Introduction
Congenital athymia is an ultra-rare (defined as prevalent in no more than 1:50,000 [
1]) pediatric condition characterized by the lack of thymic development in utero. The thymus is responsible for the maturation and selection of T-cell precursors, and, as a result, pediatric patients with congenital athymia lack naïve T cells that normally undergo positive and negative selection in the thymus and are essential for self-tolerance and antimicrobial immunity [
2,
3]. Patients with congenital athymia are most commonly identified via low or undetectable T-cell receptor excision circles (TRECs) through newborn screening for Severe Combined Immunodeficiency (SCID), which has been required in all 50 states in the USA sincē 2018 [
4,
5]. Congenital athymia is characterized by profound naïve T-cell deficiency with high susceptibility to infections, including opportunistic infections [
6‐
8]. Patients with congenital athymia frequently develop manifestations of autologous graft-versus-host disease (GVHD) such as an eczematous rash, lymphadenopathy, and enteropathy. Autologous GVHD is similar to Omenn syndrome seen in SCID and is associated with oligoclonal T-cell expansion [
8‐
10]. Patients with congenital athymia, oligoclonal T-cell expansion, and autologous GVHD are considered to have an atypical phenotype [
11]. Complicating their care, patients also often present with clinical manifestations of associated genetic or syndromic conditions such as complete DiGeorge syndrome with or without 22q11.2 deletion, CHARGE syndrome (coloboma, heart defect, choanal atresia, growth or mental retardation, genital hypoplasia, and ear anomalies or deafness), forkhead box protein N1 (FOXN1) deficiency, and diabetic embryopathy [
7,
12].
Historically, patients with congenital athymia typically die from infections or autoimmune sequelae within 2–3 years of life [
13]. Current clinical management of congenital athymia consists of supportive care, which is geared toward minimizing risk of infection and treating infections and autologous GVHD [
9,
14,
15]. Patients are recommended to be placed in immediate isolation following the diagnosis of congenital athymia (in line with procedures for primary immunodeficiencies) [
14‐
17]. In the hospital, isolation usually requires contact and droplet precautions, infection prevention protocols for hospital staff, visitation restrictions, and, at times, even specialized air-flow rooms. At home, caregivers and family members are instructed to maintain strict isolation and hygiene procedures, as any interactions with individuals outside the immediate household can potentially expose the patient to pathogens that can lead to fatal infections, though isolation recommendations may vary by hospital or treating physician. As a result of these drastic requirements, profound immunodeficiency, and clinical sequelae of autologous GVHD, patients with congenital athymia can have prolonged inpatient stays in the hospital for weeks or months. In addition, patients receive multiple medications for prophylaxis and treatment of infections, immunosuppression for autologous GVHD, and frequent monitoring with medical tests to evaluate immune function [
9,
13,
15]. Patients often require invasive procedures for their care, such as placement of a feeding tube or central line; central lines are frequently used in these patients to administer medications or draw blood [
18]. Taken together, the high medical burden associated with supportive care for these patients has substantial clinical, emotional, social, and financial impact on caregivers and families.
There is a lack of published evidence characterizing the burden of congenital athymia on families and caregivers. As congenital athymia is reported in published literature primarily in the context of genetic and syndromic conditions [
7,
12,
19], there are few data characterizing the burden of congenital athymia independently. In fact, there is no published study that utilizes a validated patient-reported outcomes scale to characterize the specific impact of congenital athymia on the patient’s health-related quality of life (HRQoL). Moreover, the burden of managing congenital athymia, including prolonged isolation and frequent healthcare utilization, on caregivers and families is unknown. Thus, this study sought to characterize the clinical, emotional, social, and financial burden of congenital athymia on pediatric patients who are receiving supportive care only as well as on their caregivers and families.
Methods
This cross-sectional study utilized primary data research methods in adult caregivers of patients with congenital athymia to characterize the impact of congenital athymia. A web-based survey captured quantitative responses and was followed by a telephone-based interview led by an expert moderator who had a doctorate in clinical psychology. The study instrument included a screener, a web-enabled questionnaire, and a discussion guide designed to collect information about the holistic burden of illness across clinical, emotional, social, and financial domains. The study instrument was designed to differentiate the burden of congenital athymia from other comorbid conditions. To accomplish this differentiation between the clinical manifestations of congenital athymia from other comorbid conditions, a list was compiled of the clinical manifestations reported in congenital athymia in the literature and those associated with underlying comorbid conditions. The authors reviewed the list and, using their clinical experience treating patients with congenital athymia, assigned cause of clinical manifestations to either congenital athymia or to underlying syndromic comorbidities. In addition, caregivers were instructed to report the frequency of clinical manifestations associated with congenital athymia and the frequency of manifestations associated with underlying comorbid conditions. The discussion guide was designed to facilitate conversations in a semi-structured manner to understand the areas of the disease that are most burdensome to the patients and families. Following the interviews, information was captured as transcribed notes in a response grid in Microsoft Excel™ (Microsoft Corporation, Redmond, WA, USA) to determine the most reported thematic elements of the interviews. Personal identifiable information was not collected.
