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Congenital heart disease
Original research
Clinical outcome of COVID-19 in patients with adult congenital heart disease
  1. Markus Schwerzmann1,
  2. Francisco Javier Ruperti-Repilado1,
  3. Helmut Baumgartner2,
  4. Berto Bouma3,
  5. Judith Bouchardy4,5,
  6. Werner Budts6,7,
  7. Laurence Campens8,
  8. Massimo Chessa9,
  9. Maria Jesús del Cerro Marin10,
  10. Harald Gabriel11,
  11. Pastora Gallego12,
  12. Rocio Garcia-Orta13,
  13. Ana Elvira Gonzalez14,
  14. Annette Schophuus Jensen15,
  15. Magalie Ladouceur16,
  16. Berta Miranda-Barrio17,
  17. Marielle Morissens18,
  18. Agnes Pasquet19,
  19. Joaquín Rueda20,
  20. Annemien E van den Bosch21,
  21. Heleen Berdina van der Zwaan22,
  22. Daniel Tobler23,
  23. Matthias Greutmann24
  24. on behalf of EPOCH
    1. 1 Center for Congenital Heart Disease, Inselspital University Hospital, Bern, Switzerland
    2. 2 Dept. of Cardiology III - Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Munster, Nordrhein-Westfalen, Germany
    3. 3 Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
    4. 4 Department of Cardiology and Cardiac Surgery, Lausanne University Hospital, Lausanne, Switzerland
    5. 5 Division of Cardiology, University Hospital of Geneva, Geneva, Switzerland
    6. 6 Congenital and Structural Cardiology, University Hospital Leuven, Leuven, Flanders, Belgium
    7. 7 Department of Cardiovascular Sciences, Catholic University Leuven, Leuven, Flanders, Belgium
    8. 8 Department of Cardiology, Ghent University Hospital, Gent, Oost-Vlaanderen, Belgium
    9. 9 ACHD UNIT - Pediatric and Adult Congenital Heart Centre, IRCCS - Policlinico San Donato, San Donato Milanese - Milan, Lombardia, Italy
    10. 10 Pediatric Cardiology and GUCH Centre, Ramon y Cajal University Hospital, Madrid, Spain
    11. 11 Department of Cardiology, Medical University of Vienna, Vienna, Austria
    12. 12 Adult Congenital Heart Disease Unit, Department of Cardiology, Hospital Universitario, Virgen del Rocio, Instituto de BioMedicina de Sevilla (IBIS) and CIBERCV, Sevilla, Spain
    13. 13 Adult Congenital Heart Disease Unit, Department of Cardiology, Hospital Universitario Virgen de las Nieves. 2 Instituto de Investigación Biosanitaria ibs, Granada, Andalucía, Spain
    14. 14 Hospital Universitario La Paz, Madrid, Spain
    15. 15 Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
    16. 16 Adult Congenital Heart Disease Unit, Centre de référence des Malformations Cardiaques Congénitales Complexes, M3C, Université de Paris, Hôpital Européen Georges Pompidou, AP-H, Paris, France
    17. 17 Integrated Adult Congenital Heart Disease Unit, Vall d’Hebron University Hospital and Santa Creu i Sant Pau University Hospital, Barcelona, Spain
    18. 18 Department of Cardiology, CHU Brugmann, Brussels, Belgium
    19. 19 Department of Cardiology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium
    20. 20 Adult Congenital Heart Disease Unit, Department of Cardiology, Hospital Universitari i Politècnic La Fe and CIBERCV, Valencia, Comunidad Valenciana, Spain
    21. 21 Department of Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands
    22. 22 Department of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands
    23. 23 Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland
    24. 24 Departament of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
    1. Correspondence to Professor Markus Schwerzmann, Center for Congenital Heart Disease, Inselspital University Hospital, Bern 3010, Switzerland; markus.schwerzmann{at}med.unibe.ch

    Abstract

    Aims Patients with adult congenital heart disease (ACHD) are a potentially vulnerable patient cohort in case of COVID-19. Some cardiac defects may be associated with a poor COVID-19 outcome. Risk estimation in ACHD is currently based on expert opinion. The aim of this study was to collect clinical outcome data and to identify risk factors for a complicated course of COVID-19 in patients with ACHD.

