Pneumonia, wheezing and asthma were more common in children after thymectomy due to open‐heart surgery

This nationwide study evaluated the clinical impact that an early thymectomy, during congenital heart defect (CHD) surgery, had on the health of children and adolescents.


| INTRODUC TI ON
The thymus is an essential primary lymphoid organ in the immune system and its primary function is to train T cells.These play a major role in adaptive immune responses against various external threats, but they can also cause autoimmunity if they are dysregulated. 1,2The thymus is almost fully developed at birth and continues to grow during the first months of life.The thymus reaches its maximum size at approximately 4 months of age and then gradually starts to shrink.This leads to decreased levels of T lymphocytes, although some thymic function continues throughout childhood and adulthood. 3congenital heart defect (CHD) is the most common structural abnormality in newborn infants and surgery is often required.
Approximately 200 children undergo open-heart surgery in Finland each year. 4,5Thymic tissue is often partially, or almost completely, removed to enable better access to the heart during surgery.][8][9][10][11][12][13][14] CD4+, CD8+ and naïve T cell counts decrease, while memory T cell counts increase.[15] The aim of this nationwide questionnaire-based study was to investigate the clinical impact of an early thymectomy on the later health of children and adolescents.We also compared the clinical symptoms and diagnoses of the cases and their matched controls.

| Study design and population
This was a nationwide study of the clinical impact of early thymec- We then retrieved all the International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes from the Care Register for Health Care for children that could be identified in the national database for paediatric cardiac surgery.The Care Register for Health Care is maintained by the National Institute for Health and Welfare, Finland and consists of data on patients discharged from inpatient and specialist outpatient care.We excluded children with ICD-10 diagnosis codes for conditions that are known to affect immunity.These were: preterm birth before 28 weeks of gestation (P07.2),low or extremely low birth weight (P07.10,P07.02, P07.01, P07.00), DiGeorge syndrome (Q87.06) and Down syndrome (Q90, Q90.9).

After retrieving data from the National Digital and Population Data
Services Agency, Finland, we excluded children if their parents did not speak Finnish or Swedish, children who had died, those who had an incorrect social security number and those families who refused to provide personal information.We also excluded children with Noonan syndrome, KAT6A syndrome, Milroy syndrome, Mulibrey nanism or a chromosome 18 translocation.Each child was matched with 10 controls, by sex, age, and hospital district, who had 95% CI 2.1-5.6),asthma (aOR 2.5, 95% CI 1.5-4.1)and wheezing (aOR 2.1, 95% CI 1.5-2.9).

Conclusion:
Hospitalisation due to infections, pneumonia, wheezing and asthma was more common in children after a thymectomy due to open-heart surgery than population-based controls, underlining the importance of immunological follow-ups.

K E Y W O R D S
congenital heart defect, heart surgery, immune system, respiratory conditions, thymus

Key notes
• This nationwide Finnish questionnaire-based study evaluated the clinical impact that an early thymectomy, during congenital heart defect (CHD) surgery, had on the health of patients aged 1-15 years.
• The CHD group reported more recurrent hospitalisations due to infections than the controls, matched for sex, age and hospital district and more pneumonia episodes, asthma and wheezing.
• The findings underline the importance of immunological follow-ups of such patients.

| 1687
not undergone heart surgery.These data were obtained from the National Digital and Population Data Services Agency.The aim was to obtain responses from at least three controls per case.

| Electronic questionnaire
We conducted a survey using Research Electronic Data Capture, a secure web application for creating and managing electronic surveys and databases, between 16 August 2021 and 5 November 2021.We prepared handouts with information on the study, and a link and quick response code to the electronic questionnaire, and sent these to the families of the cases and controls.The electronic questionnaire consisted of background questions and a total of 50 questions, divided into five sections, on rhinitis, infectious diseases, wheezing and asthma, eczema and autoimmune diseases.The questions on rhinitis, wheezing and asthma and eczema were based on the validated International Study of Asthma and Allergies in Childhood questionnaires. 18Two questionnaires were used, which had the same content but were phrased differently based on who was being asked to reply to them.The parents completed the questionnaires for subjects aged 1-12 years and the subjects aged 13-15 completed their own questionnaires, with or without input from their parents.

| Sample size
Given that 10% of children in Finland suffer from recurrent respiratory infections, 19 we considered a twofold relative risk (RR) of such infections as a clinically significant difference.We calculated that at least 155 pairs were required for the study, using the StatsDirect program (StatsDirect Ltd, Merseyside, UK), assuming a statistical power of 80% and an alpha error of 5%.We used at least three controls for each case to ensure sufficient statistical power.

