Motivos y complicaciones relacionadas con el rechazo de pruebas diagnósticas y recomendaciones terapéuticas en cardiopatías familiares. Estudio RELUCTANT / Reasons for refusing diagnostic tests and therapeutic recommendations and associated complications in inherited heart diseases. The RELUCTANT study

Introducción y objetivos: El estudio de las cardiopatías familiares implica realizar pruebas diagnósticas, a veces molestas, a familiares asintomáticos. El objetivo de este proyecto es cuantificar el rechazo a dichas pruebas y recomendaciones terapéuticas. Métodos: Se evaluó a 1.992 familias consecutivas con cardiopatías familiares para analizar el rechazo al cribado familiar. Se evaluó a 1.539 (recomendación de cardiorresonancia) y 837 (recomendación de test de provocación farmacológica). Se evaluó a 395 pacientes con indicación de desfibrilador automático implantable (DAI) y 402 con indicación de anticoagulación, para estudiar el rechazo de los tratamientos. Resultados: El 28% de las familias a las que se recomienda estudio por sospecha de cardiopatía familiar no acuden; el rechazo es menor si hay antecedentes familiares de muerte súbita. El 23% no se sometió a la resonancia; los 2 motivos más alegados son citación imposible (53%) y claustrofobia (18%). Las personas de más edad, las mujeres, los sintomáticos, los individuos con arritmias y los familiares rechazaron más la prueba. El 19% no se hizo el test de provocación farmacológica por temor (46%) o citación imposible (25%). Los individuos de más edad, los asintomáticos, aquellos con antecedente de arritmias, los familiares y aquellos con estudio genético positivo lo rechazaron en mayor proporción. Solo una minoría de pacientes rechazaron los tratamientos (el 5,1% el DAI y el 2,5% la anticoagulación). La tasa de muerte súbita entre los que rechazaron el DAI fue alta (el 4,5% al año). Conclusiones: Una quinta parte de las personas que acuden al cribado de cardiopatías familiares rechazan la realización de pruebas más sofisticadas y molestas. Se identifican varios predictores independientes asociados con el rechazo. Solo una minoría de pacientes en alto riesgo rechazan los tratamientos como la anticoagulación o el implante de DAI. (AU)

Introduction and objectives: Study of inherited heart diseases (IHD) involves performing diagnostic tests, which are sometimes inconvenient or stressful, in asymptomatic relatives. The aim of this study was to analyze refusal to undergo various diagnostic tests and follow therapeutic recommendations. Methods: We assessed 1992 consecutive families with IHD to analyze refusal to undergo family screening. The study included 1539 individuals who were recommended to undergo cardiac magnetic resonance, and 837 who were recommended a drug challenge test. To study treatment refusal, we assessed 395 patients with an indication for an implantable cardioverter-defibrillator (ICD) and 402 patients with an indication for anticoagulation. Results: A total of 28% of families who were recommended to undergo screening for suspected IHD did not attend, but refusal was lower if there was a family history of sudden cardiac death. In all, 23% did not undergo magnetic resonance, and the 2 main reasons were administrative problems (53%) and claustrophobia (18%). Refusal was more common in older people, women, symptomatic persons, individuals with arrhythmias, and relatives. Nearly one fifth (19%) did not take the drug challenge test, due to fear (46%) or administrative issues (25%). Refusal was more frequent in older individuals, asymptomatic persons, those with a history of arrhythmias, relatives, and those with a positive genetic study. Only a minority of patients rejected the treatments (5.1% ICD, 2.5% anticoagulation). The percentage of sudden cardiac death in persons rejecting ICD implantation was high (4.5% per year). Conclusions: One fifth of people attending screening for IHD refused to undergo more sophisticated and stressful tests. This study identified several independent predictors associated with refusal. Only a minority of high-risk patients refused treatments such as ICD implantation and anticoagulation. (AU)

Electrocardiographic Screening of Arrhythmogenic Cardiomyopathy in Genotype-Positive and Phenotype-Negative Relatives.

