Hospitalizations for adults with isomerism: a database study from 2005 through 2012

Introduction: Isomerism, or heterotaxy, leads to anatomic and functional abnormalities in multiple organ systems. As care improves, an increasing number of patients with isomerism live into adulthood. Complications of isomerism during adulthood are not well understood. This study is aimed to identify trends, frequent causes of admission, and independent predictors of mortality in adult isomerism admissions. Methods: A cross-sectional study was done using Nationwide Inpatient Sample data from 2005 to 2012. Admissions with isomerism were identified. Characteristics of admissions including demographics, diagnosis data, procedures, length, and cost were compared between those with and without isomerism. Next, trends in the characteristics of only isomerism admissions were compared between the years. Most frequent principle diagnoses were then identified for those with isomerism. Finally, a multivariate regression including all patients was done to identify independent risk factors for mortality. Results: 59,578,610 admissions were included. Isomerism admissions tended to be younger and have different comorbidities than non-isomerism admissions. Over the years there was minimal change in the frequency of isomerism admissions although average age, length, and cost of admission did increase. Most frequent cause of admission was found to be pneumonia with the remainder of the 10 most frequent also being cardiac or pulmonary. Isomerism was an independent risk factor for mortality along with other factors. Conclusion: Isomerism admissions, although representing a small fraction of total admissions, are longer and costlier than nonisomerism admissions. As the isomerism population lives longer and experiences more complications, admission age, length, and cost are also increasing. Correspondence to: Rohit S. Loomba, MD, Children’s Hospital of Wisconsin/ Medical College of Wisconsin, USA, E-mail: RLoomba@chw.org


Introduction
Isomerism, also known as heterotaxy, affects approximately 1 in 10,000 live births and is characterized by the presence of isomerism of the thoracic organs and random arrangement of the abdominal organs [1][2][3][4][5]. Not only can the organs be arranged improperly but they can also otherwise be malformed. More important than the anatomic abnormalities of the organs are the functional abnormalities of the organs that are also found in the setting of isomerism. Anatomic and functional abnormalities have been found in nearly every organ system although the number of affected organ systems is variable among patients [6][7][8][9][10][11][12][13][14].
Isomerism is best segregated into right and left isomerism based on the morphology of the atrial appendages. Atrial appendage morphology should be used as it is the most constant feature in isomerism, noted particularly in genetic studies involving knockout mice models, and offers the best "syndromic clustering" [15][16][17]. This allows for inferences to be made on what other anomalies, anatomic and functional, need to be evaluated for or anticipated in the future. Ultimately, this can allow for early detection and intervention. This is particularly important in respect to arrhythmias as well as splenic function [6,7,18].
Those with right isomerism are more likely to have complex congenital malformations of the heart such as atrioventricular septal defect or double outlet right ventricle requiring functionally univentricular palliation. Right isomerism is also associated with absence of a spleen, trilobed lungs bilaterally, and morphologically right bronchuses bilaterally. Left isomerism is associated with less complex congenital malformations of the heart, presence of multiple spleens, bilobed lungs bilaterally, and morphologically left bronchuses bilaterally [11,12]. Abnormal splenic function is more likely in the setting of isomerism regardless of splenic anatomy, there is increased prevalence of sinupulmonary symptoms in the setting of isomerism, and there is increased prevalence of arrhythmias in the setting of isomerism as well [6,7,18]. Postoperative complications and mortality also differ in those with isomerism when compared to those without isomerism but similar congenital malformations of the heart [19][20][21].
As cardiac palliation for these patients improves, more of these patients are surviving into adulthood. The overall characteristics of hospital admissions in these patients has not been previously described.
This study utilizes 8 years of data from the Nationwide Inpatient Sample to describe the trends in isomerism admissions and identify risk factors associated with mortality.

Methods
Institutional review board review approval was waived as this study utilizes deidentified data from a national database. Consent was not obtained by the authors for this study as the data was derived from a national database. This cross-sectional study is in compliance with the Helsinki declaration.

Nationwide inpatient sample
The Nationwide Inpatient Sample, Healthcare Cost Utilization Project (HCUP) by the Agency for Healthcare Research and Quality (AHRQ) is a large database designed to capture data from approximately 20% of all community hospital admissions in the United States. All patients cared for at these selected hospitals are included in the Nationwide Inpatient Sample. Rehabilitation and long-term acute care hospitals are excluded from this database. Patients from all regions of the United States with a variety of payer types are captured in this database. Data from a total of 44 states is captured. A majority of admissions in this database involve adult patients. The Nationwide Inpatient Sample data uses a self-weighting design to help reduce confidence intervals. Data variance from the Nationwide Inpatient Sample can be self-validated for specific iterations.

