Mortality and Complications of COVID-19 Among Adult Congenital Heart Disease Patients: A Retrospective Cohort Study Using the National Inpatient Sample Database

This study examines in-hospital mortality and complicated COVID-19 infection among adult congenital heart disease (ACHD) patients admitted with COVID-19, using the National Inpatient Sample (NIS). A total of 4219 COVID-19 patients with ACHD were included. We demonstrated that COVID-19 patients with ACHD were more likely to experience in-hospital mortality (OR 1.04, 95% CI 1.04-1.04, P < 0.01) and complicated COVID-19 infection (OR: 1.30, 95% CI: 1.11-1.53, P < 0.01). In our sub-group analysis, COVID-19 patients with tetralogy of Fallot (TOF) had higher mortality and COVID-19 patients with atrial septal defects (ASD) had a higher incidence of complicated infection when compared to COVID-19 patients with all other ACHDs. Risk factors for mortality among COVID-19 patients with ACHD include advanced age, lower income, unrepaired ACHD, malnutrition, and chronic liver disease. Accordingly, we recommend aggressive preventive care with vaccination and non-pharmacologic measures in order to improve survival for ACHD patients.


Introduction
& C oronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is implicated in the ongoing pandemic. The role of adult congenital heart disease (ACHD) in COVID-19 severity is an area of current research. 1,2,3 Due to the rarity of ACHD, previous studies are limited by small sample sizes. Therefore, we designed this study to examine the risk factors associated with mortality and COVID-19 complications among ACHD patients admitted with COVID-19 using the National Inpatient Sample (NIS), the largest database of hospitalization in the United States. Due to its large sample and weighted design, the NIS enables more accurate national estimates. 4

Data Source
The study utilized data from the 2020 NIS database. NIS is part of a family of databases and software tools developed for the Healthcare Cost and Utilization Project (HCUP). The NIS is the largest publicly available all-payer inpatient database designed to produce U.S. regional and national estimates of inpatient utilization, access, cost, quality, and outcomes. Unweighted, it contains data from around 7 million hospital stays each year. Weighted, it estimates around 35 million hospitalizations nationally. The NIS is drawn from all states participating in HCUP, covering more than 97% of the U.S. population. The NIS approximates a 20% stratified sample of discharges from U.S. community hospitals. The self-weighting design of the new version of NIS reduces the margin of error for estimates and delivers more stable and precise estimates than previous versions of the NIS. 4

Study Population and Variables
All adult patients (age 18 years and above) with COVID-19 (ICD-10 code U07.1) were included in this study. Patients transferred out of the index hospital to another acute care hospital were excluded; this was necessary as the outcome of interest (mortality and complications) may not have occurred during the index hospitalization. ACHD was divided into 8 categories based on ICD-10 codes (Table 1) and was used to formulate the ACHD cohorts. The individual ACHD categories were visually inspected for overlap; 2 patients were in both the ventricular septal defect (VSD) and the tetralogy of Fallot (TOF) cohorts. For our analysis, these 2 patients were categorized into TOF and excluded from VSD. Otherwise, there was no overlap noted. Our control group was COVID-19 patients without ACHD Patients' age, sex, insurance status, race and income quartiles based on zip code, and Elixhauser comorbidity index were extracted from the NIS; certain comorbidities such as complicated and uncomplicated hypertension, complicated and uncomplicated diabetes, solid cancers, chronic pulmonary disorders, and liver disease were directly available. The remaining comorbidities were extracted using the International Classification of Diseases, Tenth Revision, and Clinical Modification

Outcomes
Our primary outcome was in-hospital mortality. Secondary outcomes included the incidence of complicated COVID-19, which was defined as the presence of any of the following: renal replacement therapy; acute liver failure; red blood cell (RBC) transfusions; non-invasive positive pressure ventilation including bi-level positive airway pressure (BPAP), continuous positive airway pressure (CPAP), or high flow nasal cannula (HFNC); mechanical ventilation; vasopressor use; extracorporeal membrane oxygenation (ECMO); septic shock; or cardiac arrest. These variables were selected based on the criteria utilized in the Sequential Organ Failure Assessment (SOFA) score.