Background: Arrhythmogenic cardiomyopathy is a hereditary cause of ventricular arrhythmias and sudden death. Identifying the healthy genetic carriers who will develop the disease remains a challenge. A novel approach to the analysis of the digital electrocardiograms of mutation carriers through signal processing may identify early electrocardiographic abnormalities. Methods: A retrospective case-control study included a population of healthy genetics carriers and their wild-type relatives. Genotype-positive/phenotype-negative individuals bore mutations associated with the development of arrhythmogenic cardiomyopathy. The relatives included had a non-pathological 12-lead electrocardiogram, echocardiogram, and a cardiac magnetic resonance. Automatic digital electrocardiographic analyses comprised QRS and terminal activation delay duration, the number of QRS fragmentations, ST slope, and T-wave voltage. Results: Digital 12-lead electrocardiograms from 41 genotype-positive/ phenotype-negative (29 simple carriers and 12 double mutation carriers) and 73 wild-type relatives were analyzed. No differences in the QRS length, the number of QRS fragmentations, and the voltage of the T-wave were observed. After adjusting for potential confounders, double carriers showed an average ST-slope flatter than those of the simple carriers and wild type [5.18° (0.73-8.01), 7.15° (5.14-11.05), and 11.46° (3.94-17.49), respectively, p = 0.005]. There was a significant negative correlation between the ST slope and the age in genotype-positive/phenotype-negative relatives (r = 0.376, p = 0.021) not observed in their wild-type counterparts (r = 0.074, p = 0.570). Conclusions: A flattened ST segment may be an early sign of electrical remodeling that precedes T-wave inversion in healthy genetic carriers. A thorough analysis of the digital electrocardiographic signal may help identify and measure early electrical abnormalities.

Prevented Sudden Cardiac Death and Neurologic Recovery in Inherited Heart Diseases.

Introduction: Inherited cardiovascular diseases are an important cause of sudden cardiac death (SD). The use of risk scores identify high risk patients who would benefit from an implantable cardioverter-defibrillators (ICDs). The development of automated devices for out-of-hospital cardiac arrest improves early resuscitation. The objective of the study is to quantify prevented SD and the neurological recovery of patients with inherited cardiovascular diseases. Methods: Two hundred fifty-seven cases of SD (age 42 ± 18 years, 79.4% men) of non-ischemic cardiac cause were prospectively collected during the study period (2009-17). Fifty three (20.6%) had a resuscitated cardiac arrest (RCA) (age 40 ± 18 years, 64.2% male). Epidemiological, clinical and autopsy aspects were analyzed. Prevented SD was defined as a combination of RCA and appropriate ICD therapy cases. Results: An autopsy was performed in 157/204 (77.0%) cases who died. There were 19 (12.1%) cases with a negative autopsy. The diagnosis of cardiomyopathy and channelopathy was 58.0 and 18.7%, respectively. Female sex and confirmed or suspected channelopathy were associated with successful resuscitation. The percentage of prevented SD remained low during the study period (mean 35.6%). 60.4% of RCA cases presented good neurological outcome. There was no association between neurological recovery and therapeutic hypothermia, but there was association with time of resuscitation (min). Conclusion: A fifth part of non-ischemic cardiac arrests were resuscitated. Female sex and channelopathies were more prevalent among RCA. Two thirds of RCA had a good neurological recovery.

Reasons for refusing diagnostic tests and therapeutic recommendations and associated complications in inherited heart diseases. The RELUCTANT study.

INTRODUCTION AND OBJECTIVES: Study of inherited heart diseases (IHD) involves performing diagnostic tests, which are sometimes inconvenient or stressful, in asymptomatic relatives. The aim of this study was to analyze refusal to undergo various diagnostic tests and follow therapeutic recommendations. METHODS: We assessed 1992 consecutive families with IHD to analyze refusal to undergo family screening. The study included 1539 individuals who were recommended to undergo cardiac magnetic resonance, and 837 who were recommended a drug challenge test. To study treatment refusal, we assessed 395 patients with an indication for an implantable cardioverter-defibrillator (ICD) and 402 patients with an indication for anticoagulation. RESULTS: A total of 28% of families who were recommended to undergo screening for suspected IHD did not attend, but refusal was lower if there was a family history of sudden cardiac death. In all, 23% did not undergo magnetic resonance, and the 2 main reasons were administrative problems (53%) and claustrophobia (18%). Refusal was more common in older people, women, symptomatic persons, individuals with arrhythmias, and relatives. Nearly one fifth (19%) did not take the drug challenge test, due to fear (46%) or administrative issues (25%). Refusal was more frequent in older individuals, asymptomatic persons, those with a history of arrhythmias, relatives, and those with a positive genetic study. Only a minority of patients rejected the treatments (5.1% ICD, 2.5% anticoagulation). The percentage of sudden cardiac death in persons rejecting ICD implantation was high (4.5% per year). CONCLUSIONS: One fifth of people attending screening for IHD refused to undergo more sophisticated and stressful tests. This study identified several independent predictors associated with refusal. Only a minority of high-risk patients refused treatments such as ICD implantation and anticoagulation.

