ABSTRACT
Background/Objectives
Immunoglobulin (Ig) therapy is the first‐line treatment and often the single option for a substantial number of diseases. Still, Ig supply and use have experienced restrictions, aggravated during the COVID‐19 pandemic. This study assessed the clinical and economic implications of Ig use under restrictive conditions in neurological diseases and immunodeficiencies in Spain.
Methods
Hospitalization cases in neurological disorders and immunodeficiencies in which Ig is the main therapeutic option, identified by ICD‐10 codes, were retrieved from the Spanish Minimum Basic Data Set for 2019 and 2022. Comorbidities and outcomes were analyzed along with hospitalization rates and characteristics, like the length of stay (LoS) and costs, among others. Therapeutic plasma exchange (TPE) use was evaluated as the alternative treatment of choice in the conditions analyzed.
Results
In 2022 compared to 2019, hospitalizations due to relapses remained stable in patients with neurological conditions. Comorbidity and complications increased significantly in this group, as well as LoS, mofrtality (p < 0.05 for all), and TPE rates (p = 0.003). These changes were not identified for immunodeficiencies, which only experienced a decrease in hospitalization rates (p < 0.001). Hospital costs increased in both groups (7.97% in neurological conditions and 2.41% in immunodeficiencies).
Conclusions
In a period in which access to Ig may have been limited, neurological patients, but not patients with immunodeficiencies, show an increase in LoS and mortality, as well as an increased TPE. These results suggest that modifying the management strategy of patients with neurological disorders requiring Ig due to restrictive conditions could have negatively impacted their clinical outcomes.
Keywords: hospitalizations, immunoglobulin, neurological disorders, outcome assessment, therapy
This study analyzes nationwide hospitalization data from Spain to evaluate the clinical and economic impact of restrictive immunoglobulin access in neurological disorders and immunodeficiencies. Using ICD‐10–coded admissions from 2019 and 2022, changes in clinical outcomes and resource use were assessed. Worsening outcomes and increased resource use were observed in neurological patients, whereas immunodeficiencies showed limited impact despite higher costs, suggesting that management changes in neurological patients requiring immunoglobulin under restrictive conditions may have affected outcomes.
Abbreviations
- aCCI
age‐adjusted Charlson Comorbidity Index
- CIDP
chronic inflammatory demyelinating polyneuropathy
- DRG
diagnosis‐related group
- GBS
Guillain‐Barré Syndrome
- ICD
International Classification of Diseases
- ICU
intensive care unit
- Ig
human polyvalent immunoglobulin
- IQR
interquartile range
- LoS
length of stay
- NHS
National Healthcare System
- RAE‐CMBD
Specialized Health Care Activity Register, Minimum Basic Data Set
- SD
standard deviation
- TPE
therapeutic plasma exchange
1. Introduction
Human polyvalent immunoglobulins (Igs) are the standard of care treatment for a substantial number of chronic and rare clinical conditions, and their relevance led to their inclusion in the Essential Medicines Lists by the World Health Organization [1, 2]. Primary and secondary immunodeficiencies and neurological disorders, including chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain‐Barré Syndrome (GBS), paraproteinemic demyelinating neuropathy, autoimmune encephalitis, multifocal motor neuropathy, and other neuropathies, comprise an important group of Ig‐treated pathologies. Although rare, these conditions affect a large number of individuals, with GBS accounting for 1.66 cases per 100,000 in 2021 in Spain and primary immunodeficiencies alone encompassing more than 550 distinct genetic conditions that affect 1:1200–2000 individuals [3, 4].
Some of these conditions are potentially life‐threatening and associated with severe comorbidities and may pose a considerable burden to the patient. Neurological disorders are associated with a range of symptoms depending on the condition, such as progressive weakness in CIDP or neuromuscular paralysis in GBS, and patients experience frequent relapses of the disease, which can worsen their clinical condition and might require hospitalization [5, 6]. Patients with immunodeficiencies have increased susceptibility to infectious diseases, typically experiencing severe, persistent, and/or recurrent infections and an increasing number of non‐infectious complications [3, 7, 8]. Bacterial pneumonia is especially frequent and a primary cause of morbidity and mortality in these patients [9].
Altogether, thousands of patients rely on Igs as their primary, and sometimes only, therapeutic option. Ig therapy has proven beneficial in terms of life expectancy and quality of life for neurological disorders, improving symptoms such as functional disability in these patients and reducing the incidence of infections, including pneumonia, in immunodeficiencies [9, 10, 11, 12, 13, 14, 15, 16, 17]. Patient management with Igs also eases the burden on National Healthcare Systems (NHS), since it has been shown to reduce hospitalizations and emergency visits [12, 17, 18].
