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.
Keywords: Atrial fibrillation, Heart failure, Ischemic heart disease, Scrub typhus
1. 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.
2. METHODS
2.1. Data source
This study used data from the National Health Information Database (NHID) from 2006 to 2016. This is a public database on healthcare utilization, health screening, sociodemographic variables, and mortality for the entire population of South Korea (hereafter referred to as “Korea”), which was formed by the National Health Insurance Service (NHIS).14 Under universal medical coverage, all medical claims data are collected by the NHIS as the single insurer in Korea; therefore, all individuals included in the NHID were followed until 2017 unless there was a death or disqualification from National Health Insurance for an appropriate reason, such as emigration. The NHID includes an eligibility database, a national health screening database, a healthcare utilization database, a long‐term care insurance database, and a healthcare provider database.14 The healthcare utilization database is based on data collected during the processing of healthcare claims for services used and includes records of inpatient and outpatient usage (diagnosis, length of stay, treatment costs, services received) and prescription records (drug code, days prescribed, daily dosage).14 Access to the NHID can be obtained through the Health Insurance Data Service home page [http://nhiss.nhis.or.kr].
2.2. Sample size and collection
The population included in the NHID was over 49 million in 2006 and 51 million in 2016. From the NHID, during 2006 to 2016, a total of 240 329 patients with scrub typhus were selected using three criteria: (a) diagnosis code of ICD‐10 A753 (typhus fever due to Rickettsia tsutsugamushi), A752 (typhus fever due to Rickettsia typhi), or A759 (typhus fever, unspecified); (b) prescription of doxycycline or azithromycin for at least 3 days; and (c) 20 years of age or over at the time of diagnosis.12 In order to detect relevant cases, 2661 patients were excluded due to prior history of AF or acute myocarditis. Additionally, 4195 patients with missing values were excluded. Finally, a total of 233 473 patients with scrub typhus were selected as study participants. The index date (date of diagnosis) was defined as the date of first prescription.
2.3. Definition of new‐onset atrial fibrillation, acute heart failure, ischemic heart disease, and mortality
New‐onset AF was defined with a diagnosis code of ICD‐10 I48 (paroxysmal AF) within 30 days of the index date and no prior history of AF. New‐onset AHF was defined by a diagnosis code of ICD‐10 I40 (acute myocarditis), I30 (acute pericarditis), or I50 (heart failure) within 30 days of the index date. To exclude AHF induced by IHD, patients treated with coronary bypass graft surgery, primary coronary intervention, or thrombolytic agents (streptokinase, urokinase, tenecteplase) were further excluded. New‐onset IHD was defined as: (a) a diagnosis code of ICD‐10 I21 (acute myocardial infarction) or I20 (angina pectoris) within 30 days of the index date; and (b) treatment with coronary bypass graft surgery, primary coronary intervention, or thrombolytic agents (streptokinase, urokinase, tenecteplase). Three‐month all‐cause mortality was defined as death due to any cause within 90 days of the index date. Dates of deaths were obtained using each participant's unique, de‐identified number code, which is linked to mortality information from the Korean National Statistical Office.
2.4. Statistical analysis
To assess the association between new‐onset AF and the risk of AHF, IHD, and 30‐day mortality, a generalized estimating equation model with a Poisson distribution and logarithmic link function was used to estimate adjusted risk ratios (RRs) and 95% confidence intervals (CIs). Potential confounders were adjusted for using multivariable‐adjusted regression models. The participants' level of comorbidities were assessed using the diagnostic codes during the three years prior to the index date using the Quan's International Statistical Classification of Disease and Related Health Problems, 10th Revision (ICD‐10) coding algorithm of the Charlson Comorbidity Score (CCS).15 The presence of the disease categories AHF, IHD, stroke, chronic kidney disease, diabetes mellitus, hypertension, and malignancy were defined based on at least two outpatient visits or one inpatient admission with the corresponding primary or secondary diagnosis codes.
Statistical analyses were conducted using SAS software, version 9.4 (SAS Institute, Cary, North Carolina). A P value less than .05 was considered statistically significant.
3. RESULTS
3.1. Baseline characteristics
Most of the patients within the scrub typhus cohort were female residents (41.1%, male) in non‐metropolitan areas (75.0%) treated with doxycycline (93.7%). These patients and had low incidence of previous HF (1.2%), previous IHD (5.9%), chronic kidney disease (0.4%), diabetes (13.3%), or a CCS over three (5.1%).
3.2. Incidence of new‐onset AF
Of the 233 473‐scrub typhus infection records in the cohort, 2402 (1.0%) patients were diagnosed as having new‐onset AF during treatment for scrub typhus infection. Those with new‐onset AF tended to be over the age of 60 (87.2%) with significantly higher incidences of intensive care unit (ICU) hospitalization (7.7% vs 0.9%), previous HF (5.8% vs 1.2%), previous IHD (10.7% vs 5.9%), previous stroke (7.9% vs 3.5%), chronic kidney disease (1.0% vs 0.4%), diabetes (17.1% vs 13.2%), and hypertension (54.0% vs 34.0%) compared to those without new‐onset AF (Table 1).
Table 1.
