacking in specificity. However, since antibiotics are used to treat severe asthma exacerbations in a real-world setting (Citation50,Citation51), using antibiotics as a proxy and in combination with medication applied specifically in more severe asthma cases was considered to be a legitimate choice, validated by participating clinicians, in order to identify severe asthma patients. In addition, our data were collected from German databases and may not be generalizable to other countries. However, to increase the generalizability and representativeness of results for Germany, patients from two different sickness funds and regions were included in this analysis, therefore, reducing the risk of a potential regional bias.
Conclusions
Severe asthma is associated with a substantial burden for the German healthcare system. A considerable proportion of severe asthma patients receive long-term OCS therapy, while only a maximum of 50% visit a pulmonologist once a year. In order to optimize the treatment of patients with severe asthma in Germany, the referral of patients to specialists and the consideration of all treatment alternatives (e.g. biologic agents) seem to be crucial.
Ethics approval
This study used two anonymized health insurance claims datasets that were provided free of charge by AOK PLUS and AOK BW. The data sets were used under the formal agreement and legal basis of §75, Tenth Book of the Social Code (SGB X). Since all patient data provided by the sickness funds were fully anonymized, no ethical approval from an institutional review board was required to implement this study.
Abbreviations | ||
ATC | = | Anatomical Therapeutic Chemical Classification System |
DDD | = | defined daily doses |
ER | = | emergency room |
GINA | = | Global Initiative for Asthma |
HCRU | = | healthcare resource utilization |
ICS | = | inhaled corticosteroids |
ICD-10 | = | International Statistical Classification of Diseases and Related Health Problems 10 |
LABA | = | long-acting beta-agonists |
LAMA | = | long acting muscarinic antagonists |
LTRA | = | leukotriene receptor antagonists |
OCS | = | oral corticosteroids |
PPY | = | per patient year |
PZN | = | Pharmaceutical Central Number |
WHO | = | World Health Organization |
Data availability
During the current study, generated and/or analyzed datasets were available for research purposes from the sickness fund upon request in an anonymized form and used under license for the current study due to restrictions around revealing ‘patients’ confidential information. Since the findings of this study are extracted from individual patient records, the data are neither publicly available nor can be shared further.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Additional information
Funding
Notes
1 Tezepelumab was not included in the study because it did not receive approval in Europe until September 2022.
2 Dupilumab has not been considered for the identification of severe asthma patients, as it was only approved for the use in severe asthma in Europe in 2019. Thus, during the follow-up period (including 2019) Dupilumab has been observed based upon an existing ATC code (related to Dupilumab for the treatment of dermatitis; ATC code D11AH05).
3 ICS products were grouped into low medium and high dose, according to the definition derived from the German treatment guideline for asthma (12) and the defined dose per day (in microgram) for each agent.
References
- World Health Organization. Chronic respiratory diseases: asthma [Internet]. Geneva: World Health Organization; 2020. https://www.who.int/news-room/questions-and-answers/item/chronic-respiratory-diseases-asthma [updated 3 May 2021; last accessed 10 October 2022].
- Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012;67(7):835–846. doi:10.1111/j.1398-9995.2012.02832.x
- Kuruvilla ME, Lee FE-H, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol. 2019;56(2):219–233. doi:10.1007/s12016-018-8712-1
- Steppuhn H, Kuhnert R, Scheidt-Nave C. 12-month prevalence of asthma among adults in Germany. J Heal Monit. 2017;2(3):34–42. https://edoc.rki.de/bitstream/handle/176904/2820/24uudXhEQvz0c.pdf?sequence=1&isAllowed=y
- Stock S, Redaelli M, Luengen M, Wendland G, Civello D, Lauterbach KW. Asthma: prevalence and cost of illness. Eur Respir J. 2005;25(1):47–53. doi:10.1183/09031936.04.00116203
- Khan A, Sternbach N, Kamat S, Annunziata K, Jaffe D, Gouia I. Prevalence of asthma in France, Germany, Italy, Spain, and the United Kingdom, based on the 2018 European National Health and Wellness Survey. Chest. 2020;158(4):A27. doi:10.1016/j.chest.2020.08.067
- Gina Science Comitee. Global Strategy for Asthma Management and Prevention; 2021. https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf.
