Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

This is first study to quantify diagnostic delay for all RDs in Spain, based on information sourced from a national registry open to any RD, something that gives it an advantage over other studies based on surveys of patients with self-reported RDs. The reason for this is that all persons entered on the Spanish RD Patient Registry have a clinical report which makes it possible, on the one hand, to validate that they are indeed affected by a disease which fulfils the criteria for being considered a RD, and on the other, to verify their dates of symptom onset and diagnosis.

The mean time to diagnosis of a RD in Spain is 6.18 years, similar to that estimated by other international studies [19, 20]. More than half of all RD patients experience diagnostic delays in Spain (56.4%), with this being somewhat higher than the result obtained in the ENSERio study of FEDER [8], which reported a figure of 49.7% in a sample of 1576 patients. A more detailed comparison shows that both studies highlight the seriousness of this problem, with very similar percentages of diagnostic delay: 18.9% (ENSERio [8]) versus 19% (our study) of patients took 1 to 3 years, 18.1% versus 16.7% took 4 to 9 years, and 18.7% versus 20.9% waited more than 10 years to obtain a diagnosis. This thus confirms that for a high percentage of persons affected by RDs in Spain, the IRDiRC goal of obtaining diagnosis in the first year of examination has not be achieved.

In the international context, only EURORDIS’ EurordisCare 2 study offers general data for a group of 8 RDs, indicating that 25% of patients took more than 5 years to obtain their respective diagnoses [7]. Other studies report the median time to diagnosis for some RDs of the nervous system, i.e., Friedreich ataxia (36 months) [21], ataxia-telangiectasia (12 months) [22] and Duchenne muscular dystrophy (12 months) [23]. Furthermore, a time to diagnosis of less than a year has been reported for amyotrophic lateral sclerosis (11.5 months) [24] and inflammatory demyelinating polyradiculoneuropathy (5 months) [25]. In spite of the fact that there are diagnostic criteria for post-polio syndrome, 83.9% of these patients took over a year to be diagnosed (our study). Early diagnosis of this disease is complicated by the need for differential diagnosis, and even more so in the older population, by the overlapping of symptoms with other usual comorbidities. [26]

Similarly, time to diagnosis has also registered median values of over a year for some rare metabolic diseases: alpha-1 antitrypsin deficiency (22.3 years) [27], Pompe disease (12.9 years) [28], alpha-mannosidosis (72 months) [29], adult hypophosphatasia (over 3.8 years) [30], Farber’s disease (13.7 months) [31], and mucopolysaccharidosis type III (39 months) [32]. This delay in the diagnosis of rare metabolic diseases is more common among those that do not form part of neonatal screening or do not exhibit altered levels of biochemical parameters in routine biological samples [33]. In contrast, a time to diagnosis of less than a year is reported for cardiac amyloidosis (10 months) [34], mucopolysaccharidosis type I (9 months) [32] and childhood hypophosphatasia (8.4 weeks) [30].

In general, in addition to metabolic diseases which are diagnosed in neonatal screening, diseases of paediatric appearance (under age 15 years) are usually diagnosed before they present at adult age. For instance, at a paediatric level, congenital malformations predominate (39.1% of diseases of paediatric appearance), with the patients in question registering a 48.4% diagnostic delay in our study. Among adults, diseases that affect the nervous system are more frequent (35.8% of diseases of adult appearance), and patients in this group register a 64.2% delay. Regarding sex, differences in diagnostic delay have been found. Specifically, diagnostic delay is higher in women than in men in musculoskeletal, endocrine and eye and adnexa diseases. This gender gap is also observed in other studies with common diseases in which women are diagnoses later than men [35].

The difficulty of diagnosing certain RDs is due to the fact that many of them do not have specific tests and present with widely varying phenotypical manifestations [36]. In the case of RDs identified with diagnostic delay, it should be noted that such delay is especially harmful for patients affected by Usher Syndrome (our study indicates a diagnostic delay of over 75%), muscular dystrophies (Becker, Duchenne or facioescapulohumeral), Friedreich ataxia, lymphangioleiomyomatosis, hereditary angio-oedema, amyotrophic lateral sclerosis, or acquired epidermolysis bullosa. These RDs, among others, highlight the urgent need for development of solutions that would serve to reduce the delay in diagnosis [37].

In terms of time trend, the percentage of persons who experienced diagnostic delays decreased across the period between the 1960s and the present. This decrease is consistent with scientific and medical advances, increased knowledge of RDs, and improvements in diagnostic techniques. In this respect, the discovery of Next Generation Sequencing has radically changed diagnosis of certain genetic RDs, in that this is a fast, powerful and increasingly available alternative which has reduced waiting times [33]. The marked fall seen from 2018 onwards may be affected by the fact that all the study participants were persons already diagnosed with a RD, meaning that those with recent symptom onset have not yet had the opportunity to be diagnosed and included in this study. Given that mean time to diagnosis is 6 years, it would be more appropriate to pay attention to the trend registered until 2018, which shows a gradual decrease in the percentage of patients who experienced diagnostic delays in Spain. When it comes to Autonomous Regions, it should be stressed that while no evidence was found to show that diagnostic delays might vary by region, more in-depth study on this topic is nevertheless called for, since it is a matter of concern to patient associations.

It is clear that the diagnostic delay of RD is a public health problem. Therefore, it would be advisable to establish some potential measures like improving: the scientific knowledge of RDs; the accessibility to different clinicians o centres of references (sometimes by shortening the distance among them); the time spent in attending the different medical appointments; the availability of ad hoc diagnostic tests; the capacity of reffering to other centres easily or the increase of staff. In Spain there are 296 Reference Centres, Services and Units in the National Health System. They are distributed in 52 centres, includes 70 pathologies and many of them are part of the European Reference Networks. However, these centres do not cover all RD as many patients´ organizations claim.

Mention should be made of the difficulty of validating the variable, ‘time to diagnosis’. The limitations on being able to establish both disease onset and the fact that diagnosis was validly made are usual in these types of studies, if this information is not specifically recorded in the clinical report. If the first manifestations are clearly attributable to the disease, the date of symptom onset can be estimated, especially if it is connected to events in the family’s social life. The date of diagnosis can occur: (a) when it is linked to an analytical, histological or imaging test that allows for no doubt; or alternatively, (b) within the framework of a diagnostic process that is long per se. In such a case, diagnosis can be obtained with a high level of certainty in a given time, but confirmation may be altogether slower in coming, due to need to perform techniques that take time. Hence, whereas some patients might consider themselves to be already diagnosed on the basis of clinical suspicion, others would not venture to do so until receipt of the final confirmatory test, even though this may well corroborate the clinical diagnosis. These problems are further aggravated in the case of diagnoses made decades ago, though the general trend among patients insofar as it might serve to increase or decrease this time is not a systematic problem. In this study an effort was made to use the information stated in clinical reports, submitted by health professionals through medical societies, and/or recorded in the registry. Lastly, the lack of a population-based registry for RDs as a whole means that the distribution of all patients and all RDs in a specific geographical region cannot be properly ascertained. As a result, these aspects could limit extrapolation of the results obtained to RDs as whole.

Despite the limitations, the main strength of this study is that it is the first to quantify time to diagnosis of RDs in Spain, based on information sourced from a national registry open to any RD. Another point to be highlighted is that, in comparison with the only previous studies to furnish data on diagnostic delays in general for RDs in Spain [8, 38], our study not only relied on information covering a greater number of diseases and persons affected, confirmed diagnoses of RD, and a heterogeneous population in socio-demographic terms, but the data were also gathered over a long period of time.

留言 (0)

沒有登入
gif