Abstract
The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care of patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymized clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of 348 patients are registered in Switzerland, indicating an estimated minimal prevalence of 4·2 patients per 100 000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19 091 registered patients: ‘predominantly antibody disorders’ are the most common diseases observed (n = 217/348, 62%), followed by ‘phagocytic disorders’ (n = 31/348, 9%). As expected, ‘predominantly antibody disorders’ are more prevalent in adults than in children (78 versus 31%). Within this category, ‘common variable immunodeficiency disorder’ (CVID) is the most prevalent PID (n = 98/217, 45%), followed by ‘other hypogammaglobulinaemias’ (i.e. a group of non-classified hypogammaglobulinaemias) (n = 54/217, 25%). Among ‘phagocytic disorders’, ‘chronic granulomatous disease’ is the most prevalent PID (n = 27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high, with a median of 6 years for CVID and more than 3 years for ‘other hypogammaglobulinaemias’.
Keywords: common variable immunodeficiency (CVID), hypogammaglobulinaemia, patient registry, phagocyte defects, primary immunodeficiency
Introduction
Primary immunodeficiency disorders (PID) are heterogeneous diseases that result from inborn errors of the immune system. Generally, although most PID are rare diseases (affecting < 1: 2000 people), PID cause a major medical and social economic burden. Clearer understanding of the epidemiology of PID and the promotion of collaborative research projects among registry member groups are therefore major goals of the Swiss National PID Registry. Our paper presents the distribution of PID patients in Switzerland, documented between 2008 and 2014. The registry’s short-term goal is to register all diagnosed PID patients in order to clarify the prevalence of these diseases in Switzerland. The long-term objective is to build a tool that provides retrospective and prospective data for the medical community, health-care authorities, PID patients and their families to improve knowledge on PID. Linked to this, Swiss physicians’ awareness of PID and of centres providing high-quality medical care in this field should be increased, as to date many PID are still under-diagnosed and/or under-reported 1.
Materials and methods
Participating centres
The Swiss National PID Registry was initiated in 2008, and now comprises 17 medical centres with experience in the care of children or adults with PID. These centres are localized at the five Swiss academic medical centres, at four affiliated teaching hospitals and at one independent out-patient centre. These medical centres are specialized in immunology, haematology, infectious diseases and/or internal medicine (Fig. 1). A travelling fellow of the Division of Immunology at University Children’s Hospital Zurich (i.e. the only Swiss centre for Highly Specialized Medicine for paediatric PID) assisted the other centres with ethical approval and/or registration. Ethical approval was not required in all the Swiss cantons (reference numbers of cantonal ethic committees’ votes: Zurich: StV-36/06, Berne: KEK-BE 148/10, Lucerne: EK: 976).
Figure 1.
Swiss National Primary Immunodeficiency Disorders (PID) Registry. Paediatric and adult centres, March 2014 (n = 348).
Data collection
The Swiss National PID Registry is hosted on the secured online platform of the European Database for Primary Immunodeficiencies, belonging to the European Society of Immunodeficiency Diseases (ESID). The ESID online database, established in 2004, collects anonymized clinical and laboratory information on PID patients, and serves for epidemiological analyses, the development of new diagnostic and therapeutic strategies as well as the documentation of novel PID-causing genes. The ESID database platform is also used by other national registries, e.g. France, Spain, Germany and the United Kingdom, and is co-ordinated at the Centre for Chronic Immunodeficiency (CCI) at the University Medical Centre Freiburg, Freiburg, Germany 2. The structure of the ESID online database has been described in detail previously 3 (see Supporting information for more details).
Results
Between April 2008 and March 2014, 348 patients were documented in Switzerland (Table1). Three hundred and thirty-eight patients were alive, eight were deceased (patients who had given consent and had subsequently died) and two were lost to follow-up (patients who had given consent and are no longer contactable). The minimal PID prevalence was calculated as 4·2 per 100 000 inhabitants.
Table 1.
Total number of registered primary immunodeficiency disorder (PID) patients and documenting centres per year in Switzerland (source: www.esid.org, 2014).
| Country: Switzerland | |||||||
|---|---|---|---|---|---|---|---|
| Selected year | 2014 | 2013 | 2012 | 2011 | 2010 | 2009 | 2008 |
| Number of patients | 348 | 303 | 265 | 184 | 98 | 76 | 34 |
| Number of documenting centres | 11 | 10 | 8 | 6 | 5 | 2 | 1 |
Patient distribution by gender and age
The distribution of gender was almost equal, with 177 male and 171 female patients. There were more documented adults than children: 238 patients were adults aged ≥ 18 years (male n = 104 of 238, 43·7%, female n = 134 of 238, 56·3%); 110 patients were children (male n = 73 of 110, 66·4%, female n = 37, 33·6%) (Table2).
Table 2.