- Castillo JR, Peters SP, Busse WW. Asthma exacerbations: pathogenesis, prevention, and treatment. J Allergy Clin Immunol Pract. 2017;5(4):918–927. doi:10.1016/j.jaip.2017.05.001.
- Chung KF. Precision medicine in asthma: linking phenotypes to targeted treatments. Curr Opin Pulm Med. 2018;24(1):4–10. https://pubmed.ncbi.nlm.nih.gov/29036018/ doi:10.1097/MCP.0000000000000434
- Global Initiative for Asthma. Pocket guide for asthma management and prevention [Internet]. Fontana, CA: Global Initiative for Asthma; 2019. https://ginasthma.org/pocket-guide-for-asthma-management-and-prevention/ [last accessed 5 September 2022].
- Peters SP, Ferguson G, Deniz Y, Reisner C. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006;100(7):1139–1151. doi:10.1016/j.rmed.2006.03.031
- Bundesärztekammer. Nationale Versorgungsleitlinie Asthma. 3. Auflage - Langfassung. Version 1. 2018.
- Niven RM, Saralaya D, Chaudhuri R, Masoli M, Clifton I, Mansur AH, Hacking V, McLain-Smith S, Menzies-Gow A. Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study). BMJ Open. 2016;6(8):e011857. doi:10.1136/bmjopen-2016-011857
- Thomson NC, Chaudhuri, R, Omalizumab. Clinical use for the management of asthma. Clin Med Insights Circ Respir Pulm Med. 2011;6(1):27–40.
- European Medicines Agency. New add-on treatment for patients with severe asthma [Online]. Amsterdam: European Medicines Agency; 2019. https://www.ema.europa.eu/en/news/new-add-treatmentpatients-severeasthma [last accessed 5 September 2022].
- Mcgregor MC, Krings JG, Nair P, Castro M. Role of biologics in asthma. Am J Respir Crit Care Med. 2019;199(4):433–445. doi:10.1164/rccm.201810-1944CI
- European Medicines Agency. Tezspire; 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/tezspire.
- Esteban-Gorgojo I, Antolín-Amérigo D, Domínguez-Ortega J, Quirce S. Non-eosinophilic asthma: current perspectives. J Asthma Allergy. 2018;11:267–281. doi:10.2147/JAA.S153097
- Volmer T, Effenberger T, Trautner C, Buhl R. Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature. Eur Respir J. 2018;52(4):1800703. https://erj.ersjournals.com/content/erj/52/4/1800703.full.pdf doi:10.1183/13993003.00703-2018
- Selbmann HK. Nationale Versorgungs-Leitlinie Asthma. Z Arztl Fortbild Qualitatssich. 2018;100(6):409.