    Methods Twenty-five ACHD centres in nine European countries participated in the study. Consecutive patients with ACHD diagnosed with COVID-19 presenting to one of the participating centres between 27 March and 6 June 2020 were included. A complicated disease course was defined as hospitalisation for COVID-19 requiring non-invasive or invasive ventilation and/or inotropic support, or a fatal outcome.

    Results Of 105 patients with a mean age of 38±13 years (58% women), 13 had a complicated disease course, of whom 5 died. In univariable analysis, age (OR 1.3, 95% CI 1.1 to 1.7, per 5 years), ≥2 comorbidities (OR 7.1, 95% CI 2.1 to 24.5), body mass index of >25 kg/m2 (OR 7.2, 95% CI 1.9 to 28.3) and cyanotic heart disease (OR 13.2, 95% CI 2.5 to 68.4) were associated with a complicated disease course. In a multivariable logistic regression model, cyanotic heart disease was the most important predictor (OR 60.0, 95% CI 7.6 to 474.0).

    Conclusions Among patients with ACHD, general risk factors (age, obesity and multiple comorbidities) are associated with an increased risk of complicated COVID-19 course. Congenital cardiac defects at particularly high risk were cyanotic lesions, including unrepaired cyanotic defects or Eisenmenger syndrome.

    • heart defects
    • congenital

    Data availability statement

    Data are available upon reasonable request.

    http://creativecommons.org/licenses/by-nc/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    https://doi.org/10.1136/heartjnl-2020-318467

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      Introduction

      The first wave of COVID-19 caused by SARS-CoV-2 hit Europe in March 2020. As of the end of September, more than 3.3 million cases with >190 000 deaths have been counted by the European Centre for Disease Prevention and Control.1 As a response to the pandemic, European countries have developed strategies for minimising transmission of the virus, spread of the infection and disease-related morbidity and mortality. This includes the identification of vulnerable patients with underlying medical conditions associated with poor COVID-19 outcome, requiring particular protection.

      Patients with adult with congenital heart disease (ACHD) represent such a potentially vulnerable patient cohort. With an estimated ACHD prevalence of 3000 per million adults, more than 2.5 million adults with congenital cardiac defects are currently living in Europe.2 A cure of the congenital cardiac defect by surgery or other interventions is still exceptional and many patients with ACHD face a lifelong increased risk of cardiovascular complications, such as heart failure, arrhythmias, pulmonary hypertension and premature death.3 4 Respiratory diseases—in particular, pneumonia—are the most common non-cardiac cause of death in patients with ACHD, especially among patients with genetic disorders.5 Therefore, yearly influenza vaccination is recommended for most patients with ACHD.6

      Patients with ACHD with simple lesions and no genetic disorder may not be at higher COVID-19 risk than the general population, whereas patients with more complex disease (eg, Fontan physiology, cyanotic heart disease, defects with impaired subpulmonary or subaortic ventricular function) may be at risk of haemodynamic compromise, hypoxia or paradoxical embolism if COVID-19-related complications occur. These uncertainties have led to substantial concerns among patients, relatives and treating physicians. In the absence of reported data, risk estimation is currently based on expert opinion.7 The aims of this study were to collect clinical outcome data and to identify risk factors for a complicated course of COVID-19 in patients with ACHD in European reference centres.

      Methods

      As part of a research initiative within the European Collaboration for Prospective Outcome Research in Congenital Heart Disease (EPOCH, https://www.sacher-registry.com/epoch/), this collaborative study was launched among different ACHD centres across Europe.

      A total of 25 ACHD centres in nine European countries participated in the study. All patients with ACHD diagnosed with COVID-19 (positive test for SARS-CoV-2 by means of PCR test, antibody and SARS-CoV-2 antigen-based ELISA) or strong clinical suspicion (based on symptoms and thoracic CT findings) presenting to or contacting one of the participating centres were included. The study started on March 27 and data reported until 6 June 2020 were analysed. Only patients actively reporting to their centres or hospitalised for COVID-19 at the participating centres were included.

