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No treatment exists for mitochondrial dysfunction, a contributor to end-organ disease in human immunodeficiency virus (HIV). The mitochondrial antioxidant mitoquinone mesylate (MitoQ) attenuates mitochondrial dysfunction in preclinical mouse models of various diseases but has not been used in HIV. We used a humanized murine model of chronic HIV infection and polymerase chain reaction to show that HIV-1–infected mice treated with antiretroviral therapy and MitoQ for 90 days had higher ratios of human and murine mitochondrial to nuclear DNA in end organs compared with HIV-1–infected mice on antiretroviral therapy. We offer translational evidence of MitoQ as treatment for mitochondrial dysfunction in HIV. [ABSTRACT FROM AUTHOR]

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.

Background: Cytomegalovirus (CMV) infection and disease are preventable complications following pediatric liver transplantation (PLT), despite the use of prophylaxis to minimize the risk of CMV disease. We evaluated the incidence and complications of CMV disease in PLT recipients in South Africa (SA), with particular reference to potential differences in outcome between state and private sector patients. Methods: Medical records of patients younger than 16 years of age who received liver transplants between January 1, 2012, and August 31, 2018 were analyzed. Results: Records of all 150 PLT patients were retrieved. The median age at transplant was 29.2 months (95% confidence interval 15.6–58.4) and follow‐up was 46.3 months (interquartile range 27.6–63.1). Sixty‐six (44%) patients were high risk, 79 (52.7%) were intermediate risk, and five (3.3%) were low risk for CMV infection. Forty‐three (28.9%) patients had CMV DNAemia following transplantation, and 30 (20.1%) developed CMV disease. Receipt of care in the private sector was consistently associated with a lower hazard of CMV disease (adjusted hazard ratio [aHR] ranging from 0.36 to 0.43) and a consistently lower hazard of death among recipients at high risk for CMV disease and/or those who developed CMV disease (aHR ranging from 0.28 to 0.33). Conclusion: Receipt of care in the private health sector was associated with a consistently lower hazard of CMV disease and death in individuals with CMV disease and/or at high risk for CMV disease. Policies aimed at creating a more equitable healthcare system in SA may mitigate the differential burden of illness associated with CMV in PLT recipients. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection is common in people living with HIV, but multisystem CMV end-organ disease (EOD) is rare following the introduction of effective antiretroviral therapy. We present the case of a patient with advanced HIV and multisystem manifestations of CMV EOD. Contributions: This case report highlights the potential morbidity and mortality associated with CMV disease in patients with advanced HIV. Clinicians should be vigilant in considering CMV EOD in patients with advanced HIV and visual, neurological and gastointestinal symptoms.

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. [ABSTRACT FROM AUTHOR]

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.

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end-organ malfunctions. All follow the presence of persistent viral components and virions without evidence of viral replication. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways, specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding end-organ tissue damage. [ABSTRACT FROM AUTHOR]

End‐organ cytomegalovirus (CMV) disease can be life threatening to solid organ transplant recipients. Diagnosis is often complicated by variation in amount of CMV DNA in plasma and the need for an invasive procedure to obtain a biopsy of the suspected affected organ, which can delay recognition and treatment. Several inflammatory cytokines are elevated in CMV disease, and the purpose of this study was to determine if they could be used to distinguish solid organ transplant recipients with CMV DNAemia alone from those with possible end‐organ CMV disease. We found that regardless of pre‐transplant CMV serostatus, plasma interleukin (IL)‐18, tumor necrosis factor‐α (TNF‐α), and amount of CMV DNA in plasma were increased in possible end‐organ CMV disease, with elevated IL‐18 associated with increased odds of possible end‐organ CMV disease even after adjusting for amount of CMV DNA. These findings highlight IL‐18 and TNF‐α as potential non‐invasive markers of possible end‐organ CMV disease regardless of transplanted organ or serostatus in solid organ transplant recipients. [ABSTRACT FROM AUTHOR]

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end-organ malfunctions. All follow the presence of persistent viral components and virions without evidence of viral replication. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways, specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding end-organ tissue damage.

Cytomegalovirus (CMV) infection is common in people living with HIV, but multisystem CMV end-organ disease (EOD) is rare following the introduction of effective antiretroviral therapy. We present the case of a patient with advanced HIV and multisystem manifestations of CMV EOD. Contributions: This case report highlights the potential morbidity and mortality associated with CMV disease in patients with advanced HIV. Clinicians should be vigilant in considering CMV EOD in patients with advanced HIV and visual, neurological and gastointestinal symptoms. [ABSTRACT FROM AUTHOR]

Abstract: Human Herpes Virus 6 (HHV‐6) reactivation occurs in approximately half of patients following allogeneic hematopoietic stem cell transplant (HSCT). While encephalitis and delayed engraftment are well‐documented complications of HHV‐6 following HSCT, the extent to which HHV‐6 viremia causes disease in children is controversial. We performed a retrospective review of HHV‐6 reactivation and possible manifestations in pediatric allogeneic HSCT patients at a single institution. Of 89 children and young adults who underwent allogeneic HSCT over a three‐and‐a‐half‐year period, 34 patients reactivated HHV‐6 early post‐transplant. Unrelated donor stem cell source and lack of antiviral prophylaxis were risk factors for the development of HHV‐6 viremia. Viremia correlated with the presence of acute graft‐versus‐host disease, but not chronic graft‐versus‐host disease. We identified two subgroups within the viremic patients—a high‐risk viremic and tissue‐positive group that reactivated HHV‐6 and had suspected end‐organ disease and a low‐risk viremic but asymptomatic group that reactivated HHV‐6 but did not exhibit symptoms or signs of end‐organ disease. Peak viral load was found to be strongly associated with mortality. Prospective studies in larger numbers of patients are needed to further investigate the role of HHV‐6 in causing symptomatic end‐organ disease as well as the association of viral load with mortality. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest associated with this manuscript to declare., (Copyright © 2021. Published by Elsevier B.V.)

