Prior Cytomegalovirus Infection Research Articles

Human Cytomegalovirus (CMV) Infection Associated With Decreased Risk of Bronchogenic Carcinoma: Understanding How a Previous CMV Infection Leads to an Enhanced Immune Response Against Malignancy.

​Cytomegalovirus (CMV) causes a long-lasting, asymptomatic infection that reportedly has both advantageous and deleterious effects on tumor progression. The purpose of this study was to evaluate the correlation between CMV infection and the incidence of bronchogenic carcinoma. The study was conducted using a Health Insurance Portability and Accountability Act (HIPAA)compliant national database to identify patients both with and without histories of CMV infectionusing International Classification of Diseases (ICD-10 and ICD-9) codes. Access to the database was granted by Holy CrossHealth, Fort Lauderdale for the purpose of academic research with standard statistical methods used to analyze the data. 14,319 patients were included in both the control and CMV-exposed groups and matched by age range and Charlson Comorbidity Index (CCI) scores. The incidence of bronchogenic carcinomawas 1.69% (243/14,319 patients) in the CMV group and 6.08% (871/14,319 patients)in the control group. The difference was statistically significant bya p-value of less than 2.6x10-16 with anodds ratio of 0.26 (95% CI: 0.24-0.30). The two groups were also matched for treatment. Further evaluation of the CMV-specific treatment effects on outcomes was limited due to the insufficient number of treated patients in the control group. This study found a statistically significant correlation between a prior CMV infection and a reduced incidence of bronchogenic carcinoma. This study demonstrates the need for further investigation into how the tumor microenvironment and host immune system are altered by the presence of a latent CMV infection.

Incidence and risk factors of opportunistic infections after autologous stem cell transplantation: a nationwide, population-based cohort study in Korea

Several guidelines classify autologous stem cell transplantation (ASCT) as a low to intermediate risk group for infection. In a nationwide population-based study, using the Korean Health Insurance Review and Assessment Service database, patients with lymphoma and multiple myeloma (MM) who underwent ASCT from 2002 to 2016 were retrospectively analyzed. Cumulative incidence rates (CIRs) and risk factors of opportunistic infections were investigated. CIRs of fungal, Varicella zoster virus (VZV), cytomegalovirus (CMV), and Pneumocystis jirovecii infections in lymphoma were 7.9%, 16.0%, 7.4%, and 5.1%, respectively, and CIRs in MM were 6.3%, 19.1%, 4.2%, and 5.6%, respectively. Fungal infection was significantly higher in patients with previous infection (Hazard ratio (HR) 2.003, p = 0.005) in lymphoma. Incidence of CMV infection was significantly higher in patients with prior CMV infection: HR 4.920, p < 0.001 (lymphoma); HR 3.022, p = 0.030 (MM). VZV infection was significantly lower in patients receiving prophylaxis: HR 0.082, p < 0.001 (lymphoma); HR 0.096, p < 0.001 (MM). For P. jirovecii infection, busulfex and melphalan conditioning (HR 1.875, p = 0.032) and previous P. jirovecii infection (HR 4.810, p < 0.001) had a higher incidence in MM. Patients who underwent ASCT should receive VZV prophylaxis and prophylaxis for fungal and P. jirovecii may be considered in patients with previous same infection.

Environmental Interaction of Resolved Human Cytomegalovirus Infection With Crohn's Disease Location.

Lay Summary Active cytomegalovirus (CMV) infection complicates management of inflammatory bowel disease, but the relationship of resolved CMV infection to Crohn’s disease (CD) behavior or localization is unknown. This article reports a striking risk (9-fold) of Crohn’s disease localization to the colon with prior CMV infection. It also reports imputed mucosal cellular composition, HLA class 1, and KIR gene variants that delimit prior observations regarding HLA and KIR associations with Crohn’s disease risk and behavior.

Association Between Cytomegalovirus Infection and Tuberculosis Disease: A Systematic Review and Meta-Analysis of Epidemiological Studies.

