Coronavirus disease 2019 (COVID-19) pandemic has dramatically influenced our lives and healthcare provision worldwide. The rapid deployment and administration of highly effective COVID-19 vaccines have boosted the expectation of definite control of the pandemic.Reference Rafaniello, Ferrajolo and Sullo1,Reference Scavone, Mascolo and Rafaniello2 Nevertheless, although 68% people worldwide have already received at least one dose of COVID-19 vaccine to date,3 evidence of only moderate protection against infection with new viral variantsReference Andrews, Stowe and Kirsebom4,Reference Dhama, Nainu and Frediansyah5 has tempered that expectation, giving rise to a new wave of uncertainties and fear. Adults with CHD represent a population vulnerable to intercurrent infections, especially those with complex defects and significant cardiac sequelae who have been shown at higher risk of adverse outcomes in case of COVID-19 infection.Reference Broberg, Kovacs and Sadeghi6 In Italy, a nationwide vaccination campaign started on December 31, 2020: vaccines were offered to the entire population according to a priority order, accounting for vaccines availability and individual vulnerability to COVID-19. We have previously described the early effects of COVID-19 vaccination campaign in a limited number of adult CHD patients.Reference Fusco, Scognamiglio and Merola7 In this rapidly changing global scenario, we aim to describe the current state of COVID-19 vaccination including booster dosage administration, hypothesising vaccine safety at a longer follow-up and protection against COVID-19 infection among the CHD population, also highlighting fear and vaccine hesitancy among these patients with specific focus on effects on their CHD.
Methods
Patients selection and data collection
This is a prospective observational study carried out from January 2021 to June 2022 and including all consecutive CHD patients aged ≥16 years attending the outpatient clinic of the tertiary centre for Adult Congenital Heart Disease at Monaldi Hospital (Naples, South Italy). As previously described,Reference Fusco, Scognamiglio and Merola7 at our centre CHD patients with univentricular physiology, systemic right ventricle, ejection fraction <40%, severe valvular defects, and ventricular dilation/dysfunction or awaiting cardiac surgery were considered “most frail” and were therefore offered COVID-19 vaccine in our dedicated Unit in an ambulatory setting with specialised personnel and availability of anaesthesiologists and cardiologists experienced in CHD care. Data on COVID-19 infection (either before or following vaccination), COVID-19 vaccines including booster doses and any suspected or confirmed adverse events were prospectively collected during each clinical evaluations. Adverse events following immunisation are defined as “any untoward medical occurrence which follows immunisation and which does not necessarily have a causal relationship with the usage of the vaccine”.8 Demographic data, data on previous medical history including previous infection, and data on vaccine type and adverse events (type of event, symptoms’ duration, and concomitant medication) were prospectively collected from patients’ electronic records. Missing data in patients’ electronic records were collected by phone calls by the CHD team. Patients undergoing COVID-19 vaccination either locally or at our Institution were invited to contact the CHD team in case of any symptom’s occurrence during the following weeks and were instructed to fill in the adverse event report form, according to the European legislation.9 Blood samples were routinely obtained during the first clinical evaluation within 4 months from the last dose administration whenever possible, in order to quantify the antibody response expressed as antispike IgG titre and determine an eventual previous viral exposure. CE-marked Roche Elecsys® Anti-SARS-CoV-2 S binding assays were used. This is an electrochemiluminescence sandwich immunoassay that allows to obtain both qualitative detection of SARS-CoV-2 antibodies against the nucleocapsid antigen, which indicates previous exposure to SARS-CoV2 and quantitative detection of antibodies directed against the viral spike protein. The manufacturer states intra- and inter-assay precision of 1–3% and positive agreement with a virus pseudo-neutralisation assay of 92% (95% CI 64–100%) with a specificity of 99.98% (95% CI 99.91–100%). The quantification range is between 1 and 12,500 BAU/mL. Moreover, patients’ attitude towards COVID-19 vaccination was explored with a questionnaire (Table 1 Supplementary material). Post-vaccination data including COVID-19 infection and symptoms duration were routinely collected during routine outpatient clinic and retrieved from patients’ electronic medical records. The authors assert that all procedures contributing to this work comply with Helsinki Declaration of 1975, as revised in 2008, and written informed consent was obtained from participants before study inclusion. Study protocol was approved by the Ethic Committee of the Spallanzani Hospital, in agreement with special legislation from the Italian Medicine Agency for prospective studies regarding COVID-19.10
Statistical analysis
Statistical analysis was carried out using R version 4.0.5. Continuous variables were reported as mean ± SD or median [IQR], according to data distribution. Comparisons between groups were assessed with the Student t-test or with Wilcoxon rank-sum test. Categorical variables were presented as frequencies (percentage of total). Differences in proportions were evaluated with χ2. P-value < 0.05 was considered statistically significant.