Baseline characteristics of scrub typhus patients with and without new‐onset atrial fibrillation
| Variables | Total 233 473 | With new‐onset AF 2402 | Without AF 231 071 | P |
|---|---|---|---|---|
| Age | <.0001 | |||
| 20‐49 | 48 519 (20.7%) | 109 (4.5%) | 48 410 (20.9%) | |
| 50‐59 | 53 480 (22.9%) | 199 (8.2%) | 53 281 (23.0%) | |
| 60‐69 | 60 676 (25.9%) | 537 (22.3%) | 60 139 (26.0%) | |
| 70‐79 | 53 648 (22.9%) | 972 (40.4%) | 52 676 (22.8%) | |
| Over 80 | 17 150 (7.35%) | 585 (24.3%) | 16 565 (7.1%) | |
| Sex | 0.0315 | |||
| Male | 96 071 (41.1%) | 1040 (43.3%) | 95 031 (41.1%) | |
| Female | 137 402 (58.8%) | 1362 (56.7%) | 136 040 (58.8%) | |
| Insurance | ||||
| Medical aids | 12 883 (5.5%) | 207 (8.6%) | 12 676 (5.4%) | |
| Health insurance | <.0001 | |||
| 1Q | 38 844 (16.6%) | 374 (15.5%) | 38 470 (16.6%) | |
| 2Q | 42 517 (18.2%) | 383 (15.9%) | 42 134 (18.2%) | |
| 3Q | 58 837 (25.2%) | 517 (21.5%) | 58 320 (25.2%) | |
| 4Q | 80 392 (34.4%) | 921 (38.3%) | 79 471 (34.3%) | |
| Residential area | 0.1446 | |||
| Metropolitan | 58 200 (24.9%) | 568 (23.6%) | 57 632 (24.9%) | |
| Non‐metropolitan | 175 273 (75.0%) | 1834 (76.3%) | 173 439 (75.0%) | |
| Institution | <.0001 | |||
| Outpatient care | 96 057 (41.1%) | 66 (2.7%) | 95 991 (41.5%) | |
| Admission | ||||
| Less 300 | 84 847 (36.3%) | 982 (40.8%) | 83 865 (36.2%) | |
| 300‐799 | 43 253 (18.5%) | 1077 (44.8%) | 42 176 (18.2%) | |
| Over 800 | 9316 (3.9%) | 277 (11.5%) | 9039 (3.9%) | |
| Antibiotics | <.0001 | |||
| Doxycycline | 218 791 (93.7%) | 1932 (80.4%) | 216 859 (93.8%) | |
| Azithromycin | 8910 (3.8%) | 227 (9.4%) | 8683 (3.7%) | |
| Both | 5772 (2.4%) | 243 (10.1%) | 5529 (2.3%) | |
| ICU care | <.0001 | |||
| Yes | 2342 (0.1%) | 185 (7.7%) | 2157 (0.9%) | |
| Medical history | ||||
| Past scrub typhus | <.0001 | |||
| Yes | 7300 (3.1%) | 42 (1.7%) | 7258 (3.1%) | |
| Congestive heart failure | <.0001 | |||
| Yes | 2973 (1.2%) | 140 (5.8%) | 2833 (1.2%) | |
| Ischemic heart disease | <.0001 | |||
| Yes | 13 995 (5.9%) | 258 (10.7%) | 13 737 (5.9%) | |
| Stroke | <.0001 | |||
| Yes | 8355 (3.5%) | 190 (7.9%) | 8165 (3.5%) | |
| Chronic kidney disease | <.0001 | |||
| Yes | 1121 (0.4%) | 26 (1.0%) | 1095 (0.4%) | |
| Diabetes mellitus | <.0001 | |||
| Yes | 31 072 (13.3%) | 412 (17.1%) | 30 660 (13.2%) | |
| Hypertension | <.0001 | |||
| Yes | 80 059 (34.2%) | 1299 (54.0%) | 78 760 (34.0%) | |
| Malignancy | 0.7353 | |||
| Yes | 9979 (4.2%) | 106 (4.4%) | 9873 (4.2%) | |
| Charlson Comorbidity Score | <.0001 | |||
| 0 | 142 097 (60.8%) | 1227 (51.0%) | 140 870 (60.9%) | |
| 1 | 57 174 (24.4%) | 710 (29.5%) | 56 464 (24.4%) | |
| 2 | 22 228 (9.5%) | 294 (12.2%) | 21 934 (9.4%) | |
| Over 3 | 11 974 (5.1%) | 171 (7.1%) | 11 803 (5.1%) | |
| Calendar year | <.0001 | |||
| 2006 | 22 470 (9.6%) | 221 (9.2%) | 22 249 (9.6%) | |
| 2007 | 19 413 (8.3%) | 187 (7.7%) | 19 226 (8.3%) | |
| 2008 | 21 238 (9.0%) | 199 (8.2%) | 21 039 (9.1%) | |
| 2009 | 22 726 (9.7%) | 197 (8.2%) | 22 529 (9.7%) | |
| 2010 | 19 924 (8.5%) | 228 (9.4%) | 19 696 (8.5%) | |
| 2011 | 18 435 (7.8%) | 180 (7.4%) | 18 255 (7.9%) | |
| 2012 | 24 784 (10.6%) | 230 (9.5%) | 24 554 (10.6%) | |
| 2013 | 24 547 (10.5%) | 241 (10.0%) | 24 306 (10.5%) | |
| 2014 | 17 916 (7.6%) | 243 (10.0%) | 17 673 (7.6%) | |
| 2015 | 20 397 (8.7%) | 303 (12.6%) | 20 094 (8.7%) | |
| 2016 | 21 623 (9.2%) | 173 (7.2%) | 21 450 (9.2%) |
3.3. 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).