Tuberculosis is one of the leading causes of mortality worldwide from an infectious disease. This review aimed to investigate the association between prior cytomegalovirus infection and tuberculosis disease. Six bibliographic databases were searched from their respective inception to 31 December 2021. Data were pooled using random-effects meta-analysis. Of 5476 identified articles, 15 satisfied the inclusion criteria with a total sample size of 38 618 patients. Pooled findings showed that individuals with cytomegalovirus infection had a higher risk of tuberculosis disease compared to those not infected with cytomegalovirus (odds ratio [OR], 3.20; 95% confidence interval [CI], 2.18-4.70). Age was the only covariate that exerted a significant effect on the result of the association. Meta-analysis of risk estimates reported in individual studies showed a marked and significant correlation of cytomegalovirus infection with active tuberculosis (adjusted hazard ratio, 2.92; 95% CI, 1.34-4.51; adjusted OR, 1.14; 95% CI, .71-1.57). A clear dose-response relation was inferred between the levels of cytomegalovirus antibodies and the risks of tuberculosis events (OR for high levels of cytomegalovirus antibodies, 4.07; OR for medium levels of cytomegalovirus antibodies, 3.58). The results suggest an elevated risk of tuberculosis disease among individuals with a prior cytomegalovirus infection.

Current Tolerance-Associated Peripheral Blood Gene Expression Profiles After Liver Transplantation Are Influenced by Immunosuppressive Drugs and Prior Cytomegalovirus Infection

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplant (LTx) recipients weaned off immunosuppressive drugs (IS). Several previous studies have investigated whether peripheral blood gene expression profiles could identify operational tolerance in LTx recipients. However, the reported gene expression profiles differed greatly amongst studies, which could be caused by inadequate matching of clinical parameters of study groups. Therefore, the purpose of this study was to validate differentially expressed immune system related genes described in previous studies that identified tolerant LTx recipients after IS weaning. Blood was collected of tolerant LTx recipients (TOL), a control group of LTx recipients with regular IS regimen (CTRL), a group of LTx recipients with minimal IS regimen (MIN) and healthy controls (HC), and groups were matched on age, sex, primary disease, time after LTx, and cytomegalovirus serostatus after LTx. Quantitative Polymerase Chain Reaction was used to determine expression of twenty selected genes and transcript variants in PBMCs. Several genes were differentially expressed between TOL and CTRL groups, but none of the selected genes were differentially expressed between HC and TOL. Principal component analysis revealed an IS drug dosage effect on the expression profile of these genes. These data suggest that use of IS profoundly affects gene expression in peripheral blood, and that these genes are not associated with operational tolerance. In addition, expression levels of SLAMF7 and NKG7 were affected by prior cytomegalovirus infection in LTx recipients. In conclusion, we found confounding effects of IS regimen and prior cytomegalovirus infection, on peripheral blood expression of several selected genes that were described as tolerance-associated genes by previous studies.

Large Granular Lymphocytosis With Cytopenias After Allogeneic Blood or Marrow Transplantation: Clinical Characteristics and Response to Immunosuppressive Therapy

Large granular lymphocytosis (LGL)-or LGL leukemia-is a T- or NK-cell lymphoproliferative disorder that often results in cytopenias and autoimmune phenomena. Several studies have described LGL in a subset of patients after allogeneic blood or marrow transplantation (alloBMT), almost exclusively in the setting of asymptomatic lymphocytosis. Some have suggested an association with improved transplant-related outcomes. In contrast, clinically significant LGL after alloBMT is only described in small case reports. This study sought to assess the characteristics, significance, and response to treatment of LGL associated with unexplained anemia, thrombocytopenia, or neutropenia after alloBMT. We performed a retrospective analysis of 150 patients who were evaluated for LGL by peripheral blood flow cytometry (LGL flow) for unexplained cytopenias following initial engraftment after alloBMT from January 1 2012 to July 1, 2019. We identified patients with abnormally increased populations of LGL cells (LGL+) as assessed by Johns Hopkins Hematopathology. We collected demographic, transplantation, and LGL treatment information from electronic medical records. We compared LGL+ patients to patients with unexplained cytopenias with negative flow cytometry for LGL (LGL-) in this cohort. We also assessed change in blood counts after 4 weeks of immunosuppressive therapy in LGL+ patients. Cytopenias occurred at a median of 5.7 months (range 1-81) after alloBMT. The majority of the transplants were nonmyeloablative from haploidentical donors, and all patients received post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis, consistent with the overall alloBMT characteristics at our center. We identified 70 patients with LGL and cytopenias, representing 47% of those evaluated by flow cytometry. There were no significant demographic or transplant-related differences between LGL+ patients and LGL- patients. The median age was 59, and 63% were male. LGL+ patients were more likely to have had cytomegalovirus (CMV) viremia (73% versus 28%, P < .0001), but not acute or chronic graft-versus-host disease. LGL+ patients had higher absolute lymphocyte counts (1500 versus 485/ mm3, P < .0001), a trend toward lower absolute neutrophil count (660 versus 965/mm3, P=.17), and lower neutrophil to lymphocyte ratio (0.39 versus 1.71, P < .001). There were no differences in overall survival or relapse-free survival. Of those with T-cell LGL, 45 were assessed for T-cell receptor clonality. In all, 22% were clonal, 53% oligoclonal, 4% polyclonal, and 20% indeterminate. Thirty (43%) LGL+ patients received immunosuppressive therapy (IST) for cytopenias. First-line treatment was corticosteroids for 25 (83%). Among those treated, there was an increase in median absolute neutrophil count from 720 before treatment to 1990/mm3 after 4 weeks (P=.0017). Thrombocytopenia and anemia showed at most a mild improvement with IST. LGL was a common association with otherwise unexplained cytopenias after alloBMT, almost always after prior CMV infection. LGL in the setting of cytopenias did not predict improved transplantation outcomes compared to those with cytopenias without presence of LGL. IST was effective at improving neutropenia associated with LGL after alloBMT.

