key: cord-0925715-gve7rwt7
authors: Park, Jin; Shin, Jae Il; Kim, Dong‐Hyeok; Park, Junbeom; Jeon, Jimin; Kim, Jinkwon; Song, Tae‐Jin
title: Association of atrial fibrillation with infectivity and severe complications of COVID‐19: A nationwide cohort study
date: 2022-02-17
journal: J Med Virol
DOI: 10.1002/jmv.27647
sha: 9443b2b52d99e438960a9ce272f5f90c76a5e4d6
doc_id: 925715
cord_uid: gve7rwt7

Infection is associated with the occurrence, recurrence, and progression of atrial fibrillation (AF), and is also closely related to poor prognosis. However, studies of the relationship between infectivity and severe complications of coronavirus infectious disease‐19 (COVID‐19) with a history of AF are limited. To estimate infectivity and severity of complications in COVID‐19 patients with a history of AF, this study was done. From the Korean nationwide COVID‐19 dataset, 212 678 participants with at least one severe acute respiratory syndrome coronavirus 2 (COVID‐19) test were included between January 1 and June 4, 2020. AF was defined according to at least two outpatient hospital visits or one admission with an ICD‐10 code of “I48” before the COVID‐19 test. To investigate the association of AF with infectivity and severe complications of COVID‐19, 1:4 ratio propensity score matching (PSM) was performed. Severe complications of COVID‐19 were defined as a composite outcome of mechanical ventilation, intensive care unit admission, and death within 2 months after COVID‐19 diagnosis. Among 212 678 participants who underwent the COVID‐19 test, there were 7713 COVID‐19 positive patients. After PSM, COVID‐19 PCR positivity did not show a significant difference according to the presence of AF (odds ratio [OR]: 0.79, 95% confidence interval [CI]: [0.60–1.04]). Of 7713 COVID‐19 patients, 62 (0.8%) had a history of AF and severe complications occurred in 444 (5.7%) patients. After PSM, AF was associated with the development of severe complications (OR: 2.04, 95% CI: [1.10–3.79]) and mortality (OR: 2.09, 95% CI: [1.01–4.31]) of COVID‐19. We found that AF was associated with an increased risk of severe complications in COVID‐19 infected patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive sense, single-stranded RNA coronavirus in genetic sequence, which is contagious to humans and is the cause of coronavirus infectious disease-19 . Most patients infected with COVID-19 complain of asymptomatic or mild flulike symptoms, but respiratory insufficiency or hypoxemia is also accompanied in some cases. 1 Additionally, a COVID-19 infection may require mechanical ventilation treatment, hospitalization in an intensive care unit (ICU), or may lead to death. 1 Therefore, it is essential to differentiate and treat patients likely to develop severe complications due to COVID-19. Until recently, several studies have suggested factors, such as diabetes mellitus, heart failure, cancer, allergic diseases, and chronic kidney diseases that are associated with a poor prognosis after COVID-19

infection. [2] [3] [4] Infection is associated with the occurrence, recurrence, and progression of atrial fibrillation (AF), and is also closely related to poor prognosis. 5, 6 Recently, a relationship between COVID-19 infection and AF has been proposed, 7 with the likelihood of AF being increased in COVID-19 patients. 8 In addition, there have been some metaanalyses on the mortality in COVID-19 patients with or without AF. [9] [10] [11] However, most individual studies are retrospective, some meta-analyses did not use the adjusted odds ratio, which could cause biased results. In addition, other important severe complications of COVID-19 such as mechanical ventilation or ICU admission have rarely been investigated and statistical methods to reduce bias such as propensity score matching (PSM) have rarely been applied in previous studies.

Therefore, the purpose of our study was to investigate the relationship of AF with infectivity and severe complications of COVID-19, including mechanical ventilation, ICU admission, and mortality, in a nationwide population-based COVID-19 dataset.

