key: cord-0947464-mk3hydjo
authors: Yang, Jee Myung; Moon, Sung Yong; Lee, Joo Young; Agalliu, Dritan; Yon, Dong Keon; Lee, Seung Won
title: COVID-19 morbidity and severity in patients with age-related macular degeneration: a Korean nationwide cohort study
date: 2021-06-06
journal: Am J Ophthalmol
DOI: 10.1016/j.ajo.2021.05.024
sha: cb15aaf687ce6d5653495d41408e26db78570584
doc_id: 947464
cord_uid: mk3hydjo

OBJECTIVE: To determine the potential association of age-related macular degeneration (AMD), a representative chronic age-related degenerative disease of the retina associated with inflammation and aging, with susceptibility to SARS-CoV-2 infection and severe COVID-19 outcomes. DESIGN: Nationwide cohort study with propensity-score matching. SETTING: Population-based nationwide cohort in Korea. STUDY POPULATION: Data were obtained from the Health Insurance Review & Assessment Service of Korea, including all patients older than 40 years who underwent SARS-CoV-2 testing in South Korea between January 1, 2020, and May 15, 2020 (excluding self-referral). MAIN OUTCOME MEASURES: SARS-CoV-2 test positivity was the primary outcome and severe clinical outcome of COVID-19 was the secondary outcome. RESULTS: The unmatched cohort consisted of 135,435 patients who were tested for SARS-CoV-2; 4531 (3.3%) tested positive for SARS-CoV-2; 5493 (4.1%) patients had AMD. After propensity score matching, exudative AMD was associated with an increased likelihood of susceptibility to SARS-CoV-2 infection (adjusted odds ratio [aOR], 1.50; 95% confidence interval [CI], 1.03-2.25), and a considerably greater risk of severe clinical outcomes of COVID-19 (aOR, 2.26; 95% CI, 1.02 to 5.26), but not any AMD and non-exudative AMD. CONCLUSIONS: In a Korean nationwide cohort, our data suggest that clinicians should be aware of the greater risk of susceptibility to severe clinical outcomes of COVID-19 in patients with exudative AMD. Our findings provide an improved understanding of the relationship between the pathogenesis of COVID-19 and chronic neurological disorders.

Coronavirus disease 2019 resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global emergency. 1 Recent studies on factors that increase susceptibility to COVID-19 or worsen clinical outcomes of this disease have focused on common diseases and conditions such as cardiopulmonary disorders, cancer, and diabetes mellitus. 2, 3 Although little attention has been paid to extrapulmonary comorbidities, associations between chronic central nervous system comorbidity and COVID-19 outcomes have been reported. 4, 5 Age-related macular degeneration (AMD), a major vision-threatening disease of the retina, is a representative chronic age-related degenerative disease of the retina associated with inflammation and aging (termed "inflammaging"). [6] [7] [8] Because AMD is one of the common comorbidities of chronic lung diseases and advanced stage of AMD is associated with all-cause mortality, a possible association between AMD and the clinical outcomes of COVID-19 could be suspected. 9, 10 Importantly, inflammatory mechanisms that facilitate the development of AMD, such as aberrant innate immunity (e.g., macrophages and the complement pathway), also contribute to the development of severe Recently, Ramlall et al 12 identified that patients with macular degeneration have a 25% greater risk of severe COVID-19 outcomes by analyzing 11,116 patients who presented to a single medical center. The study comprehensively demonstrated that an impaired complement system, one of the major pathogenic mechanisms of AMD development, may predispose patients to adverse clinical outcomes following SARS-CoV-2 infection. However, this study was limited as it involved a relatively small 6 number of total patients and patients with macular degeneration in a single center.

Moreover, the study lacked data on the association between AMD and susceptibility to SARS-CoV-2 infection and did not adjust for confounders, including known systemic risk factors for AMD. Importantly, failure to classify AMD as non-exudative vs. exudative may bias results since AMD subtypes may have different pathophysiologies. Therefore, additional research is warranted to offer validated information regarding the association between AMD and COVID-19.

We hypothesized that inflammaging, represented as AMD, might be associated with increased susceptibility to SARS-CoV-2 infection and/or severe COVID-19 outcomes (i.e., admission to the intensive care unit, mechanical ventilation, oxygen supplementation, or death). Using a large-scale Korean nationwide cohort, this study aimed to evaluate whether the presence of AMD is associated with increased susceptibility to SARS-CoV-2 infection and/or severe clinical outcomes in COVID-19, overall or stratified by AMD disease status (non-exudative vs. exudative).