Ig demand is gradually growing in Europe, partially prompted by improved diagnostic protocols and clinical evidence pointing towards new indications, together with the chronic nature of most of its clinical indications [19, 20]. Further, off‐label use of Ig therapy to treat non‐indicated conditions or disorders currently under research has significantly contributed to this demand [20, 21]. The European Ig consumption is estimated to have increased by around one‐third in the 2017–2025 period, whereas the production is projected to cover only around 56% of this demand [20]. Spain is experiencing a similar problem; Ig use increased an annual mean of 11% in the 2012–2019 period and this trend is projected to continue until 2025 [2]. Although plasma donations are on an uptrend, they covered just around 34% of Ig demand in 2019, making Spain highly dependent on foreign Ig production [2]. Being a plasma‐derived medicinal product, Ig supply is limited and has experienced intermittent shortages, deepened by the COVID‐19 pandemic, which can restrict patient access to this therapy [22]. Major efforts are in place to optimize and prioritize Ig use and establish a reliable network of plasma donation at a national and regional level [2, 20, 23, 24, 25]. In this respect, the Catalan Healthcare System defined in 2021 a list of recommendations to prioritize and optimize Ig treatment, while a protocol for the rational use of Igs was developed in Madrid [24, 25]. Prioritized use for certain diseases, discontinuation in cases without a clear indication for immunoglobulin or when an equivalent alternative was not available, dose adjustment, switching Ig products, or changing to alternative treatments are some of the recommendations mentioned. Despite alternative therapies being available for certain conditions, changing treatments or even Ig presentations might impact the course of the disease and potentially lead to adverse effects or reduced effectivity [6, 26, 27]. Prioritization or dose reduction strategies might lead to undertreatment and a consequent worsening of the disease.
A previous study evaluating the impact of the COVID‐19 pandemic, and the strategies put in place to optimize Ig use, identified a decrease in Ig consumption and costs in Catalonia [24]. Still, the clinical implications of these situations and their potential associated healthcare costs in Spain are yet to be unveiled. The objective of the present study was to estimate the clinical and economic impact of Ig use in restrictive conditions, including the COVID‐19 situation, in patients with neurological conditions requiring Ig therapy that were affected by these situations, according to experts, and in patients with immunodeficiencies, whose treatment may have been prioritized and not so impacted.
2. Materials and Methods
2.1. Data Source and Study Design
Data on hospitalizations for adult patients (≥ 18years), for 2019 and 2022, with autoimmune neurological diseases requiring Ig treatment or immunodeficiencies (Table 1), specified as primary or secondary diagnoses, were obtained from the Specialized Health Care Activity Register, Minimum Basic Data Set (RAE‐CMBD) through a request to the Ministry of Health [28]. This national mandatory administrative database coded using the International Classification of Diseases, 10th Revision (ICD‐10), provides fully anonymized hospitalization‐level data, and therefore evaluation by an ethical committee is not required for individual studies [29, 30]. To ensure accuracy, cases with multiple records referring to the same hospitalization were linked and merged following methodologies described in recent research, thereby preventing duplication and ensuring the correct representation of each patient case [29, 30].
TABLE 1.
ICD‐10 codes for neurological conditions and immunodeficiencies.
| Neurological conditions | ICD‐10 codes |
|---|---|
| Guillain‐Barré syndrome | G61.0 |
| Chronic Inflammatory demyelinating polyneuropathy | G61.81 |
| Paraproteinemic demyelinating neuropathy (IgA, IgG or IgM) | G61.89, D89.2 |
| Autoimmune encephalitis | G04.81 |
| Other immune mediated neuropathies | G61.8, G61.89, G61.9 |
| Multifocal motor neuropathy | G61.82 |
| Other neuropathies | G61.1 |
| Immunodeficiencies | ICD‐10 codes |
|---|---|
| Agammaglobulinemia | D80.1 |
| Other immunodeficiencies | D80.2, D80.4, D80.5, D80.6, D80.7 |
| Common variable | D83, D83.0, D83.1, D83.2, D83.8, D83.9 |
| IgG subclass deficiencies | D80.3 |
| Unspecific antibody deficiencies | D80.9, D80.8 |
| Congenital hypogammaglobulinemia | D80.0 |
| Severe combined immunodeficiency | D81.0, D81.1, D81.2 |
The analysis focused on changes between 2019 and 2022, 2019 was chosen as the state of the art for the management of the considered diseases prior to restrictions on Ig supply caused by the COVID‐19 pandemic and associated measures, and 2022 as the last available year to best evaluate potential consequences of the restrictions while minimizing the impact of the COVID‐19 pandemic itself on hospitalization trends and complications, among others.