This is a retrospective observational study using a nationwide COVID-19 dataset from South Korea. South Korea has a public single-payer health insurance system, the National Health Insurance Service (NHIS). The NHIS had a national health insurance claims database of hospital visits, diagnoses (recorded by

Health Problems [ICD]-10 codes), medical procedures, prescriptions, and mortality for the whole South Korean population. 12, 13 In the face of the COVID-19 pandemic, the Korea Disease Control and Prevention Centers and NHIS released a nationwide COVID-19 dataset consisting of Koreans who underwent realtime reverse transcription-polymerase chain reaction (RT-PCR) assays of nasal and pharyngeal swabs to COVID-19 from January 1 to June 4, 2020 for academic research. 14 The RT-PCR assays followed World Health Organization guidelines and were validated by the Korea Disease Control and Prevention Centers. 15 Due to its nature as a retrospective analysis based on a fully anonymized dataset, this study was approved by the Institutional Review Board of our institution (Seoul Hospital Ewha Woman's University College of Medicine 2020-10-021), and the requirement for informed consent was waived.

In this study, AF was defined by at least two outpatient hospital visits or one admission with the diagnostic code of "I48" before the COVID-19 RT-PCR test. 16 The diagnostic accuracy of AF using this algorithm was 94.1% of the positive predictive value. 16, 17 

The current study evaluated the risk of infectivity to COVID-19 and prognosis after COVID-19 infection by AF. In an analysis for COVID-19 infectivity, the study outcome was the positivity in patients who underwent the COVID-19 test. In an analysis for COVID-19 prognosis, the study outcome was the development of severe complications in COVID-19 patients. Severe complications of COVID-19 were defined as a composite of mechanical ventilation, admission to the ICU, and mortality during the 2-month period after COVID-19 diagnosis. Mechanical ventilation was identified using claim codes of mechanical ventilation (M5850, M5857, M5858, and M5860). 18 Admission to the ICU was defined using the related claims codes (AH110, AH150, AH180-95 AH190-5, AH210, AH250, AH280-9, AH28A, AH290-9, AH380-9, AH38A, AH390-9, AH501, AJ001-AJ011, AJ020-1, AJ031, AJ100-390, AJ2A0, AJ3A0, AJ500-590, V5100, V5200, V5210-20, V5500-5520). Mortality and time of death data were provided by NHIS and were previously validated. 19, 20 

We acquired demographic information regarding sex, age, and household income level (tertiles). In the nationwide COVID-19 dataset, age is presented in 10-year intervals to preserve privacy. Therefore, we divided age categories by the median value and dichotomized data based on a cutoff age of 60 years. The definition of comorbidities regarding hypertension, diabetes mellitus, stroke, heart failure, coronary artery disease, asthma, chronic kidney disease, and malignancy was described in Supporting Information Methods. 21 PARK ET AL. | 2423

To investigate the association of AF with infectivity and severe complications of COVID-19, 1:4 ratio PSM was performed with the Greedy nearest-neighbor algorithm to compare samples with and without AF, to balance the baselines of both groups and to reduce potential confounding. To determine whether PSM was appropriate, standardized mean differences were used. If the standardized mean differences were less than 0.1, we considered PSM to be appropriate. There are prior reports that smoking is an important risk factor for worse outcomes of COVID-19. 22 Therefore, we performed subgroup analysis with 3934 COVID-19 infected patients whose smoking history (current smoking or not) was available from the national health screening check-up program results (2015-2018). 12 Of them, 1:4 ratio PSM was performed to match patients with AF and without AF, and current smoking was additionally included as a covariate in the PSM.

F I G U R E 1 Study flow of a nationwide cohort study of COVID-19 and atrial fibrillation between January 1 and June 4, 2020. Atrial fibrillation was identified by at least two outpatient hospital visits or one admission with International Classification of Diseases 10th Revision (ICD-10) code of "I48" before COVID-19 real-time reverse transcriptionpolymerase chain reaction (RT-PCR) test Statistical analyses were executed using R software, version (Table 1 ).

There were 7713 with positivity for the COVID-19 RT-PCR test.

Then, we applied 1:4 ratio PSM for 14 880 individuals without AF and 3720 individuals with AF, which were appropriately matched ( Figure 1 and Table 1 ). After PSM, COVID-19 PCR positivity did not show a significant difference according to AF history (OR: 0.79, 95% CI: (0.60-1.04), p = 0.087) ( Table 2 ).