Results
Study population
As of June 2022, 490 CHD (36 ± 13 years, 53% male) patients were enrolled. Clinical and demographics data are summarised in Table 1: there was a prevalence of patients with moderate and complex disease (94%) and advanced physiological stage (63% in stage C–D as defined by the 2018 American Heart Association guidelines for the management of adults with CHDReference Stout, Daniels and Aboulhosn11). Forty-four (9%) had univentricular physiology and 99 (20%) had a systemic right ventricle. Forty-seven (9.5%) patients had a history of symptomatic COVID-19 infection 4.3 [1–5.2] months before the first dose of vaccination, mainly presenting with mild symptoms with a median duration of 9 [2.2–15] days. Of them, only one required hospitalisation
Demographics and clinical characteristics of the study population.
Abbreviations: ACEi=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blockers; ASD=atrial septal defect; AS=aortic stenosis; AVSD=atrioventricular septal defect; BAV=bicuspid aortic valve; ccTGA=congenitally corrected transposition of the great arteries; DILV=double inlet left ventricle; DIRV=double inlet right ventricle; DOLV=double outlet left ventricle; DORV=double outlet right ventricle; EF=ejection fraction; HF=heart failure; HLHS=hypoplastic left heart syndrome; ICD=implantable defibrillator/cardioverter; MVD=mitral valve disease; TA=tricuspid atresia; TGA=transposition of the great arteries; TOF=tetralogy of Fallot; PA=pulmonary atresia; PAH=pulmonary arterial hypertension; PAPVD=partial anomalous pulmonary venous drainage; PMK=pacemaker; PS=pulmonary stenosis; sRV=systemic right ventricle; VSD=ventricular septal defects.
COVID-19 vaccination
The primary vaccination cycle consisted of two doses in 457 (93%) patients and one dose in 33 (6%) due to recent SARS-CoV2 infection or administration of the Janssen Vaccine. Of them, 301 (61%) received a booster dose following at least 120 days from primary vaccination completion. The type of vaccine administered in the primary vaccination series was Pfizer–BioNTech mRNA vaccine in 433 (88%) patients, Moderna mRNA vaccine in 31 (6%), AstraZeneca–Oxford ChAdOx1 nCov-19 vaccine in 23 (5%), and Janssen Vaccine in 3 (0.6%). COVID-19 vaccination was administered in our Unit to 110 (22%) patients. Ten (2%) received a mixed vaccine regimen. M-RNA vaccines were administered as booster dose after at least 6 months from the last dose. Specifically, 230/310 (74%) received Pfizer–BioNTech vaccine and 80/310 (26%) received Moderna vaccine.
Follow-up after COVID-19 vaccination and antibody response
The median follow-up after the first dose was 1.53 [1.41–1.58] years. Adverse events were reported by 59, 51, and 40% of participants after the first, second, and booster dose, respectively (Table 2). However, symptoms were mainly mild. The most common adverse events included pain at the site of injection, headache, fever, muscle pain, gastrointestinal disturbs, fatigue, and dizziness. No major allergic reactions occurred. One patient complaining of chest pain was diagnosed with acute pericarditis 4 days after the second dose with Pfizer–BioNTech vaccine and was successfully treated with non-steroidal anti-inflammatory drugs. During the study period, four patients with complex disease (three univentricular heart with Fontan palliation and one with transposition of the great arteries following atrial switch repair) died from cardiac reasons, unrelated to COVID-19 vaccination. Antispike IgG titre obtained after a median of 1.4 [0.7–3.3] months from the last dose was available for 280 (57%) CHD patients. The median antispike IgG titre was 2381 [901–8307] BAU/ml. Sixty (12%) patients also showed positive antinucleocapsid antibodies, demonstrating previous SARS-COV2 exposure. However, 35 out of 60 patients with positive antinucleocapsid antibodies did not report a history of previous COVID-19 infection, suggesting mildly symptomatic disease.
COVID-19 vaccines adverse events in CHD patients.