      The following data were collected: type of cardiac defect, complexity of cardiac defect according to the most recent European ACHD guidelines,8 defect-related residual cardiac problems, gender, age (in years), weight category, most clinically relevant comorbidity according to the treating cardiologist’s perception, number of comorbidities, clinical course and outcome. Definitions for categories within these different study characteristics are provided as online supplemental material 1. A complicated disease course was defined as hospitalisation for COVID-19 requiring non-invasive or invasive ventilation and/or inotropic support, extracorporeal membrane oxygenation or a fatal outcome. In patients with a complicated disease course, further detailed information on patient characteristics and disease course was obtained from the treating physicians of the pertinent centre. The presumed causal relationship between the congenital heart defect and the COVID-19 outcome was adjudicated after discussion with the treating physician and within the steering committee of the study (MS, JR, DT and MG). The following categories were discriminated: death or complicated disease course due to SARS-CoV-2 infection (COVID-19 was the main reason for outcome), death or complicated disease course with coincidental SARS-CoV-2 infection (pre-existing disease was the main reason for outcome).

      Supplemental material

      Data were analysed using STATA 15.1 statistical software. Distribution of continuous variables was assessed using visual inspection of the histogram and expressed as mean and SD for symmetrically distributed variables variables and as median and IQR for other data. Between-group comparisons in table 1 were performed using an unpaired Student’s t-test or a χ2 test for continuous and nominal variables. Predictors of the main variable of interest (complicated clinical course, table 2) were analysed by univariable logistic regression. Due to the low number of events, multivariable analysis was restricted to variables with univariable OR of >5 (and a 95% CI with the lower margin >1) and was calculated with cluster-robust SEs. Due to the sparsity of the outcome data, the ORs were recalculated in a second model with an exact logistic regression fit (see online supplemental material). In all analyses, the null hypothesis was rejected for p values of <0.05.

      View this table:
      Table 1

      Characteristics of patients with ACHD and COVID-19 disease course

      View this table:
      Table 2

      OR for complicated disease course

      Patient and public involvement

      There was no public or patient involvement in this study.

      Results

      By 6 June, a total of 105 patients with ACHD were included in this study. Table 3 summarises the number of patients with ACHD per country reported to have COVID-19 and the number of yearly patient visits at the corresponding centres. Overall, 78 (74%) patients had a confirmed diagnosis of COVID-19 by testing, while in 27 patients (26%) the diagnosis was based on clinical grounds.

      View this table:
      Table 3

      Participating centres and reported cases

      At the time of data analysis, five patients (5%) had died, and COVID-19 was still ongoing in nine cases (9%). The infection had cleared in 2 patients (2%) with sequelae, and 89 patients (85%) recovered without additional new health problems. A total of 73 patients (70%) had a mild course and did not require hospitalisation. Overall, a complicated disease course was observed in 13 cases (12%), representing 41% (13/32) of the hospitalised patients. Table 1 summarises the characteristics of patients with ACHD in relation to the course of COVID-19. Details on patient characteristics and clinical history of patients with a complicated disease course are outlined in table 4.

      View this table:
      Table 4

      Patients with complicated COVID-19 course

      Patients with a complicated disease course were older and more likely overweight than patients with ACHD with uncomplicated COVID-19. In addition, these patients had more additional comorbidities. There was no significant gender difference in patients with and without a complicated COVID-19 course. Patients with two or more comorbidities were particularly at risk of complications. Overall cardiac defect complexity did not differ between patients with or without complicated COVID-19. A complicated disease course was more likely in patients with cyanotic heart disease, including Eisenmenger syndrome: four out of seven patients (57%) had a complicated disease course. Among defect-related residual cardiac problems, pulmonary hypertension, present in seven patients (including five patients with Eisenmenger syndrome), had the strongest association with a complicated disease course.

      In univariable analysis, age, overweight and multiple comorbidities were predictive of a complicated disease course (see table 2). When using a Body Mass Index (BMI) of >25 kg/m2 as cut-off, the corresponding OR was 7.2 (95% CI 1.9 to 28.3, p=0.004). Among specific heart defects, highest risk for a complicated disease course was observed in unrepaired cyanotic heart defects or patients with Eisenmenger syndrome (figure 1). In a multivariable analysis of these three variables, all were independently associated with complications, and cyanotic heart disease was by far the most important predictor of a complicated disease course.

      Figure 1
      Figure 1

      Univariable significant COVID-19 risk factors in patients with adult congenital heart disease and the corresponding ORs. We propose to stratify patients based on age, number of comorbidities, weight and presence of a high-risk cardiac lesion (cyanotic heart disease). BMI, Body Mass Index.