Among 7713 patients with COVID-19, 62 (0.8%) had a history of AF in the unmatched cohort ( Figure 1 and Table 3 ). During 2 months after the diagnosis of COVID-19, the overall primary outcome occurred in 444 (5.7%) patients, including 171 (2.2%) cases of mechanical ventilation, 265 (3.4%) cases of ICU admission, and 224 (2.9%) cases of death (Table 4 ). In the unmatched cohort, severe complications of COVID-19 were more frequently noted in individuals with AF (overall p < 0.001) ( Table 4 ). We applied PSM for 248 individuals without AF and 62 individuals with AF who were appropriately matched ( Figure 1 and Table 3 and 299 (7.6%) were current smokers in the unmatched cohort ( Figure S1 and Abbreviations: AF, atrial fibrillation; CI, confidence interval; SMD, standard mean difference; T, tertile. a A standardized difference in the matched cohort. All standardized mean difference values were less than 0.10 in the propensity score-matched cohort. and all covariates, including current smoking, were balanced appropriately (Table S1 ). In the matched cohort (Table S2) 

The key findings of this study based on a nationwide COVID-19 database is that COVID-19 patients with AF are more likely to suffer severe complications, particularly mortality by propensity score matching analysis. In our study, OR for the risk of death in COVID-19 patients with AF was 9.36 but it was decreased to 2.09 after propensity score matching, which suggests that unadjusted OR for this outcome is highly biased. Similarly, some important outcomes such as mechanical ventilation and admission to ICU, were statistically significant before propensity score matching, but those became nonsignificant after propensity score matching. In addition, infectivity for COVID-19 infection was not different according to a history of AF.

During the pandemic period, the morbidity and mortality of COVID-19 have continued to disrupt health systems around the world. This requires a concentration of medical resources for critically ill patients, and therefore, studies of risk factors that predict progression to severe COVID-19 are being conducted. Cardiovascular diseases, including cardiac arrhythmia, are known risk factors for adverse outcomes and mortality in COVID-19 infected patients. 7, 23 A previous single-center study showed that 7.2% of cardiac arrhythmias were documented during COVID-19 hospitalization, detected a significant correlation between cardiac arrhythmia and disease severity, and identified risk factors for adverse outcomes including age, congestive heart failure, and troponin levels. 24 AF is T A B L E 4 Severe complication in COVID-19 patients with and without atrial fibrillation before and after propensity score matching patients showed that patients with AF were at a 2.4-fold higher risk of all-cause mortality than patients without AF. 9 Our results were in line with these previous studies and suggested AF is a significant risk factor associated with poor prognosis in COVID-19 infection.

It is difficult to demonstrate how AF worsens outcomes of COVID-19 using the findings presented here, but there is some evidence for a possible explanation ( Figure 2 ). First, in the closely connected cardio-respiratory system, COVID-19 patients with respiratory failure may be at risk of increased cardiac injury.

Cardiac dysfunctions such as cardiomyopathy, cardiac arrhythmias, and hemodynamic instability are known as acute COVID-19 cardiovascular syndrome. 25 with AF are at higher risk of severe respiratory failure and mortality than patients with no history of AF. 26, 27 Second, systematic inflammatory response followed by SARS-CoV-2 infection may worsen outcomes in patients with AF. Higher C-reactive protein (CRP) and interleukin-6 (IL-6) levels in AF patients support the increase of inflammation burden in AF patients. 28 The severity of inflammation during COVID-19 is also associated with adverse clinical outcomes and mortality. Elevation of inflammation biomarkers including CRP, IL-6, and lactate dehydrogenase can predict severe COVID-19, and at the same time, early normalization of these markers has been observed in patients with better prognosis. 29, 30 Third, thromboembolism (TE) is another potential mechanism since SARS-Cov-2 contagion can contribute to immunothrombosis. 31, 32 As is well known, TE is one of the major cardiovascular complications in patients with COVID-19, presumably due to the inflammatory response of SARS-Cov-2, with endothelial dysfunction observed in multiple organs and abnormal coagulation. 33 patients have AF. 35 Various factors such as design, population, duration of follow-up, ethnicity, and comorbidity of the study may have induced these discrepancies between our results and those of other researchers. Therefore, it is necessary to refer to studies involving a larger number of people or considering other races.