The study protocol was approved by the Institutional Review Board of Sejong University (no. SJU-HR-E-2020-012). 13 The requirement for written consent was waived by the ethics committee due to urgent medical needs during the pandemic. This study adhered to the tenets of the Declaration of Helsinki.

Data were based on a Korean national health insurance claims-based database as well as national COVID-19 registers. This large nationwide cohort included all patients who had undergone SARS-CoV-2 testing in South Korea from January 1 to May 15, 2020 Prevention, and the Ministry of Health and Welfare (https://hira-covid19.net). 2, 14, 15 Amidst the ongoing COVID-19 pandemic, the Korean government supported obligatory and complementary health services and insurance for every COVID-19 patient. Medical information provided from the national health insurance claimsbased database consisted of personal data, information abstracted from inpatient and outpatient healthcare visits during the past 3.5 years (January 1, 2017 to May 15, 2020) , including data on healthcare and pharmaceutical visits, prescriptions, diagnoses, and procedures. COVID-19 information obtained from national registers included COVID-19 associated clinical outcomes and death records. All patient data were anonymized by the Korean government to ensure patient confidentiality. 16 

This study included patients aged >40 years who received SARS-CoV-2 testing in South Korea from January 1 to May 15, 2020. Testing was conducted by referral through the Center of Disease Control on South Korea Government (KCDC) and/or licensed doctors based on relevant signs and symptoms (excluding asymptotic selfreferrals), for a total enrollment of n=135,435. SARS-CoV-2 testing results were based on RT-PCR assays of nasal or pharyngeal swabs, authorized by the Korea Centers for Disease Control and Prevention and established by the guidelines of the WHO. 2, 14 Exposure AMD was defined based on International Classification of Diseases (10th revision; ICD-10) codes recorded at inpatient or outpatient visits during the study period (January 1, 2017 to May 15, 2020) . Since AMD can be classified as non-exudative (early stage) or exudative (advanced stage) according to the progression of the disease, for the purposes of this study, AMD was classified into any AMD (H35.3), non-exudative AMD (H35.30), and exudative AMD (H35.31). If ICD-10 codes for non-exudative AMD and exudative AMD were both present during the observational period, AMD was classified as exudative within statistical analyses. 17

The primary outcome was defined as a positive RT-PCR test result for SARS-CoV-2 infection among participants who received the SARS-CoV-2 testing. Secondary outcome was considered as severe clinical outcomes (requirement for oxygen therapy, intensive care unit admission, invasive mechanical ventilation, or death) among COVID-19 patients. 2, 14 Covariates Information on age, sex, and region of residence was obtained from insurance eligibility data. The region of residence was defined as rural or urban, as reported previously. 2, 14, 18 The appropriate ICD-10 code was used to define disease history, as previously described. 2, 14 The Charlson comorbidity index score was calculated as reported previously. 19 Pharmaceutical visits and prescriptions at inpatient or outpatient visits were used to define previous medication use (within 180 days of the prescription) before the SARS-CoV-2 test, as reported previously. 2, 14 

We used logistic regression model with adjustment for potential confounders and propensity-score matching to reduce the potential bias of confounders and to balance the baseline covariate of the two groups. Potential confounders within propensity-score matching and covariate adjustment for logestic regression model included: age (continuous); sex; region of residence (urban vs. rural) 20 ; history of diabetes mellitus, cardiovascular disease, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), asthma, hypertension, and/or chronic kidney disease; the Charlson comorbidity index; and previous use of medication including aspirin, metformin, statins, and systemic steroids. Although the most common implementation of propensity-score matching is 1:1 matching, 1:1 matching caused a significant loss of sample size of AMD subjects, which increased the maximum propensity score difference as well as the width of the confidence intervals in our cohort. We optimized 1:M matching that minimized the loss of the sample size and demonstrated adequate P value with precise CI and choose 3 for M in our study. 21, 22 From the predicted probability of 1) patients with AMD vs. those without AMD (among patients who received SARS-CoV-2 testing; n=135,435); 2) patients with non-exudative AMD vs. those without AMD among patients who received SARS-CoV-2 testing; 3) patients with exudative AMD vs. those without AMD among patients who received SARS-CoV-2 testing; 4) patients with AMD vs. those without AMD among COVID-19 patients (n=4,531); 5) patients with non-exudative AMD vs. those without AMD among COVID-19 patients; and 6) patients with exudative AMD vs.

those without AMD among COVID-19 patients. Comparison of propensity score densities (Figures S1 and S6) and standardized mean differences (SMDs) were used to validate the acceptability of matching.