Distribution of gender Swiss National Primary Immunodeficiency Disorder (PID) Registry versus European Society for Primary Immunodeficiencies (ESID) online database 2014 (source: www.esid.org, 2014).
| Registry, March 2014 | Female | % | Male | % | Total | % |
|---|---|---|---|---|---|---|
| Swiss | 171 | 49·1 | 177 | 50·9 | 348 | 100 |
| Swiss < 18 years | 37 | 33·6 | 73 | 66·4 | 110 | 31·6 |
| Swiss >= 18 years | 134 | 56·3 | 104 | 43·7 | 238 | 68·4 |
| ESID | 8233 | 42·7 | 11 053 | 57·3 | 19 287 | 100 |
Distribution of PID
More than half the registered patients in Switzerland were diagnosed with ‘predominantly antibody deficiencies’ (Fig. 2), which are much more prevalent in adults than in children (Supporting information, Figs S1 and S2). Within this disease category the most frequent diagnosis in adults is ‘common variable immunodeficiency’ (CVID) while ‘other hypogammaglobulinaemias’ is the most frequently documented PID entity in children. The second largest group comprises patients suffering from ‘phagocytic disorders’. This PID entity is more prevalent in children than in adults. This is also the case for all other remaining disease groups, with the exception of ‘complement deficiencies’. The distribution of all PID categories in children and adults, also including ‘other well-defined PIDs’, ‘T cell deficiencies’, ‘autoinflammatory diseases’, ‘defects of innate immunity’ and ‘autoimmune and immune dysregulation syndromes’, is shown in Table3.
Figure 2.
Distribution of PID categories among total registered patients, Swiss National Primary Immunodeficiency Disorder (PID) Registry, March 2014.
Table 3.
Distribution of primary immunodeficiency disorder (PID) by age Swiss National Primary Immunodeficiency Disorder Registry (source: www.esid.org, 2014).
| PID | Total patients (n = 348) | Alive patients < 18 years (n = 109) | Alive patients >= 18 years (n = 229) |
|---|---|---|---|
| Autoimmune and immune dysregulation syndromes | 8 (2·3%) | 6 (5·5%) | 2 (0·9%) |
| Autoinflammatory syndromes | 12 (3·4%) | 11 (10·1%) | 1 (0·4%) |
| Complement deficiencies | 16 (4·6%) | 1 (0·9%) | 14 (6·1%) |
| Defects in innate immunity | 7 (2%) | 6 (5·5%) | 1 (0·4%) |
| Other well-defined PIDs | 29 (8·3%) | 19 (17·4%) | 9 (3·9%) |
| Phagocytic disorders | 31 (8·9%) | 13 (11·9%) | 16 (7%) |
| Predominantly antibody disorders | 217 (62·4%) | 34 (31·2%) | 179 (78·2%) |
| Common variable immunodeficiency | 98 (28·2%) | 1 (0·9%) | 93 (40·6%) |
| Other hypogammaglobulinaemias | 54 (15·5%) | 17 (15·6%) | 37 (16·2%) |
| Predominantly T cell deficiencies | 23 (6·6%) | 18 (16·5%) | 3 (1·3%) |
The Supporting information, Table S1, gives an overview of the different PID diseases within each PID category. This complete list of diseases also includes details on the number of patients with known genetic mutation, consanguinity and familial background.
Time to diagnosis
Diagnostic delay is defined as the time between first documented onset of symptoms and/or laboratory findings and the time of PID diagnosis. In most cases PID was diagnosed during childhood (55%, n = 159 of 292 patients in total where data were available), with the exception of CVID (87·5% diagnosed in adulthood) (Fig. 3, and data not shown). The highest median diagnostic delay was observed in CVID (n = 69, 5·95 years), followed by ‘isolated IgG subclass deficiencies’ (n = 14, 4·6 years), ‘deficiency of specific IgG’ (n = 8, 3·7) and ‘other hypogammaglobulinaemias’ (n = 46, 3·17 years). In a single patient with ‘hyper IgE syndrome’ (HIES), the highest diagnostic delay was 42 years, followed by ‘IgA with IgG subclass deficiency’ (n = 1, 23 years), ‘immunodeficiency-centromeric instability-facial anomalies’ (ICF) (n = 2, 11·2 years), ‘ataxia telangiectasia’ (AT) (n = 1, 8·4 years) and ‘autoimmune lymphoproliferative syndrome’ (ALPS) (n = 2, 6·5 years) (data not shown).
Figure 3.
Diagnostic delay. In years of primary immunodeficiency disorder (PID) with five or more registered patients/PID entity, Swiss National PID Registry, March 2014.