- Breekveldt-Postma NS, Erkens JA, Aalbers R, Van De Ven MJT, Lammers JWJ, Herings RMC. Extent of uncontrolled disease and associated medical costs in severe asthma - a PHARMO study. Curr Med Res Opin. 2008;24(4):975–983. https://pubmed.ncbi.nlm.nih.gov/18282372/ doi:10.1185/030079908x280518
- Cataldo D, Louis R, Michils A, Peché R, Pilette C, Schleich F, Ninane V, Hanon S. Severe asthma: oral corticosteroid alternatives and the need for optimal referral pathways. J Asthma. 2021;58(4):448–458. doi:10.1080/02770903.2019.1705335
- Bloechliger M, Reinau D, Spoendlin J, Chang S-C, Kuhlbusch K, Heaney LG, Jick SS, Meier CR. Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study with a nested case-control analysis. Respir Res. 2018;19(1):75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921395/ doi:10.1186/s12931-018-0742-y
- Hossny E, Caraballo L, Casale T, El-Gamal Y, Rosenwasser L. Severe asthma and quality of life. World Allergy Organ J. 2017;10:28. https://pubmed.ncbi.nlm.nih.gov/28855973/ doi:10.1186/s40413-017-0159-y
- Caminati M, Senna G. Uncontrolled severe asthma: starting from the unmet needs. Curr Med Res Opin. 2019;35(2):175–177. https://www.tandfonline.com/action/journalInformation?journalCode=icmo20 doi:10.1080/03007995.2018.1528218
- Wang E, Wechsler ME, Tran TN, Heaney LG, Jones RC, Menzies-Gow AN, Busby J, Jackson DJ, Pfeffer PE, Rhee CK, et al. Characterization of severe asthma worldwide: data from the international severe asthma registry. Chest. 2020;157(4):790–804. doi:10.1016/j.chest.2019.10.053
- Chen S, Golam S, Myers J, Bly C, Smolen H, Xu X. Systematic literature review of the clinical, humanistic, and economic burden associated with asthma uncontrolled by GINA Steps 4 or 5 treatment. Curr Med Res Opin. 2018;34(12):2075–2088. https://www.tandfonline.com/action/journalInformation?journalCode=icmo20 doi:10.1080/03007995.2018.1505352
- Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–373. https://erj.ersjournals.com/content/43/2/343 doi:10.1183/09031936.00202013
- Taube C, Bramlage P, Hofer A, Anderson D. Prevalence of oral corticosteroid use in the German severe asthma population. ERJ Open Res. 2019;5(4):00092–2019. doi:10.1183/23120541.00092-2019
- Hoffmann F. Prevalence of asthma among German adults: analysis of the German national telephone survey. J Asthma. 2007;44(6):433–436. doi:10.1080/02770900701421922
- Birnbaum HG, Ivanova JI, Yu AP, Hsieh M, Seal B, Emani S, Rosiello R, Colice GL. Asthma severity categorization using a claims-based algorithm or pulmonary function testing. J Asthma. 2009;46(1):67–72. doi:10.1080/02770900802503099
- Ivanova JI, Bergman R, Birnbaum HG, Colice GL, Silverman RA, McLaurin K. Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma. J Allergy Clin Immunol. 2012;129(5):1229–1235. doi:10.1016/j.jaci.2012.01.039.
- Viinanen A, Lassenius MI, Toppila I, Karlsson A, Veijalainen L, Idänpään-Heikkilä JJ, Laitinen T. The burden of adult asthma in Finland: impact of disease severity and eosinophil count on health care resource utilization. J Asthma. 2020;57(10):1092–1102. doi:10.1080/02770903.2019.1633664
- Song HJ, Blake KV, Wilson DL, Winterstein AG, Park H. Medical costs and productivity loss due to mild, moderate, and severe asthma in the United States. J Asthma Allergy. 2020;13:545–555. doi:10.2147/JAA.S272681
- Sicras-Mainar A, Capel M, Navarro-Artieda R, Nuevo J, Orellana M, Resler G. Real-life retrospective observational study to determine the prevalence and economic burden of severe asthma in Spain. J Med Econ. 2020;23(5):492–500. doi:10.1080/13696998.2020.1719118
- Rogliani P, Sforza M, Calzetta L. The impact of comorbidities on severe asthma. Curr Opin Pulm Med. 2020;26(1):47–55. https://journals.lww.com/co-pulmonarymedicine/Abstract/2020/01000/The_impact_of_comorbidities_on_severe_asthma.9.aspx doi:10.1097/MCP.0000000000000640
- Steppuhn H, Langen U, Scheid-Nave C, Keil T. Major comorbid conditions in asthma and association with asthma-related hospitalizations and emergency department admissions in adults: results from the German national health telephone interview survey (GEDA) 2010. Pulm Med. 2010;13(46). doi:10.1186/1471-2466-13-46#citeas
- Akmatov MK, Ermakova T, Holstiege J, Steffen A, von Stillfried D, Bätzing J. Comorbidity profile of patients with concurrent diagnoses of asthma and COPD in Germany. Sci Rep. 2020;10(1):1–9. doi:10.1038/s41598-020-74966-1
- Voorham J, Xu X, Price DB, Golam S, Davis J, Zhi Jie Ling J, Kerkhof M, Ow M, Tran TN. Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma. Allergy Eur J Allergy Clin Immunol. 2019;74(2):273–283. doi:10.1111/all.13556
- Jacob C, Bechtel B, Engel S, Kardos P, Linder R, Braun S, Greiner W. Healthcare costs and resource utilization of asthma in Germany: a claims data analysis. Eur J Health Econ. 2016;17(2):195–201. doi:10.1007/s10198-015-0671-3.