Caregivers were recruited through online advocacy groups and social media support groups for families caring for patients with congenital athymia. To be considered eligible for the study, caregivers had to meet the following requirements: current caregivers had to be aged at least 18 years, have a caregiver-reported physician diagnosis of congenital athymia for the patient under their care, and be able to complete both the web-based survey and phone interview in English. Caregivers of the following patients were excluded from the study: deceased patients with congenital athymia and patients with hypothymia (low thymic function, but not absent). Only the primary caregiver for each patient was included in the study; in cases where there were coprimary caregivers, only one was included. All data on the impact of congenital athymia on patients, caregivers, and families were captured from the caregiver’s perspective. Data were collected between November 2020 and January 2021 from respondents in the USA.
Caregivers of patients meeting the above criteria were included in the study. For patients currently receiving supportive care, all questions were framed for the past 12 months. For patients who had previously received investigational cultured human thymus tissue implantation, all questions were framed for the most recent 12 months they were receiving supportive care. To mitigate the potential recall bias for caregivers, a previously published self-reported confidence rating was used to assign a confidence score to each question for the respondents in this cohort [
20]. Respondents were asked to rate how sure they were about the accuracy of their responses on a scale of 1 = very unsure to 5 = very sure.
The questionnaire also included a validated patient-reported outcome scale—the parent proxy version of the Pediatric Quality of Life Inventory 4.0 Generic Core Scale (PedsQL) for ages 2–4 years [
21]. The PedsQL consists of 23 items, which can be used to calculate a total score and component physical health summary score and psychosocial health summary score. The PedsQL ranges from 0 to 100, with a higher score representing a higher HRQoL. The scale is validated to be used with a 1-month recall and was only administered to caregivers of patients aged 2–4 years currently receiving supportive care.
Analyses were conducted using Q Research Software (Q Professional version 5.8.2.0, Displayr, Glebe, New South Wales, Australia) and Microsoft Excel (Microsoft Corp.). Descriptive statistics were used to assess all quantitative data; medians with interquartile ranges (IQR) or means with standard deviations (SD) were derived for continuous variables and frequencies or percentages were derived for categorical variables, where appropriate. Data from qualitative interviews were systematically grouped into themes to identify similarities and dissimilarities between respondent experiences. Responses were grouped into tables, coded by 1 researcher, and cross-checked by another researcher. Subsequently, authors grouped these themes into categories and evaluated the most pertinent findings from the interviews.
Compliance with Ethics Guidelines
This study was reviewed by ADVARRA, a central Institutional Review Board (IRB, Identification Pro00047613). Following IRB review, this study was determined to have an exempt status (as defined by the US Department of Health and Human Services regulations found at 45 CFR 46.104[d][2]). This study was conducted in line with research ethics in accordance with the Helsinki Declaration of 1964 and its later amendments.
Discussion
To our knowledge, this is the first study evaluating the clinical, emotional, social, and financial burden of congenital athymia on patients, caregivers, and their families. To date, the existing literature on congenital athymia has been restricted to characterizing the clinical manifestations of the condition, largely in the context of other associated genetic and syndromic conditions [
7,
12,
19]. As a result, there is no reliable published information on incidence and prevalence of congenital athymia. Between 2017 and 2020, 71 patients were diagnosed and referred to Duke University for investigational cultured human thymus tissue implantation (on average, about 18 patients annually). The inclusion criteria for entry into the clinical trial of investigational cultured human thymus tissue implantation at Duke University are athymia with circulating CD3
+ CD45RA
+ CD62L
+ T cells of < 50/mm
3 or < 5% of the total T-cell count on two separate flow cytometry analyses, one performed within 3 months and one within 1 month prior to implantation [
22]. The number of patients referred to Duke captures most cases of congenital athymia, as investigational treatment at Duke is the only current option for these patients in the US. Thus, the sample size in this study (
n = 18) is reasonable, as it is similar to the number of patients referred to Duke annually and a fair estimation for the annual incidence of the disorder in the US.
