Trends in mortality risk of patients with congenital heart disease during the COVID-19 pandemic.

BACKGROUND: Cardiovascular conditions are considered risk factors for poor outcomes associated with COVID-19. However, the effect of the COVID-19 pandemic on the mortality of patients with congenital heart disease (CHD) is unclear. Our study aims to examine the trends in mortality risk of CHD patients during the COVID-19 pandemic. METHODS: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for CHD. We included patients having US residence and direct identifiers; death events were captured by matching with the National Death Index. The observation window (2017-2022) was divided into pre-COVID-19 and COVID-19 era defined around the national onset of COVID-19 disease in 2020. Stratified Cox model was used to assess all-cause mortality between the pre- and the COVID-19 era. RESULTS: Among 45,130 patients with CHD (median age in 2017: 23.3 years, IQR: 19.0-28.4), 503 deaths occurred during the pandemic with 44 deaths (8.7%) attributed to COVID-19 (COVID-19 mortality rate of 0.09%). The overall risk of death for patients with all types of CHD during the pandemic was significantly higher compared to the pre-COVID-19 era (aHR 1.28, 95%CI: 1.08-1.53), with a differential trend towards increased risk in patients with two-ventricle (aHR 1.44, 95% CI: 1.19-1.76) vs unchanged risk for those with single ventricle CHD (aHR = 0.83, 95% CI: 0.57-1.21). Adjusted subgroup analysis revealed a higher risk of death during the pandemic for CHD patients with male and chromosomal abnormalities. The excess deaths during the pandemic were attributed to COVID-19 itself rather than CHD or cardiovascular conditions. CONCLUSION: In this large CHD cohort study, there was a higher risk of death among CHD patients with male and chromosomal abnormalities. A differential trend towards higher risk for those with two vs. unchanged risk for single ventricle CHD was presented. The excess mortality was attributed to the COVID-19 itself and not to conditions potentially related to deferral of care. These results justify targeted protective measures towards the CHD population and may provide guidance for public health and medical care response in future epidemics.

Association of patient-level characteristics with long-term outcomes after Fontan palliation: Rationale, design, and baseline characteristics of the Pediatric Cardiac Care Consortium Fontan cohort study.

BACKGROUND: The Fontan operation is used to palliate single ventricle congenital heart defects (CHD) but poses significant morbidity and mortality risks. We present the design, planned analyses, and rationale for a long-term Fontan cohort study aiming to examine the association of patient characteristics at the time of Fontan with post-Fontan morbidity and mortality. METHODS AND RESULTS: We used the Pediatric Cardiac Care Consortium (PCCC), a US-based, multicenter registry of pediatric cardiac surgeries to identify patients who underwent the Fontan procedure for single ventricle CHD between 1 and 21 years of age. The primary outcomes are in-hospital Fontan failure (death or takedown) and post-discharge mortality through 2022. A total of 1461 (males 62.1%) patients met eligibility criteria and were included in the analytical cohort. The median age at Fontan evaluation was 3.1 years (IQR: 2.4-4.3). While 95 patients experienced in-hospital Fontan failure (78 deaths and 17 Fontan takedown), 1366 (93.5%) survived to discharge with Fontan physiology and formed the long-term analysis cohort. Over a median follow-up of 21.2 years (IQR: 18.4-24.5) 184 post-discharge deaths occurred. Thirty-year post Fontan survival was 75.0% (95% CI: 72.3%-77.8%) for all Fontan types with higher rates for current techniques such as lateral tunnel and extracardiac conduit 77.1% (95% CI: 73.5-80.8). CONCLUSION: The PCCC Fontan study aims to identify predictors for post-Fontan morbidity and mortality, enabling risk- stratification and informing surveillance practices. Additionally, the study may guide therapeutic interventions aiming to optimize hemodynamics and enhance Fontan longevity for individual patients.

Long-Term Survival and Causes of Death in Children with Trisomy 21 After Congenital Heart Surgery.