Multidrug antiviral “Rescue” therapy for severe cytomegalovirus infection after lung transplantation: a case report

Introduction Primary cytomegalovirus (CMV) infection or re-activation of prior latent CMV infection are common complications after lung transplant (LTX), associated with high morbidity and mortality [1]. Anti-CMV strategy usually includes antiviral drug prophylaxis and monitoring of CMV viral load after transplant [2]. Recently, CMV drug resistance is emerging as a severe postoperative complication with an incidence up to 4,7% [3]. Methods A 32-year-old woman, affected by pulmonary veno-occlusive disease, was listed for bilateral LTX. She had a history of Sharp's syndrome, needing high dose of steroid. Both the patient and the donor anti-CMV IgG and CMV DNA were not detectable. Because of severe pulmonary hypertension (mean pulmonary arterial pressure >60mmHg), LTX was performed with pre-emptive VA-ECMO support that was prolonged until postoperative day (POD) 7. Since POD1, both induction immunosuppressive therapy (intravenous (iv) Methylprednisolone 0,5mg/kg/die, Mycophenolate-Mophetil 2g/die, and iv Cyclosporine 1mg/kg/die with plasmatic Cyclosporine concentration target of 200ng/mL) and CMV prophylaxis (iv CMV-hyperimmune-globulin 75IU/kg every 4 days) have been started. Results On POD30 the patient developed abdominal pain, diarrhoea and lower gastrointestinal bleeding. Colonoscopy suggested an acute CMV colitis (Fig.1) and CMV-DNA was revealed in blood (>1million IU/mL) and feces. High dose Ganciclovir was promptly started, while Cyclosporine was stopped. However, the patient clinically deteriorated due to severe peritonitis. A CT scan showed diffuse pulmonary ground glass with tree-in-bud pattern (Fig.2A) and bowel distension with colon perforation (Fig.2B). A right hemicolectomy and ileostomy were immediately performed. Subsequently, the patient developed severe septic shock and acute respiratory failure (PaO2/FiO2 5milion IU/mL), despite high dose of Ganciclovir (10mg/kg/die). Because of a strong clinical suspicion of CMV drug resistance, specific molecular analysis was performed, but no relevant CMV DNA mutations potentially causing Ganciclovir resistance were found. However, iv Foscarnet (80mg/die, adjusted according to creatinine clearance) was empirically added and iv CMV-hyperimmune-globulin was potentiated (up to 75IU/kg/die). Six days later, CMV viral load started to decrease, until negativization on POD60 (Fig.3), with a significant improvement in patient clinical conditions. Unfortunately, the patient died on POD75 due to septic shock related to bronchial anastomosis dehiscence and Klebsiella Pneumoniae infection. Discussion This case has several peculiarities: - early onset of CMV infection after LTX (reported median time of 253 days [1]) despite prophylaxis; - very high viremia peak (>5million IU/mL on POD33); - rapidly progressive CMV infection, with severe abdominal complication requiring surgery; - poor response to Ganciclovir, needing multidrug antiviral therapy, despite no molecular sign of drug resistance.

