Association of cytomegalovirus diseases with newly developed myocardial infarction and congestive heart failure: data from a national population-based cohort.

Introduction: Anti-cytomegalovirus (CMV) IgG seropositive and/or titer are associated with a higher risk of cardiovascular diseases (CVD). However, it is not clear whether CMV end-organ disease may have a relation with development of CVD or chronic heart diseases. Material and methods: In matched cohort study, the National Health Insurance Database covering 50 million people was used to identify 667 patients with CMV diseases and aged ≥ 20 years between 2010 and 2014. 6,670 control subjects without CMV diseases were matched by age, sex, type 2 diabetes mellitus (DM), hypertension, dyslipidemia, and cohort entry year. Data on CMV disease and heart disease events of myocardial infarction (MI), congestive heart failure (CHF), and atrial fibrillation (AF) were retrieved. Previous events before CMV disease or cohort entry were excluded until January 2006. Subjects were followed until December 2015 in subjects without events and until date of events in subjects with events. Results: The multivariate regression model adjusted by age, sex, low-income status, type 2 DM, hypertension, dyslipidemia, solid organ transplantation, and hematopoietic stem cell transplantation showed a significantly higher incidence rate of MI (odds ratio (OR) = 2.1, 95% confidence intervals (CI): 1.0-4.5) and CHF (OR = 3.8, 95% CI: 2.1-6.8) but not AF (OR = 1.9, 95% CI: 0.9-4.0) in patients with CMV disease. The age group of 40-64 years with CMV disease had the highest risk for new-onset CHF in this regression model (OR = 9.4, 95% CI: 4.12-21.44, p = 0.029). Conclusions: Symptomatic CMV tissue-invasive diseases were associated with a higher risk of new-onset MI and CHF.

Epidemiological changes in cytomegalovirus end-organ diseases in a developed country: A nationwide, general-population-based study.

BACKGROUND: Cytomegalovirus (CMV) can cause tissue-invasive diseases in various organs after primary infection or through reactivation of latent-to-lytic switch over a lifetime. The number of individuals who are at risk of CMV diseases, such as elderly or immunocompromised patients, is constantly increasing; however, recent epidemiological changes associated with CMV disease have not been fully evaluated. METHODS: We used claims data of about 50 million individuals between 2010 and 2015 from the Korean Health Insurance Review and Assessment Service nationwide database. The code for CMV end-organ diseases in the 'Relieved Co-payment Policy' program matches the ICD-10 code of B25, except for congenital CMV infection and mononucleosis. A 628 cases of CMV and 3140 controls (without CMV disease), matched for age and sex, were selected from this dataset in order to evaluate the effect of adult CMV diseases on all-cause death. RESULTS: The overall unadjusted incidence rate (IR) of CMV end-organ diseases was 0.52/100,000 individuals. The standardized IR, adjusted for age and sex, have continuously increased from 0.32/100,000 in 2010 to 0.75/100,000 in 2015. The overall unadjusted IR in adult population was highest in 70-79 years for six years (0.96/100,000). In the model adjusted for age, sex, immunocompromised status including solid-organ or hematopoietic stem cell transplant recipients, hematologic malignancies, and human immunodeficiency virus diseases, the hazard ratio of case group was 5.2 (95% confidence interval, 3.6-7.4) for all-cause mortality. CONCLUSION: Nationwide data indicates that CMV end-organ disease has steadily increased in the past six years and is associated with higher mortality.

The Incidence and Effect of Cytomegalovirus Disease on Mortality in Transplant Recipients and General Population: Real-world Nationwide Cohort Data.