The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted. [ABSTRACT FROM AUTHOR]

We studied the main clinical features, outcome, and laboratory parameters in a group of solid organ transplant (SOT) patients with immunohistochemically proven cytomegalovirus (CMV) disease. Confirmed CMV cases were obtained through databases. Demographics, clinical data, transplantation type, immunosuppressive regimens, donor and recipient CMV serostatus, therapy, outcome and laboratory results, pp65 antigenemia, and qualitative polymerase chain reaction (PCR) for CMV were analyzed. From 1995 to 2004, 31 cases with complete medical records were identified. Disease appeared between 24 and 2538 days after transplantation but most cases presented in the first 100 days. Gastrointestinal CMV disease was the most frequent form (71%), while thrombocytopenia was present in 50% of cases, and leukopenia was less common (35.5%). CMV pp65 antigenemia was positive in 58% of patients, but its sensitivity increased to 71% if performed during the first 6 months. A qualitative CMV PCR technique gave similar results during this period (71.4%). Most patients were treated with intravenous ganciclovir ( n=25; 80.6%). In 4 cases (19.4%), use of foscarnet alone or a sequential regimen with ganciclovir–foscarnet was deemed necessary. Surgical procedures were necessary in 5 patients (16%). The death rate reached 13%. CMV end-organ disease can be a life-threatening infection in SOT patients. Gastrointestinal disease was the most frequent end-organ disease. CMV antigen detection is best suited for the early period after transplantation. [ABSTRACT FROM AUTHOR]

Active infection with cytomegalovirus (CMV) occurs in patients who are immunocompromised and may produce the high viral loads required to cause end-organ disease. Such patients have complex medical histories and many experienced physicians have speculated that CMV may, additionally, contribute to adverse clinical outcomes. In 1989, Dr Bob Rubin coined the term "indirect effects" to describe this potential relationship between virus and patient. Examples include accelerated atherosclerosis in patients after heart transplant or with underlying HIV infection, the number of days patients require ventilation after admission to intensive care units, the development of immunosenescence in the elderly and mortality in many groups of patients, including the general population. It is difficult to distinguish between CMV acting as causal contributor to such diverse pathology or simply having a benign bystander effect. However, recruitment of patients into placebo-controlled randomised trials of antiviral drugs with activity against CMV offers such a potential. This article describes the studies that have been conducted to date and emphasises that mortality after stem cell transplant (not attributed to CMV end-organ disease) has recently become the first proven indirect effect of CMV now that letermovir has significantly reduced non-relapse deaths. The implications for CMV vaccines are then discussed. Vaccines are already predicted to be highly cost-effective if they can reduce CMV end-organ disease. Health planners should now consider that cost effectiveness is likely to be enhanced further through reduction of the indirect effects of CMV. A prototype scheme for assessing this possibility is provided in order to stimulate discussion within the field. This article forms part of an online symposium on the prevention and therapy of DNA virus infections, dedicated to the memory of Mark Prichard. • CMV is a common infection normally controlled by the immune system. • Replication to high viral loads may cause end-organ disease. • Replication is also associated with adverse clinical outcomes, termed indirect effects. • The results of randomised clinical trials of antiviral drugs can prove that CMV is the cause of these indirect effects. • These indirect effects may also be reduced by vaccines able to prevent active CMV infection. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Termedia & Banach.)

Background The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ >500 cells/µL) vs deferred (to CD4+ <350 cells/µL or AIDS) antiretroviral therapy (ART) initiation reduced risk for AIDS and serious non-AIDS (SNA). We investigated associations of inflammation, coagulation, and vascular injury biomarkers with AIDS, SNA or death, and the effect of immediate ART initiation. Methods Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry. Results Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37–1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%–21%. Conclusions These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naïve and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART. [ABSTRACT FROM AUTHOR]

Background: Human cytomegalovirus (HCMV) is an important pathogen in HIV exposed infants with pneumonia. However, the diagnosis of HCMV pneumonia in this setting is challenging due to limited access to bronchoscopy, lung biopsy and direct sampling of the lower respiratory tract. HCMV viraemia is more accessible, but their diagnostic performance in this context has not been studied., Objective: To describe the prevalence of HCMV viraemia and evaluate its clinical utility in HIV exposed infants., Study Design: In this cross-sectional study, we performed qualitative and quantitative PCR to detect HCMV viraemia in HIV exposed asymptomatic infants and in infants with severe pneumonia in the Western Cape province of South Africa., Results: 283 asymptomatic HIV exposed infants and 142 HIV exposed infants with severe pneumonia were studied. Infants with pneumonia had a higher prevalence of HCMV viraemia compared to asymptomatic infants (68% vs 24% OR 6.7, 95% CI 4.2-10.8). This increased prevalence remained significant (OR 4.3 95% CI 2.6-7.0) after adjusting for HIV infection. Of the infants with pneumonia, the level of HCMV viraemia was significantly higher in a subset of infants diagnosed with HCMV pneumonia (median HCMV viral load 4.6 vs 2.5 log copies/ml p<0.001). Receiver operator characteristic (ROC) analysis showed the area under the curve was 0.78 (95% CI 0.71-0.86) and a threshold of 4.1 log copies/ml was able to correctly identify 70% of HCMV pneumonia cases., Conclusion: Prevalence and level of HCMV viraemia in sub-Saharan HIV-exposed and infected infants peaks at 3-4 months of age. Quantitative HCMV PCR may be useful in diagnosing HCMV pneumonia., (Copyright © 2013 Elsevier B.V. All rights reserved.)