A study of the pathogenicity of variants in familial heart disease. The value of cosegregation.

With the development of deep sequencing, a significant proportion of mutations already listed in studies have inconclusive pathogenicity. We aim to establish the proportion of cases in which familial studies are possible and cosegregation analysis is informative. We also compare cosegregation analysis with in silico software and a proposed pathogenicity score. 204 consecutive positive tests were reviewed. 4 different in silico software programs were used. Spaendonck-Zwarts' pathogenicity score was also calculated. A total of 73 of the missense variants could be classified by the score as being likely or definitively pathogenic. A high percentage of nonsense variants were found in desmosomal genes and missense variants in sarcomeric genes. 36.3% of the missense variants in our cohort classified as very likely or definitively pathogenic were novel. Cosegregation analysis was positive in 19.5% and could be discarded in 15.6%. There was a significant discrepancy between the in silico tools used in the setting of inherited heart disease. Multiparametric scoring systems which include cosegregation and functional studies seem to perform better than individual prediction software.

Factores que influyen en la expresión fenotípica de la miocardiopatía hipertrófica en portadores genéticos / Factors influencing the phenotypic expression of hypertrophic cardiomyopathy in genetic carriers

Introducción y objetivos: La miocardiopatía hipertrófica (MCH) es una enfermedad con expresión variable, causada principalmente por mutaciones en genes sarcoméricos, aunque otros factores podrían estar modulando el fenotipo. El objetivo es determinar si el sexo, la hipertensión arterial o la actividad física son moduladores de la gravedad de la enfermedad y establecer su papel en la penetrancia en relación con la edad al diagnóstico de la MCH. Métodos: Se evaluó a 272 individuos (media de edad, 49 ± 17 años; el 57% varones) procedentes de 72 familias con mutación causal y se estudió la relación del sexo, la hipertensión y la actividad física con la hipertrofia ventricular izquierda. Resultados: La proporción de afectados aumenta con la edad. Se diagnosticó a los varones una mediana ajustada de 12,5 años (IC95%, -17,52 a -6,48; p < 0,001) antes que a las mujeres. A los pacientes hipertensos, se les diagnosticó MCH una mediana ajustada de 10,8 años (IC95%, 6,28-17,09; p < 0,001) más tarde que a los normotensos. A los individuos que hacían ejercicio, se los diagnosticó significativamente antes (mediana ajustada, 7,3 años; IC95%, -14,49 a -1,51; p = 0,016). El sexo, la hipertensión y el ejercicio no resultaron significativamente asociados con la gravedad de la hipertrofia del ventrículo izquierdo. Los factores explorados no influyen en la supervivencia ajustada libre de muerte súbita y el evento combinado. Conclusiones: Se diagnostica a los varones y los deportistas portadores de mutaciones sarcoméricas antes que a las mujeres y los individuos sedentarios. Los portadores de mutaciones sarcoméricas hipertensos tienen un retraso en el diagnóstico. El sexo, la hipertensión y el ejercicio no se asocian con la gravedad de la enfermedad en portadores de mutaciones causales de MCH (AU)

Introduction and objectives: Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. Methods: We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. Results: The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. Conclusions: Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations (AU)

Factors Influencing the Phenotypic Expression of Hypertrophic Cardiomyopathy in Genetic Carriers.

INTRODUCTION AND OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. METHODS: We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. RESULTS: The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. CONCLUSIONS: Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations.

Direct oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation.