      Discussion

      This is the first report on the outcome of COVID-19 in a sizeable cohort of European patients with ACHD with different types of congenital cardiac defects. The main findings of our study are the observation that risk factors derived from the general population, in particular, age, overweight and multiple comorbidities, are equally important for determining outcome in the ACHD population, in addition to the congenital cardiac defect. Congenital cardiac defects with very high risk for a complicated disease course in case of COVID-19 were unrepaired cyanotic heart disease or severe pulmonary hypertension with Eisenmenger syndrome. Such defects were present in 4 of 13 patients with a complicated course but represent only ca. 2% of all patients under follow-up at the participating centres. For other complex lesions, that is, univentricular physiology after Fontan palliation or defects with subaortic right ventricles, no such strong association was observed.

      SARS-CoV-2 infection can cause both pulmonary and systemic inflammation, leading to acute respiratory distress syndrome and respiratory failure, sepsis, cardiac injury and thromboembolic complications, both in the venous and arterial circulations.9 10 Patients with cyanotic heart disease, including patients with Eisenmenger syndrome, exhibit chronic hypoxaemia with often markedly decreased resting oxygen saturations as a result of both a right-to-left shunt and severe abnormal pathobiology of the pulmonary tissue and pulmonary vascular bed. Such patients are at risk of rapid deterioration in case of respiratory tract infections with impaired oxygenation. In case of severe COVID-19, pre-existing hypoxaemia can be exacerbated by an increase in right-to-left shunting due to the rise in pulmonary vascular resistance and an inflammation-related decrease in systemic vascular resistance.11 These patients are furthermore at increased risk of paradoxical embolism. The potentially increased prothrombotic risk due to pre-existing haemostatic abnormalities, venous stasis, endothelial injury and inflammatory response may also contribute to a worse outcome in these patients.9

      Our study underscores the importance of a comprehensive risk assessment, not only taking into account the underlying congenital defect but also, more importantly, considering general risk factors and comorbidities for risk estimation in case of COVID-19. The most important general risk factor for COVID-19-related mortality is age.12 13 In line with previous studies, we observed an increasing risk of complications with advancing age. At present, the median age of patients with ACHD followed up at specialised centres is 35 years, and the prevalence of adults with CHD older than 60 years is estimated at 5%–10% of the entire ACHD population only.14 15 This young age may make them less susceptible for virus invasion, and hence patients with ACHD tend to have a milder COVID-19 course.16 This may explain why patients with univentricular physiology after Fontan palliation—mostly young adults—were at lower risk of a complicated disease course as intuitively anticipated by the anatomical absence of a subpulmonary ventricle.

      Overweight emerged as a risk factor in our study, independent of other comorbidities and defect complexity. This was not the case in a large cohort study from New York, with a median patient age of 62 years, and 46% of them being obese,17 nor in the first reports from China12 or Italy.18 In line with our findings, Kass et al described an inverse correlation between age and BMI among patients admitted with COVID-19 to the Johns Hopkins Hospital, in which younger individuals with severe disease were more likely obese.19 Our study supports their hypothesis that, among younger patients with less comorbidities, obesity may play a more important role than among elderly patients with multiple comorbidities for predicting COVID-19 outcomes.

      Acquired cardiovascular and other comorbidities associated with fatal COVID-19 outcomes are infrequently found in the ACHD population. In the Spanish ACHD cohort, 75% of patients were younger than 45 years, and the prevalence of hypertension, diabetes and ischaemic heart disease was only 14%, 2.7% and 1.5%, respectively. Still, even in young patients with ACHD with fewer comorbidities than encountered in an elderly population, the presence of multiple comorbidities confers a markedly increased risk of a complicated disease course. The observed OR of two or more comorbidities for a complicated disease course in this study was 7.1 (95% CI 2.1 to 24.5) in the univariable regression model and 6.7 (95% CI 1.2 to 35.8) in the multivariable regression model. Hence, patients with ACHD with multiple comorbidities should be considered as vulnerable patients, independent of the underlying defect complexity.