Background: In addition to the conventional opportunistic infections in solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) recipients, cytomegalovirus (CMV) infection is associated with various chronic inflammatory diseases or poor outcomes in non-immunocompromised critically ill patients. To evaluate the burden or outcome of CMV replication in non-transplant individuals, we compared the incidence rates (IRs) for CMV disease and all-cause mortality between SOT recipients, HSCT recipients, and non-transplant population. Methods: The SOT (N=16,368) and HSCT (N=10,206) cohorts between 2010 and 2015 were established using the WHO ICD-10 from the whole population-based large database of the Health Insurance Review & Assessment Service (HIRA). CMV cases, defined as symptomatic disease with isolation of virus, DNA, pp65 antigen, and pathology except CMV syndrome, were extracted with the unique codes for relief of medical costs of HIRA in the same dataset. Cox's proportional hazard regression analyses and log-rank test in the Kaplan-Meier curves were performed to compare all-cause mortality between the three groups. Results: The CMV IRs adjusted by age and sex were significantly higher in the SOT (adjusted IR [95% confidence intervals], 33.1 [28.8-38.0] per 1,000 person-years) and HSCT recipients (5.1 [4.6-6.1] per 1,000 person-years) than in the whole population (0.58 [0.49-0.67] per 100,000 person-years). However, SOT recipients with CMV (18/283, 6.4%) had significantly lower all-cause mortality than non-transplant individuals with CMV (207/1,258, 16.5%) (adjusted hazard ratio [95% CI], 0.42 [0.25-0.67], log-rank P < 0.001). Conclusion: These data suggest that CMV disease in patients without transplants is associated with poor outcomes.

Characteristics of community-acquired respiratory viruses infections except seasonal influenza in transplant recipients and non-transplant critically ill patients.

BACKGROUND/PURPOSE: Transplant recipients are vulnerable to life-threatening community-acquired respiratory viruses (CA-RVs) infection (CA-RVI). Even if non-transplant critically ill patients in intensive care unit (ICU) have serious CA-RVI, comparison between these groups remains unclear. We aimed to evaluate clinical characteristics and mortality of CA-RVI except seasonal influenza A/B in transplant recipients and non-transplant critically ill patients in ICU. METHODS: We collected 37,777 CA-RVs multiplex real-time reverse transcription-polymerase chain reaction test results of individuals aged ≥18 years from November 2012 to November 2017. The CA-RVs tests included adenovirus, coronavirus 229E/NL63/OC43, human bocavirus, human metapneumovirus, parainfluenza virus 1/2/3, rhinovirus, and respiratory syncytial virus A/B. RESULTS: We found 286 CA-RVI cases, including 85 solid organ transplantation recipients (G1), 61 hematopoietic stem cell transplantation recipients (G2), and 140 non-transplant critically ill patients in ICU (G3), excluding those with repeated isolation within 30 days. Adenovirus positive rate and infection cases were most prominent in G2 (p < 0.001). The median time interval between transplantation and CA-RVI was 30 and 20 months in G1 and G2, respectively. All-cause in-hospital mortality was significantly higher in G3 than in G1 or G2 (51.4% vs. 28.2% or 39.3%, p = 0.002, respectively). The mechanical ventilation (MV) was the independent risk factor associated with all-cause in-hospital mortality in all three groups (hazard ratio, 3.37, 95% confidence interval, 2.04-5.56, p < 0.001). CONCLUSIONS: This study highlights the importance of CA-RVs diagnosis in transplant recipients even in long-term posttransplant period, and in non-transplant critically ill patients in ICU with MV.

Effects of Multidrug-resistant Bacteria in Donor Lower Respiratory Tract on Early Posttransplant Pneumonia in Lung Transplant Recipients Without Pretransplant Infection.

BACKGROUND: Multidrug-resistant (MDR) bacteria in the lower respiratory tracts of allografts may be risk factors for early posttransplant pneumonia (PTP) that causes detrimental outcomes in lung transplant recipients (LTRs). We evaluated the effects of immediate changes in MDR bacteria in allografts on early PTP and mortality rates in LTRs. METHODS: We reviewed 90 adult bilateral LTRs without pretransplant infections who underwent lung transplantation between October 2012 and May 2018. Quantitative cultures were performed with the bronchoalveolar lavage fluids of the allografts preanastomosis and within 3 days posttransplant. The International Society for Heart and Lung Transplantation consensus defines early PTP as pneumonia acquired within 30 days posttransplant and not associated with acute rejection. RESULTS: MDR Acinetobacter baumannii (11/34, 32.4%) and Staphylococcus aureus (9/34, 26.5%) were identified in 24.4% (22/90) of the preanastomosis allografts. Four LTRs had the same MDR bacteria in allografts preanastomosis and posttransplant. Allograft MDR bacteria disappeared in 50% of the LTRs within 3 days posttransplant. Early PTP and all-cause in-hospital mortality rates were not different between LTRs with and without preanastomosis MDR bacteria (P = 0.75 and 0.93, respectively). MDR bacteria ≥10 CFU/mL in the lungs within 3 days posttransplant was associated with early PTP (odds ratio, 5.8; 95% confidence interval, 1.3-27.0; P = 0.03). CONCLUSIONS: High levels of preexisting MDR bacteria in allografts did not increase early PTP and mortality rates in LTRs. Despite the small and highly selective study population, lung allografts with MDR bacteria may be safely transplanted with appropriate posttransplant antibiotic therapy.