Figure 1.
Comparison of survival rate free from, A, acute heart failure, B, ischemic heart disease, C, all‐cause mortality in patients diagnosed as scrub typhus between with and without new‐onset atrial fibrillation (NAF)
Table 2.
Incidence risk ratio for the occurrence of acute heart failure according to the development of new‐onset atrial fibrillation among scrub typhus patients
| Cumulative incidence | Crude model | Adjusted model | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Variables | Events | At risk | % | Relative risk | 95% confidence interval | P | Adjust relative risk | 95% confidence interval | P | ||
| New‐onset AF | |||||||||||
| No | 3273 | 231 071 | 1.42 | 1.00 | 1.00 | ||||||
| Yes | 446 | 2402 | 18.57 | 13.11 | 11.98 | 14.35 | <.0001 | 4.12 | 4.55 | 3.73 | <.0001 |
| Age | |||||||||||
| 20‐49 | 235 | 48 519 | 0.48 | 1.00 | 1.00 | ||||||
| 50‐59 | 349 | 53 480 | 0.65 | 1.35 | 1.14 | 1.59 | .0004 | 1.27 | 1.49 | 1.07 | .0052 |
| 60‐69 | 711 | 60 676 | 1.17 | 2.42 | 2.09 | 2.80 | <.0001 | 2.02 | 2.35 | 1.74 | <.0001 |
| 70‐79 | 1450 | 53 648 | 2.70 | 5.58 | 4.86 | 6.40 | <.0001 | 3.59 | 4.15 | 3.10 | <.0001 |
| Over 80 | 974 | 17 150 | 5.68 | 11.73 | 10.18 | 13.51 | <.0001 | 5.46 | 6.36 | 4.69 | <.0001 |
| Sex | |||||||||||
| Male | 1335 | 96 071 | 1.39 | 0.80 | 0.75 | 0.86 | <.0001 | 0.94 | 1.00 | 0.88 | .0536 |
| Female | 2384 | 137 402 | 1.74 | 1.00 | 1.00 | ||||||
| Insurance | |||||||||||
| Medical aids | 352 | 12 883 | 2.73 | 1.00 | 1.00 | ||||||
| Health insurance | |||||||||||
| 1Q | 630 | 38 844 | 1.62 | 0.59 | 0.52 | 0.68 | <.0001 | 0.89 | 1.01 | 0.78 | .0737 |
| 2Q | 531 | 42 517 | 1.25 | 0.46 | 0.40 | 0.52 | <.0001 | 0.78 | 0.89 | 0.68 | .0002 |
| 3Q | 803 | 58 837 | 1.36 | 0.50 | 0.44 | 0.57 | <.0001 | 0.80 | 0.91 | 0.71 | .0004 |
| 4Q | 1403 | 80 392 | 1.75 | 0.64 | 0.57 | 0.72 | <.0001 | 0.78 | 0.88 | 0.70 | <.0001 |
| Residential area | |||||||||||
| Metropolitan | 865 | 58 200 | 1.49 | 1.00 | 1.00 | ||||||
| Non‐metropolitan | 2854 | 175 273 | 1.63 | 0.91 | 0.85 | 0.98 | .0178 | 0.97 | 1.05 | 0.90 | .5052 |
| Institution | |||||||||||
| Outpatient care | 115 | 96 057 | 0.12 | 1.00 | 1.00 | ||||||
| Antibiotics | |||||||||||
| Doxycycline | 3016 | 218 791 | 1.38 | 1.00 | 1.00 | ||||||
| Azithromycin | 382 | 8910 | 4.29 | 3.11 | 2.80 | 3.45 | <.0001 | 1.59 | 1.77 | 1.43 | <.0001 |
| Both | 321 | 5772 | 5.56 | 4.03 | 3.61 | 4.51 | <.0001 | 1.52 | 1.70 | 1.35 | <.0001 |
| ICU care | |||||||||||
| No | 3510 | 231 131 | 1.52 | 1.00 | 1.00 | ||||||
| Yes | 209 | 2342 | 8.92 | 5.88 | 5.14 | 6.72 | <.0001 | 2.46 | 2.84 | 2.13 | <.0001 |
| Medical history | |||||||||||
| Past scrub typhus | |||||||||||
| No | 3628 | 226 173 | 1.60 | 1.00 | 1.00 | ||||||
| Yes | 91 | 7300 | 1.25 | 0.78 | 0.63 | 0.96 | .0169 | 0.81 | 0.99 | 0.66 | .0417 |
| Congestive heart failure | |||||||||||
| No | 3492 | 230 500 | 1.52 | 1.00 | 1.00 | ||||||
| Yes | 227 | 2973 | 7.64 | 5.04 | 4.43 | 5.74 | <.0001 | 2.20 | 2.53 | 1.92 | <.0001 |