Although several published studies report the occurrence of clinical manifestations in patients with congenital athymia [
3,
6,
8,
23], the data are not always captured systematically across patients, and this information is frequently described only in case reports [
7,
9]. We set out to characterize the volume of clinical burden, considering both the number of patients experiencing each type of clinical manifestation and the frequency with which they occur, in patients with congenital athymia over a 12-month period. Overall, most patients experienced numerous and frequent clinical manifestations associated with congenital athymia across multiple organs, including otolaryngologic, skin, lung, gastrointestinal, and genitourinary disorders or infections as well as endocrine system disorders. A notable finding was that nearly a quarter of patients with congenital athymia experienced sepsis every 3–4 months.
As a result of the strict isolation required for patients with congenital athymia [
14‐
17], patients are unable to physically explore the world beyond their homes or socialize and bond with extended family or peers, potentially causing patients to miss critical milestones. In fact, several caregivers reported concern that their child had already experienced or would experience delays in psychosocial and emotional development associated with their sustained isolation. The unique contribution of prolonged isolation on development is difficult to differentiate from cognitive delays or intellectual disability associated with syndromic comorbidities, such as 22q11.2 deletion syndrome. However, data demonstrating the value of social interaction in infancy and childhood [
24] suggest it is possible that these patients experience long-term effects of early isolation.
Remarkably, 100% of caregivers reported the need to live in isolation and caregiver emotional burden as the top ways that congenital athymia affected them and their families. Given that patients with congenital athymia have historically died within the first 2–3 years of life with only supportive care, parents of these patients expressed considerable fear that their child would die and an overwhelming feeling of responsibility for keeping their child safe. This study revealed that these feelings were compounded by isolation from support systems of extended family and friends, with caregivers seemingly having to navigate many experiences alone and mourn the loss of normalcy in their lives. Moreover, social isolation and loneliness have been shown to be associated with depression and impaired cognitive health, and potentially an increased economic burden [
25‐
27]. Older siblings were also impacted, as siblings were frequently withdrawn from school and homeschooled following the patient’s diagnosis, causing siblings to miss out on critical social interactions and possibly learning progression. In addition, caregivers voiced concerns about siblings needing to maintain isolation to minimize infection risk for the patient. Caregivers worry that the inability of siblings to freely interact with families and friends outside their household or participate in team sports would negatively impact their social development. Collins et al. recently published recommendations for supportive care of patients with congenital athymia [
28], but no national or international consensus guidelines exist for managing patients with congenital athymia. Consensus guidelines would ensure that isolation procedures are adequate for minimizing infection risk without unnecessarily increasing the considerable burden of isolation on patients and their families.
Due to the extensive clinical burden, patients with congenital athymia experience high healthcare resource utilization, primarily in the form of lengthy inpatient hospital stays in specialty units such as pediatric intensive care units and multiple medical procedures. Patients with congenital athymia also required multiple medications to minimize their risk of infection and manage manifestations of autologous GVHD. These medications, primarily antimicrobials and immunosuppressants, can lead to adverse reactions as evidenced by the 33% of patients who developed kidney damage due to frequent and long-term use of nephrotoxic medications. The prophylactic antibiotics, antivirals, or antifungal medications that were utilized by nearly all patients have the potential to predispose patients to antimicrobial-resistant infections. Mohammadinejad et al. [
29] found that antibiotic resistance appears to be higher among patients with primary immunodeficiencies who receive significant antibiotic prophylaxis and treatment compared with immunocompetent patients.
Caregivers also reported multiple indirect costs associated with managing their child’s congenital athymia. Nearly all caregivers reported one parent needing to give up or take time off from their work to take care of their child full time, resulting in loss of income. Only half of caregivers reported utilizing home healthcare services. Caregivers reported that the fear of exposing their child to infection kept them from getting much needed nursing help, requiring caregivers to spend significant time providing direct medical care to patients and traveling to doctors’ appointments. Nearly one-third of caregivers reported needing to drive ≥ 2 h to receive care at a medical center; likely this was due to the patient’s need to receive care at a tertiary medical center. Several caregivers also reported having to permanently move to be in closer proximity to a medical center. Frequent hospital visits and complex medical care associated with this condition also impacted the primary income-earner’s career because of absences from work to address medical issues or because of a lack of productivity while working due to concerns for their child’s health. Caregivers reported giving up desirable career choices for fear of negative impact on their sick child (such as declining a career move to avoid losing current health insurance benefits), and educational sacrifices were noted across the family members. Caregivers reported changing or delaying plans to pursue education that would benefit their career and earning potential to care for the patient.