According to the published recommendations for Ig use, prioritization of treatment for some diseases, dose reductions, discontinuations, switches to other Ig products or to alternative treatments may have taken place, which may lead to clinical complications related to the pathology, AEs, associated healthcare costs, and even mortality. To capture the potential effects of managing these patients under restrictive Ig supply conditions, various outcomes were therefore analyzed. For neurological conditions, the primary outcome was the number of relapses, identified through admissions in which the disease‐specific code was recorded as the primary diagnosis. For immunodeficiencies, the primary outcome was non‐COVID‐19‐related pneumonia admissions (Supporting Information). The number of hospitalizations and their characteristics, including length of stay (LoS), urgent admission, intensive care unit (ICU) admissions, ICU LoS, and hospitalization costs, were also analyzed, as well as patient comorbidities—using age‐adjusted Charlson Comorbidity Index (aCCI) [31] based on an algorithm defined for ICD‐10 codes [32]—, complication profile and mortality.
The complication profile was defined as the number of complications during hospitalization and derived from Patient on Admission characteristics associated with up to 20 recorded diagnoses.
Additionally, the use of therapeutic plasma exchange (TPE) was evaluated as an alternative treatment to Igs recommended by clinical guidelines [33, 34]. TPE was identified using RAE‐CMBD‐registered procedures corresponding to the following ICD‐10 codes: 6A550Z0, 6A550Z1, 6A550Z2, 6A550Z3, 6A550ZT, 6A550ZV, 6A551Z0, 6A551Z1, 6A551Z2, 6A551Z3, 6A551ZT, 6A551ZV. To contextualize this use, the trend of TPE procedures relative to electromyography (ICD‐10 codes 4A0F33Z, 4A0FX3Z) was examined specifically for patients with GBS, in whom electromyography is a standard procedure that is assumed not to be affected by restrictions. This approach allows verification of whether changes in TPE use reflect a shift in treatment patterns or are merely an artifact caused by hospitalization trends.
To better control for one of the main confounders in hospitalizations, particularly in pneumonia‐related cases, several exclusion criteria regarding COVID‐19 were applied. First, all pneumonia cases caused by COVID‐19, coronavirus, or SARS were excluded as outcomes for analysis. Second, all admissions with any diagnostic code related to COVID‐19, any coronavirus, or SARS were excluded (Table S1). This restrictive approach was adopted because COVID‐19 coding was broadly introduced in 2020 but not systematically implemented until 2022. As a result, prior to 2022, infections and/or complications from COVID‐19 may have been recorded under other coronavirus‐related or SARS codes. This ensures that both admissions and pneumonia cases analyzed are unrelated to COVID‐19.
2.2. Statistical Approach
First, a descriptive analysis of patient characteristics was conducted, including age, sex, and the previously mentioned outcomes. Continuous variables were presented as mean (standard deviation—SD) and median [interquartile range—IQR]. Categorical variables were shown as the number of cases (%).
The costs associated with admissions were estimated in EUR2022 values. Costs records in the RAE‐CMBD database are determined based on the combination of diagnosis‐related group (DRG) and severity level [35]. Costs from 2022 for each DRG‐severity level combination were used to update costs from 2019, following the approach adopted in recent publications [29, 30]. For DRG‐severity level combinations without entries in 2022, the Consumer Price Index was applied to update the costs.
Admissions, relapses, TPE, ICU admissions, urgent admissions, and mortality standardized rates by sex, age, and year per 105 inhabitants were calculated considering the available seasonal population (person‐years) data from the National Statistics Institute.
Independent samples of continuous variables were analyzed using t‐tests or ANOVA for parametric distributions and U Mann–Whitney or Kruskal‐Wallis tests when the data did not meet normality assumptions. To assess normality, the Shapiro–Wilk test or the Kolmogorov–Smirnov test (with Lilliefors correction) was used. For categorical variables, Fisher's exact test or the Chi‐square test was employed. Paired continuous variables were examined using paired t‐tests or Wilcoxon signed‐rank tests, depending on the distribution. Paired categorical variables were assessed using McNemar's test. Chi‐square tests were used to analyze differences in standardized rates. For differences in the TPE/electromyography ratio, the Cochran‐Armitage trend test was applied. Statistical analysis was performed using R software version 4.1.2 (Posit Software, PBC, formerly RStudio). 250 Northern Avenue Suite 420, Boston, 02210 MA, USA.