| Ischemic heart disease | |||||||||||
| No | 3251 | 219 478 | 1.48 | 1.00 | 1.00 | ||||||
| Yes | 468 | 13 995 | 3.34 | 2.26 | 2.05 | 2.48 | <.0001 | 1.28 | 1.42 | 1.16 | <.0001 |
| Stroke | |||||||||||
| No | 3439 | 225 118 | 1.53 | 1.00 | 1.00 | ||||||
| Yes | 280 | 8355 | 3.35 | 2.19 | 1.95 | 2.47 | <.0001 | 1.09 | 1.23 | 0.96 | .1742 |
| Chronic kidney disease | |||||||||||
| No | 3673 | 232 352 | 1.58 | 1.00 | 1.00 | ||||||
| Yes | 46 | 1121 | 4.10 | 2.60 | 1.95 | 3.45 | <.0001 | 1.05 | 1.42 | 0.78 | .7467 |
| Diabetes mellitus | |||||||||||
| No | 2978 | 202 401 | 1.47 | 1.00 | 1.00 | ||||||
| Yes | 741 | 31 072 | 2.38 | 1.62 | 1.50 | 1.76 | <.0001 | 1.02 | 1.10 | 0.94 | .6843 |
| Hypertention | |||||||||||
| No | 1713 | 153 414 | 1.12 | 1.00 | 1.00 | ||||||
| Yes | 2006 | 80 059 | 2.51 | 2.24 | 2.11 | 2.39 | <.0001 | 1.16 | 1.25 | 1.08 | <.0001 |
| Malignancy | |||||||||||
| No | 3539 | 223 494 | 1.58 | 1.00 | 1.00 | ||||||
| Yes | 180 | 9979 | 1.80 | 1.14 | 0.98 | 1.32 | .0852 | 0.86 | 1.02 | 0.72 | .0767 |
| Charlson Comorbidity Score | |||||||||||
| 0 | 1838 | 142 097 | 1.29 | 1.00 | 1.00 | ||||||
| 1 | 1036 | 57 174 | 1.81 | 1.40 | 1.30 | 1.51 | <.0001 | 0.95 | 1.02 | 0.88 | .1554 |
| 2 | 544 | 22 228 | 2.45 | 1.89 | 1.72 | 2.08 | <.0001 | 1.09 | 1.21 | 0.99 | .0896 |
| Over 3 | 301 | 11 974 | 2.51 | 1.94 | 1.72 | 2.19 | <.0001 | 0.96 | 1.11 | 0.83 | .5876 |
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).
Table 3.
Incidence risk ratio for the occurrence of ischemic heart disease according to the development of new‐onset atrial fibrillation among scrub typhus patients
| Cumulative incidence | Crude model | Adjusted model | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Variables | Events | At risk | % | Relative risk | 95% confidence interval | P | Adjust relative risk | 95% confidence interval | P | ||
| New‐onset AF | 1.00 | ||||||||||
| No | 278 | 231 071 | 0.12 | 1.00 | |||||||
| Yes | 27 | 2402 | 1.12 | 9.34 | 6.31 | 13.84 | <.0001 | 1.95 | 3.04 | 1.25 | .0032 |
| Age | |||||||||||
| 20‐49 | 8 | 48 519 | 0.02 | 1.00 | 1.00 | ||||||
| 50‐59 | 26 | 53 480 | 0.05 | 2.95 | 1.34 | 6.51 | .0075 | 2.99 | 6.64 | 1.35 | .0071 |
| 60‐69 | 65 | 60 676 | 0.11 | 6.50 | 3.12 | 13.54 | <.0001 | 5.45 | 11.51 | 2.58 | <.0001 |
| 70‐79 | 128 | 53 648 | 0.24 | 14.47 | 7.08 | 29.56 | <.0001 | 9.60 | 19.94 | 4.62 | <.0001 |
| Over 80 | 78 | 17 150 | 0.45 | 27.58 | 13.33 | 57.09 | <.0001 | 14.65 | 31.00 | 6.92 | <.0001 |
| Sex | |||||||||||
| Male | 164 | 96 071 | 0.17 | 1.66 | 1.33 | 2.08 | <.0001 | 1.96 | 2.46 | 1.56 | <.0001 |
| Female | 141 | 137 402 | 0.10 | 1.00 | 1.00 | ||||||
| Insurance | |||||||||||
| Medical aids | 42 | 12 883 | 0.33 | 1.00 | 1.00 | ||||||
| Health insurance | |||||||||||
| 1Q | 47 | 38 844 | 0.12 | 0.37 | 0.24 | 0.56 | <.0001 | 0.61 | 0.92 | 0.40 | .0197 |
| 2Q | 44 | 42 517 | 0.10 | 0.32 | 0.21 | 0.48 | <.0001 | 0.55 | 0.86 | 0.36 | .0078 |