S2852 Tissue Invasive Cytomegalovirus Enteritis With Gastric Outlet Obstruction in an Immunocompetent Patient

INTRODUCTION: Cytomegalovirus (CMV) usually causes asymptomatic or mononucleosis-like syndrome in immunocompetent individuals. We present a case of severe tissue invasive gastrointestinal CMV in an immunocompetent individual complicated by gastric outlet obstruction. CASE DESCRIPTION/METHODS: A 72-year-old man with a history of hypertension presented with vomiting, postprandial abdominal pain, and hematochezia for one week. He had also lost 40lbs in three months. Physical examination was normal except for epigastric tenderness. The previous colonoscopy done 5 years ago was normal. No personal or family history of inflammatory bowel disease, gastrointestinal malignancy, or lymphoma. He had never had immunosuppressive therapy, organ transplantation, or any other biological agent. Initial blood work revealed Hemoglobin 10.9 g/dl, AST 64 IU/l, ALT 83 IU/l, and ALP 350 IU/l. His HIV and Tuberculosis screening were negative. Ultrasound and CT scan of the abdomen and pelvis were normal except for increased gallbladder wall thickness (3mm). An Esophagogastroduodenoscopy (EGD) revealed esophagitis, pyloric channel ulcer, and duodenal ulcer. Colonoscopy revealed an ulcer at the ileocecal valve. The biopsy of all the ulcers revealed ulcerated mucosa, architectural distortion, and reactive epithelial atypia suspicious of CMV infection which was later confirmed by immunohistochemical staining (IHC) [Figure 1]. Quantitative CMV DNA PCR analysis showed levels of 1739 IU/ml. He was started on intravenous ganciclovir while inpatient and sent home on oral valganciclovir for 21 days. His symptoms improved significantly after treatment. CMV DNA levels decreased to 1230 IU/ml post-treatment. The patient returned with symptoms of gastric outlet obstruction a few months later which were getting worse. His barium X-ray revealed a delayed gastric emptying time with pyloric stenosis and partial malrotation of the small bowel [Figure 2]. A repeat EGD revealed pyloric stenosis with an inner diameter of 11 mm, which was dilated endoscopically. The biopsy taken from an antral ulcer was negative for CMV on IHC staining. There were no other signs of prior CMV infection on the EGD. DISCUSSION: The gastric outlet obstruction in the patient is likely a long term sequela of CMV. Due to the undertreatment and delay in diagnosis, CMV infections can lead to long term and potentially life-threatening complications. Therefore, gastrointestinal CMV should be considered in immunocompetent patients and aggressively treated.Figure 1.: Medium power (100×) Immunohistochemical staining for CMV with hematoxylin counter-stain. A representative high power view demonstrating strong focal CMV immunoreactivity.Figure 2.: Barium Xray reveals pyloric stenosis (black arrow) and malrotation with the first loop of jejunum to the right.

The Evolution of Monoclonal Gammopathy of Undetermined Significance in Kidney Transplant Recipients.

Background.It is unclear if immunosuppression increases the likelihood of malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and whether adverse renal outcomes in kidney transplant recipients with MGUS are more frequent.Methods.We performed a retrospective cohort study of kidney transplant recipients at the Centre Hospitalier de l’Université de Montréal between 2000 and 2016.Results.Among 755 study participants, 13 (1.7%) were found to have MGUS before transplant. Two evolved to smoldering multiple myeloma and 2 presented paraprotein-induced allograft injury from light chain deposition disease. Forty-six patients developed posttransplant MGUS (2.5% 5-y cumulative incidence) of which 1 progressed to multiple myeloma and 1 experienced kidney allograft loss from light chain deposition disease. None of the patients with a malignant transformation or paraprotein-induced renal disease after transplantation had had a systematic workup before transplantation to exclude hematologic malignancies and paraprotein-related kidney injury. Nine posttransplant MGUS (21%) were transient. Multivariable analysis revealed that age at transplant (hazard ratio 1.05 per 1-y increase, 95% confidence intervals, 1.02-1.08) and prior cytomegalovirus infection (hazard ratio 2.22, 95% confidence intervals, 1.07-4.58) were associated with the development of MGUS after transplantation. Of 7 posttransplant lymphoproliferative disorders, none were preceded by MGUS.Conclusions.Our results suggest that the identification of MGUS in a transplant candidate should lead to further investigations to exclude a plasma cell neoplasm and monoclonal gammopathy of renal significance before transplantation. MGUS arising after transplantation appears to carry a favorable evolution.