Our study has limitations. First, the current study had a retrospective observational design based on an already existing health claims database, causal relationships could not be explored.

Due to the limitation of claims data, there are uncovered covariates that could be confounding factors on the association between AF and COVID-19, such as physical activity or body mass index. 36, 37 Second, it is difficult to generalize our results because our dataset represents the Korean general population. Third, detailed information regarding severity, type, or characteristics of AF could not be acquired because our dataset did not include the information, including the electrocardiograms. Fourth, our dataset did not include the information of COVID-19 related symptoms that could be related to prognosis or infectivity in the participants In conclusion, we demonstrated that a history of AF is associated with an increased risk of severe complications of COVID-19. Patients with AF may have poor prognoses if infected with COVID-19, therefore, careful management and monitoring of such patients is necessary.

Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Covid-19: risk factors for severe disease and death

Associations of heart failure with susceptibility and severe complications of COVID-19: a nationwide cohort study

Update on the association of inflammation and atrial fibrillation

Association between atrial fibrillation, myocardial infarction, heart failure and mortality in patients with nontuberculous mycobacterial infection: a nationwide populationbased study

COVID-19 and cardiac arrhythmias

COVID-19 associated atrial fibrillation: incidence, putative mechanisms and potential clinical implications

Prevalence and impact of atrial fibrillation in hospitalized patients with COVID-19: a systematic review and meta-analysis

Preexisting atrial fibrillation is associated with increased mortality in COVID-19 Patients

Meta-analysis of atrial fibrillation in patients with COVID-19

Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea

Improved oral hygiene is associated with decreased risk of new-onset diabetes: a nationwide population-based cohort study

Association between mental illness and COVID-19 susceptibility and clinical outcomes in South Korea: a nationwide cohort study

Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching

Clinical implication of an impaired fasting glucose and prehypertension related to new onset atrial fibrillation in a healthy Asian population without underlying disease: a nationwide cohort study in Korea

Physical activity and risk of atrial fibrillation: a nationwide cohort study in general population

Association between renin-angiotensinaldosterone system inhibitors and COVID-19 infection in South Korea

Cardiovascular risks of periodontitis and oral hygiene indicators in patients with diabetes mellitus

Cohort profile: the national health insurance service-national sample cohort (NHIS-NSC), South Korea

Better oral hygiene is associated with lower risk of stroke

Smoking is associated with worse outcomes of COVID-19 particularly among younger adults: a systematic review and meta-analysis

COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives

Cardiac arrhythmias amongst hospitalised Coronavirus 2019 (COVID-19) patients: Prevalence, characterisation, and clinical algorithm to classify arrhythmic risk

Description and proposed management of the acute COVID-19 cardiovascular syndrome

Incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis. A cohort study

Risk factors and outcomes associated with new-onset atrial fibrillation during acute respiratory distress syndrome

Predictors and prognostic implications of cardiac arrhythmias in patients hospitalized for COVID-19

Longitudinal changes of inflammatory parameters and their correlation with disease severity and outcomes in patients with COVID-19 from Wuhan

C-reactive protein and clinical outcomes in patients with COVID-19

Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia

Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: a different phenotype of thrombotic disease?

SARS-CoV-2 and viral sepsis: observations and hypotheses

Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study

Covid-19 cases in a no-Covid-19 geriatric acute care setting. A sporadic occurrence?

Physical activity and the risk of SARS-CoV-2 infection, severe COVID-19 illness and COVID-19 related mortality in South Korea: a nationwide cohort study

Associations between bodymass index and COVID-19 severity in 6·9 million people in England: a prospective, community-based, cohort study

Allergic disorders and susceptibility to and severity of COVID-19: A nationwide cohort study

Association of atrial fibrillation with infectivity and severe complications of COVID-19: A nationwide cohort study

The authors declare that there are no conflicts of interest. Tae-Jin Song http://orcid.org/0000-0002-9937-762X

The peer review history for this article is available at https://publons. com/publon/10.1002/jmv.27647