| 3Q | 61 | 58 837 | 0.10 | 0.32 | 0.21 | 0.47 | <.0001 | 0.51 | 0.77 | 0.34 | .0013 |
| 4Q | 111 | 80 392 | 0.14 | 0.42 | 0.30 | 0.60 | <.0001 | 0.52 | 0.74 | 0.36 | .0003 |
| Residential area | |||||||||||
| Metropolitan | 81 | 58 200 | 0.14 | 1.00 | 1.00 | ||||||
| Non‐metropolitan | 224 | 175 273 | 0.13 | 1.09 | 0.84 | 1.40 | .5105 | 1.16 | 1.50 | 0.90 | .2538 |
| Institution | |||||||||||
| Outpatient care | 19 | 96 057 | 0.02 | 1.00 | 1.00 | ||||||
| Antibiotics | |||||||||||
| Doxycycline | 221 | 218 791 | 0.10 | 1.00 | 1.00 | ||||||
| Azithromycin | 35 | 8910 | 0.39 | 3.89 | 2.72 | 5.55 | <.0001 | 1.97 | 2.86 | 1.35 | .0004 |
| Both | 49 | 5772 | 0.85 | 8.40 | 6.17 | 11.44 | <.0001 | 3.45 | 4.79 | 2.48 | <.0001 |
| ICU care | |||||||||||
| No | 259 | 231 131 | 0.11 | 1.00 | 1.00 | ||||||
| Yes | 46 | 2342 | 1.96 | 17.53 | 12.84 | 23.92 | <.0001 | 5.63 | 7.99 | 3.97 | <.0001 |
| Medical history | |||||||||||
| Past scrub typhus | |||||||||||
| No | 289 | 226 173 | 0.13 | 1.00 | 1.00 | ||||||
| Yes | 16 | 7300 | 0.22 | 1.72 | 1.04 | 2.84 | .0354 | 2.08 | 3.44 | 1.25 | .0046 |
| Congestive heart failure | |||||||||||
| No | 290 | 230 500 | 0.13 | 1.00 | 1.00 | ||||||
| Yes | 15 | 2973 | 0.50 | 4.01 | 2.39 | 6.73 | <.0001 | 1.50 | 2.54 | 0.88 | .1342 |
| Ischemic heart disease | |||||||||||
| No | 247 | 219 478 | 0.11 | 1.00 | 1.00 | ||||||
| Yes | 58 | 13 995 | 0.41 | 3.68 | 2.77 | 4.90 | <.0001 | 2.00 | 2.71 | 1.47 | <.0001 |
| Stroke | |||||||||||
| No | 281 | 225 118 | 0.12 | 1.00 | 1.00 | ||||||
| Yes | 24 | 8355 | 0.29 | 2.30 | 1.52 | 3.49 | <.0001 | 0.94 | 1.45 | 0.61 | .7672 |
| Chronic kidney disease | |||||||||||
| No | 293 | 232 352 | 0.13 | 1.00 | 1.00 | ||||||
| Yes | 12 | 1121 | 1.07 | 8.49 | 4.78 | 15.07 | <.0001 | 2.67 | 5.16 | 1.38 | .0035 |
| Diabetes mellitus | |||||||||||
| No | 232 | 202 401 | 0.11 | 1.00 | 1.00 | ||||||
| Yes | 73 | 31 072 | 0.23 | 2.05 | 1.58 | 2.67 | <.0001 | 1.22 | 1.62 | 0.92 | .1583 |
| Hypertension | |||||||||||
| No | 130 | 153 414 | 0.08 | 1.00 | 1.00 | ||||||
| Yes | 175 | 80 059 | 0.22 | 2.58 | 2.06 | 3.24 | <.0001 | 1.25 | 1.62 | 0.96 | .0929 |
| Malignancy | |||||||||||
| No | 287 | 223 494 | 0.13 | 1.00 | 1.00 | ||||||
| Yes | 18 | 9979 | 0.18 | 1.40 | 0.87 | 2.26 | .1616 | 0.93 | 1.61 | 0.54 | .8009 |
| Charlson Comorbidity Score | |||||||||||
| 0 | 140 | 142 097 | 0.10 | 1.00 | 1.00 | ||||||
| 1 | 89 | 57 174 | 0.16 | 1.58 | 1.21 | 2.06 | .0007 | 1.02 | 1.34 | 0.77 | .8893 |
| 2 | 43 | 22 228 | 0.19 | 1.96 | 1.40 | 2.76 | .0001 | 0.98 | 1.41 | 0.69 | .9271 |
| Over 3 | 33 | 11 974 | 0.28 | 2.80 | 1.92 | 4.09 | <.0001 | 0.97 | 1.61 | 0.58 | .8956 |
3.4. 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 IRR of 1.8 to 10.2 for 3‐month mortality, and those admitted to the ICU had an IRR for 3‐month mortality of 4.5. Interestingly, those with better economic or health status also showed a lower IRR for mortality than those with poorer economic or health status (Table 4, Figure 1C).
Table 4.
