Article Text

Anatomical complexity does not predict outcomes after COVID-19 in adults with congenital heart disease
  1. Su Yuan,
  2. Erwin Oechslin
  1. Medicine, University Health Network, Peter Munk Cardiac Centre, Toronto ACHD Program, and University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Professor Erwin Oechslin, Medicine, University Health Network, Toronto, ON M5G 2N2, Canada; erwin.oechslin{at}

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Few could have guessed the global devastation of COVID-19 when it was first reported more than a year ago. Community spread has been a major route of transmission as COVID-19 has a lower case fatality rate (2.3%) but much greater infectivity compared with previous outbreaks (severe acute respiratory syndrome, 2002–2003; Middle Eastern respiratory syndrome, 2012–ongoing).1 Most patients experienced mild infection (81%), while 5% developed critical illness.1 Risk factors for death that have been identified include age, disease severity and comorbidities such as cardiovascular disease, diabetes, hypertension, chronic respiratory disease and cancer.1 Patients with congenital heart disease (CHD) were perceived to be especially vulnerable to infection due to their fragile physiology, particularly those with moderate to severe complex anatomy such as repaired tetralogy of Fallot, status post atrial or arterial switch procedure or Fontan circulation.2 3 Data to quantify this risk have been limited—until now.

In this issue of Heart, Schwerzmann et al4 describe the clinical course of 105 patients with CHD with COVID-19 infection, based on either a positive biochemical test (by PCR or ELISA) or strong clinical suspicion (based on symptoms and chest CT findings). This was a collaboration between 25 centres in nine countries, as part of the European Collaboration for Prospective Outcome research in Congenital Heart Disease. It is the largest multicentre cohort study thus far and the first publication of its kind.

The authors aimed to identify patient characteristics associated with ‘complicated’ infection, which they defined as either death or hospitalisation requiring non-invasive/invasive ventilation and/or inotropic support after COVID-19 infection. In total, 73/105 patients (70%) had mild disease, while 13 patients (12%) experienced a complicated infection (online supplemental table S1). At study conclusion, 91 patients (87%) had recovered; 9 cases (9%) were ongoing; and 5 patients (5%) had died. Two patients with Eisenmenger syndrome chose palliative care after diagnosis, which is an important reminder of the importance of advance care planning for patients with CHD. Cyanotic CHD (highest risk), Body Mass Index (BMI) of >25 kg/m2 and ≥2 non-CHD-related comorbidities (see online supplemental table S1 and figure 1B for a full list) were identified as independent risk factors for complicated infection. Age was significant in univariate analysis but was omitted from multivariate analysis by study design because its OR was less than 5. Interestingly, other CHD-related features were not associated with complicated infection: underlying anatomical disease complexity (simple, moderate or complex) and main defect-related problems (valvular problem, heart failure, arrhythmia or pulmonary arterial hypertension) were not statistically significant in univariate analysis, though the study may have been underpowered for these analyses. Also, rather than using a unifying definition for comorbidities such as heart failure or renal failure, study authors relied on the discretion of individual clinicians at each study centre. Finally, it is unclear how many patients had a genetic syndrome in the entire cohort as only one patient with a complicated infection had this reported as a comorbidity in the authors’ table 4.

Figure 1

Conceptualisation of risk in patients with ACHD after COVID-19 infection. (A) Proposed interactions between the physiology of CHD and its end organ sequelae, and the pathophysiology of COVID-19 infection and its treatment. (B) Proposed risk stratification strategy based on current literature, adapted from Diller et al with permission.3 4 6 ACHD, adult congenital heart disease; ARDS, acute respiratory distress syndrome; BMI, Body Mass Index; CHD, congenital heart disease; mPAP, mean pulmonary artery pressure; NYHA, New York Heart Association; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance.

What did we already know?

Radke et al2 were the first to describe an institutional approach to disease prevention, management and risk stratification in adult congenital heart disease (ACHD), based on data from non-congenital patients and anecdotal experience. Subsequently, the European Society of Cardiology Working Group of Adult Congenital Heart Disease and the International Society for Adult Congenital Heart Disease recommended risk stratifying patients using a combination of anatomy and physiology.3 This was based on our understanding of the likely interactions between the physiology of CHD and its end organ sequelae, and the pathophysiology of COVID-19 infection and its treatment (figure 1A).