      There are limitations inherent to this study. First, we did not systematically test all patients with ACHD under follow-up at participating centres for COVID-19. Hence, we may have missed cases, with most likely mild disease course. As a consequence, we are not able to provide data regarding the prevalence and disease course of COVID-19 among the ACHD population. Currently, the paper describes outcome data of only 0.2% of the ACHD population followed by the centres in the past year, a number certainly lower than the prevalence of COVID-19 among the general population. Second, despite data collection in 25 European ACHD centres with more than 46 000 yearly patient visits, the absolute number of COVID-19 cases among patients with ACHD was still small, limiting statistical analysis. The small sample size may also explain the non-significant p value for gender differences related to a complicated COVID-19 course, despite different proportions observed between the groups. Due to the lack of observational data at the beginning of the pandemic, many patients with ACHD were routinely advised to adhere to the concept of physical distancing and personal protection with strict hygiene measures. These recommendations, backed up by a self-perception of being at risk, may have effectively prevented COVID-19 cases and contributed to the overall low number of infected patients with ACHD. The small sample size resulted in large CIs. Further confirmation of our results by other study groups is necessary. In this respect, the results of another cohort study supported by the International Society for Adult Congenital Heart Disease are eagerly awaited.

      In conclusion, our study provides first evidence that, among patients with ACHD advanced age, obesity and multiple comorbidities are associated with an increased risk of a complicated COVID-19 course, independent of the underlying cardiac defect. Congenital cardiac defects at particular high risk of a complicated disease course in case of COVID-19 were cyanotic lesions, including unrepaired cyanotic defects or severe pulmonary hypertension with Eisenmenger syndrome. These data can be used to identify patients with ACHD more vulnerable for a complicated COVID-19 course. Given the paucity of data so far, further confirmation of our findings is needed.

      Key messages

      What is already known on this subject?

      • The novel SARS-CoV-2 responsible for COVID-19 is thought to interact with the cardiovascular system on multiple levels, leading to increased morbidity and mortality in patients with underlying cardiovascular diseases.

      What might this study add?

      • Whether patients with adult congenital heart disease (ACHD) should be considered to be at increased risk of poor outcomes if suffering from COVID-19 is unclear. This is the first observational study providing clinical evidence in this respect.

      How might this impact on clinical practice?

      • So far, COVID-19 risk stratification in patients with ACHD was based on expert opinion. Our cohort study provides observational evidence regarding COVID-19 risk factors in patients with ACHD and improves tailoring of recommendations for preventive measures in individual patients.

      Data availability statement

      Data are available upon reasonable request.

      Ethics statements

      Ethics approval

      The study complied with the Declaration of Helsinki and was approved by local research ethics committees according to local ethical policies and country-specific regulations.

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      Supplementary materials

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • DT and MG are joint senior authors.

      • Twitter @MarkusSchwerzm1, @apgalgar

      • Collaborators European Collaboration for Prospective Outcome Research in Congenital Heart Disease: Anissa Boubrit, Université de Paris, Hôpital Européen Georges Pompidou, Paris, France; Francisco Buendía Fuentes, Adult Congenital Heart Disease Unit, Department of Cardiology, Hospital Universitari i Politècnic La Fe and CIBERCV, València, Spain; Julie De Backer, Department of Cardiology, Ghent University Hospital, Ghent, Belgium; Michèle De Hosson, specialist nurse, Department of Cardiology, Ghent University Hospital, Ghent, Belgium; Laura Dos Subirà. Unitat Integrada de Cardiopaties Congènites de l'Adolescent i de l'Adult Vall d'Hebron-Sant Pau, Department of Cardiology, Vall d'Hebron University Hospital and CIBERCV, Barcelona, Spain; Eduardo Moreno Escobar, Adult Congenital Heart Disease Unit, Department of Cardiology. Hospital Universitario Virgen de las Nieves. Granada. Spain. 2 Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain; Dorte Guldbrand Nielsen, Department of Cardiology, Skejby, Aarhus University Hospital, Denmark; Sophie Pierrad, Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Divisions of Cardiology and Cardiothoracic Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Maria-Jose Rodriguez-Puras, Adult Congenital Heart Disease Unit, Department of Cardiology, Hospital Universitario Virgen del Rocio. Sevilla, Spain.

      • Contributors MS, FJR-R, DT, MG and JB contributed in the drafting of the manuscript, conception of the research, critical revision of the manuscript for important intellectual content and supervision. All other authors contributed in the patient recruitment and data collection, critical revision of the manuscript for important intellectual content and supervision.

      • Funding The European Collaboration for Prospective Outcome Research in Congenital Heart Disease is funded by internal grants without support from the pharmaceutical industry.

      • Competing interests WB declared being proctor of Abbott and Occlutech.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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