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.

Clinical Implication of Candida Score in Multidrug-Resistant Pneumonia with Airway Candida Colonization.

BACKGROUND: The growth of Candida in respiratory secretions is usually considered colonization, and antifungal therapy is rarely required. The role of Candida colonization in the progression of bacterial pneumonia remains controversial. The aim of this study was to identify the clinical implication of Candida score by analyzinge the relationship with multidrug-resistant (MDR) pneumonia and prognosis in patients with airway Candida colonization. MATERIALS AND METHODS: This study was a retrospective review of patients with airway Candida colonization by bronchial washing or bronchoalveolar lavage. The Candida score was calculated according to the four factors (severe sepsis, surgery at baseline, total parenteral nutrition, and multifocal Candida colonization). Pneumonia related mortality or hopeless discharge expecting death was defined as a poor outcome. RESULTS: A total of 148 patients were enrolled in the study. In a multivariate analysis model, Candida score was identified as an independent predictor of poor outcomes (odds ratio 2.23; 95% confidential interval 1.57 - 3.17; P <0.001) in pneumonia patients with airway Candida colonization. With a Candida score of three or higher compared with low score group, it was associated with bacterial pneumonia, especially methicillin-resistant Staphylococcus aureus (MRSA) infection (0.0% vs. 15.2%, P = 0.004). In addition, patients with a high Candida score had a longer hospital stay (13 vs. 38 days, P <0.001), longer duration of intensive care (7 vs. 18 days, P <0.001), and higher pneumonia-related mortality (0.0% vs. 45.5%, P <0.001) as compared to the low Candida score group. The Candida score showed a positive correlation with other pneumonia severity scales such as CURB-65 (Confusion, Urea, Respiratory rate, Blood pressure, and age ≥65 years) (r = 0.461, P <0.001), Pneumonia Severity Index (r = 0.397, P <0.001), and predisposition, insult, response, and organ dysfunction (PIRO) score (r = 0.425, P <0.001). CONCLUSION: This study revealed that Candida is no longer a bystander of airway colonization, and that it affects the progression of bacterial pneumonia, including multidrug-resistant pathogens, particularly MRSA infection. Also Candida score can be used to predict the prognosis of patients with pneumonia.

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.

Incidence rate of active tuberculosis in solid organ transplant recipients: Data from a nationwide population cohort in a high-endemic country.

BACKGROUND: The management of active tuberculosis (TB) in solid organ transplantation (SOT) recipients is challenging given the pharmacological interaction and the potential delays in diagnosis due to atypical presentation. The incidence rates (IRs) of post-SOT TB from the whole recipients' cohort in a high-endemic country have not been evaluated. METHODS: We established a SOT cohort (n = 15 598) and confirmed cases of TB between 2011 and 2015 from the Korean National Health Insurance Database using ICD-10 codes. After excluding 1302 and 180 SOT-recipients due to age (<18 years) and presence of pre-SOT TB and/or treatment for latent TB during wash-out period between 2006 and cohort entry, we analyzed 14 116 SOT recipients and 70 580 individuals with no history of SOT matched by age and sex. The hazard ratios (HRs) of IRs were adjusted for age, sex, low-income status, diabetes mellitus, chronic co-morbidities, and anti-TNF-α therapy. RESULTS: The IR of TB was significantly higher (adjusted HR [aHR]: 6.1, 95% confidence interval [CI]: 4.5-7.6) in SOT recipients (4.9/1000 person-years) than in non-SOT individuals (0.8/1000 person-years). Of the transplanted organs, the pancreas (pancreas alone and simultaneous pancreas-kidney) and lung had the highest IR (aHR: 16.3 [6.1-42.2] and 16.1 [5.9-43.8], respectively). The use of anti-thymocyte globulin and azathioprine was associated with a higher IR (aHR: 1.53 [1.01-2.43] and 3.92 [1.21-12.47], respectively), but basiliximab was associated with a lower IR (aHR: 0.67 [0.48-0.98]). CONCLUSION: The IR of TB in SOT recipients, especially in the pancreas and lung, was significantly higher than that in the non-SOT population.

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.

Incidence of herpes zoster in adult solid organ transplant recipients: A meta-analysis and comprehensive review.

BACKGROUND: Chronic immunosuppressive therapy in solid organ transplant (SOT) recipients can trigger latent varicella zoster virus reactivation even in those with stable graft function. The inactivated herpes zoster (HZ) vaccine can be effective in preventing post-transplant HZ, which can cause severe neuralgia or disseminated disease. This meta-analysis aims to assess the incidences of HZ across transplant organs in SOT recipients. METHODS: We included 12 observational studies (6560 recipients) from a PubMed and EMBASE search of articles through October 2019 and collected data from single-center dating from January 2001 to December 2017 (3498 recipients). The pooled HZ incidence and its differences between subgroups were obtained from random-effect models and meta-analysis of variance tests using R package. RESULTS: The overall pooled crude incidence was 9.1% (95% confidence interval [CI], 7.6%-10.8%). The pooled incidence was similar between sexes but significantly different between transplanted organs (P < .001). Heart transplants (HT) (n = 644) have the highest pooled incidence with 15.2% (95% CI, 12.7%-18.2%), followed by lung transplants (LTX) (n = 780) with 11.0% (8.3%-14.4%). Kidney transplants (n = 5435) have the lowest incidence of 6.7 (5.1%-8.8%). The meta-regression analysis revealed that HZ development had a relationship with past graft rejection (P = .024). CONCLUSION: These data support the need for subunit HZ vaccination in SOT recipients with a high risk for HZ, especially HT and LTX recipients, without respect to the late post-transplant period.

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.

Association between cytomegalovirus end-organ diseases and moderate-to-severe dementia: a population-based cohort study.

BACKGROUND: The association between cytomegalovirus (CMV) and dementia remains controversial. Previous studies have suggested that CMV serostatus, as assessed by serum immunoglobulin G, plays a role in neurodegeneration with cognitive impairment. We aimed to evaluate the association between CMV tissue-invasive end-organ diseases and moderate-to-severe dementia. METHODS: The ICD 10th revision codes from the National Health Insurance Database covering the entire population of the Republic of Korea were used to classify patients into exposed (n = 687, age ≥ 40 years, with CMV disease) and unexposed (n = 3435, without CMV disease) groups, matched by age and sex at a 1:5 ratio of exposed: unexposed. All non-HIV-1-infected subjects selected during 2010-2014 with a washout period of the previous 4 years were followed up until December 2016 to identify newly diagnosed cases of moderate-to-severe dementia. RESULTS: Multivariate regression model (M3) adjusted for age, sex, low income, body mass index, transplantation status, malignant neoplasms, end-stage renal disease on dialysis, type 2 diabetes mellitus, hypertension, and dyslipidaemia showed a significantly higher incidence of dementia (odds ratio: 1.9; 95% confidence interval: 1.2-2.8) in the exposed group than that in the unexposed group. The risk of vascular dementia (2.9, 1.1-7.5) was higher than that of Alzheimer's disease (1.6, 1.0-2.6) in the exposed group in M3. In M3, patients aged 40-59 years with CMV diseases had a significantly higher risk of all kinds of dementia than those aged 60-79 and ≥ 80 years (11.7, 2.5-49.4 vs. 1.8, 1.1-3.2 vs. 1.3, 0.5-2.8; P = 0.025). CONCLUSIONS: CMV diseases may be associated with the risk of moderate-to-severe dementia.

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.