Human cytomegalovirus seroprevalence and titres in solid organ transplant recipients and transplant donors in Seoul, South Korea.

BACKGROUND: Human cytomegalovirus (HCMV) can cause poor outcomes in solid organ transplant (SOT) recipients; moreover, it is associated with cardiovascular diseases (CVD) in the general population. Accordingly, anti-HCMV immunoglobulin G (IgG) seroepidemiology may be useful in identifying the risk of post-SOT HCMV infection or disease as well as immunosenescence or CVD. However, HCMV seroprevalence and titre have not been fully evaluated with regard to age distribution or compared between SOT recipients and healthy individuals in South Korea. METHODS: We retrospectively retrieved all unduplicated anti-HCMV IgG results of individuals aged > 1 year evaluated between July 2006 and November 2017 at Severance Hospital in Seoul. The cohort, excluding haematopoietic stem cell transplant recipients and subjects with equivocal values, included 2184 SOT recipients and 3015 healthy transplant donors. All IgG results in the SOT recipients were measured during the pre-transplant period. RESULTS: The overall IgG seroprevalence and titres were significantly higher among SOT recipients than among healthy donors (98.7% vs. 88.6%, p < 0.001, and 64.7 ± 44.3 vs. 49.8 ± 20.6 arbitrary units/mL, p < 0.001, respectively). The lowest seropositive rate in the SOT group was observed in recipients aged between 11 and 15 years (70.6%). The frequency of seropositivity among adults aged ≥41 years increased to ≥90% in SOT recipients and healthy donors. Age was independently associated with higher HCMV seroprevalence (41-60 years, OR, 76.4, 95% CI, 24.5-238.9, p < 0.001; ≥ 61 years, OR, 4.4, 95% CI, 1.3-14.9, p < 0.001, compared to ≤40 years). The healthy donor group had an independently low HCMV seropositive rate (OR, 0.1, 95% CI, 0.1-0.2, p < 0.001). CONCLUSIONS: HCMV seropositivity was the lowest among school-aged children and adolescents. IgG testing revealed an intermediate serostatus risk of post-transplant HCMV infection and disease for most adult SOT recipients in South Korea.

Impact of Cytomegalovirus Disease on New-Onset Type 2 Diabetes Mellitus: Population-Based Matched Case-Control Cohort Study.

BACKGROUND: A latent cytomegalovirus (CMV) cause chronic inflammation through undesirable inflation of cell-mediated immune response. CMV immunoglobulin G has been associated with cardiovascular disease and type 1 diabetes mellitus. We evaluated impact of CMV diseases on new-onset type 2 diabetes mellitus (T2DM). METHODS: From the Korean Health Insurance Review and Assessment Service claim database of entire population with 50 million, we retrieved 576 adult case group with CMV diseases diagnosed with International Statistical Classification of Diseases and Related-Health Problems 10th Revision (ICD-10) B25 code between 2010 and 2014 after exclusion of patients with T2DM to 2006. The 2,880 control patients without T2DM from 2006 to cohort entry point were selected between 2010 and 2014 by age, sex matching with case group. The subjects without new-onset T2DM were followed until 2015. T2DM, hypertension (HTN), dyslipidemia (DYS), and end-stage renal disease (ESRD) were coded as ICD-10. RESULTS: The frequency of new-onset T2DM in case group was significantly higher than that in control (5.6% vs. 2.2%, P<0.001). The group with T2DM (n=95) had higher incidence of CMV diseases than the group without T2DM (n=3,361) (33.7% vs. 16.2%, P<0.001). In multivariate regression model adjusted by age, sex, lower income, HTN, and DYS, the incidence rate (IR) of T2DM in case group was significantly higher than that in the control group (IR per 1,000, 19.0 vs. 7.3; odds ratio, 2.1; 95% confidence interval, 1.3 to 3.2). The co-existence of HTN, DYS, and ESRD with CMV diseases did not influence the IR of T2DM. CONCLUSION: CMV diseases increase the patients' risk of developing T2DM.