- Molimard M, Buhl R, Niven R, Le Gros V, Thielen A, Thirlwell J, Maykut R, Peachey G. Omalizumab reduces oral corticosteroid use in patients with severe allergic asthma: real-life data. Respir Med. 2010;104(9):1381–1385. doi:10.1016/j.rmed.2010.06.001.
- Melero Moreno C, Quirce S, Huerta A, Uría E, Cuesta M. Economic impact of severe asthma in Spain: multicentre observational longitudinal study. J Asthma. 2019;56(8):861–871. doi:10.1080/02770903.2018.1499035
- Fuchs J, Scheidt-Nave C, Kuhnert R. 12-Monats-Prävalenz von Osteoporose in Deutschland. J Heal Monit. 2017;2(3):61–65. www.geda-studie.de
- Pfau N, Kern AO, Wolfram C, Kalcklösch M, Prütz F. Blindheit und Sehbehinderung - GBE-Themenheft. Gesundheitsberichterstattung Des Bundes. 2017. http://edoc.rki.de/docviews/abstract.php?id=5025%0Aurn:nbn:de:0257-10051713%0Ahttps://www.rki.de/DE/Content/Gesundheitsmonitoring/Gesundheitsberichterstattung/GBEDownloadsT/blindheit.pdf?__blob=publicationFile
- Jeffery MM, Shah ND, Karaca-Mandic P, Ross JS, Rank MA. Trends in omalizumab utilization for asthma : evidence of suboptimal patient selection. J Allergy Clin Immunol Pract. 2018;6(5):1568–1577. doi:10.1016/j.jaip.2017.07.034
- Numata T, Miyagawa H, Nishioka S, Okuda K, Utsumi H, Hashimoto M, Minagawa S, Ishikawa T, Hara H, Araya J, et al. Efficacy of benralizumab for patients with severe eosinophilic asthma: a retrospective, real-life study. BMC Pulm Med. 2020;20(1):1–10. doi:10.1186/s12890-020-01248-x
- Bjerrum AS, Skjold T, Schmid JM. Oral corticosteroid sparing effects of anti-IL5/anti-IL5 receptor treatment after 2 years of treatment. Respir Med. 2021;176:106260. doi:10.1016/j.rmed.2020.106260
- Langner I, Ohlmeier C, Zeeb H, Haug U, Riedel O. Individual mortality information in the German Pharmacoepidemiological Research Database (GePaRD): a validation study using a record linkage with a large cancer registry. BMJ Open. 2019;9(7):e028223. doi:10.1136/bmjopen-2018-028223
- Hartmann J, Weidmann C, Biehle R. Validierung von GKV-Routinedaten am Beispiel von geschlechtsspezifischen Diagnosen. Gesundheitswesen. 2016;78(10):e162–e167.
- Darcey J, Qualtrough A. Difficult-to-treat & severe Asthma in adolescent and adult patients - diagnosis and management. Glob Initiat Asthma. 2019;214:493–509.
- Arfè A, Blasi F, Merlino L, Corrao G. Respiratory drugs and macrolides prevent asthma exacerbations: a real-world investigation. Respir Med. 2016;119:7–12. doi:10.1016/j.rmed.2016.05.004