Patient identification
Data regarding hospital admissions was obtained 8 iterations of the Nationwide Inpatient Sample covering the years 2005 through 2012. Patients with isomerism were identified using the International Classification of Diseases, Ninth Revision (ICD-9) code 746.87. Patients with situs inversus were not included in this group as not all situs inversus portends isomerism.
No patients were excluded from this analysis. Unfortunately it is not possible from the Nationwide Inpatient Sample data to determine which admissions represented readmissions within the same year so this could not be accounted for.

Data identification and collection
Demographic information including, gender, and race were collected for each admission. Admission characteristics such as admission month, length of stay, and cost of stay were collected as well. Information regarding comorbid conditions was also collected. Data of interest in regards to isomerism included cardiac anatomy as well splenic anatomy. The following congenital cardiac malformations commonly associated with isomerism were collected: functionally univentricular hearts using 745.3, double outlet right ventricle using 745.11, atrioventricular septal defect using 745.60 and 745.69, partial anomalous pulmonary venous connection using 747.42, and total anomalous pulmonary venous connection using 747.41. Splenic abnormality, either absence of a spleen or presence of multiple spleens, was collected using 759.0. It was not possible to distinguish between those with absence of a spleen or multiple spleens due to the ICD-9 coding strategy.

Statistical analysis
A cross-sectional study was conducted. Continuous variables are reported using mean and standard deviation while categorical variables are reported using absolute frequency and percentages. Continuous variables were analyzed using a student t-test or Mann-Whitney-U test as appropriate with categorical variables being analyzed using chi-square analysis. Baseline characteristics such as age, gender, race, and comorbid conditions were compared between those with and without isomerism. Hospitalization characteristics including length of admission, cost of admission, and number of procedures during the admission were also compared between those with and without isomerism. Next, the number of isomerism admissions was compared by each year.
Only isomerism admissions were then compared throughout the years. Characteristics such as mortality, race, gender, age, length of admission, and cost of admission were compared by year. Finally, the principle diagnosis for all isomerism admissions was identified to determine the most frequent cause of admission. For some patients, isomerism or data regarding congenital malformations of the heart were coded as the principle diagnosis. These were excluded from this analysis.
Finally, a multivariate logistic regression was done to determine independent predictors of death. All patients were included in this analysis. The dependent variable was mortality. The following independent variables were entered into the regression: age, year of admissions, gender, race, current smoking status, isomerism, diabetes mellitus, hyperlipidemia, myocardial infarction, heart failure double outlet right ventricle, functionally univentricular heart, partial anomalous venous connection, total anomalous venous connection, obesity arrhythmia, and splenic anomaly.
All statistical analysis was done utilizing SPSS Version 20.0 (Chicago, IL). A p-vale of less than 0.05 was considered statistically significant.

Results
A total of 59,578,610 admissions were included in the analysis. Of these, 6,587 (0.011%) were isomerism admissions. Characteristics of admissions with and without isomerism did have significant differences. Those with isomerism tended to be younger and male (p< 0.0001). Average age of isomerism admissions was 27.49 years compared to 50.97 years for non-isomerism admissions. Current smoking (odds ratio 0.395, 95% confidence interval 0.352 to 0.444), hyperlipidemia (odds ratio 0.413, 95% confidence interval 0.351 to 0.486), type 2 diabetes mellitus (odds ratio 0.424, 95% confidence interval 0.390 to 0.461), and overweight/obesity (odds ratio 0.554, 95% confidence interval 0.491 to 0.624) were less likely with isomerism. When characteristics of only isomerism admissions were compared by year, significant differences were noted as well. Age of admission, length of hospitalization, and cost of hospitalization all increased over the study period (p<0.0001). Mortality did not demonstrate a significant change over the years (p=0.052) ( Table 3).
The 10 most frequent principle diagnoses for isomerism admissions are listed in Table 4. The most frequent principle diagnosis was pneumonia which was present in 327 (5.0) admissions, with unspecified heart failure being the second most common being present in 221 (3.4) admissions, and the third most common being atrial fibrillation in 102 (1.5) admissions.