COVID-19 infection following vaccination
Eighty-two fully vaccinated patients contracted COVID-19 during follow-up: 48 after the primary vaccination cycle at a median of 5.4 [4.3–6.5] months from the last dose and 34 after a median of 1.6 [0.5–2.5] months from the booster dose. Of them, five patients tested positive for COVID-19 twice, before and after COVID-19 vaccination, and one of them with Fontan palliation required hospitalisation in both cases. One patient with Ebstein’s disease died from severe COVID-19, 6 months following the booster dose. Symptoms’ duration in patients tested positive after vaccination was 5.5 [3–8] days, which was significantly shorter than the symptoms' duration in the group that tested positive before vaccination (9 [2.2–15] days, p = 0.04).
Vaccine perception and hesitancy in CHD patients
Data on vaccine attitude were available for 437 (89%) patients: their replies to our vaccine perception questionnaire are summarised in Figure 1. Twenty-nine percent appeared to have concerns regarding vaccine safety before discussing it with their general practitioner or cardiologist, 42% reported fearing potential effects of the vaccine on their cardiac disease, and 43% were at least partially influenced by the discussion with their CHD cardiologist in their decision to undergo COVID-19 vaccination. Sixty-two percent of those vaccinated in situ declared that undergoing vaccination at the CHD centre made them feel safer.
Patients’ answers to the vaccine perception questionnaire. Questions are reported in Table 1 of Supplementary material.
Discussion
After COVID-19 outbreak, healthcare delivery modalities had to be promptly readjusted to meet the new needs of patients worldwide, especially for those who are potentially more vulnerable to the life-threatening effects of COVID-19 infection, like adults with CHD. Those deep changes involved not only a new organisation of the in-hospital care,Reference Scognamiglio, Fusco, Merola, Palma, Correra and Sarubbi12 but also COVID-19 vaccination administration for fragile patients. Between the end of 2020 and the beginning of 2021, in an unprecedented global effort to contain the pandemic, a worldwide imunisation campaign was launched and every country independently started to administer COVID-19 vaccination to the general population. At that time, several scientific statements recommended to prioritise adults with CHD patients in the vaccine allocation strategy.Reference Driggin, Maddox and Ferdinand13–Reference Sabatino, Di Salvo and Calcaterra15
We carried out an observational study with the aim to evaluate the safety profile of COVID-19 vaccines in patients diagnosed with CHD. We previously reported for the first time the early real-life data on COVID-19 vaccination in a small CHD group.Reference Fusco, Scognamiglio and Merola7 However, despite early evidence of success of COVID-19 vaccines in reducing rate of hospitalisation and death, the apparent resolution of the pandemic crisis has led to a more relaxed approach to COVID-19 vaccination in the general population. Nevertheless, very recent news of pandemic resurgence in China with constantly rising numbers of cases16 should bring back the public and political attention to the importance of protecting fragile populations. In this view, data on long-term results of COVID-19 vaccination in CHD patients are essential to adequately plan the future direction of the vaccination campaign.
Our data provide reassurance of a good mid-term safety profile of the vaccines in the CHD population, confirming our preliminary results.Reference Fusco, Scognamiglio and Merola7 Indeed, post-vaccination adverse events were transient and mild in most cases and included those already mentioned in the summary of product characteristics of these vaccines.17,18 There was no increased incidence of serious adverse effects in subjects with CHD compared to the general populationReference Beatty, Peyser and Butcher19 and the events reported were generally not serious and resolved spontaneously. In line with our results, another observational study carried out in a similar frail population of patients receiving COVID-19 vaccines reported comparable results of adverse events’ type, seriousness, and outcome.Reference Maniscalco, Scavone and Mascolo20 Post-vaccination acute myopericarditis is a particularly fearsome event in the CHD population, especially in case of presentation with impaired systolic function. However, in our population, it occurred only in one case and was completely resolved after medical treatment. Our data seem to point out a much higher incidence in CHD patients compared to previously reported rate in the available literature, even amongst the highest risk group of young men.Reference Patone, Mei and Handunnetthi21,Reference Oster, Shay and Su22 Nevertheless, this unexpected finding is mostly likely the effect of a random occurrence and no definite conclusions should be drawn from this one event in a limited sample. Further evaluation is needed to ascertain whether the CHD population is at higher risk for post-vaccination myopericarditis. In the meanwhile, a cautious approach with postvaccination surveillance in CHD patients aimed to detect early symptoms suggestive of myocarditis deserving medical attention may be reasonable. Another worrisome complication is the potential exacerbation of gastrointestinal symptoms in patients on chronic diuretic treatment or with Fontan failure. In our series, gastrointestinal disturbs occurred following the first dose, the second, and the booster dose in 10, 4, and 3% of patients, respectively, and were always self-limited. Other rare adverse events were limited in number, required medical treatment on a low proportion of cases and did not seem to cause mid-term complications.
CHD patients developed overall a satisfactory antibody response to COVID-19 vaccines and COVID-19 vaccination was effective in reducing the symptoms duration in case of infection. It is interesting to note that despite multiple risk factors for severe disease in case of viral exposure, 12% of patients with no history of SARS-COV2 infection had positive nucleocapsid antibodies, suggesting a history of asymptomatic or minimally symptomatic prior disease. Vaccine hesitancy was slightly less than what has been reported in other subsets,Reference Xu, Shi, Zheng, Tung and Zhang23,Reference Smith, Sim and Amlôt24 likely due to the effect of the health-related education received since childhood. Patients’ answers to our questionnaire highlightened the crucial role of the CHD team to ensure a smooth vaccination acceptance. Nearly all cardiologists are now frequently requested to provide counselling for vaccine hesitancy in patients with cardiac disease. Therefore, educating patients with CHD by pointing out the central role of vaccination during the clinical consultation for the prevention of a potentially life-threatening infection is essential to vaccine acceptance.
Limitations
Our study is limited by sample size, non-randomised design, the lack of cellular immunity, and neutralisation assay testing. Thus, our findings should be considered exploratory since it cannot be excluded that missing clinical data might potentially have influenced our results. Moreover, our population was predominantly composed of subjects with moderate-complex CHD, reflecting the case mix of patients attending a tertiary CHD centre, whereas those with simple defects are more likely followed at local facilities. Furthermore, only 57% of patients attending the clinic in the 4 months following immunisation underwent blood test to quantify IgG titre. Nevertheless, to the best of our knowledge, this is the first study carried out in a real-life context among CHD patients with the aim to describe the current state of COVID-19 vaccination including booster dosage administration, vaccines’ safety at a longer follow-up, and protection against COVID-19 infection. The use of our questionnaire is a non-standardised method and could be subject to bias as CHD patients are asked about sentiments prior to the vaccine only after the actual vaccination. However, despite the obvious limits of the questionnaire, it may be a useful tool to explore CHD patients’ attitude towards COVID-19 vaccination, allowing to provide the first systematical data on vaccine hesitancy among this population with specific focus on the potential effects of their CHD, addressing safety concerns that these patients might have.
Conclusion
Our study provides the first mid-term real-world evidence of safety and immunogenicity of COVID-19 vaccines in 490 adults with CHD patients, including predominantly individuals with moderate and complex disease. Our data showing lack of a clear trend towards an increased incidence of serious adverse events in adults with CHD patients compared to the general population may be helpful to raise awareness on the safety profile of COVID-19 vaccination and to garner vaccine acceptance in this complex population, though additional reports may be necessary. Moreover, COVID-19 vaccination resulted in a significant reduction of symptoms duration in case of infection among adults with CHD patients, supporting the role of future vaccination campaigns in this peculiar clinical setting, especially in view of possible new pandemic waves.
Supplementary material
To view supplementary material for this article, please visit https://doi.org/10.1017/S1047951123000689
Aknowledgements
We thank Dr Assunta Carandente, lead of the ACHD Unit nursing staff for her tremendous effort in maintaining high-quality standard of care for our complex patients throughout the COVID-19 pandemic; Dr Luigi Atripaldi for his essential contribution in data interpretation; Dr Daniela Costagliola for coordinating the COVID-19 vaccination for patients at risk at AORN dei Colli; Dr Cecilia Spinelli Barrile, Dr Gabriella Piccolo, Dr Nadia Puzone, and Dr Tiziana Varriale for their important work in organizing COVID-19 vaccination in ACHD patients at our centre.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of interest
None.
Ethical standards
The authors assert that all procedures contributing to this work comply with Helsinki Declaration of 1975, as revised in 2008. Study protocol was approved by the Ethics Committee of Spallanzani Hospital, in agreement with special legislation for prospective studies regarding COVID-19.