Categorical data were described as numbers and percentages (%) and continuous data were described as means and standard deviations (SD). Data were analyzed using a logistic regression model and presented by adjusted odds ratios (aORs) with 95% confidence intervals (CIs) after adjusting for the aforementioned covariates.

In this cohort study, the "exposure" category consisted of diagnosis of any AMD, nonexudative AMD, and/or exudative AMD; the "primary outcome" was SARS-CoV-2 test positivity among patients who received SARS-CoV-2 testing; and the "secondary outcome" was severe COVID-19 outcomes among COVID-19 patients. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Twosided P values with a threshold of 0.05 were defined as statistically significant.

The characteristics of 135,435 patients (age ≥40 years) who received SARS-CoV-2 testing are described in Table were more frequently male (45.3% vs. 62.2%; P <0.001), and were more likely to present with a history of comorbidities (P <0.001) ( Table 1, Table S1 ). There were no differences in medication use between groups. A positive SARS-CoV-2 test result was observed in 4,381 (3.4%) patients without AMD and 150 patients (2.7%) with AMD ( Figure 1 ).

We performed propensity score matching in patients who received SARS-CoV-2 testing (n = 135,435; Table 2 and Figures S1 to S3) and observed no significant differences in baseline characteristics between each matching group (all SMDs <0.08). In matching 1 (patients without AMD vs. those with AMD), the positivity rate of SARS-CoV-2 test result was 458/16,435 (2.8%) in patients without AMD and 150/5488 (2.7%) in those with AMD (Table 2 and Figure 2 ; fully aOR, 1.00; 95% CI, 0.83-1.21). In matching 2 (patients without AMD vs. those with non-exudative AMD), the positivity rate of SARS-CoV-2 test result was 373/12,902 (2.9%) in patients without AMD and 114/4303 (2.6%) in patients with non-exudative AMD (fully aOR, 0.94; 95% CI, 0.76-1.16). In matching 3 (patients without AMD vs. those with exudative AMD), the positivity rate of SARS-CoV-2 test result was 74/3542 (2.1%) in patients without AMD and 36/1185(3.0%) in patients with exudative AMD (fully aOR, 1.50; 95% CI, 1.03-2.25). For patients aged 55 years and over, the SARS-CoV-2 positivity rate was 69/3,291 (2.1%) in patients without AMD and 35/1,105 (3.2%) in patients with exudative AMD (fully aOR, 1.54; 95% CI, 1.03-2.33).

Propensity-score matching was performed in COVID-19 patients (n=4,531) and the association with severe COVID-19 outcomes (Figures S4 to S6) revealed no significant differences between the group (Table 3; 

Here, we investigated potential associations between SARS-CoV-2 infection incidence and AMD among patients who received SARS-CoV-2 testing, and between severe COVID-19 outcomes and AMD among COVID-19 patients. This study was conducted in a Korean nationwide cohort (total n=135,435). We found that AMD and non-exudative AMD were not associated with the risk of a positive SARS-CoV-2 test or with COVID-19 severity, though patients with exudative AMD had a higher likelihood of having a positive SARS-CoV-2 test as well as worse COVID-19 clinical outcomes.

The risk factors and co-morbidities associated with severe COVID-19 outcomes need to be elucidated and are currently an urgent issue, given the global severity of the COVID-19 pandemic. Identified risk factors include old age, diabetes, obesity, cardiovascular disease, chronic kidney diseases, and allergic condition, and it is noteworthy that most of these conditions involve "inflammaging" as the underlying pathophysiology. 2, 7, 8 "Inflammaging" is a term that describes human aging characterized by chronic, low-grade systemic inflammation. 10 This chronic low-grade inflammatory condition is known to contribute to age-related degenerative diseases in the CNS, such as the brain (e.g., Alzheimer's disease) and the retina (e.g., AMD). 8 In addition, inflammaging is a known risk factor for both morbidity and mortality in older individuals. 23 Importantly, the increase in baseline inflammation has implications for age-associated immune fragility, especially to those with overwhelming inflammation, such as in Along with the immune fragility that may increase susceptibility to infection, baseline inflammation and defective resolution of immune response due to senescent cells may act synergistically to exacerbate COVID-19. Therefore, the patient"s inflammatory status may serve as a potential prognostic factor for morbidity and severity of COVID-19.