BACKGROUND: Chronic anticoagulation with vitamin K antagonists (VKAs) is recommended in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF). Direct oral anticoagulants (NOACs) are an alternative to VKAs but there are limited data to support their use in HCM. We sought to describe the pattern of use, thromboembolic events, bleeding and quality of life in patients with HCM and AF treated with NOACs. METHODS: Data from patients treated with NOACs (n=99) and VKA (n=433) at 9 inherited cardiac diseases units were retrospectively collected. Annual rates of embolic events, serious bleeding and death were analysed and compared. Quality of life and treatment satisfaction were evaluated with SF-36 and SAFUCA questionnaires in 80 NOAC-treated and 57 VKA-treated patients. RESULTS: After median follow-up of 63 months (IQR: 26-109), thromboembolic events (TIA/stroke and peripheral embolism) occurred in 10% of patients on oral anticoagulation. Major/clinically relevant bleeding occurred in 3.8% and the global mortality rate was 23.3%. Thromboembolic event rate was 0.62 per 100patient-years in the NOAC group vs. 1.59 in the VKA group [subhazard ratio (SHR) 0.32;95%CI:0.04-2.45; p=0.27]. Major/clinically relevant bleeding occurred in 0.62 per 100person-years in the NOAC group vs. 0.60 in the VKA group (SHR 1.28;95%CI 0.18-9.30; p=0.85). Quality of life scores were similar in both groups; however, NOAC-treated patients achieved higher scores in the SAFUCA. CONCLUSIONS: HCM patients with AF on NOACs showed similar embolic and bleeding rates to those on VKA. Although quality of life was similar in both groups, the NOAC group reported higher treatment satisfaction.

Genetics of myocarditis in arrhythmogenic right ventricular dysplasia.

BACKGROUND: Myocarditis occasionally is related to arrhythmogenic right ventricular dysplasia (ARVD) and sometimes overlaps during the early stages, which may lead to misdiagnosis. Acute myocarditis may reflect an active phase of ARVD. OBJECTIVE: The purpose of this study was to evaluate the genetic basis of myocarditis in ARVD and to investigate the association with a poorer prognosis and a higher risk of ventricular arrhythmias. METHODS: Two groups were analyzed: group A, which consisted of 131 affected patients-84 with ARVD (62% male, age 45 years [range 33-55 years]) and 47 with left-sided forms (arrhythmogenic left ventricular dysplasia [ALVD]) (47% male, age 45 years [range 25-61 years]); and group B, which consisted of 64 nonaffected mutation-carrying relatives (36% male, age 42 years [range 22-56 years]; 23 from classic ARVD families and 41 from ALVD families). RESULTS: Seven patients (3.5%) presented with a clinical diagnosis of acute myocarditis over median follow-up of 34 months. Myocarditis was the first clinical presentation in 6 of 7 cases. In 2 patients, acute myocarditis preceded worsening of left ventricular systolic function. In 1 case, myocarditis was associated with an increased gadolinium pattern in cardiac magnetic resonance. Two patients presented with ECG changes weeks after myocarditis resolution. Myocarditis preceded the development of ventricular tachycardia in 2 other patients. Myocarditis clustered in families bearing DSP Q447* and LDB3 c.1051A>G. CONCLUSION: Acute myocarditis reflects an active phase of ARVD that leads to changes in phenotype and abrupt progression of the disease. An active phase should be suspected in a patient with myocarditis associated with a family history of ARVD. Certain mutations may increase the susceptibility to superimposed myocarditis in ARVD.

Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype.

AIMS: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype-phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations. METHODS AND RESULTS: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging. CONCLUSION: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.

Evaluación clínica detallada de una familia española con enfermedad de Anderson-Fabry, nueva mutación en GLA y fenotipo cardiaco grave / Comprehensive clinical evaluation of a large Spanish family with Anderson-Fabry disease, novel GLA mutation and severe cardiac phenotype