Incidence risk ratio of demographic characteristics and comorbidities for mortality in scrub typhus patients
| Cumulative incidence | Crude model | Adjusted model | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Variables | Events | At risk | % | Relative risk | 95% confidence interval | P | Adjust relative risk | 95% confidence interval | P | ||
| New‐onset AF | |||||||||||
| No | 1347 | 231 071 | 0.58 | 1.00 | 1.00 | ||||||
| Yes | 105 | 2402 | 4.37 | 7.50 | 6.17 | 9.11 | <.0001 | 1.34 | 1.07 | 1.68 | .0106 |
| Acute heart failure | |||||||||||
| No | 1243 | 229 754 | 0.54 | 1.00 | 1.00 | ||||||
| Yes | 209 | 3719 | 5.62 | 10.39 | 9.00 | 11.98 | <.0001 | 2.41 | 2.04 | 2.84 | <.0001 |
| Ischemic heart disease | |||||||||||
| No | 1292 | 233 168 | 0.55 | 1.00 | 1.00 | ||||||
| Yes | 160 | 305 | 52.46 | 94.67 | 83.98 | 106.73 | <.0001 | 13.72 | 11.03 | 17.07 | <.0001 |
| Age | |||||||||||
| 20‐49 | 62 | 48 519 | 0.13 | 1.00 | 1.00 | ||||||
| 50‐59 | 121 | 53 480 | 0.23 | 1.77 | 1.30 | 2.40 | .0003 | 1.80 | 1.33 | 2.44 | .0001 |
| 60‐69 | 217 | 60 676 | 0.36 | 2.80 | 2.11 | 3.71 | <.0001 | 2.39 | 1.79 | 3.18 | <.0001 |
| 70‐79 | 569 | 53 648 | 1.06 | 8.30 | 6.39 | 10.78 | <.0001 | 5.33 | 4.06 | 7.02 | <.0001 |
| Over 80 | 483 | 17 150 | 2.82 | 22.04 | 16.93 | 28.69 | <.0001 | 10.29 | 7.76 | 13.65 | <.0001 |
| Sex | |||||||||||
| Male | 751 | 96 071 | 0.78 | 1.53 | 1.38 | 1.70 | <.0001 | 1.68 | 1.51 | 1.87 | <.0001 |
| Female | 701 | 137 402 | 0.51 | 1.00 | 1.00 | ||||||
| Insurance | |||||||||||
| Medical aids | 181 | 12 883 | 1.41 | 1.00 | 1.00 | ||||||
| Health insurance | |||||||||||
| 1Q | 233 | 38 844 | 0.60 | 0.43 | 0.35 | 0.52 | <.0001 | 0.77 | 0.63 | 0.94 | .0118 |
| 2Q | 215 | 42 517 | 0.51 | 0.36 | 0.30 | 0.44 | <.0001 | 0.73 | 0.60 | 0.90 | .0033 |
| 3Q | 308 | 58 837 | 0.52 | 0.37 | 0.31 | 0.45 | <.0001 | 0.70 | 0.58 | 0.85 | .0002 |
| 4Q | 515 | 80 392 | 0.64 | 0.46 | 0.39 | 0.54 | <.0001 | 0.63 | 0.52 | 0.75 | <.0001 |
| Residential area | |||||||||||
| Metropolitan | 302 | 58 200 | 0.52 | 1.00 | 1.00 | ||||||
| Non‐metropolitan | 1150 | 175 273 | 0.66 | 0.79 | 0.70 | 0.90 | .0003 | 0.86 | 0.75 | 0.98 | .0292 |
| Institution | |||||||||||
| Outpatient care | 72 | 96 057 | 0.08 | 1.00 | 1.00 | ||||||
| Admission | |||||||||||
| Antibiotics | |||||||||||
| Doxycycline | 952 | 218 791 | 0.44 | 1.00 | 1.00 | ||||||
| Azithromycin | 310 | 8910 | 3.48 | 8.00 | 7.05 | 9.07 | <.0001 | 3.43 | 2.97 | 3.96 | <.0001 |
| Both | 190 | 5772 | 3.29 | 7.57 | 6.49 | 8.82 | <.0001 | 2.45 | 2.07 | 2.90 | <.0001 |
| ICU care | |||||||||||
| No | 1241 | 231 131 | 0.54 | 1.00 | 1.00 | ||||||
| Yes | 211 | 2342 | 9.01 | 16.78 | 14.59 | 19.30 | <.0001 | 4.51 | 3.77 | 5.39 | <.0001 |
| Medical history | |||||||||||
| Past scrub typhus | |||||||||||
| No | 1388 | 226 173 | 0.61 | 1.00 | 1.00 | ||||||
| Yes | 64 | 7300 | 0.88 | 1.43 | 1.11 | 1.83 | .0051 | 1.19 | 0.91 | 1.55 | .213 |
| Congestive heart failure | |||||||||||
| No | 1385 | 230 500 | 0.60 | 1.00 | 1.00 | ||||||
| Yes | 67 | 2973 | 2.25 | 3.75 | 2.94 | 4.78 | <.0001 | 1.45 | 1.10 | 1.91 | .0083 |
| Ischemic heart disease | |||||||||||
| No | 1294 | 219 478 | 0.59 | 1.00 | 1.00 | ||||||
| Yes | 158 | 13 995 | 1.13 | 1.91 | 1.62 | 2.26 | <.0001 | 1.01 | 0.85 | 1.20 | .9023 |
| Stroke | |||||||||||
| No | 1316 | 225 118 | 0.58 | 1.00 | 1.00 | ||||||
| Yes | 136 | 8355 | 1.63 | 2.78 | 2.34 | 3.32 | <.0001 | 1.10 | 0.91 | 1.32 | .3361 |
| Chronic kidney disease | |||||||||||
| No | 1412 | 232 352 | 0.61 | 1.00 | 1.00 | ||||||
| Yes | 40 | 1121 | 3.57 | 5.87 | 4.31 | 8.00 | <.0001 | 1.18 | 0.81 | 1.72 | .3797 |
| Diabetes mellitus | |||||||||||
| No | 1120 | 202 401 | 0.55 | 1.00 | 1.00 | ||||||