3. Results
A total of 7786 hospitalizations for immune‐mediated neurological diseases and 7342 for immunodeficiencies were analyzed. The distribution of diseases comprising these groups is presented in the Table S2. Additional sample characteristics of the analyzed groups, such as age and sex, are presented in Table 2.
TABLE 2.
Descriptive summary of neurological conditions and immunodeficiencies.
| Levels | Neurological conditions | Immuno deficiencies | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 2019 | 2022 | Method | p | 2019 | 2022 | Method | p | ||
| Sample characteristics | |||||||||
| n | 3884 | 3902 | 3809 | 3533 | |||||
| Age (mean (SD)) | 63.94 (16.83) | 64.35 (16.87) | — | — | 63.20 (17.52) | 63.61 (17.13) | — | — | |
| Age (median [IQR]) | 66.00 [53.00, 77.00] | 67.00 [54.00, 77.00] | Wilcoxon | < 0.001 | 66.00 [52.00, 76.00] | 66.00 [53.00, 76.00] | Wilcoxon | < 0.001 | |
| Age Categorical (%) | Under 60 | 1506 (38.77) | 1456 (37.31) | Chi‐square | 0.469 | 1437 (37.73) | 1311 (37.11) | Chi‐square | 0.765 |
| Between 61 and 65 | 371 (9.55) | 405 (10.38) | 404 (10.61) | 404 (11.44) | |||||
| Between 66 and 70 | 435 (11.20) | 429 (10.99) | 439 (11.53) | 431 (12.20) | |||||
| Between 71 and 75 | 454 (11.69) | 491 (12.58) | 488 (12.81) | 434 (12.28) | |||||
| Between 76 and 80 | 446 (11.48) | 468 (11.99) | 405 (10.63) | 366 (10.36) | |||||
| Over 80 | 672 (17.30) | 653 (16.74) | 636 (16.70) | 587 (16.61) | |||||
| Sex (%) | Female | 1482 (38.16) | 1423 (36.47) | Fisher | 0.128 | 1997 (52.43) | 1910 (54.06) | Fisher | 0.167 |
| Male | 2402 (61.84) | 2479 (63.53) | 1812 (47.57) | 1623 (45.94) | |||||
| aCCI (mean (SD)) | 3.85 (3.01) | 3.95 (2.94) | — | — | 4.09 (2.80) | 4.08 (2.73) | — | — | |
| aCCI (median [IQR]) | 3.00 [2.00, 6.00] | 4.00 [2.00, 6.00] | Wilcoxon | < 0.001 | 4.00 [2.00, 6.00] | 4.00 [2.00, 6.00] | Wilcoxon | < 0.001 | |
| Result variables | |||||||||
| Pneumonia (%) | 172 (4.43) | 157 (4.02) | Fisher | 0.398 | 522 (13.70) | 495 (14.01) | Fisher | 0.710 | |
| Relapses (%) | 1668 (42.95) | 1577 (40.42) | Chi‐square | 0.025 | 39 (1.02) | 36 (1.02) | Fisher | 1.000 | |
| Complication profile (mean (SD)) | 0.51 (1.54) | 0.60 (1.79) | — | — | 0.40 (1.25) | 0.43 (1.33) | — | — | |
| Complication profile (median [IQR]) | 0.00 [0.00, 0.00] | 0.00 [0.00, 0.00] | Wilcoxon paired | < 0.001 | 0.00 [0.00, 0.00] | 0.00 [0.00, 0.00] | Wilcoxon | < 0.001 | |
| TPE (%) | 91 (2.34) | 138 (3.54) | Chi‐square | 0.002 | 9 (0.24) | 16 (0.45) | Fisher | 0.159 | |
| LoS (mean (SD)) | 14.54 (24.57) | 15.25 (30.08) | — | — | 10.25 (13.06) | 10.03 (13.99) | — | — | |
| LoS (median [IQR]) | 8.00 [4.00, 16.00] | 8.00 [4.00, 16.00] | Wilcoxon | < 0.001 | 7.00 [4.00, 12.00] | 7.00 [3.00, 12.00] | Wilcoxon | < 0.001 | |
| ICU (%) | 333 (8.57) | 380 (9.74) | Fisher | 0.077 | 188 (4.94) | 209 (5.92) | Fisher | 0.071 | |
| ICU LoS (mean (SD)) | 1.62 (11.52) | 2.18 (18.89) | — | — | 0.37 (4.09) | 0.46 (3.92) | — | — | |
| ICU LoS (median [IQR]) | 0.00 [0.00, 0.00] | 0.00 [0.00, 0.00] | Wilcoxon | < 0.001 | 0.00 [0.00, 0.00] | 0.00 [0.00, 0.00] | Wilcoxon | < 0.001 | |
| Death (%) | 220 (5.66) | 267 (6.84) | Chi‐square | 0.036 | 166 (4.36) | 154 (4.36) | Fisher | 1.000 | |
| Urgent (%) | 2946 (75.85) | 3060 (78.42) | Chi‐square | 0.007 | 2988 (78.45) | 2820 (79.82) | Fisher | 0.151 | |
| Cost (mean (SD)) | 8144.75 (8979.23) | 8793.72 (10622.09) | — | — | 6016.35 (6894.23) | 6161.31 (7272.46) | — | — | |
| Cost (median [IQR]) | 6073.71 [4041.37, 8855.36] | 6226.92 [3973.29, 8855.36] | Wilcoxon paired | < 0.001 | 4118.46 [3573.83, 6029.25] | 4118.46 [3454.33, 6223.09] | Wilcoxon | < 0.001 | |
Note: n (%), mean (SD), or median [IQR].