OBJECTIVE: To evaluate long-term transplant-free survival and causes of death in the trisomy 21 (T21) population after surgery for congenital heart disease (CHD) in comparison with patients who are euploidic. STUDY DESIGN: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, enriched with prospectively collected data from the National Death Index and the Organ Procurement and Transplantation Network for patients with sufficient direct identifiers. Kaplan-Meier survival plots were generated and multivariable Cox proportional hazards models were used to examine risk factors for mortality between patients with T21 and 1:1 matched patients with comparable CHD who are euploidic. RESULTS: A long-term survival analysis was completed for 3376 patients with T21 (75 155 person-years) who met inclusion criteria. The 30-year survival rate for patients with T21 ranged from 92.1% for ventricular septal defect to 65.3% for complex common atrioventricular canal. Of these, 2185 patients with T21 were successfully matched with a patient who was euploidic. After a median follow-up of 22.86 years (IQR, 19.45-27.14 years), 213 deaths occurred in the T21 group (9.7%) compared with 123 (5.6%) in the euploidic comparators. After adjustment for age, sex, era, CHD complexity, and initial palliation, the hazard ratio of CHD-related mortality was 1.34 times higher in patients with T21 (95% CI, 0.92-1.97; P = .127). CONCLUSIONS: CHD-related mortality for patients with T21 after cardiac surgical intervention is comparable with euploidic comparators. Children with T21 require lifelong surveillance for co-occurring conditions associated with their chromosomal abnormality.

Early characteristics of bone deficits in children with Fontan palliation.

BACKGROUND: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation. METHODS: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls. RESULTS: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex. CONCLUSIONS: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.

The thoracic duct and the Fontan patient.

BACKGROUND: Ultrasound imaging of adults with heart failure and increased central venous pressure (CVP) has shown significant thoracic duct (TD) dilation from impedance in lymphatic drainage. Elevated CVP and abnormal lymphatic drainage are implicated in severe Fontan complications, including protein losing enteropathy (PLE) and plastic bronchitis (PB). Systematic studies of TD and lymphatic circulation in children are limited, and their cervical TD normative values have not been established. METHODS: Thoracic duct imaging was attempted prospectively during routine echocardiograms performed 7/2014-9/2016 in children 5-21 years old with normal cardiovascular physiology and Fontan palliation. TD insertion to the central venous system (lympho-venous junction) was assessed with an S12-4 MHz transducer. For the first 34 patients, only TD ostia were measured, but ostium shape variability at the lympho-venous junction led to including the TD arch 5-10 mm proximal to the ostium for the remaining cohort. RESULTS: Seventy-nine total subjects were studied: 58 controls, 13 Fontan patients with normal systemic ventricular ejection fraction (EF) (>50%), and 8 Fontan patients with decreased EF (≤50%). Combined Fontan subjects had larger TD ostial diameters compared to controls when normalized by body surface area (median 2.6 mm/m2 vs. 2 mm/m2 ) (P=.04). CONCLUSION: To our knowledge, this is the first systematic study of ultrasonographic TD imaging in children. Fontan patients have larger TD diameters, reflecting the impaired lymphatic circulation in patients with this physiology. Further research may provide important associations between sonographic TD features with the functional status of patients with Fontan circulation.

Abnormalities in serum biomarkers correlate with lower cardiac index in the Fontan population.

BACKGROUND: Fontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients. Methods and results This study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman's Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6-33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (-0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (-0.32, p<0.01). Area under the curve for the three individual biomarkers was 0.63-0.69. Area under the curve for the three-biomarker panel was 0.75. Comparison of cardiac index above and below the receiver operating characteristic curve-identified cut-off points revealed significant differences for each biomarker (p<0.01) and for the composite panel [median cardiac index for higher-risk group=2.17 L/minute/m2 versus lower-risk group=2.96 L/minute/m2, (p<0.01)]. CONCLUSIONS: Higher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.

A comparison of retesting rates using alternative testing algorithms in the pilot implementation of critical congenital heart disease screening in Minnesota.