Treatment
Immunoglobulin (Ig) replacement was the most frequently reported permanent treatment. Of all registered alive patients, 31·9% (n = 108 of 338) received Ig replacement therapy via the intravenous (i.v.) (n = 81 of 108, 75%) or subcutaneous (s.c.) (n = 27 of 108, 25%) routes; 16·7% of alive children (n = 18 of 108) and 58·3% alive adults (n = 63 of 108) received i.v. Ig replacement, whereas 8·3% of children (n = 9 of 108) and 16·7% adults (n = 18 of 108) received SC Ig replacement (Table4). From 2008 to 2014, 3·45% of PID patients were treated by haematopoietic stem cell transplantation (HSCT) (n = 12 of 348) and 0.29% were treated by gene therapy (n = one of 348) (data not shown).
Table 4.
Route of replacement therapy as available data, Switzerland, March 2014 (source: www.esid.org, 2014).
| Immunoglobulin replacement therapy | Alive patients on immunoglobulin | Age | Age | |||
|---|---|---|---|---|---|---|
| Route of administration | n | % | <18 years | % | >18 years | % |
| Intravenous | 81 | 75·0 | 18 | 66·7 | 63 | 77·8 |
| Subcutaneous | 27 | 25·0 | 9 | 33·3 | 18 | 22·2 |
| Total | 108 | 100·0 | 27 | 100·0 | 81 | 100·0 |
Discussion
We present the first report on the distribution of PID from the Swiss National PID Registry. There were 338 alive patients registered with PID. Based on a population of 8·04 million in Switzerland in 2014, documented alive patients (n = 338) allow a cautious estimation of a prevalence of 4·2 PID patients per 100 000 living inhabitants. During the course of a medical thesis 4, a previous study in 1988 had collected data on 313 PID patients, and in 1993 a nationwide survey documented 518 PID patients 5. The latter survey included all PID patients seen in consultation or hospitalized in Switzerland, Swiss inhabitants and internationally referred patients. In contrast, the present registry includes only PID patients currently living in Switzerland. A further explanation for the discrepancy in documented patient numbers might be the fact that in 2014 not all the 17 Swiss centres had started to register their PID patients. Some are still waiting for ethical approval or patient’s consent to start registration. In addition, a significant percentage of patients, predominantly adults, do not wish to provide consent for registration of their data. Also, in some parts of Switzerland PID patients are treated in general medical institutions without the capacity to document and enter relevant data into the Swiss National Registry for PID. Therefore, the number of currently registered PID patients most probably does not reflect the true geographical distribution and true prevalence of PID in Switzerland.
Despite the mentioned difficulties in data collection and registering PID patients in Switzerland, comparing the prevalence of PID patients to the other documenting centres within the ESID online database, Switzerland is in third place, with 4·2 registered patients per 100 000 inhabitants, after France and Spain, countries with centralized health care systems for PID and centralized registries (Fig. 4a,b).
Figure 4.
(a) Prevalence of primary immunodeficiency disorder (PID) in registered alive patients per 100 000 inhabitants in Europe (source: www.esid.org, 2014). The map shows the minimal prevalence rates calculated from the number of documented PID patients in the European Society for Primary Immunodeficiencies (ESID) database. This comprises patients treated outside their country of residence but registered in Switzerland. (b) Total number of registered PID patients within ESID database of the top 12 ESID documenting countries, January 2014 (source: www.esid.org, 2014).
In different countries the overall published prevalence of PID was found to range from 2·5 (Ireland) 6 to 5·3 per 100 000 inhabitants (Norway) 7.
The gender distribution for male and female PID patients in Switzerland is almost equal (50·9% male versus 49·1% female). Particularly in patients < 18 years, we observed more male patients (66·3%), which might be linked to the fact that X-linked PIDs (such as severe combined immunodeficiency, chronic granulomatous disease or Wiskott–Aldrich syndrome) are severe, so that the affected males might not survive into adulthood. There was a female preponderance (56·3%) in adult patients which might be linked to the prevalence of CVID, which is the predominant PID of adult patients (83% females versus 16·6% males).
The frequency distribution of PID categories in Switzerland was comparable, overall, with distribution in the other countries registering patients in the ESID online database (compare Fig. 2 with Fig. 5): ‘predominantly antibody disorders’ is the most frequent PID category, with an estimated prevalence of 2·71 per 100 000 inhabitants (range in other ESID countries of 2·93–1·27 per 100 000 1). Within this category in Switzerland, CVID is the most frequent PID, with a prevalence of 1·22 per 100 000 inhabitants comparable to a range of 0·55 per 100 000 in Spain 8 to 2·1 per 100 000 in (Norway) 7. In other national registries, ‘other hypogammaglobulinaemias’, with a prevalence of 0·67 per 100 000 inhabitants in Switzerland, ranged from 0·0 in Ireland 6,10 to 1·51 per 100 000 inhabitants in Australia 9.
Figure 5.
Distribution of PID categories in Europe among total registered patients in the European Society for Primary Immunodeficiencies (ESID) registry, March 2014 (source: www.esid.org, 2014).