| Yes | 332 | 31 072 | 1.07 | 1.93 | 1.71 | 2.18 | <.0001 | 1.29 | 1.13 | 1.47 | .0001 |
| Hypertension | |||||||||||
| No | 704 | 153 414 | 0.46 | 1.00 | 1.00 | ||||||
| Yes | 748 | 80 059 | 0.93 | 2.04 | 1.84 | 2.26 | <.0001 | 0.94 | 0.84 | 1.06 | .3192 |
| Malignancy | |||||||||||
| No | 1327 | 223 494 | 0.59 | 1.00 | 1.00 | ||||||
| Yes | 125 | 9979 | 1.25 | 2.11 | 1.76 | 2.53 | <.0001 | 0.99 | 0.77 | 1.26 | .9164 |
| Charlson Comorbidity Score | |||||||||||
| 0 | 565 | 142 097 | 0.40 | 1.00 | 1.00 | ||||||
| 1 | 443 | 57 174 | 0.77 | 1.95 | 1.72 | 2.21 | <.0001 | 1.32 | 1.16 | 1.49 | <.0001 |
| 2 | 227 | 22 228 | 1.02 | 2.57 | 2.20 | 2.99 | <.0001 | 1.31 | 1.11 | 1.55 | .0015 |
| Over 3 | 217 | 11 974 | 1.81 | 4.56 | 3.90 | 5.32 | <.0001 | 1.76 | 1.43 | 2.17 | <.0001 |
4. DISCUSSION
In this nationwide scrub typhus infection cohort, patients with new‐onset 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, 19 The FROG‐ICU trial demonstrated that new‐onset AF occurred in 19% of all patients in the ICU and had an incidence risk of 2.2‐fold for 1‐year mortality compared to those without new‐onset AF.20 The present study demonstrates that new‐onset AF occurred in the 7.7% of all patients in the ICU and had an incidence risk of 4.5‐fold for 3‐month mortality compared to those without new‐onset AF. It is noteworthy that new‐onset AF in scrub typhus infection developed less frequently, but had a higher risk of mortality than in the other infectious diseases. The reason for the higher mortality and adverse cardiac complications could be explained by the unique pathophysiology of scrub typhus infection,17 which 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, 27, 28 Coronary vasculitis also might induce direct endothelial dysfunction and vascular injury causing atherosclerotic plaque growth or rupture during the pathogenesis of IHD.29, 30 In particular, ECG or rhythm surveillance for cardiac complications could be a necessary monitoring of scrub typhus infection because of the risk of developing atrial or ventricular arrhythmia and changes in the ST segment of ECG as a result of active inflammation in the myocardium.11 Available ECG‐based new‐onset AF or ST segment change could be more readily evaluated31 than time and cost‐consuming echocardiogram‐based AHF or angiogram‐based IHD32 under the care of non‐cardiologic department. ECG or rhythm‐based surveillance for the development of cardiac complications is crucial for preventing scrub typhus infection from developing life‐threatening outcomes.33 This could provide an additional method for reducing adverse cardiac complications in scrub typhus infection.
4.1. 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.
5. 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.
CONFLICT OF INTEREST
The authors declare no potential conflict of interests.
AUTHOR CONTRIBUTIONS
K.W. K. contributed to the study design, interpretation of the analyzed data, and revised final manuscript. S.Y. J. collected and analyzed the data. J. H. K., B. K., J. Y. C., S. H. P., Y. J. C., K.T. J., and S.K. L. interpreted the data and drafted the manuscript.
ETHICS STATEMENT
This study was approved by the Institutional Review Board of Eulji University (EMC 2017‐10‐006) and adhered to the principles of the Declaration of Helsinki.
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.
Jang S‐Y, Kang K‐W, Kim JH, et al. New‐onset atrial fibrillation predicting for complicating cardiac adverse outcome in scrub typhus infection. Clin Cardiol. 2019;42:1210–1221. 10.1002/clc.23276
Funding information Korean Healthcare Technology R&D project, Grant/Award Number: (2017R1D1A3B03030919).
Suk‐Yong Jang and Ki‐Woon Kang contributed equally to this study.