Cycloplegic Refraction in Hyperopic Children: Effectiveness of a 0.5% Tropicamide and 0.5% Phenylephrine Addition to 1% Cyclopentolate Regimen.

PURPOSE: To evaluate the effectiveness of a cycloplegic regimen using 0.5% tropicamide and 0.5% phenylephrine (Tropherine, Hanmi Pharm), in addition to 1% cyclopentolate, in hyperopic children. METHODS: The medical records of hyperopic patients below the age of 14 years who had undergone cycloplegic retinoscopy were retrospectively reviewed. Cycloplegic refractions were performed using one of two cycloplegic regimens. Regimen 1 was a Tropherine-added regimen comprising the administration of one drop of 1% cyclopentolate followed by two to three drops of Tropherine added at 15-minute intervals. Regimen 2 was a cyclopentolate-only regimen comprising the administration of three to four drops of 1% cyclopentolate at 15-minute intervals. The mean difference between noncycloplegic and cycloplegic refraction was compared between the two regimens. RESULTS: A total of 308 eyes of 308 hyperopic children were included. The mean difference (±standard deviation) in the spherical equivalent (SE) between cycloplegic and noncycloplegic refraction was significantly larger in regimen 2 than in regimen 1, with values of +1.70 ± 1.03 diopters (D) and +1.25 ± 0.89 D, respectively (p=0.001). The SE change after cycloplegia was significantly different between the two regimens only in patients aged 5 years or younger (p=0.001), particularly in those with high hyperopia with an SE ≥5 D (p=0.005) or fully accommodative esotropia (p=0.009). There was no significant difference between the two regimens in patients older than 5 years, regardless of the presence of high hyperopia or fully accommodative esotropia. CONCLUSIONS: The Tropherine-added regimen exerted a weaker cycloplegic effect than the cyclopentolate-only regimen, particularly in children under the age of 5 years with high hyperopia or fully accommodative esotropia. However, the difference in refraction between the two regimens was small. A Tropherine-added regimen can be effective in hyperopic children, with less associated discomfort than the instillation of cyclopentolate.

RETINAL PIGMENT EPITHELIAL TEAR AFTER INTRAVITREAL RANIBIZUMAB TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the risk factors for retinal pigment epithelium (RPE) tears after intravitreal ranibizumab injections in neovascular age-related macular degeneration (nAMD) and to determine the efficacy of continued ranibizumab treatment after RPE tears. METHODS: A total of 407 treatment-naïve eyes (377 patients) with nAMD were retrospectively included. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline characteristics and pigment epithelial detachment (PED) lesion features were evaluated as potential risk factors for RPE tear. The visual and anatomical outcomes after treatment during 12 months were also evaluated. RESULTS: By 12 months, RPE tears developed in 32 eyes (7.9%). Pigment epithelial detachment height was associated with a higher risk of RPE tear (odds ratio [OR], 1.318; 95% confidence interval [CI], 1.217-2.031, P = 0.018). Fibrovascular PED compared with serous PED had a higher risk of developing tears (OR, 9.129; 95% CI, 6.228-32.124, P = 0.039), and typical nAMD (OR, 4.166; 95% CI, 2.030-14.913, P = 0.031) and retinal angiomatous proliferation (OR, 3.778; 95% CI, 2.185-9.277, P = 0.040) had a higher risk of developing tears compared with polypoidal choroidal vasculopathy. Mean best-corrected visual acuity (BCVA) of RPE tear patients showed no significant improvement after treatment at 12 months; however, patients with RPE tears without foveal involvement (19 eyes) showed significant BCVA improvement at 12 months (P = 0.034). CONCLUSION: PED type and nAMD subtype are associated with the development of RPE tears after intravitreal ranibizumab injections. Continued ranibizumab therapy after RPE tear development can maintain visual acuity when the fovea is not involved.

Retinal Pigment Epithelial Tear After Intravitreal Ranibizumab Treatment for Retinal Angiomatous Proliferation.

