Serious Infections in People with Scleroderma: A National U.S. Study

Objective: To study incidence, time-trends and outcomes of serious infections in scleroderma. Methods: We used the 1998-2016 U.S. National Inpatient Sample data. We examined the epidemiology, time-trends and outcomes of five serious infections (opportunistic infections (OI), skin and soft tissue infections (SSTI), urinary tract infection (UTI), pneumonia, and sepsis/bacteremia) in hospitalized people with scleroderma. We performed multivariable-adjusted logistic regression analyses to analyze independent association of factors with healthcare utilization (hospital charges, length of hospital stay, discharge to non-home setting), and in-hospital mortality. Results: There were 49,904,955 hospitalizations with serious infections in people without scleroderma and 61,615 in those with scleroderma. During 1998-2016, the most common serious infections in scleroderma were pneumonia (45%), sepsis (32%), SSTI (19%), UTI (3%) and OI (3%). In 2013-14, sepsis surpassed pneumonia as the most common serious infection; by 2015-16, sepsis was 1.8-times more common than pneumonia. Over the study period, hospital charges increased, while length of hospital stay and in-hospital mortality decreased, overall and for each serious infection. Multivariable-adjusted analyses showed that sepsis, age ≥80 years and Deyo-Charlson score ≥2 were associated with significantly higher odds of healthcare utilization and in-hospital mortality; and Medicare or Medicaid insurance payer, Northeast location, urban teaching or non-teaching hospital, and medium or large hospital bed size with significantly higher odds of healthcare utilization. Conclusions: Outcomes in people with scleroderma hospitalized with serious infections have improved over time, except higher hospital charges. Identification of factors associated with higher healthcare utilization and in-hospital mortality allows for developing interventions to improve outcomes.


Background
Systemic sclerosis, also called scleroderma, is a multisystem autoimmune disease, associated with high morbidity and mortality [1] and frequent hospitalizations [2]. In an analysis of national U.S. data from 2002-2003, the most common reasons for scleroderma hospitalizations were diseases of the circulatory, gastrointestinal, musculoskeletal followed respiratory system [3]. Respiratory infection (8%) was the third leading cause of mortality (principal diagnoses) in hospitalized scleroderma patients and ranked higher than heart failure [3]. In a study of 116 patients with scleroderma examined over 14 years with a median follow-up of 2-years, of the 31 people who died, 13 (11%) died of infections [4]. In a systematic review of infections in connective tissue diseases, most studies were limited to lupus, and only one study included people with scleroderma [5]. Therefore, while infection has a significant contribution to mortality in people with scleroderma [3,4], few studies have examined the epidemiology of hospitalized infections and their outcomes in scleroderma [5].
Therefore, our study objective was to examine the epidemiology, time-trends, healthcare utilization and mortality of serious infection hospitalizations in scleroderma in a national U.S. cohort.

Data Source and Study Cohort Selection
Our study cohort included five, common serious infection hospitalizations in people with scleroderma in the U.S. NIS 1998-2016 sample. The NIS is a 20% stratified sample of discharge records from all participating community hospitals from all participating states [6]. The NIS is the largest publicly available, de-identified all-payer inpatient health care database in the U.S. It has been used for epidemiological studies of hospitalization, mortality and costs, since it represents all hospitalizations in the U.S. The Institutional Review Board at the University of Alabama at Birmingham (UAB) approved this study.
We identified five types of serious infections based on the presence of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in the primary diagnosis position for  [7,8]. These diagnostic codes have been shown to be valid in administrative datasets, with positive predictive values of 70% to 100% in people with rheumatoid arthritis [9]. We also used the ICD-10-CM codes for infections for the 2015-2016 data due to a coding system change to ICD-10-CM in 2015 in the U.S. (Appendix 1).

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Composite infection was defined as any of the serious infection occurring as primary diagnosis for hospitalization. Scleroderma was identified based on the presence of an International Classification of Diseases, ninth or tenth revision, clinical modification (ICD-9-CM or ICD-10-CM) code for scleroderma (710.1 or M34) in a non-primary position during the index hospitalization. A previous study showed sensitivity of 81% and specificity of 95% using a diagnostic code approach for scleroderma [10].

Covariates and Outcomes
We adjusted each regression model for covariates/confounders, including age, sex, race, serious infection type (OI, SSTI, UTI, pneumonia, sepsis [reference]), median household income, the insurance payer, hospital characteristics (region, location/teaching status, bed size) and Deyo-Charlson comorbidity index, a validated measure of medical comorbidity that includes 17 comorbidities, with higher score indicating more comorbidity load.
We examined healthcare utilization and in-hospital mortality, details are as follows: (1) health care utilization: total hospital charges above the median for each calendar year; the length of hospital stay above the median of 3 days; and discharge to non-home settings (rehabilitation or an inpatient facility); and (2) in-hospital mortality.

Statistical Analyses
We followed the survey analysis procedures that account for the weights, clusters and strata as defined in NIS, including the modified weights with the change in sampling in 2012. We compared the summary statistics using chi-square or student's t-test, as appropriate. Rates were calculated per 100,000 NIS claims. We analyzed time-trends in rate of each serious infection using Cochran Armitage test. We performed multivariable-adjusted logistic regression analyses for each study outcome, adjusting for all covariates listed in the section above. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. We used SAS 9.3 (Cary, N.C.) for all analyses. We considered a p-value <0.05 to be statistically significant, which corresponds to a 95% CI that excludes unity.