Prior to state-wide implementation of newborn screening for critical congenital heart disease (CCHD) in Minnesota, a pilot program was completed using the protocol recommended by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC). This report compares the retesting rates for newborn screening for CCHDs using the SACHDNC protocol and four alternative algorithms used in large published CCHD screening studies. Data from the original Minnesota study were reanalyzed using the passing values from these four alternative protocols. The retesting rate for the first pulse oximeter measurement ranged from 1.1 % in the SACHDNC protocol to 9.6 % in the Ewer protocol. The SACHDNC protocol generated the lowest rate of retesting among all tested algorithms. Our data suggest that even minor modifications of CCHD screening protocol would significantly impact screening retesting rate. In addition, we provide support for including lower extremity oxygen saturations in the screening algorithm.

Ultrasonographic imaging of the cervical thoracic duct in children with congenital or acquired heart disease.

Conditions that increase central venous pressure lead to secondary dilation of the thoracic duct and impaired lymphatic circulation. We report the use of ultrasound to directly image the cervical part of the thoracic duct in children without the need for invasive techniques or contrast agents. Systematic evaluation of the thoracic duct may be useful in cardiovascular conditions with congestion of the lymphatic system such as single ventricle following Glenn or Fontan procedures.

Atrioventricular septal defect with an imperforate right-sided component of the common atrioventricular valve: anatomic and embryologic considerations.

We describe an atypical case of an atrioventricular septal defect with a common atrioventricular junction in which the right-sided component of the common atrioventricular valve was imperforate, producing tricuspid atresia with a severely hypoplastic right ventricle and an ostium primum defect. We discuss the implications of the anatomic findings with regard to concepts of cardiac development, drawing a comparison with similar cases previously reported.

Long-term Outcomes After Surgical Intervention for Congenital Supravalvar Aortic Stenosis in Children.

BACKGROUND: Primary supravalvar aortic stenosis (SVAS) is a rare congenital cardiovascular condition that can coexist with Williams-Beuren syndrome, coronary artery involvement, aortic coarctation, and pulmonary artery stenosis. SVAS repair can be achieved with low perioperative mortality, but long-term survival remains less well understood. We used the Pediatric Cardiac Care Consortium, a multicenter United States-based registry for pediatric cardiac operations, to assess long-term outcomes after SVAS repair. METHODS: We used Kaplan-Meier plots and Cox proportional hazards regression to examine factors associated with postdischarge deaths. These included sex, age-group, weight z-score, coexisting conditions (Williams-Beuren syndrome, coronary artery involvement, coarctation, and pulmonary artery stenosis), surgical techniques, and era, defined as early (1982-1995) or late (1996-2003). Survival was assessed by matching with the National Death Index through 2021. RESULTS: Of 333 patients who met inclusion criteria, 313 (94.0%) survived to discharge and 188 (60.1%) had identifiers for National Death Index matching. Over a median follow-up of 25.2 years (interquartile range, 21.1-29.4 years), 17 deaths occurred. The 30-year survival after discharge from SVAS repair was 88.7% (95% CI, 82.9%-94.8%). Infantile surgery and non-Williams-Beuren syndrome were associated with decreased 30-year survival. From the various repairs, the 2-sinus technique had better outcomes compared with all other types, except the 3-sinus technique (nonsignificant difference). Adjusted analysis revealed infantile age and type of repair as associated with postdischarge probability of death. CONCLUSIONS: These data demonstrate favorable long-term outcomes after SVAS repair, except for the infantile group that was associated with more diffuse arteriopathy. As techniques continue to evolve, future studies are warranted to investigate their long-term outcomes.

Surgical volume and center effects on early mortality after pediatric cardiac surgery: 25-year North American experience from a multi-institutional registry.