Background and objective: Fabry disease is an X-linked multisystemic lysosomal-storage condition. We describe a large family with a novel GLA mutation: p.M187R/g7219 T > G. Patients and methods: Anamnesis/physical-exam, blood/urine analysis, a-Gal-A activity and/or genetic study of at-risk individuals and multidisciplinary evaluation in confirmed cases. Results: 4 males and 13 heterozygous-females displayed the mutation. Cardiac/renal/neurological disease was diagnosed at a mean age of 41/29/39 years in males and 51/56/46 years in females. Onset mean age was 20 years versus 42 years. 9/15 had cardiomyopathy. Delta wave suggestive of accessory pathway was identified in 1 male and 2 females. 1 female had cardiac arrest (ventricular fibrillation, 61 years). 2 females and 1 male died suddenly (63, 64 and 57 years). Cardiac-subscore of Mainz Severity- Score-Index was severe for males and females over 40 years. 4/15(26%) developed early renal disease. 2 males needed dialysis. 1 male died at 69 years in spite of kidney-heart transplant. Conclusion: We describe the largest genetically confirmed Spanish family using multidisciplinary evaluation and MSSI calculation. The novel mutation p.M187R/g7219 T > G is associated with a particularly malignant cardiac phenotype in males and females over 40 years. Severity was higher than that of the largest Spanish FOS-cohort. Short-PR with delta is being reported for the first time (AU)

Fundamento y objetivo: La enfermedad de Fabry es un trastorno sistémico por depósito lisosomal ligado a X. Describimos una familia grande con una mutación nueva en GLA: p.M187R/g7219 T > G. Pacientes y Métodos: Anamnesis/exploración, análisis sangre/orina), actividad alfa-Gal-A y/o estudio genético a individuos en riesgo y evaluación multidisciplinar de casos confirmados. Resultados: Cuatro varones/12 mujeres presentaban la mutación. Se diagnosticó enfermedad cardiaca/ renal/neurológica a los 41/29/39 años como media en varones, y a los 51/56/46 años en mujeres. La media de inicio fue 20 años frente a 42. Presentaban miocardiopatı' a 9/15. Se identificó onda delta indicativa de vía accesoria en un varón y 2 mujeres. Una mujer sufrió parada cardiorrespiratoria (fibrilación ventricular, 61 años). Dos mujeres y un varón murieron súbitamente (63, 64 y 57 años, respectivamente). El subscore cardiaco del Mainz Severity Score Index (MSSI) fue grave en hombres y mujeres mayores de 40 años. Presentaron enfermedad renal temprana 4/15 (26%). Dos varones precisaron diálisis. Un varón murió a los 69 años pese a trasplante cardiorrenal. Conclusión: Describimos la mayor familia española confirmada gene' ticamente con evaluación multidisciplinar y cálculo del MSSI. La nueva mutación p.M187R/g7219 T > G asocia un fenotipo cardiaco especialmente grave en hombres y mujeres mayores de 40 años. La gravedad fue superior a la de la mayor cohorte-FOS española publicada. Se describen por primera vez ondas delta asociadas a PR-corto (AU)

Comprehensive clinical evaluation of a large Spanish family with Anderson-Fabry disease, novel GLA mutation and severe cardiac phenotype.

BACKGROUND AND OBJECTIVE: Fabry disease is an X-linked multisystemic lysosomal-storage condition. We describe a large family with a novel GLA mutation: p.M187R/g7219 T>G. PATIENTS AND METHODS: Anamnesis/physical-exam, blood/urine analysis, α-Gal-A activity and/or genetic study of at-risk individuals and multidisciplinary evaluation in confirmed cases. RESULTS: 4 males and 13 heterozygous-females displayed the mutation. Cardiac/renal/neurological disease was diagnosed at a mean age of 41/29/39 years in males and 51/56/46 years in females. Onset mean age was 20 years versus 42 years. 9/15 had cardiomyopathy. Delta wave suggestive of accessory pathway was identified in 1 male and 2 females. 1 female had cardiac arrest (ventricular fibrillation, 61 years). 2 females and 1 male died suddenly (63, 64 and 57 years). Cardiac-subscore of Mainz Severity-Score-Index was severe for males and females over 40 years. 4/15(26%) developed early renal disease. 2 males needed dialysis. 1 male died at 69 years in spite of kidney-heart transplant. CONCLUSION: We describe the largest genetically confirmed Spanish family using multidisciplinary evaluation and MSSI calculation. The novel mutation p.M187R/g7219 T>G is associated with a particularly malignant cardiac phenotype in males and females over 40 years. Severity was higher than that of the largest Spanish FOS-cohort. Short-PR with delta is being reported for the first time.