Characteristics and outcomes of people with vs. without scleroderma admitted with serious Infection
There were 49,904,955 hospitalizations with serious infections in people without scleroderma and 61,615 in those with scleroderma. The average age of patients with scleroderma with a serious infection was 61.4 years (median of 61.7 years; Appendix 2), similar to all scleroderma hospitalizations.
Compared to patients admitted with serious infection without scleroderma, people with scleroderma were younger (median age, 65 vs. 62 years), and were more likely to be female (52% vs. 84%), or have Deyo-Charlson score of 2 or more (42% vs. 64%; Appendix 2).
Scleroderma patients hospitalized with pneumonia or sepsis were 5 year older than those admitted with OI (Appendix 3).
The median length of hospital stay over the study period was the highest for OI hospitalizations at 6.1 days and the lowest for UTI at 2.8 days (Appendix 3). Serious infections led to above median length of hospital stay in 61-79% of discharges except for UTI, with 45% of the people. Median hospital charges were highest for hospitalizations with sepsis at $38,118 and lowest for UTI, $13,646 (Appendix 3).

Time-trends in serious infection hospitalization in Scleroderma
We noted a significant increase in the frequency and rate of sepsis, and possibly OI and UTI The reduction was the greatest for OI, from 9.5 to 5.8 days. In-hospital mortality also decreased from 10.3% for composite serious infection to 7.8%, respectively. The largest reductions were for OI, 21.2% to 7.7%, sepsis, 22.5% to 13.2%, and pneumonia, 9.8% to 2.8% (Appendix 7).

Predictors of healthcare utilization and mortality in scleroderma admitted with serious infection
Multivariable-adjusted analyses showed that compared to sepsis, other infections were significantly associated with lower healthcare utilization and mortality; Age ≥80 years and Deyo-Charlson score ≥2 were also significantly associated ( Table 1). Medicare or Medicaid insurance payer. Northeast location, urban teaching or non-teaching status, medium or large hospital bed size were associated with higher odds of healthcare utilization only ( Table 1).

Discussion
In this national study of people with scleroderma hospitalized with serious infection, we found that compared to patients hospitalized with serious infection without scleroderma, people with scleroderma had higher healthcare utilization and in-hospital mortality. Hospital charges and the length of hospital stay were the highest for OI and/or sepsis and the lowest for UTI.
The frequency and rate of sepsis increased over time. Sepsis surpassed pneumonia as the most common serious infection in scleroderma in 2013-14. By 2015-16, sepsis was twice as common as pneumonia. This is an important observation. This trend in scleroderma cohort may reflect the increase in hospitalizations with sepsis in the general population [11]; systematic up-coding of severe infections to sepsis and misclassification error with sepsis diagnostic codes has been noted [12,13]; and/or related to the increased infection risk related to scleroderma and its treatments.
We noted a reduction in the in-hospital mortality from 10. Multivariable-adjusted analyses showed that lower odds for healthcare utilization and in-hospital mortality for all serious infections compared to sepsis. The reduction in odds were 28-62% for healthcare utilization and 54-98% for in-hospital mortality. These important differences separate sepsis from other serious infections in scleroderma, with regards to outcomes.
Several other factors were also independently associated with poorer healthcare utilization and inhospital mortality outcomes. A higher Deyo-Charlson score ≥ 2 was associated with higher healthcare utilization and in-hospital mortality, odds were increased by 37-54%. Our finding validates findings from another study that showed that diabetes, anxiety and depression increased in-hospital mortality in hospitalized scleroderma patients [15], and extends it to scleroderma patients hospitalized with serious infections.
Our finding of an independent association of unmodifiable factors such as older age, Medicare or Medicaid insurance payer. Northeast location, urban teaching or non-teaching status, medium or large hospital bed size with higher odds of healthcare utilization can help in a better understanding of associated healthcare utilization.
Our study has several limitations. Misclassification bias is possible, since we used the ICD-9-CM or ICD-10-CM codes to identify people with scleroderma and infections. However this bias may be minimal since the diagnostic codes for scleroderma [10] and serious infections [7][8][9] have been shown to be valid in previous studies. Since the NIS counts discharges, longitudinal outcome analyses were not possible at a patient-level, including 30-and 90-day post-discharge readmission and mortality risk. The NIS does not include data from the military or Veterans Affairs hospitals, which can lead to some selection bias.
The strengths of our study are the use of national U.S. data that can produce national estimates of mortality, charges and healthcare utilization, the inclusion of several covariates and confounders in regression analyses resulting in robust estimates of association, and inclusion of a large sample size.

Conclusions
In conclusion, we found important differences in hospitalized serious infection patients between scleroderma vs. non-scleroderma. In the U.S., the most common serious infection in hospitalized scleroderma patients was pneumonia followed by sepsis; sepsis was the most common in the most recent study-period. We noted a significant increase in the rate of sepsis, and possibly OI and UTI.
Hospital charges increased, and the duration of hospital stay and in-hospital mortality decreased from 1998-2000 to 2015-2016. We identified several modifiable and non-modifiable independent risk factors for poorer outcomes, that can help policy makers and spark new interventions for improving outcomes. The contact information for requesting the data is as follows: