New‐onset atrial fibrillation predicting for complicating cardiac adverse outcome in scrub typhus infection

Abstract Background Scrub typhus is a well‐known infectious disorder of the Asia‐Pacific region. However, adverse cardiac outcomes are an under‐recognized complication of scrub typhus infection, and new‐onset AF has been reported to be a prognostic factor in other, more common infectious diseases. The present study investigated whether new‐onset atrial fibrillation (AF) is significantly associated with 3‐month mortality and adverse cardiac complications in scrub typhus infection. Methods We examined data from the National Health Information Database (NHID) which covers nearly the entire population of South Korea, from 2006 to 2016. In total, 233 473 patients diagnosed with scrub typhus infection were selected as study participants. New‐onset AF, acute heart failure (AHF), ischemic heart disease (IHD), and 3‐month mortality were analyzed using a generalized estimating equation model with a Poisson distribution. Results Of these, 2402 patients (1%) were diagnosed with new‐onset AF (87.2% were over 60 years of age, 43.3% were male). Those with new‐onset AF were more likely to have underlying cardiovascular disease compared to those without new‐onset AF. After being adjusted for demographic factors and comorbidities, those with new‐onset AF had a higher incidence risk of concurrent AHF (4.1‐fold) and IHD (1.9‐fold) compared with those without new‐onset AF. In particular, the 3‐month mortality was also significantly associated with new‐onset AF (1.3‐fold), concurrent AHF (2.4‐fold), and IHD (13.7‐fold). Conclusions New‐onset AF was significantly associated with 3‐month mortality and concurrent AHF and IHD. Therefore, new‐onset AF could be a poor prognostic factor for 3‐month mortality and cardiac complications in scrub typhus infection.


| INTRODUCTION
Scrub typhus is a well-known, seasonal infection caused by Orientia tsutsugamushi, which mainly confined to Southeastern Asia and the Western Pacific rim. 1,2 Recently, the geographical distribution of its endemic area has been widening with its overall mortality rate increasing. However, scrub-typhus-induced adverse cardiovascular complications remain remarkably under-recognized. 3 The majority of scrub typhus infections resolve with proper antibiotics and supportive treatment without any complications. 4 However, with regards to scrub typhus infection complications, [5][6][7] the overall mortality rate has been reported to range from overall 16% to 30%, which might be attributed to cardiovascular complications. 8,9 In particular, new-onset atrial fibrillation (AF) has been reported as a poor prognostic factor in common infectious disorders, 10,11 which points to the need for investigating the association between scrub typhus infection and subsequent adverse cardiac events. New-onset AF, acute heart failure (AHF), and ischemic heart disease (IHD) have been recognized as the major cardiac manifestations of public health adverse outcomes and the primary end points of infection-induced cardiovascular outcomes. [11][12][13] Therefore, we investigated whether new-onset AF was significantly associated with 3-month mortality and concurrent AHF and IHD in a nationwide cohort of scrub typhus infection.

| Statistical analysis
To assess the association between new-onset AF and the risk of

| Incidence risk ratio for cardiovascular complication
Those with new-onset AF had an incidence risk ratio (IRR) of 4.1 for AHF within a few days of scrub typhus infection diagnosis compared with those without new-onset AF ( Figure 1A). Furthermore, patients over 50 years of age had an increased IRR of 2.0 to 5.4 for AHF.
Patients admitted to the ICU or having a previous diagnosis of HF or IHD had an IRR for AHF of 2.4, 2.2, and 1.2, respectively, after being adjusted for demographic factors and comorbidities ( Table 2).
Those with new-onset AF had an IRR of 1.9 for IHD compared with those without new-onset AF ( Figure 1B). Patients over the age of 50 also had an increased IRR for IHD of 2.9 to 14.6. Those admitted to the ICU, or having a past scrub typhus infection, HF or IHD had an IRR for IHD of 5.6, 2.0, 1.5, and 2.0, respectively, after being adjusted for demographic factors and comorbidities (Table 3).

| Cardiovascular complications and mortality
New-onset AF, AHF and IHD had an IRR for 3-month mortality of 1.3, 2.4, and 13.7, respectively, after controlling for demographic factors and comorbidities. Increased age over 50 years also had an increased  Figure 1C).

| DISCUSSION
In this nationwide scrub typhus infection cohort, patients with newonset AF were more likely to be hospitalized in the ICU and had higher 3-month mortality rates. In particular, new-onset AF was significantly associated with concurrent AHF or IHD during treatment for scrub typhus infection. Unlike the adverse cardiac complications occurring as a result of common infections, 16,17 evidence to date has been unclear concerning an association between scrub typhus infection and adverse cardiac outcomes. 11 The present study is the first to demonstrate that new-onset AF was significantly associated with 3-month mortality and adverse cardiac complications in scrub typhus infection.
Occurrence of new-onset AF has been known to be associated with infection which may be triggered by acute inflammatory condition. 18 In critically-ill patients with common infectious diseases, new-onset AF has been reported to be significantly associated with all-cause mortality in the ICU. 10 initiates at the site of skin inoculation, evolves into regional lymphadenopathy and spreads to vasculitis with subsequent target organ damage. 21 Subsequently, induced myocardial inflammation could develop electrical, functional, and structural remodeling during the pathogenesis of new-onset AF and AHF. [22][23][24][25][26] The present study also demonstrates that AHF concurrent with new-onset AF could develop within only a few days of the index diagnosis of scrub typhus infection ( Figure 1A). In addition, new-onset AF was also associated with a greater risk for developing IHD in the critically-ill status including complicating scrub typhus infection. 11

| Limitations
There are several limitations to the present study. First, the national cohort data does not include lifestyle information, such as alcohol intake, smoking habits, body mass index or family history, all of which are potential confounding factors in this study. Second, old age, hypertension, diabetes and previous HF are well-known comorbidities strongly correlated with new-onset AF. Therefore, we adjusted for these comorbidities to minimize the influence of AHF or IHD on 3-month mortality. Third, living in a metropolitan area or being treated with azithromycin for a refractory or complicated type of scrub typhus infection also might induce treatment bias. Fourth, the cohort data were selected according to ICD codes, which may potentially have misclassification bias. Fifth, there was no control group of patients without scrub typhus infection. Therefore, our results might not be fully generalizable, and a prospective, randomized controlled trial should be conducted to overcome these limitations.

| CONCLUSION
New-onset AF was significantly associated with 3-month mortality and concurrent cardiac adverse outcomes. Therefore, new-onset AF may be a poor prognostic factor for 3-month mortality and adverse cardiac complications in scrub typhus infection. Further investigation is warranted to prospectively validate these results.

ACKNOWLEDGMENTS
This study was supported by a grant from the Korean Healthcare Technology R&D project, which is funded by the Ministry of Health & Welfare (2017R1D1A3B03030919). This study is also based on data from the Korean National Health Insurance Service (research administration number, NHIS-2018-1-011), and the results of the study are not related to the National Health Insurance Service.