| Statistical analysis
We excluded those children who were likely to have persistent cardiac or respiratory complaints after CHD surgery.These included children with tetralogy of Fallot, pulmonary stenosis, pulmonary atresia, trachea stenosis or a functionally univentricular heart with limited pulmonary blood flow. 20We then conducted the logistic regression analysis and calculated the adjusted odds ratio (aORs) for sex, age and hospital district for prespecified outcomes.A sensitivity analysis was then conducted in the subgroup of children who had undergone open-heart surgery under 1 year of age.In addition, we reported results for all children without exclusions.The data were analysed with SPSS statistics, version 27.0 (IBM Corp, New York, USA). 21e study plan was approved by the Review Board of the

| RE SULTS
A total of 450 cases who have undergone paediatric cardiac surgery CHD were identified from the national database: 365 (81%) had undergone a complete or partial thymectomy and 45 (10%) underwent complete or partial removal of the lobe.The other 9% comprised 39 patients with an unverified thymus operation and one patient who did not have their thymus removed.We also retrieved 4500 controls from the national Digital and Population Data Services Agency (Figure 1).This meant that 4950 children and their representatives were invited to take part in the study.We received a total of 1663 responses: 260/450 (58%) from the CHD surgery group agreed to participate, as did 1403/4500 (31%) from the control group.The mean number of controls per case was 3.2 (range 0-7).The parents were asked to respond on behalf of the cases aged 1-12 and children aged 13-15 had their own version of the questionnaire and could respond, with, or without, the help of their parents.The respective responses from the parents of the cases in the surgery and control groups were 73/110 (66%) versus 349/1100 (32%) for children aged 1-3 years and 83/157 (53%) versus 461/1570 (29%) for those aged 5-7 years.We also received 104/183 (57%) versus 593/1830 (32%) replies from the adolescents aged 13-15 years in the surgery and control groups.
As baseline, the 260 cases (57% boys) and 1403 controls (56% boys) had mean and standard deviation ages of 8.8 (5.1) and 9.1 (5.1) years, respectively (Table 1).The most common reasons for CHD surgery were shunt lesions and outflow tract obstructions.After we excluded the cases with persistent cardiac or respiratory complaints following CHD surgery, there were 187 cases.The number of controls remained unchanged.
Cases in the CHD surgery group also reported more instances of poor weight or height gain (19% vs. 6.2%, aOR 3.6, 95% CI 2.3-5.7)(Table 2).In the age-specific analyses, cases in the CHD surgery group reported more pneumonia episodes in all age groups (Table 3).
Analyses of all the children, without excluding those with probable persistent cardiac or respiratory complaints after CHD surgery, are presented in Tables S2 and S3 and analyses of all the children who Age, years, mean (SD) 2.7 (0.5) 6. had undergone open-heart surgery before 1 year of age are presented in Tables S4-S7.
In the analysis from which the patients with persistent cardiac or respiratory complaints after CHD surgery were excluded, there were no significant differences between the cases and their controls in the reported occurrence of otitis media (aOR 1.1, 95% CI 0.74-1.5),sinusitis, sneezing, runny nose or hay fever (Tables 2 and   S1).In the age-specific analyses, parents in the CHD surgery group reported more otitis media episodes in the children aged 5-7 years (aOR 2.5, 95% CI 1.2-5.4)(Table 3).

| Wheezing, asthma and eczema
The CHD surgery group reported more wheezing (aOR 2.1, 95% CI 1.5-2.9),chronic mucus hypersecretion (aOR 2.4, 95% CI 1.6-3.4),wheezing during or after exercise (aOR 2.3, 95% CI 1.5-3.7),asthma (aOR 2.5, 95% CI 1.5-4.1)and dry cough at night (aOR 1.6, 95% CI 1.0-2.7)than did those in the control group (Tables 2 and S1, Figure 2).In the age-specific analyses, the cases in the CHD surgery group reported more asthma in the children aged 5-7 years and 13-15 years (Table 3).Analyses of all the children, including those likely to have persistent cardiac or respiratory complaints after CHD, are presented in Tables S2 and S3 and analyses of all the children who had undergone open-heart surgery before 1 year of age are presented in Tables S4 and S7.
In the analysis excluding cases with persistent cardiac or respiratory complaints after CHD surgery, there were no significant differences between the cases and controls in the reported occurrence of rash, eczema, or recurrent herpes virus infections (Tables 2 and S1).
Similarly, no significant differences were found between the cases and controls in the age-specific analyses (Table 3).

| Autoimmune diseases
There were few children and adolescents with autoimmune diseases in both, the CHD surgery group (n = 6/187, 3.2%) and the control group (n = 42/1402, 3.0%).After excluding cases with persistent cardiac or respiratory complaints after open-heart surgery, there were no statistically significant differences between the cases and controls in the reported occurrences of autoimmune or autoinflammatory diseases (Tables 2 and S1, Figure 2).Similarly, no significant differences were found between the cases and the controls in the age-specific analyses (Table 3).Analyses of all the children, without excluding those with probable persistent cardiac or respiratory complaints after CHD surgery, are presented in Tables S2 and S3 and analyses of all the children who had undergone open-heart surgery before 1 year of age are presented in Tables S4-S7.In children operated before 1 year of age, more autoimmune diseases were reported at the age of 13-15 years in the CHD surgery group (aOR 2.4, 95% CI 1.0-5.7)(Table S7).

| DISCUSS ION
This nationwide study showed that pneumonia, wheezing and asthma were more common in children who had undergone thymectomy due to open-heart surgery than population-retrieved controls.
In addition, hospitalisations due to infections were more common in children after thymectomy.The present results support the suggested immunological follow-up of children who have undergone thymectomy due to open-heart surgery.
Thus, an immunological evaluation of patients who have undergone thymectomy has been suggested after open-heart surgery. 23Our present results support this proposal.The optimal implementation, that is the extent and timing of the immunological follow-up, has yet to be evaluated.Further studies are needed to clarify the relationship between symptoms and immunological findings in patients who have undergone thymectomy and to investigate which properties of T lymphocytes are involved in this immunological process.
Gudmundsdottir et al. 24 discovered that near-total thymectomy during infancy was related to reduced multiplicity of both the CD4 + and CD8 + T cell receptor repertoire, and suggested that this reduced repertoire diversity may affect adaptive immune functions and lead F I G U R E 2 Adjusted odds ratios (aORs) for adolescents aged 13-15 years or parent-reported occurrence of infectious diseases, wheezing, asthma, eczema and autoimmune diseases.
to increased susceptibility to infections, autoimmune diseases and malignancies. 24Furthermore, in a later study by Gudmundsdottir et al., 11 individuals who had undergone thymectomy under the age of 5 years during open-heart surgery for CHD had an increased risk of hypothyroidism, juvenile rheumatoid arthritis, rheumatic diseases, celiac disease, type 1 diabetes, asthma and infections relative to controls.In our study, asthma was reported more frequently in the CHD surgery group than in the control group, which is in line with the immunological findings in the recent study by Kooshesh et al. 25 in adult patients.In adults who had undergone thymectomy, levels of type 2 helper T cell promoting factors (thymic stromal lymphopoietin and interleukin-33) were higher compared with that in demographically matched controls. 25In contrast to previous investigations, we did not find an increased risk of autoimmune and autoinflammatory diseases after CHD surgery in our study.Children operated before 1 year of age, however, had more reported autoimmune diseases at the age of 13-15 years in the present study.

| Strengths and limitations
The present work had several strengths.We received a total of 1663 responses, representing an excellent response rate of around 60% in the CHD surgery group.Moreover, we designed identical electronic questionnaires for both the children under 13 years of age and adolescents aged 13-15 years who had undergone thymectomy and their population-retrieved controls in order to render the results comparable.The prespecified sample size was achieved.This study had some limitations.The cases in the thymectomy group responded more often than did those in the control group, which may have led to bias.An additional limitation was that the differences between the children and adolescents who had undergone thymectomy and their controls may be explained by factors or complications related to the CHD surgery other than the thymectomy.However, we excluded children and adolescents who were likely to have persistent cardiac or respiratory complaints after CHD surgery to minimise this bias.An ideal control group would have consisted of children and adolescents who had undergone open-heart surgery, but not thymectomy.There were very few patients in our cohort, however, whose thymus had remained intact or whose thymus surgery type had not been confirmed.In the future, magnetic resonance imaging of the thymus could be a useful tool for estimating the size of thymus. 22

| CON CLUS ION
This nationwide study showed that pneumonia, wheezing, and asthma were more common in children after thymectomy than in their population-retrieved controls.In addition, hospitalisations due to infections were more common.The findings support the suggested immunological follow-up for children after thymectomy due to open-heart surgery.
tomy on immunity and health later in life in paediatric patients who had undergone a partial or complete thymectomy during open-heart surgery in infancy or early childhood.Patients who had undergone CHD surgery were identified from the Finnish national database for paediatric cardiac surgery which includes information on such cases.The database is maintained by the University Children's Hospital, Helsinki, which is where all CHD surgery is performed in Finland.The children were divided into three age groups: 1-3 years, born from 1 January 2018 to 31 December 2019, 5-7 years, born from 1 January 2014 to 31 December 2015, and 13-15 years, born between 1 January 2006 to 31 December 2007.These age groups were chosen because they were partly the recommended ages for investigating immunity in children with DiGeorge syndrome, 17 a known immunodeficiency that can be accompanied by a decrease in thymus function.
National Institute for Health and Welfare, Helsinki, Finland (THL/2291/5.05.00/2019) and the Ethical Committee of the North Ostrobothnia Hospital District (EETTMK 109/2018).The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.Informed consent or assent was provided by responding to the questionnaire.

F I G U R E 1
Study profile.TA B L E 1 Baseline characteristics of the study population.
Parent-reported and self-reported later health in children and adolescent with congenital heart disease after open-heart surgery.a a Thymus removed completely or close to completely during open-heart surgery.bOnelobe of the thymus removed partially or completely during open-heart surgery.TA B L E 2Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; N/D, not defined.a The table reports the numbers of yes responses to the electronic questionnaire for both the cases and controls.b Odds ratios adjusted for sex, age, and hospital district.