Concerning treatment of patients with antibody disorders, we have shown that most adults were treated via i.v. (77·8%) compared to s.c. (22·2%) Ig substitution. This proportion was also seen in children, with slightly higher numbers of patients on s.c. Ig substitution (patients < 18 years 33·3%, adults 22·2% on s.c. Ig replacement), which could be due eventually to difficult venous access in some children compared to adults.
In Switzerland the median diagnostic delay for the main PID categories such as ‘predominantly antibody deficiencies’ was high: the longest diagnostic delay was observed in CVID, which might be due to relatively mild symptoms in the early years of the disease. In contrast, there was a relatively short diagnostic delay for patients with DiGeorge syndrome. This may be the explained by the high coincidence of congenital heart defects, which are detected early. In SCID and CGD the diagnostic delay was also relatively short, due probably to the severe course with an early onset of recurrent life-threatening infections.
Compared to national registries in France 10, the United Kingdom 1 and Germany 2, the median Swiss diagnostic delay in CVID was similar to France (6 years), but higher than in Germany and the United Kingdom (4 and 5 years, respectively). We observed a shorter median diagnostic delay in CGD with 0·75 years compared to 0·9 years in France, the United Kingdom (1 year) and Germany (1–2 years).
Early diagnosis and treatment are imperative for preventing significant PID disease-associated morbidity. Diagnostic delay can lead to permanent organ damage or even death from overwhelming infection 11. Therefore, immediate consultation with a clinical immunologist or PID specialist is essential in the case of clinical suspicion of PID. Once the correct diagnosis is established, therapy needs to be initiated quickly to avoid or reduce organ damage and to achieve optimal outcome with reasonable quality of life for PID patients. In addition to continuous high-quality education and teaching of our medical students, general practitioners, paediatricians and other specialists, the consistent and complete documentation of all PID patients remains extremely important and may be the first step to improve the diagnostic delay in PID.
Conclusion
Based on the analysis of the first 6 years of data from the Swiss National PID Registry, ‘predominantly antibody disorders’ are the most frequent PID in Switzerland and other European countries.
As in other countries, the diagnostic delay is high, accounting for the need for better medical education and postgraduate teaching to increase awareness and to shorten the time to achieve adequate treatment.
The registry has helped to build up a network of expert physicians in Switzerland, allowing for fruitful medical and scientific collaboration with the goal of improvement of patient care and access to treatment all over Switzerland.
Acknowledgments
We thank the members of all participating centres for their work and helpful discussions, and all patients with their families participating in the Swiss National Registry for PID. H.M. was supported by an educational grant from Baxter, Biotest, CSL Behring, Kedrion and Octapharma. Dr Antonios Kolios helped with the patient data registry in University Hospital Zurich, Department of Immunology. The ESID database is supported by the PPTA (Plasma Protein Therapeutics Association, http://www.pptaglobal.org). H.C. was supported by a research grant SNSF 310030_153059 from the SNF. The authors are responsible for the contents of this publication.
Disclosure
The authors declare no competing financial or commercial interests that could be construed as a potential conflict of interest. R.M. was supported by a professorship grant PP00P3_144863 from the Swiss National Science Foundation (SNF).
Collaborators of the Swiss PID Registry Working Group
F. Angelini (Lausanne), J. Bonhoeffer (Basel), T. Braschler (Lucerne), B. Brazzola (Bellinzona), A. Dierig (Basel), K. Eberhardt-Walther (Basel), F. Fahrni (Lucerne), M. Hofer (Lausanne), C. Kahlert (St Gallen), A. Kolios (Zurich), F. Spertini (Lausanne), H. Oezsahin (Geneva), J. Pachlopnik Schmid (Zurich), N. Ritz (Basel), H. Ubieto (St Gallen).
Supporting Information
Additional Supporting information may be found in the online version of this article at the publisher’s web site:
Fig. S1. Distribution of primary immunodeficiency disorder (PID) categories in adults (n = 229) in alive patients, Swiss National PID Registry, March 2014.
Fig. S2. Distribution of primary immunodeficiency disorder (PID) categories in children (n = 109) in alive patients, Swiss National PID Registry, March 2014.
Table S1. Distribution of patients in Swiss National Primary Immunodeficiency Disorder (PID) Registry as of March 2014 (patients with available data).
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Associated Data
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Supplementary Materials
Fig. S1. Distribution of primary immunodeficiency disorder (PID) categories in adults (n = 229) in alive patients, Swiss National PID Registry, March 2014.
Fig. S2. Distribution of primary immunodeficiency disorder (PID) categories in children (n = 109) in alive patients, Swiss National PID Registry, March 2014.
Table S1. Distribution of patients in Swiss National Primary Immunodeficiency Disorder (PID) Registry as of March 2014 (patients with available data).