Discussion
Isomerism is a complex clinical entity that can lead to anatomic and functional abnormalities in nearly any organ system. Congenital malformations of the heart are common and are often complex and require multiple cardiac surgeries. Improvements in the care for these patients has led to an increased number surviving into adulthood. This study is the first large study to characterize hospital admissions of adults with isomerism. This study demonstrates that the percentage of total admissions that are isomerism admissions has seemed to remain constant over the study period with about 1 in 10,000 admissions being isomerism admissions. Over the study period, age at admission, length of hospitalization, and cost of hospitalization all increased for isomerism admissions. Multivariate analysis found that isomerism is an independent risk factor for mortality.
The 10 most common principle diagnoses for isomerism admissions were all either cardiac or pulmonary in nature. The 3 most common were pneumonia, heart failure, and atrial fibrillation. Those with isomerism will often have splenic dysfunction even if they have a normally located, normal appearing spleen [18]. This puts them at increased risk for infection, particularly from encapsulated organisms [22,23]. The risk of bacteremia from such splenic dysfunction appears to be greatest in the first 3 years of life [23]. This in fact has been noted in the isomerism and sickle cell population, both of whom can have splenic dysfunction. Since splenic function and specific splenic anatomy could not be delineated in great detail for each patient in the database it was not possible to determine the cause of pneumonia in this particular population of patients.
The prevalence of heart failure admissions in adults with isomerism can easily be understood as these patients will often have complex congenital malformations of the heart [11,17,[24][25][26]. Most commonly these consist of atrioventricular septal defect and/or double outlet Acute on chronic systolic heart failure 58 (0.9) 9 Obstructive chronic bronchitis, acute exacerbation 53 (0.8) 10 Acute upper respiratory infection 50 (0.8) right ventricle, some of these patients who will require functionally univentricular palliation. Such repair requires staged palliation that eventually redirects all systemic venous return directly into the lungs and leaves the functional single ventricle to handle output to the systemic circulation. Often times this will be a morphologic right ventricle which over time begins to fail against systemic resistance.
The increased prevalence of arrhythmias and related admissions is also well described in children and adults with isomerism and is often due to abnormalities in how the conduction system has formed [6,7]. For instance, dual sinoatrial nodes may be present in the setting of right isomerism while there may be absence in the setting of left isomerism. Dual atrioventricular nodes are also often present in isomerism with variability in the connections between the atrioventricular nodes and the ventricular conduction system [27].
This study also demonstrates that isomerism admissions are now increasing in age, length, and cost. This can be explained by the improved care for these patients which is now allowing them to longer into adulthood. This it is not surprising that the average age of isomerism admissions is increasing. As these patients live longer, however, more complications from their underlying disease as well as surgical palliations is becoming manifest, likely contributing to the increase in length and cost of admissions. These issues include failing Fontan physiology, plastic bronchitis, protein losing enteropathy, pulmonary hypertension, arrhythmias, and heart failure [28][29][30].
Caring for adults with isomerism requires thorough understanding of the possible manifestations of isomerism, both anatomic and functional. It is vital to obtain complete knowledge of surgical palliations and comorbidities that these patients already have as this can greatly impact the care they receive. Treatment efficacy and adverse effects may have different implications in these patients. Understanding the trends of a contemporary cohort of these patients allows for anticipation of what may be expected for these patients but can also help guide patient education so that patients can have increased vigilance for signs and symptoms of developing conditions and receive earlier care that may prevent inpatient admission. Reevaluation of trends throughout the years is also important as it allows for assessment of how care has evolved and whether improvements have been made in decreasing the morbidity and mortality associated with isomerism. Thus, this analysis provides a comparative point for future analysis.
This analysis benefits from a large sample size which allows for the analysis of even rare conditions, such as is the case with isomerism. Additionally, enough data is present to be able to collect data on several coexisting conditions and thus account for these in multivariate models.
This study is not without its limitations, however. Firstly, we were unable to segregate isomerism into the right or left. Additionally, coding for congenital cardiac malformations is not ideal to help extract precise information about the cardiac anatomy that would be needed to assign an isomerism subtype using surrogate markers. Other anatomic findings to help segregate into right and left isomerism, such as splenic anatomy, are also not precise as both absence of a spleen and presence of multiple spleens were coded with a single code. Properly capturing the arrangement of the abdominal organs was not possible for similar reasons. Also, not all ICD-9 codes have been validated over the years, particularly those used to code for congenital cardiac malformations. Congenital cardiac malformations may be undercoded once these patients reach adulthood and thus the numbers provided here may be underestimates of the true prevalence.

Conclusion
Isomerism admissions are associated with increased length, cost, and mortality when compared to non-isomerism admissions. The frequency of such admissions has not changed over the last decade although the admission are occurring at older ages and are becoming longer and costlier. Isomerism is an independent risk factor for mortality.