Abbreviations: aCCI, age‐adjusted Charlson Comorbidity Index; ICU, intensive care unit; IQR, interquartile range; LoS, length of stay; SD, standard deviation; TPE, therapeutic plasma exchange.
The main outcomes analyzed, relapses in neurological conditions and pneumonia in immunodeficiencies, did not show significant changes when comparing 2019 vs. 2022 (rates 3.58 × 105 vs. 2.29 × 105 inhab., p = 0.064; 1.13 × 105 vs. 1.03 × 105 inhab, p = 0.334, respectively; Table 2).
Total hospitalizations, through standardized rates, significantly decreased for immunodeficiencies (8.20 × 105 inhab. in 2019 and 7.36 × 105 inhab. in 2022; p < 0.001), but not for neurological conditions (8.36 × 105 inhab. in 2019 and 8.13 × 105 inhab. in 2022; p = 0.841). Patients with neurological conditions exhibit significantly higher comorbidity in 2022 compared to 2019 (median aCCI of 4 and 3 respectively; p < 0.001). A longer average LoS is observed in 2022 compared to 2019 for neurological conditions (15.25 and 14.54 days, respectively), while immunodeficiencies show lower LoS in 2022 when compared with 2019 (10.03 and 10.25 days, respectively). The number of complications experienced during the stay (complication profile) is also higher in 2022 in both groups (Table 2). Specifically, the average number of complications per admission increased by 0.1 (17.65%) in neurological conditions and 0.03 (7.50%) in immunodeficiencies.
During the hospital stay, the TPE use in patients with neurological conditions showed a significant increase when comparing 2019 vs. 2022 in both proportions (2.34% vs. 3.54%, p = 0.002) and standardized rates (0.2 vs. 0.29 × 105 inhabitants, p = 0.003). The additional analysis performed to show that the increase of TPE was not an artifact of analysis or inherent to the studied period, in relation to electromyography in patients with GBS (Figure 1), showed that electromyography did not change significantly between the analyzed years, neither in proportion to hospitalizations (22.78% vs. 23.53%, p = 0.621) nor in standardized rates (0.783 vs. 0.845 per 105 inhabitants, p = 0.215). The analysis showed a significantly higher ratio TPE to electromyography in 2022 than in 2019 (0.252 and 0.167, respectively; p = 0.019). These numbers indicate that TPE increased six times more than electromyography in hospitalizations of patients with GBS.
FIGURE 1.
Therapeutic plasma exchange vs. Electromyography in Guillain‐Barré Syndrome. Ratio, Therapeutic plasma exchange/Electromyography. *Cochran–Armitage trend test.
Hospital admission costs showed a significant increase in both groups (Table 3) between 2019 and 2022 (7.97% in neurological conditions and 2.41% in immunodeficiencies). Mortality in patients with neurological conditions showed a significant increase when comparing 2019 vs. 2022 in both proportions (5.66% vs. 6.84%, p = 0.036) and standardized mortality rates (0.48 vs. 0.56 × 105 inhabitants, p = 0.048), while no significant changes were observed in immunodeficiencies (Table 3).
TABLE 3.