Mortality after pediatric cardiac surgery varies among centers. Previous research suggests that surgical volume is an important predictor of this variation. This report characterizes the relative contribution of patient factors, center surgical volume, and a volume-independent center effect on early postoperative mortality in a retrospective cohort study of North American centers in the Pediatric Cardiac Care Consortium (up to 500 cases/center/year). From 1982 to 2007, 49 centers reported 109,475 operations, 85,023 of which were analyzed using hierarchical multivariate logistic regression analysis. Patient characteristics varied significantly among the centers. The adjusted odds ratio (OR) for mortality decreased more than 10-fold during the study period (1982 vs. 2007: OR, 12.27, 95 % confidence interval [CI], 8.52-17.66; p < 0.0001). Surgical volume was associated inversely with odds of death (additional 100 cases/year: OR, 0.84; 95 % CI, 0.78-0.90; p < 0.0001). In the analysis of interactions, this effect was fairly consistent across age groups, risk categories (except the lowest), and time periods. However, a volume-independent center effect contributed substantially more to the risk model than did the volume. The Risk Adjusted Classification for Congenital Heart Surgery, version 1 (RACHS-1) risk category remains the strongest predictor of postoperative mortality through the 25-year study period. In conclusion, center-specific variation exists but is only partially explained by operative volume. Low-risk operations are safely performed at centers in all volume categories, whereas regionalization or other quality improvement strategies appear to be warranted for moderate- and high-risk operations. Potentially preventable mortality occurs at centers in all volume categories studied, so referral or regionalization strategies must target centers by observed outcomes rather than assume that volume predicts quality.

Thirty-Year Survival After Cardiac Surgery in Children With Williams-Beuren Syndrome (from the Pediatric Cardiac Care Consortium Study).

Williams-Beuren syndrome (WBS) is a genetic condition frequently requiring interventions for associated congenital heart disease (CHD). Long-term survival data after cardiac interventions for children with WBS are sparse. This is a retrospective cohort study aiming to describe the 30-year survival outcomes of children with WBS after interventions for CHD using the Pediatric Cardiac Care Consortium (PCCC), a large North American-based registry of interventions for pediatric heart diseases, between 1982 and 2009. Outcomes were obtained from the PCCC and by linkage with the National Death Index through 2020. Survival of patients with WBS and their major subgroups was assessed by Kaplan-Meier survival curves and Cox regression. A total of 200 patients met the inclusion criteria of having their first intervention for CHD at a US PCCC center and age <21 years at time of intervention. The most common lesions were left heart obstructive lesions (LHOL), either in isolation (37%) or in combination with right heart obstructive lesions (RHOL) (49.0%), whereas isolated RHOL accounted for 11% of the total. The first procedure was surgery for 85.5% of the group, and the remainder underwent a transcatheter procedure. There were 5 in-hospital deaths (2.5%), and among survivors to hospital discharge, 164 had sufficient identifiers for National Death Index linkage. Over a median period of postdischarge follow-up of 23.7 years (interquartile range 18.7 to 27.3), 16 deaths occurred, with an overall 30-year survival rate of 90%. Survival rates ranged from 96.1% for isolated LHOL or RHOL to 83.4% for patients with combined disease (adjusted hazard ratio 4.7, 95% confidence intervals 1.35 to 16.59).

Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease.

BACKGROUND: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. OBJECTIVES: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. METHODS: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. PRIMARY ENDPOINT: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. RESULTS: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. CONCLUSIONS: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).

Transient Global Ventricular Hypertrophy in a Patient With Multisystem Inflammatory Syndrome in Children (MIS-C) Correlated With High-Dose Glucocorticoid Treatment: A Case Report.

Multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection has been shown to lead to depressed cardiac function. Standard treatment includes high-dose glucocorticoids (GC). We present the unusual case of a teenager who developed transient echocardiographic global ventricular hypertrophy following GC administration during his treatment for MIS-C, with the resolution of the hypertrophy after cessation of GC.

Long-Term Outcomes of Cardiovascular Operations in Children With Connective Tissue Disorders.

Connective tissue disorders can be associated with significant cardiovascular morbidity needing cardiac surgery during childhood. In this retrospective study, we used the Pediatric Cardiac Care Consortium, a multicenter United States-based registry of pediatric cardiac interventions, to describe the long-term outcomes of patients who underwent their first surgery for connective tissue-related cardiovascular conditions aged <21 years. Between 1982 and 2003, a total of 103 patients were enrolled who underwent cardiac surgery for a connective tissue-related cardiovascular disorder, including 3 severe infantile cases operated on within the first year of life. Most patients underwent aortic site surgery (n = 85) as a composite graft (n = 50), valve-sparing (n = 33), or other aortic surgery (n = 2). The remaining patients underwent atrioventricular valve surgery (mitral 17, tricuspid 1). Of the 99 patients surviving to discharge, 80 (including the 3 infantile) had adequate identifiers for tracking long-term outcomes through 2019 through linkage with the National Death Index and the Organ Procurement. Over a median period of 19.5 years (interquartile range 16.0 to 23.1), 29 deaths and 1 transplant occurred in the noninfantile group, whereas all 3 infantile patients died before the age of 4 years. The postdischarge survival for the noninfantile group was 92.2%, 68.2%, and 56.7% at 10, 20, and 25 years, respectively. Cardiovascular-related pathology contributed to all deaths in the infantile and 89% (n = 27) of deaths for the noninfantile cases after hospital discharge. The significant late attrition from cardiovascular causes emphasizes the need for close monitoring and ongoing management in this population.