Despite this, no CNS disorder as a manifestation of inflammaging has been evidenced as a significant risk factor of COVID-19. 24 Pathogenesis of AMD involves baseline chronic inflammation and dysregulation of immune-mediated processes such as complement activation in the retina and the choroid at an advanced stage of the disease. 25 A previous study reported that late AMD was associated with all-cause mortality as well as mortality, independent of cardiovascular diseases or cancer. 9 Furthermore, pulmonary disorders, such as emphysema, and the presence of the respiratory symptoms were associated with exudative AMD in the cohorts of the Beaver Dam Eye Study, suggesting mutual interaction between chronic lung disease and exudative AMD. 10 Since AMD serves as a biomarker of biological aging and chronic CNS inflammation 7 , increased risk of mortality in patients with exudative AMD in our cohort strongly supports that inflammaging might be one of the risk factors for severe clinical outcomes of COVID-19. 23 However, future studies involving other inflammaging-related neurodegenerative diseases (e.g. Alzeheimer"s disease,

Parkinson"s disease, etc.) are necessary to strengthen the validity of this association.

Notably, patients with exudative AMD had a greater incidence of SARS-CoV-2 positivity in our study. Understanding susceptibility to SARS-CoV-2 infection is critical for determining the degree of social distancing for a particular subset of patients.

though this topic remains highly understudied. 1 Previous studies have reported that AMD is associated with community-acquired pneumonia 26 and Chlamydia Although Ramlall et al. have demonstrated that patients with macular degeneration have a greater risk of severe COVID-19 clinical outcomes using a multimodal analytical approach, this study presented with several weaknesses in terms of the clinical analysis. However, our study compensates for the weaknesses of Ramlall"s study. 12 First, our study provides more confident statistics that involve a larger number of participants (total n = 135,435; AMD n = 5493) compared to Ramllal"s study (total n = 11,161; AMD n = 88). Second, we performed meticulous matching and adjustments to minimize the effect of confounding by known COVID-19 risk factors (e.g., age, sex, history of diabetes, cardiovascular diseases), 2, 3, 14 while

Ramllal"s study did not adjust for key covariates. Third, we classified AMD as nonexudative and exudative. This classification is critical for both prognostic information and the treatment plan, while Ramllal"s study evaluated the AMD as a whole without subcategorizing into subtypes. Although non-exudative and exudative forms of AMD share basic pathomechanisms, exudative AMD is more advanced and more active and additionally involves retinochoroidal vascular pathology compared to the nonexudative forms. 12, 23, 29 Thus, classifying AMD into subtypes is necessary for elucidating the pathophysiology of COVID-19 associated with AMD.

SARS-CoV2 employs the angiotensin-converting enzyme 2 (ACE2) receptor, a negative regulator of the renin-angiotensin system (RAS 

The present study has several limitations. First, as we defined AMD based on ICD codes, the accuracy of AMD diagnoses could not be verified by a review of medical charts. However, the observed prevalence of AMD (4.1%) was comparable to past studies, 38 and claims-based definitions of AMDs are widely used in epidemiologic investigations. 39, 40 In addition, the Korean National Health Insurance program has strict criteria and review processes in place for the diagnosis of rare, intractable diseases such as exudative AMD. Though the review of diagnosis by the government as well as similar prevalence rates observed across studies may ensure the reliability of the operational definition of AMD, subsequent studies involving medical chart review would be valuable in clarifying and validating this literature.

Second, given the urgency of data processing during a global pandemic, the COVID-19-related information provided by the Korean government includes three years of patient history. Therefore, patients who were diagnosed with AMD 3 years prior to the pandemic or who had not visited an ophthalmologist within 3 years could have been excluded from the AMD cohort. However, most patients with AMD visit clinics regularly, and access to hospital-based healthcare is easy in South Korea. In addition, patients with exudative AMD receive financial support from the government, with reduced coinsurance rates for medical expenses. Given these conditions, the possibility of missing diagnoses is likely to have been minimal. Third, our analysis did not adjust for potential confounders such as alcohol consumption and cigarette smoking, though these covariates may affect the status and progression of AMD.

Our study included patients with a history of known systemic diseases that have a close association with these factors, such as cardiovascular disease, diabetes, and respiratory disease, and we adjusted for these conditions as confounding variables.

However, first-hand information on alcohol usage and smoking history was not accessible from official governmental data. Further studies adjusting for alcohol Despite these limitations, our large-scale study uniquely highlights the potential association of AMD with susceptibility to COVID-19 as well as COVID-19 severity within a Korean nationwide cohort using propensity score matching. In addition to a large sample size (n=135,435), our study is supported by a well-designed statistical analysis utilizing robust propensity score-matching that increases the generalizability and reliability of our results.