Standardized rates of neurological conditions and immunodeficiencies.
| Variable | Level | Neurological conditions | Immuno deficiencies | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 2019 | 2022 | Total | p * | 2019 | 2022 | Total | p * | |||
| Seasonal population | 47,009,905 | 47,455,781 | 94,465,686 | 47,009,905 | 47,455,781 | 94,465,686 | ||||
| Total hospitalizations | n | 3884 | 3902 | 7786 | 0.841 | 3809 | 3533 | 7342 | < 0.001 | |
| Rate (/100,000 inhab) | 8.36 | 8.13 | 8.24 | 8.20 | 7.36 | 7.77 | ||||
| 95% LCL | 8.10 | 7.88 | 8.06 | 7.94 | 7.12 | 7.59 | ||||
| 95% UCL | 8.63 | 8.39 | 8.43 | 8.47 | 7.61 | 7.95 | ||||
| Relapses/pneumonia + | n | 1668 | 1577 | 3245 | 0.064 | 552 | 495 | 1017 | 0.334 | |
| Rate (/100,000 inhab) | 3.58 | 3.29 | 3.44 | 1.13 | 1.03 | 1.08 | ||||
| 95% LCL | 3.41 | 3.13 | 3.32 | 1.03 | 0.94 | 1.01 | ||||
| 95% UCL | 3.76 | 3.46 | 3.56 | 1.23 | 1.13 | 1.14 | ||||
| TPE | n | 91 | 138 | 229 | 0.003 | 9 | 16 | 25 | 0.239 | |
| Rate (/100,000 inhab) | 0.2 | 0.29 | 0.24 | 0.02 | 0.03 | 0.03 | ||||
| 95% LCL | 0.16 | 0.24 | 0.21 | 0.10 | 0.02 | 0.02 | ||||
| 95% UCL | 0.24 | 0.34 | 0.28 | 0.04 | 0.06 | 0.04 | ||||
| ICU admissions | n | 333 | 380 | 713 | 0.110 | 188 | 209 | 397 | 0.363 | |
| Rate (/100,000 inhab) | 0.72 | 0.79 | 0.76 | 0.41 | 0.44 | 0.42 | ||||
| 95% LCL | 0.64 | 0.72 | 0.70 | 0.35 | 0.38 | 0.38 | ||||
| 95% UCL | 0.80 | 0.88 | 0.81 | 0.47 | 0.50 | 0.46 | ||||
| Urgent admissions | n | 2946 | 3060 | 6006 | 0.275 | 2988 | 2820 | 5808 | 0.011 | |
| Rate (/100,000 inhab) | 6.34 | 6.38 | 6.36 | 6.44 | 5.88 | 6.15 | ||||
| 95% LCL | 6.11 | 6.15 | 6.20 | 6.21 | 5.66 | 5.99 | ||||
| 95% UCL | 6.57 | 6.61 | 6.52 | 6.67 | 6.1 | 6.31 | ||||
| Mortality | n | 220 | 267 | 487 | 0.048 | 166 | 154 | 320 | 0.484 | |
| Rate (/100,000 inhab) | 0.48 | 0.56 | 0.52 | 0.36 | 0.32 | 0.34 | ||||
| 95% LCL | 0.41 | 0.49 | 0.47 | 0.31 | 0.27 | 0.30 | ||||
| 95% UCL | 0.54 | 0.63 | 0.56 | 0.42 | 0.38 | 0.38 | ||||
Abbreviations: ICU, intensive care unit; LCL, lower confidence limit; TPE, therapeutic plasma exchange; UCL, upper confidence limit.
Relapses are shown for neurological conditions and pneumonia for immunodeficiencies.
The chi‐square test was used.
4. Discussion
Patients with clinical conditions treated with Igs are vulnerable to supply restrictions due to the limited availability of this plasma‐derived medicinal product in Spain, a situation deepened during the COVID‐19 pandemic. This is the first observational study assessing the clinical and economic impact of the use of Igs under restrictive conditions in neurological disorders in Spain.
The present analysis identified a change in the hospital management of neurological disorders with indicated Ig treatment at a national level. The number of TPE procedures registered in relation to the considered neurological conditions significantly increased in 2022 compared to 2019. This change is not related to general hospitalization trends in neurological patients, as TPE showed a significant increase in relation to the variations in electromyography, a standard procedure unaffected by restrictions in GBs in the study period [24]. Interventional protocols to allocate Ig treatment in situations of limited supply commonly advocate for prioritized Ig use for certain indications, starting with primary immunodeficiencies [24, 25, 36]. For instance, a Spanish clinical guideline for Ig use recommends long‐term Ig treatment in immunodeficiencies in all situations, including limited availability, whereas selective treatment is proposed for neurological conditions depending on clinical factors such as severity [36]. On the other hand, healthcare services from some Spanish regions elaborate their own clinical guidelines for disease management, and at least one has been identified that recommends TPE and Ig therapy with the same level of evidence for certain neurological conditions [37]. Altogether, these measures might have tipped the balance towards TPE as an alternative approach for neurological disorders in response to restrictive Ig supply in Spain.