Statistical Analysis
Descriptive analysis was done to determine the mean for continuous variables and the proportion for categorical variables. Univariate logistic regression was done to determine the predictors of complications and mortality in ACHD. Variables with P < 0.05 were considered significant and used in the multivariate logistic regression. Similar approach was done to determine if the individual ACHDs were associated with adverse COVID-19 outcomes. Analysis was carried out using StataCorp. 2021. Stata Statistical Software: Release 17. College Station: StataCorp LLC, BE version. Stata's svy command and appropriate weights were used in all estimations. The study was exempt from institutional review board approval as the database uses previously collected de-identified data.
After univariate regression, chronic kidney disease, congestive heart failure, complicated diabetes mellitus, malnutrition, and chronic liver disease were associated with increased mortality. However, after multivariate analysis, only malnutrition (aOR 2.16, 95% CI 1.35-3.44) and chronic liver disease (aOR 5.55, 95% CI 3.13-9.82) were associated with increased mortality. Higher Elixhauser comorbidity index scores were also associated with increased mortality (Tables 2 and  Table 3).
Out of all ACHDs, the ASD group was the oldest (mean age of 63.4 years, 95% CI: 62.0-64.9), and patients with cardiac chamber defects were the youngest (mean age of 30.8 years, 95% CI: 26.2 years-35.4 years). Patients with septal defects had the highest proportion of females (66.6%, 95% CI: 33.3%-99.9%), and patients with aortic or mitral valve defects had the lowest proportion of females (27.5%, 95% CI: 20.2%-36.4%). Hypertension was the most common comorbidity among all ACHD patients, except for those with TOF or cardiac chamber defects, in which malnutrition was the most common comorbidity (Supplementary Table 2).