PURPOSE: To evaluate the incidence and associated risk factors of retinal pigment epithelium (RPE) tears after intravitreal ranibizumab injection treatment for retinal angiomatous proliferation (RAP). DESIGN: Retrospective, observational case series. METHODS: Ninety-eight treatment-naïve RAP eyes (86 patients) that received intravitreal ranibizumab injections were included. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline characteristics and features were evaluated as potential risk factors for RPE tearing. The visual and anatomic outcomes after treatment were evaluated at 12 months from baseline. RESULTS: RPE tears had developed in 8.2% (8) of the eyes by 12 months. Of these, all had pigment epithelium detachment (PED) at baseline, and the majority (7) had developed an RPE tear within 3 months. Multiple regression analysis showed that higher PED (odds ratio [OR] = 1.411, 95% confidence interval [CI] = 1.199-1.888, P = .011) and thinner choroid (OR = 0.815, 95% CI = 0.719-0.912, P = .023) were associated with a higher risk of RPE tearing. The mean best-corrected visual acuity of the patients with RPE tearing (0.56 ± 0.49 logarithm of the minimal angle of resolution [logMAR]) was significantly worse at 12 months than that of patients without RPE tearing (0.74 ± 0.55 logMAR, P = .009) after treatment. CONCLUSIONS: RPE tears developed in 8.2% of eyes with RAP during the 12 months following ranibizumab injections. Higher PED height and thinner subfoveal choroidal thickness were associated with the development of RPE tears after ranibizumab treatment for RAP.

Short-term efficacy of intravitreal triamcinolone acetonide for macular edema secondary to retinal vein occlusion that is refractory to intravitreal bevacizumab.

AIMS: To evaluate the 1-month efficacy of intravitreal triamcinolone acetonide (TA) in treating macular edema secondary to retinal vein occlusion (RVO) that was refractory to intravitreal bevacizumab. MATERIALS AND METHODS: This retrospective, observational study included 23 eyes from 23 patients with macular edema secondary to RVO. Macular edema that did not respond to two or more consecutive intravitreal bevacizumab injections was treated with intravitreal TA. Central foveal thickness (CFT) and best-corrected visual acuity (BCVA) were compared before and one month after TA injection. RESULTS: Fifteen eyes were diagnosed with central RVO, and eight eyes were diagnosed with branch RVO. All patients were previously treated with 2.4 ± 0.6 intravitreal bevacizumab injections. The TA injection was performed, on average, 5.8 ± 1.4 weeks after the last bevacizumab injection. The CFT before TA injection was 516.6 ± 112.4 µm and significantly decreased to 402.3 ± 159.7 µm after TA therapy (P < 0.001). The logarithm of the minimal angle of resolution BCVA was 0.72 ± 0.34 before TA therapy and was not significantly improved by the treatment (0.67 ± 0.35, P = 0.119), despite a decrease in CFT. However, seven eyes (30.4%) had a BCVA gain of one or more lines. CONCLUSIONS: Intravitreal TA therapy was beneficial in some patients with macular edema secondary to RVO that was refractory to intravitreal bevacizumab therapy. This study suggests that intravitreal TA should be considered as a treatment option for refractory macular edema.

Risk factors for geographic atrophy after intravitreal ranibizumab injections for retinal angiomatous proliferation.

PURPOSE: To describe the risk factors for the development of geographic atrophy (GA) following intravitreal ranibizumab injection treatment for retinal angiomatous proliferation (RAP). DESIGN: Retrospective interventional series. METHODS: Forty-three eyes (38 South Korean patients) from patients being treated for naïve RAP with intravitreal ranibizumab injection were included in this study. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline ocular characteristics and lesion features assessed using fluorescein angiography (FA), indocyanine angiography (ICGA), and spectral-domain optical coherence tomography (SD OCT) were evaluated as potential risk factors for GA through 2 years of follow-up. RESULTS: At 2 years follow-up, GA had developed in 16 of 43 eyes (37.2%). The mean number of ranibizumab injections was 7.52 ± 2.11. Using multiple logistic regression, thinning of the subfoveal choroid at baseline (odds ratio [OR], 0.955; 95% confidence interval [CI], 0.929-0.982; P = .002), presence of reticular pseudodrusen (OR, 1.092; 95% CI, 1.017-1.485; P = .039), and presence of GA in the fellow eye at baseline (OR, 1.433; 95% CI, 1.061-1.935; P = .025) were identified as significant risk factors for GA development. CONCLUSIONS: GA developed in 37.2% of eyes with RAP during the 24 months following intravitreal ranibizumab injections. Subfoveal choroidal thinning at baseline, the presence of reticular pseudodrusen, and the presence of GA in the fellow eye at baseline were associated with increased risk of GA development after treatment.