Ig therapy and TPE have demonstrated similar efficacy in distinct neurological diseases, with mild adverse reactions, but Igs are generally better tolerated [38, 39]. Further, patients with neurological diseases exhibit a higher risk of TPE‐related complications, particularly hypotension [40, 41]. TPE has also been linked to the incidence of other adverse effects such as fever or nausea, among others, in addition to increased risk of infections [6, 26, 27]. No differences were observed in the number of relapses associated with neurological conditions. Yet, the complication profile of these patients worsened in 2022 compared to 2019, and the increase (both absolute and relative) was higher in neurological conditions than in immunodeficiencies. Specifically, there was one additional complication per 10 admissions in patients with neurological conditions and one per 33 admissions in patients with immunodeficiencies. This enhanced increase in the complication profile, although not necessarily directly linked, may be related to some extent to a swift in treatment towards TPE in neurological patients. Still, the worsening of patient outcomes described herein for neurological conditions could be driven by a complex network of factors, for instance, the delay in surgical procedures and follow‐up care some chronic diseases experienced as a consequence of the pandemic [42, 43].
With regards to hospitalizations, a significant decrease in its rate was observed for immunodeficiencies, but not for neurological conditions. Importantly, deaths, along with LoS, significantly increased for neurological conditions in the present study, whereas it was not the case for immunodeficiencies. No differences in LoS have been reported between Ig treatment and TPE for certain neurological conditions, like GBS, but previously published evidence points out towards shorter LoS in patients with MG treated with Ig, even in those patients suffering from exacerbations [38, 39, 44]. Slightly faster recovery times were reported for Ig‐treated patients with certain neurological conditions compared to TPE, which might also impact hospitalizations and LoS [39, 45]. Further, the present analysis identified an increase in comorbidity for these patients in 2022, which might affect their susceptibility to other complications and risk of mortality [46].
From an economic perspective, the cost per hospitalization was significantly higher in 2022 than in 2019 for neurological diseases, which might be partly related to the longer LoS and increased complication profile registered in this patient population. Considering the information published by the Ministry of Health on its statistical portal (data on file) and updating it to EUR2022 using the Consumer Price Index, as done for other costs in the present analysis, we observe that the mean general hospital admission costs for the general population have not increased over the analyzed years. Thus, the higher mean hospitalization costs observed for neurological conditions and immunodeficiencies are not an artifact of general trends, the increase being much more pronounced in neurological patients. Taken together, these results suggest that modifying the management strategy of patients with neurological disorders requiring Ig therapy due to restrictive conditions may have negatively impacted their clinical outcomes.
4.1. Limitations
Our analysis is subject to several limitations. It is a retrospective observational study based on hospital discharge data across Spain. Consequently, the clinical information available is limited to the hospital stay, which does not allow for the assessment of health status or outcomes beyond discharge.
The extent of the Ig use in the clinical conditions analyzed in the study is unknown, as the RAE‐CMBD database does not collect data on treatments, including Ig dosing. Provided this type of information were available at some point, changes in Ig dose could be assessed to determine whether the supply restrictions could have led to lower‐dose Ig treatment in certain diseases. In this line, corticosteroid use, an alternative therapy recommended for some of the pathologies evaluated in this study, such as CIDP [47], could not be assessed as part of the analysis. Yet, if data were available at some point, it would be certainly interesting to evaluate corticosteroid use in these patients, since this therapy has demonstrated differential clinical outcomes compared to Ig use, for instance, response rates are worse with corticosteroids compared with Ig therapy [48, 49, 50]. However, change in patient management over the considered period was evaluated in this case by assessing the trends on TPE as the main alternative therapy to Igs [33].
This limitation in availability of treatment information does not allow for a thorough economic analysis of Ig therapy compared to alternative treatments, that is TPE and corticosteroids. A previous study unveiled lower costs for TPE compared to Ig therapy in Spain, proposing the first as a good therapeutic option in those patients who would benefit equally from these treatments. This study, given the nature of the databases, focuses on the impact on costs derived from patient outcomes in a context of Ig supply restrictions use.