Psychological Outcomes and Interventions for Individuals With Congenital Heart Disease: A Scientific Statement From the American Heart Association.

Although resilience and high quality of life are demonstrated by many individuals with congenital heart disease, a range of significant psychological challenges exists across the life span for this growing patient population. Psychiatric disorders represent the most common comorbidity among people with congenital heart disease. Clinicians are becoming increasingly aware of the magnitude of this problem and its interplay with patients' physical health, and many seek guidance and resources to improve emotional, behavioral' and social outcomes. This American Heart Association scientific statement summarizes the psychological outcomes of patients with congenital heart disease across the life span and reviews age-appropriate mental health interventions, including psychotherapy and pharmacotherapy. Data from studies on psychotherapeutic, educational' and pharmacological interventions for this population are scarce but promising. Models for the integration of mental health professionals within both pediatric and adult congenital heart disease care teams exist and have shown benefit. Despite strong advocacy by patients, families' and health care professionals, however, initiatives have been slow to move forward in the clinical setting. It is the goal of this scientific statement to serve as a catalyst to spur efforts for large-scale research studies examining psychological experiences, outcomes, and interventions tailored to this population and for integrating mental health professionals within congenital heart disease interdisciplinary teams to implement a care model that offers patients the best possible quality of life.

Multicentre comparative analysis of long-term outcomes after aortic valve replacement in children.

OBJECTIVE: The ideal valve substitute for surgical intervention of congenital aortic valve disease in children remains unclear. Data on outcomes beyond 10-15 years after valve replacement are limited but important for evaluating substitute longevity. We aimed to describe up to 25-year death/cardiac transplant by type of valve substitute and assess the potential impact of treatment centre. Our hypothesis was that patients with pulmonic valve autograft would have better survival than mechanical prosthetic. METHODS: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a multi-institutional US-based registry of paediatric cardiac interventions, linked with the National Death Index and United Network for Organ Sharing through 2019. Children (0-20 years old) receiving aortic valve replacement (AVR) from 1982 to 2003 were identified. Kaplan-Meier transplant-free survival was calculated, and Cox proportional hazard models estimated hazard ratios for mechanical AVR (M-AVR) versus pulmonic valve autograft. RESULTS: Among 911 children, the median age at AVR was 13.4 years (IQR=8.4-16.5) and 73% were male. There were 10 cardiac transplants and 153 deaths, 5 after transplant. The 25-year transplant-free survival post AVR was 87.1% for autograft vs 76.2% for M-AVR and 72.0% for tissue (bioprosthetic or homograft). After adjustment, M-AVR remained related to increased mortality/transplant versus autograft (HR=1.9, 95% CI=1.1 to 3.4). Surprisingly, survival for patients with M-AVR, but not autograft, was lower for those treated in centres with higher in-hospital mortality. CONCLUSION: Pulmonic valve autograft provides the best long-term outcomes for children with aortic valve disease, but AVR results may depend on a centre's experience or patient selection.

Familial pseudocoarctation of the aorta.

Pseudocoarctation of the aorta (PCOA) is an unusual congenital malformation of the aortic arch characterized by an acute anterior angulation of the aortic arch at the level of the ligamentum arteriosum with little or no obstruction. This report describes the occurrence of PCOA and other aortic arch abnormalities including true coarctation, right aortic arch, and aneurysms of the proximal and distal aortic arch in three generations of a single family. To our knowledge, a familial form of PCOA has not been described.