As measured by the validated PedsQL scale, patients with congenital athymia had a substantially lower mean total score compared with published literature of healthy pediatric patients (56.60 versus 80.87) [
21]; the PedsQL takes into account patients’ overall HRQoL, not the experience specific to their congenital athymia. The total score in patients with congenital athymia was also lower compared with other conditions, such as pediatric cancer (69.70) and end-stage renal disease (67.02) [
30,
31]. To contextualize the impact of congenital athymia on HRQoL, scores also were compared with similarly debilitating congenital conditions with substantial burden for patients and families. The total score of patients with congenital athymia was similar to that of patients with spinal muscular atrophy (53.35) and 22q11.2 deletion syndrome (50.98) on the PedsQL parent proxy report [
32,
33]. To the authors' knowledge, this is the first study evaluating quality of life in patients with congenital athymia.
There are several limitations that should be considered while reviewing this study. The first is the extremely rare nature of congenital athymia and limited sample size of the evaluated cohort. Given that there are 17 to 24 incident cases in the US annually, the sample size of 18 patients appears appropriate. To help account for the more limited sample size, the authors structured the study methods to be able to account for a breadth of potential experiences by utilizing qualitative interviewing, which introduces another limitation, as not all results could be quantified. In addition, only four patient caregivers were eligible to complete the PedsQL. Because the PedsQL is only validated in patients aged 2 years and older for a 1-month recall period, the sample was limited to caregivers of patients (≥ 2 years old) that were currently receiving supportive care (n = 4). However, the sample size appears reasonable given the low estimated prevalence of congenital athymia. Another limitation of the study is that responses of certain caregivers may be subject to recall bias as respondents may not be able to remember previous events or experiences, omit details, or experience memories that are influenced by subsequent events and experiences. In the study, a potential for recall bias was present for caregivers of patients who had previously received supportive care (n = 13) and were asked to recall the 12 months when they were last receiving supportive care. To help mitigate this bias, these caregivers were asked to rate, for each question, their assessment of the accuracy of their response on a 1–5 scale (5 being the highest confidence). Additionally, some questions were asked with categorical response options instead of continuous response options for this cohort.
Another potential limitation is that certain clinical manifestations associated with congenital athymia in these patients may have overlapping features of underlying syndromic comorbidities. For example, patients may have chronic sinus/ear, nose, and throat problems due to an anatomical abnormality or due to a chronic respiratory viral infection. In this study, care was taken to distinguish the clinical manifestations associated with congenital athymia from those stemming from other genetic malformations, including getting consensus from expert advisors on the list of clinical manifestations associated with congenital athymia versus comorbid conditions included in the survey and instructing caregivers to report clinical manifestations associated with congenital athymia separately from other comorbid conditions. Although we did not ask caregivers to provide patients’ associated genetic or syndromic conditions, congenital athymia can be associated with FOXN1 deficiency, complete DiGeorge syndrome with or without 22q11.2 deletion, CHARGE syndrome, and diabetic embryopathy [
28].
In our study, 13 patients had previously received investigational cultured human thymus tissue implantation. Although our study was not designed to evaluate changes to disease burden or quality of life post-implantation, patients treated with investigational cultured human thymus tissue implantation have been shown to have a significant decrease in the number of infections 6 to ≤ 12 months versus the first 6 months post-implantation (
p < 0.001), with a Kaplan-Meier estimated survival rate of 76% 2 years post-implantation [
22]. Future research is warranted to evaluate the change in disease burden and quality of life in patients with congenital athymia and their families post-investigational cultured human thymus tissue implantation.
A final consideration for the data is that caregivers included in this study were recruited through advocacy/support groups for congenital athymia and thus likely had more access to resources and support, which may have biased their responses compared with other caregivers’ responses. Moreover, although only caregivers of living patients were included, patients with congenital athymia typically die within the first 3 years of life with only supportive care. Taken together, it is possible that results of this study may underestimate the full burden of congenital athymia across all families. Therefore, in the future, areas to consider exploring include the long-term impact (i.e., > 12 months) of congenital athymia on the patient and caregiver’s lives, social development, potential post-traumatic stress, or other elements of psychosocial development.
Acknowledgements
We thank Megan Cooper, MD, PhD (Associate Professor, Rheumatology/Immunology, Department of Pediatrics, Washington University School of Medicine), for her expert advice on the therapeutic area and her contribution to study design. We also thank Bhagyashree Oak, PhD (Trinity Life Sciences), for her contribution to study design and data analysis, and Lisa Bailey, PhD (Trinity Life Sciences), for serving as the expert moderator during cognitive interviews. Megan Cooper, Bhagyashree Oak, and Lisa Bailey received consulting fees from Enzyvant Therapeutics, Inc. We thank the participants of the study.