Although submitting hospital information to the RAE‐CMBD is mandatory, coding or recording errors may occur. While measures have been taken to minimize these errors, as detailed in the methodology, they may still affect the accuracy of the results. Another related aspect is outpatient visits, which are not systematically recorded in the RAE‐CMBD. Day hospital visits and procedures could not be assessed, which may have led to an underestimation in resource use related to Ig restrictive use, as management of potential adverse events resulting from treatment switches. Nonetheless, relapses in patients with neurological conditions typically require hospitalization due to their severity, so this is unlikely to be a source of error in this specific part of the study.
The aCCI may be underestimated in our analysis, as comorbidities are not extracted from the complete clinical history but rather from the diagnoses recorded at hospital admission that the healthcare professionals deem relevant for the specific hospitalization. While this directly affects the calculated measure of the aCCI, it is important to highlight that it should not impact the result of the analysis, as this bias is likely to occur in all analyzed years.
COVID‐19 represents a confounding factor that could significantly impact hospital admission data during the pandemic. Cases associated with a set of ICD‐10 codes related to COVID‐19 were excluded from the study to minimize the infection's effect on the results.
5. Conclusions
The present study has shown different clinical and economic trends in patients with neurological diseases and immunodeficiencies between 2019 and 2022. While no significant changes in clinical outcomes could be identified in the immunodeficiencies group, the group of neurological conditions showed an increase in comorbidities, complications, and mortality. A significant rise in the use of TPE for neurological conditions was observed. Hospitalization costs increased for both groups, more markedly in neurological diseases, reflecting longer LoS and a higher complication burden. Although no causality can be inferred from the present study, the results suggest that modifying the management strategy of patients with neurological disorders requiring Ig therapy due to restrictive conditions could have negatively impacted their clinical outcomes.
Author Contributions
Luis Querol: conceptualization, supervision, writing – review and editing, validation. J. Bruno Montoro‐Ronsano: conceptualization, validation, supervision, writing – review and editing. Pere Soler‐Palacín: conceptualization, validation, supervision, writing – review and editing. Jonathan Galduf: conceptualization, writing – review and editing. Óscar Martínez‐Pérez: conceptualization, methodology, investigation, formal analysis, data curation, visualization, writing – original draft, writing – review and editing. Helena Díaz‐Cuervo: conceptualization, methodology, investigation, writing – original draft, writing – review and editing.
Funding
This study was funded by CSL Behring Europe. The company was involved in shaping the research scope and methodology. The analysis and interpretation of the results were conducted independently.
Conflicts of Interest
J.B.M.R., and P.S.‐P, received honoraria and consulting fees from C.S.L. Behring. P.S.‐P, received honoraria and consulting fees from Takeda and Grifols. L.Q., received research grants from Instituto de Salud Carlos III, CIBERER, GBS‐CIDP Foundation International, ArgenX ans UCB; received honoraria fees from Sanofi, Annexon, Alnylam and ArgenX; received payment for expert testimony from Lycia Therapeutics, Annexon, ArgenX, CSL Behrin, Johnson and Johnson, Merck, Novartis, Roche, Takeda, Sanofi‐Genzyme, U.C.B., Pharma, Dianthus, Avilar, Alnylam and Nuvig; received support for attending congresses from Alnylam and Sanofi; has participated as member of steering committee for clinical trials for U.C.B., Sanofi and ArgenX; is member of board of directors in the Peripheral Nerve Society. J.G. is employed at CSL Behring. OMP and HD are consultants of Axentiva Solutions S.L., which received consultancy fees from CSL Behring and, during the conduct of this study, from other pharmaceutical companies on unrelated projects.
Supporting information
Data S1: CIE‐10 pneumonia codes.
Table S1: ICD‐10 codes related to COVID‐19 as exclusion criteria.
Table S2: Neurological conditions and Immunodeficiency diseases distribution.
Acknowledgements
We gratefully acknowledge the Spanish Ministry of Health for providing access to high‐quality data, which enabled the generation of valuable insights for this research.
Data Availability Statement
The data that support the findings of this study are available from Registro de Atención Especializada. Ministerio de Sanidad. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from https://www.sanidad.gob.es/estadEstudios/estadisticas/estadisticas/estMinisterio/SolicitudCMBD.htm with the permission of the Ministry of Health.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1: CIE‐10 pneumonia codes.
Table S1: ICD‐10 codes related to COVID‐19 as exclusion criteria.
Table S2: Neurological conditions and Immunodeficiency diseases distribution.
Data Availability Statement
The data that support the findings of this study are available from Registro de Atención Especializada. Ministerio de Sanidad. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from https://www.sanidad.gob.es/estadEstudios/estadisticas/estadisticas/estMinisterio/SolicitudCMBD.htm with the permission of the Ministry of Health.