Our large-scale nationwide cohort study supports the hypothesis that exudative AMD is associated with an increased risk of susceptibility to SARS-CoV-2 infection and devastating outcomes of COVID-19. Therefore, our findings provide insight into the association between the pathophysiology of COVID-19 and chronic neurological disorders. Although the prevalence of AMD is relatively low, the scale and expandability of the current SARS-CoV2 crisis means that even a low prevalence of AMD could lead to a large number of cases and may affect disease severity. Special attention must be paid to people with exudative AMD who may be vulnerable to COVID-19.

Dr DKY had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the 

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

The authors appreciate healthcare professionals dedicated to treating COVID-19 patients in Korea, the Ministry of Health and Welfare, and the Health Insurance

Review & Assessment Service of Korea for sharing invaluable national health insurance claims data in a prompt manner. (6):621-6. . Density plot of the propensity scores before and after matching 5. Figure S6 . Density plot of the propensity scores before and after matching 6. 3. Well-designed statistical analysis using robust propensity-score matching that increases the generalizability and reliability of our results

In this Korean nationwide cohort study with a total 135,435 patients older than 40 years who were tested for SARS-CoV-2 infection, exudative AMD was associated with an increased likelihood of susceptibility to SARS-CoV-2 infection and a considerably greater risk of severe clinical outcomes of COVID-19, but not nonexudative AMD.

Nationwide Results of COVID-19 Contact Tracing in South Korea: Individual Participant Data From an Epidemiological Survey

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

Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. The Lancet Psychiatry

The Lancet N. The neurological impact of COVID-19

Inflammaging: should this term be suitable for age related macular degeneration too?

Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases

Age and Age-Related Diseases: Role of Inflammation Triggers and

Association of Age-Related Macular

Degeneration With Risk of All-Cause and Specific-Cause Mortality in the National Health and Nutrition Examination Survey

Pulmonary disease and age-related macular degeneration: the Beaver Dam Eye Study

Eye Diseases Direct Interest to Complement Pathway and Macrophages as Regulators of Inflammation in COVID-19

Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection

Proton pump inhibitors and the risk of severe COVID-19: a post-hoc analysis from the Korean nationwide cohort

Severe clinical outcomes of COVID-19

associated with proton pump inhibitors: a nationwide cohort study with propensity score matching

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

Association between mental illness and COVID-19 in South Korea: a post-hoc analysis. The Lancet Psychiatry

The Association Between Diabetes and Age

AMD, age-related macular degeneration

chronic obstructive pulmonary disease; COVID-19, coronavirus disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation

AMD, age-related macular degeneration

COPD, chronic obstructive pulmonary disease

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SMD, standardized mean difference; OR, odds ratio. Propensity score-matched covariates: age, sex, region of residence, history of diabetes mellitus, cardiovascular disease, cerebrovascular disease, COPD, asthma, hypertension, or chronic kidney disease

§ Fully adjusted for age, sex, region of residence, history of diabetes mellitus, cardiovascular disease, cerebrovascular disease, COPD, asthma, hypertension, or chronic kidney disease

and previous use of medication (aspirin, metformin, statin, or systemic steroid)

‡ An SMD below 0.1 indicates no major imbalance

AMD, age-related macular degeneration

COPD, chronic obstructive pulmonary disease

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SMD, standardized mean difference; OR, odds ratio. Propensity score-matched covariates: age, sex, region of residence, history of diabetes mellitus, cardiovascular disease, cerebrovascular disease, COPD, asthma, hypertension, or chronic kidney disease

Severe clinical outcomes of COVID-19 comprised requirement for oxygen therapy, admission to the intensive care unit, invasive ventilation

‡ Fully adjusted for age, sex, region of residence, history of diabetes mellitus, cardiovascular disease, cerebrovascular disease, COPD, asthma, hypertension, or chronic kidney disease

and previous use of medication (aspirin, metformin, statin, or systemic steroid)

All SMD values were less than 0.1 in the propensity scorematched cohort, except Charlson comorbidity index among patients without AMD versus those with AMD and history of hypertension among patients without AMD versus those with non-exudative AMD. Numbers in bold indicate significant differences

He completed Ph.D. in vascular biology and informatics at KAIST (mentor: Injune Kim). He further studied retinal vascular biology at Nagoya City University

Dr Yang published more than 40 peer-reviewed papers, including publications as a major author in high-impact journal such as Circulation Research