Discussion
There are 1.5 million adults with ACHD in the United States. 5 ACHD patients generally have an increased risk of complication from respiratory viruses such as influenza. 6 There is mounting evidence that ACHD patients also have an increased risk of mortality and morbidity from COVID-19 infection. [1][2][3] In our study, we characterized the risk factors of COVID-19 related mortality and complications among ACHD patients and performed a sub-group analysis of individual ACHDs and their associated risks for COVID-19 mortality and complications. Primarily, we found that COVID-19 patients with ACHD were more likely to experience in-hospital mortality and complicated COVID-19 infection. Among COVID-19 patients with ACHD, we observed that increasing age was associated with increased mortality. Additionally, patients residing in affluent zip codes (75th-100th percentile mean income) had lower Adjusted for age, sex, race, stroke, chronic kidney disease, heart failure, malnutrition, and chronic liver disease mortality compared to patients living in lower income zip codes (0-25th percentile mean income). This likely reflects the complexity and burden of healthcare associated with ACHD patients generally, such that those with lower socioeconomic status are disproportionately affected. These finding are similar to overall COVID-19 mortality, which is directly correlated with socioeconomic status and age, as demonstrated in multiple previous studies. 8 Notably, we found no association between sex, race, insurance status, or hospital characteristics and mortality among COVID-19 patients with ACHD. This is distinct from existing literature regarding general COVID-19 infection, as both gender and race have been identified as risk factors for mortalityÀspecifically male gender and minority race status (African American, Hispanic, and Native American). 8,9 The pathophysiologic basis of increased COVID-19 mortality in males is hypothesized to stem from increased expression of angiotensin-converting enzyme-2 receptor as well as immunological differences and medical comorbidities. The lack of increased COVID-19 mortality in male COVID-19 patients with ACHD is likely due to the homogenous pattern of mortality among ACHD patients overall; the CONgenital CORvitia (CONCOR) study demonstrated no differences in ACHD patient mortality based on sex. 10 With respect to medical comorbidities, as expected a higher Elixhauser comorbidity index score was associated with increased mortality among COVID-19 patients with ACHD. However, when analyzed in more detail, only malnutrition (aOR: 2.16, 95% CI: 1.35-3.44) and chronic liver disease (aOR: 5.55, 95% CI: 3.13-9.82) were independently associated with increased mortality among COVID-19 patients with ACHD after multivariate adjustment. Protein calorie malnutrition in ACHD patients is independently associated with an increased risk of major cardiovascular events (MACE). 11 Protein calorie malnutrition is also an independent risk factor for COVID-19 mortality and severe sepsis, likely modulated by immune dysfunction. 8,12 Secondly, we found that chronic liver disease was the strongest risk factor for mortality among COVID-19 patients with ACHD. It has been established that COVID-19 patients with chronic liver disease have higher mortality when compared to COVID-19 patients without chronic liver disease, irrespective of ACHD. 8 This finding is likely driven by hepatic immune dysfunction (similar to malnutrition), coagulopathy, and intestinal dysbiosis. 13,14 ACHDs (especially those characterized by a single functional ventricle) are also associated with hepatic fibrosis, termed cardiac cirrhosis, as a function of long-standing congestive heart failure. 1 Thus, our result likely reflects the complications of liver disease as well as the hemodynamic consequences of the underlying ACHD. Finally, although pulmonary arterial hypertension (PAH) is an important risk factor for general ACHD mortality, our study did not support this. 2 We believe that the extracted ICD-10 data may not have captured all diagnoses of PAH, thereby affecting our analysis.
In our ACHD subtype analysis, we found that after multivariate regression, only COVID-19 patients with TOF have increased mortality. This is consistent with the physiology of the disease as well as literature, which indicates that TOF patients are more prone to physiologic decompensation typified by pulmonary valvular regurgitation, pulmonary arterial hypertension, and sudden cardiac death; consequently these patients are expected to have higher mortality. 2 It is worth noting that in the United States, with universal early surgical repair most patients have corrected TOF. However, TOF is the most common cyanotic ACHD to reach adulthood without repair through the development of aortopulmonary collaterals, so there may be a small number of high-risk patients in our sample who may be contributing to the high mortality in this group. 15,16 Similarly, after multivariate adjustment, COVID-19 patients with ASD were the only ACHD patients to have disproportionately higher incidence of complicated COVID-19 infection. While COVID-19 patients with ASD were older and had more comorbidities, predisposing them to severe infection, ASD remained independently associated with complicated COVID-19 infection in our study. We believe that this may be related to disease physiology, with increased pulmonary blood flow from ASDs leading to higher pulmonary infection risk. 7 Interestingly, we found that only 2.2% of COVID-19 patients with ACHD had a documented corrective cardiac surgery for their congenital heart defect. As mentioned earlier, uncorrected ACHD is unusual in the United States. We believe that this finding is likely the result of underdiagnosis or inadequate documentation and thus should be interpreted with caution. Nonetheless, COVID-19 patients with repaired ACHD had significantly less mortality than COVID-19 patients without repaired ACHD. While anatomic class is a traditionally useful predictor of overall mortality in ACHD patients, we have shown that severe anatomic class is not associated with increased COVID-19 mortality and complications. In more basic terms, anatomic class is not a useful predictor of mortality among COVID-19 patients with ACHD, which aligns with existing literature. 2

Limitations
Our study has several limitations. First, the NIS is an inpatient database that does not track non-hospitalized or discharged patients. Secondly, the NIS is also an administrative database that relies primarily on ICD-10 codes. This presents a possibility of under diagnosis and is inferior to manual chart review, especially in a complex ACHD population. 17 There is less clinical information available on anatomic complexity, physiologic status, echocardiographic findings, surgical repair, and medication regimens, all of which are key predictors of outcomes. Finally, despite being the largest study of COVID-19 patients with ACHD, our sample size did not allow for the analysis of individual ACHDs, but rather a categorical-based analysis of ACHDs utilizing ICD-10 codes. Lastly, as with all retrospective observational studies, associations may not imply causation, and conclusions should be examined appropriately.

Conclusions
Our study demonstrates that COVID-19 patients with ACHD were more likely to experience in-hospital mortality and complicated COVID-19 infection. In our sub-group analysis, COVID-19 patients with tetralogy of Fallout had higher mortality and COVID-19 patients with ASD had a higher incidence of complicated infection when compared to COVID-19 patients with all other ACHDs. Risk factors for mortality among COVID-19 patients with ACHD include advanced age, lower income, unrepaired ACHD, malnutrition, and chronic liver disease. Consequently, we recommend aggressive preventive care with vaccination and non-pharmacologic measures in order to improve survival for ACHD patients.