Few studies examining COVID-19 infection in patients with CHD were published prior to Schwerzmann et al. Table S1 in the online supplemental material summarizes the 4 available cohorts/case series with more than 50 patients with CHD. Importantly, these additional studies also found that most patients with CHD experienced mild COVID-19 infection:

92% of adults in Sabatino et al5 and 84% of adults in Lewis et al6 compared with 70% of patients in Schwerzmann et al4 did not require hospitalisation. However, these numbers include varying proportions of suspected COVID-19 cases. Lewis et al6 also assessed the determinants of moderate/severe illness, which they defined as death, hospitalisation or need for new or increased supplemental oxygen. Their multivariate analysis (which included 10 children) found that moderate/severe infection was associated with a genetic syndrome (five patients had Down syndrome, and one had DiGeorge syndrome) and ACHD physiological stage C or D.6 This is congruent with previous studies in which Down syndrome was associated with death or hospitalisation after COVID-19 infection and overlaps with variables identified by Schwerzmann et al.4 7 Relatedly, both single-ventricle/Fontan physiology and complex congenital anatomy were not significant in univariate analysis, while pulmonary hypertension and obesity (BMI≥30 kg/m2) were not significant after adjustment for multiple comparison.6 Lastly, at least mild systolic dysfunction of the subaortic or subpulmonary ventricle was associated with longer hospitalisation (median of 18 days compared with 9 days, p=0.0004).6

Anatomy does not predict COVID-19 infection severity

Taken together, the aforementioned data suggest that though patients with CHD with COVID-19 infection are decades younger as a cohort than those infected in the general population, their trajectories share important similarities. First, most patients with CHD experienced mild infection, which ranged from 70%–92% in the studies discussed.4–6 Similarly, 81% of patients in the general cohort had experienced mild infection.1 Second, the main predictors of moderate/severe infection in CHD remain patient characteristics, such as advanced age, increased BMI and multiple comorbidities including a genetic syndrome.4 6 This contrasts with our previous perception of increased risk in patients with CHD, particularly those with CHD of moderate or great complexity, regardless of relevant sequelae.2 3

These studies also identified two CHD-specific risk factors for severe COVID-19 infection: cyanotic heart disease and ACHD physiological stage C or D.4 6 Unfortunately, the overlap between these variables makes it difficult to determine the relative importance of features such as cyanosis, pulmonary arterial hypertension, Eisenmenger syndrome, heart failure and ventricular dysfunction. Relatedly, Schwerzmann et al’s assessment of heart failure as a determinant of patient outcome after COVID-19 infection may be limited by small numbers, as they found 10 patients with heart failure as their main defect-related residual problem, of which only one patient experienced a complicated infection.4 Furthermore, the number of patients with pre-existing clinical heart failure in the authors’ table 4 highlights the fact that their analysis of heart failure as a main defect-related residual problem may not capture the full contribution of clinical heart failure or ventricular dysfunction to patient outcomes after COVID-19 infection.4 Similarly, Lewis et al6 found that more than mild ventricular dysfunction was associated with duration of hospitalisation but not moderate/severe infection, yet ACHD physiological stage C or D, which was associated with moderate/severe infection, includes characteristics such as NYHA class III/IV, moderate/severe ventricular dysfunction, pulmonary arterial hypertension and Eisenmenger syndrome. One has the impression that some combination of these variables may be predictive of outcome after COVID-19 infection but not yet clearly how. More consistently, these studies seem to agree that anatomical classification of CHD complexity is not a major determinant of outcome after COVID-19 infection. Figure 1 shows a proposed, modified framework for risk stratification based on these results.

This synthesis is limited by several considerations. First, these studies examined hospital-based cohorts of patients who presented to care. There may be an uncaptured cohort of minimally symptomatic patients who did not seek assessment, or patients who were treated or died elsewhere. Second, the authors’ definition of COVID-19 infection included suspected cases, which may overestimate the proportion of patients who did not require hospitalisation. Third, though Schwerzmann et al4 describe the largest prospective cohort of patients with CHD with COVID-19 infection, the event rate of complicated infection was still low (13/105 patients). Comparatively, Lewis et al6 and Sabatino et al5 reported even fewer patients with an outcome of interest in their studies. Finally, that the study authors all used different definitions of COVID-19 infection, moderate/severe infection, as well as their independent variables limits comparison across studies. It is difficult to conclude with certainty the independent predictors of severe infection. Many risk factors need further examination and questions remain, such as the possible role of ACE inhibitor/angiotensin receptor blockers or the immune response of patients with a genetic syndrome or immunocompromise.

Lessons learned and to learn

The studies discussed here offer some reassurance that most patients with CHD experienced mild illness after COVID-19 infection. Contrary to our previous conceptualisation of risk, anatomical complexity does not appear to predict severe infection or death. Rather, patient-specific risk factors similar to those in the non-CHD cohort remain important, while strong CHD-specific risk factors for severe illness or death after COVID-19 infection were cyanotic heart disease and physiological stage. These results help us to tailor patient recommendations but require further confirmation in large international, multicentre studies that are sufficiently powered to answer our remaining questions. Newly published results from the very large worldwide COVID-19 study provide additional support for the aforementioned risk factors discussed.8


Dr Erwin Oechslin currently holds the Bitove Family Professorship of Adult Congenital Heart Disease.


Supplementary materials

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  • Contributors SY and EO reviewed the literature on COVID-19 and adult congenital heart disease. They designed, drafted and finalised this editorial comment.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally 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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