REFERENCES
- 1. Sittiwangkul R, Pongprot Y, Silviliarat S, Oberdorfer P, Jittamala P, Sirisanthana V. Acute fulminant myocarditis in scrub typhus. Ann Trop Paediatr. 2008;28(2):149‐154. [DOI] [PubMed] [Google Scholar]
- 2. Weitzel T, Dittrich S, Lopez J, et al. endemic scrub typhus in South America. N Engl J Med. 2016;375(10):954‐961. [DOI] [PubMed] [Google Scholar]
- 3. Walker DH. Scrub typhus ‐ Scientific neglect, ever‐widening impact. N Engl J Med. 2016;375(10):913‐915. [DOI] [PubMed] [Google Scholar]
- 4. Peter JV, Sudarsan TI, Prakash JA, Varghese GM. Severe scrub typhus infection: clinical features, diagnostic challenges and management. World J Crit Care Med. 2015;4(3):244‐250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Wang CC, Liu SF, Liu JW, Chung YH, Su MC, Lin MC. Acute respiratory distress syndrome in scrub typhus. Am J Trop Med Hyg. 2007;76(6):1148‐1152. [PubMed] [Google Scholar]
- 6. Thap LC, Supanaranond W, Treeprasertsuk S, Kitvatanachai S, Chinprasatsak S, Phonrat B. Septic shock secondary to scrub typhus: characteristics and complications. Southeast Asian J Trop Med Public Health. 2002;33(4):780‐786. [PubMed] [Google Scholar]
- 7. Parola P, Miller RS, McDaniel P, et al. Emerging rickettsioses of the Thai‐Myanmar border. Emerg Infect Dis. 2003;9(5):592‐595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Lee CS, Hwang JH, Lee HB, Kwon KS. Risk factors leading to fatal outcome in scrub typhus patients. Am J Trop Med Hyg. 2009;81(3):484‐488. [PubMed] [Google Scholar]
- 9. Taylor AJ, Paris DH, Newton PNA. Systematic Review of Mortality from Untreated Scrub Typhus (Orientia tsutsugamushi). PLoS Negl Trop Dis. 2015;9(8):e0003971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Moss TJ, Calland JF, Enfield KB, et al. New‐onset atrial fibrillation in the critically ill. Crit Care Med. 2017;45(5):790‐797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Chin JY, Kang KW, Moon KM, Kim J, Choi YJ. Predictors of acute myocarditis in complicated scrub typhus: an endemic province in the Republic of Korea. Korean J Intern Med. 2018;33:323‐330. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Chung WS, Lin CL, Hsu WH, Kao CH. Scrub typhus increases the risk of developing acute coronary syndrome: a nationwide cohort study. Heart. 2014;100(23):1844‐1850. [DOI] [PubMed] [Google Scholar]
- 13. Freiberg MS, Chang CH, Skanderson M, et al. Association between HIV infection and the risk of heart failure with reduced ejection fraction and preserved ejection fraction in the antiretroviral therapy era: results from the Veterans Aging Cohort Study. JAMA Cardiol. 2017;2(5):536‐546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Cheol Seong S, Kim YY, Khang YH, et al. Data resource profile: The National Health Information Database of the National Health Insurance Service in South Korea. Int J Epidemiol. 2017;46(3):799‐800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD‐9‐CM and ICD‐10 administrative data. Med Care. 2005;43(11):1130‐1139. [DOI] [PubMed] [Google Scholar]
- 16. Warren‐Gash C, Smeeth L, Hayward AC. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect Dis. 2009;9(10):601‐610. [DOI] [PubMed] [Google Scholar]
- 17. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614‐622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Walkey AJ, Benjamin EJ, Lubitz SA. New‐onset atrial fibrillation during hospitalization. J Am Coll Cardiol. 2014;64(22):2432‐2433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Klein Klouwenberg PM, Frencken JF, Kuipers S, et al. Incidence, predictors, and outcomes of new‐onset atrial fibrillation in critically ill patients with sepsis. A cohort study. Am J Respir Crit Care Med. 2017;195(2):205‐211. [DOI] [PubMed] [Google Scholar]
- 20. Arrigo M, Ishihara S, Feliot E, et al. New‐onset atrial fibrillation in critically ill patients and its association with mortality: A report from the FROG‐ICU study. Int J Cardiol. 2018;266:95‐99. [DOI] [PubMed] [Google Scholar]
- 21. Allen AC, Spitz SA. Comparative study of the pathology of scrub typhus (tsutsugamushi disease) and other rickettsial diseases. Am J Pathol. 1945;21(4):603‐681. [PMC free article] [PubMed] [Google Scholar]
- 22. Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol. 2007;50(21):2021‐2028. [DOI] [PubMed] [Google Scholar]
- 23. Aviles RJ, Martin DO, Apperson‐Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation. 2003;108(24):3006‐3010. [DOI] [PubMed] [Google Scholar]
- 24. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow‐up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm. 2012;9(4):632‐696. e621. [DOI] [PubMed] [Google Scholar]
- 25. Mountantonakis SE, Grau‐Sepulveda MV, Bhatt DL, Hernandez AF, Peterson ED, Fonarow GC. Presence of atrial fibrillation is independently associated with adverse outcomes in patients hospitalized with heart failure: an analysis of get with the guidelines‐heart failure. Circ Heart Fail. 2012;5(2):191‐201. [DOI] [PubMed] [Google Scholar]
- 26. Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation. 2009;119(18):2516‐2525. [DOI] [PubMed] [Google Scholar]
- 27. Adegbala O, Olagoke O, Akintoye E, et al. Predictors, burden, and the impact of arrhythmia on patients admitted for acute myocarditis. Am J Cardiol. 2019;123(1):139‐144. [DOI] [PubMed] [Google Scholar]
- 28. Michniewicz E, Mlodawska E, Lopatowska P, Tomaszuk‐Kazberuk A, Malyszko J. Patients with atrial fibrillation and coronary artery disease ‐ double trouble. Adv Med Sci. 2018;63(1):30‐35. [DOI] [PubMed] [Google Scholar]
- 29. Corrales‐Medina VF, Madjid M, Musher DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis. 2010;10(2):83‐92. [DOI] [PubMed] [Google Scholar]
- 30. Schmitt J, Duray G, Gersh BJ, Hohnloser SH. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J. 2009;30(9):1038‐1045. [DOI] [PubMed] [Google Scholar]
- 31. Deluigi CC, Ong P, Hill S, et al. ECG findings in comparison to cardiovascular MR imaging in viral myocarditis. Int J Cardiol. 2013;165(1):100‐106. [DOI] [PubMed] [Google Scholar]
- 32. Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol. 2012;59(9):779‐792. [DOI] [PubMed] [Google Scholar]
- 33. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373(10):929‐938. [DOI] [PubMed] [Google Scholar]