The Association of 25-Hydroxyvitamin D Levels with Late Cytomegalovirus Infection in Kidney Transplant Recipients: the Wisconsin Allograft Recipient Database.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in kidney transplant recipients. Vitamin D has an integral role in proper immune function, and deficiency is common among kidney transplant recipients. It remains unclear whether 25-hydroxyvitamin D [25(OH)D] level is associated with CMV infection in kidney transplant recipients. We examined the relationship between 25(OH)D levels, measured at least 6 months posttransplant, and subsequent CMV infection in 1976 recipients free of prior CMV infection. Of 1976 recipients, 251 (12.7%) were vitamin D deficient [25(OH)D <20 ng/mL] and 548 (27.7%) were insufficient (20-29 ng/mL) at the time of the first 25(OH)D measurement. A total of 107 recipients had a CMV infection within 1 year of a 25(OH)D measurement. Vitamin D deficiency was associated with a 1.81-fold higher risk (relative hazard = 1.81; 95% confidence interval [CI], 1.06-3.09) than vitamin D sufficiency after adjustment for baseline characteristics and concurrent graft function and blood calcineurin inhibitor concentration. Each 1 ng/mL lower 25(OH)D was associated with a 2% higher risk of infection (95% CI, 0%-4%) in continuous analyses after adjustment. Low 25(OH)D is common in kidney transplant recipients and associated with late CMV infection. These results highlight the need for interventional trials to assess the potential for vitamin D supplementation to reduce infectious complications in kidney transplant recipients.

Predictors of persistent diarrhea in norovirus enteritis after solid organ transplantation.

Solid organ transplant (SOT) recipients may develop protracted diarrheal illness from norovirus. We performed a retrospective chart review between January 2010 and April 2014 to identify predictors of persistent diarrhea in transplant recipients with norovirus enteritis. A total of 152 SOT recipients with mean age of 31.5years (SD 23.1) were included: 43.4% male, 34.2% pediatric patients. Allograft types were abdominal 136 (89.5%) (kidney [39.5%], liver-small bowel [23%], other [27%]) and thoracic 16 (10.5%). The median time to diagnosis of first norovirus enteritis episode from date of transplantation was 1.7 (0.3-5.3)years. At time of presentation, diarrhea was present in 141 (93%). Thirty percent had persistent diarrhea at 2weeks. Hospitalization was required for treatment in 121 (80%) of episodes with the mean length of stay of 10±15.2days. Most (91%) infections were due to norovirus genogroup II, and gastrointestinal coinfections were seen in 23 (19%) norovirus enteritis episodes. Nausea at time of diagnosis (P=.002) and cytomegalovirus (CMV) infection in the preceding 90days (P=.036) were identified as independent risk factors for persistent diarrhea using univariate and multivariable logistic regression. Our study shows that nausea on presentation and prior CMV infection were associated with persistent diarrhea in patients with norovirus enteritis.

Predictors of Persistent Diarrhea in Norovirus Enteritis After Solid Organ Transplantation

Solid organ transplant recipients may develop protracted diarrheal illness from norovirus. We performed a retrospective chart review between January 2010 and April 2014 to identify predictors of persistent diarrhea in transplant recipients with norovirus enteritis.152 solid organ transplant recipients with mean age of 31.5 years (SD 23.1) were included: 43.4% male, 34.2% pediatric patients. Allograft types were abdominal 136 (89.5%) [kidney (39.5%), liver-small bowel (23%), other (27%)] and thoracic 16 (10.5%). The median time to diagnosis of first norovirus enteritis episode from date of transplantation was 1.7 (0.3 – 5.3) years. At time of presentation, diarrhea was present in 141 (93%). Thirty percent had persistent diarrhea at 2 weeks. Hospitalization was required for treatment in 121 (80%) of episodes with the mean length of stay of 10 ±15.2 days. Most (91%) infections were due to norovirus genogroup II, and gastrointestinal co-infections were seen in 23 (19%) norovirus enteritis episodes. Nausea at time of diagnosis (p=0.002) and CMV infection in the preceding 90 days (p=0.036) were identified as independent risk factors for persistent diarrhea using univariate and multivariable logistic regression. Our study shows that nausea on presentation and prior cytomegalovirus infection were associated with persistent diarrhea in patients with norovirus enteritis. This article is protected by copyright. All rights reserved.

Outbreak of Pneumocystis Pneumonia in Renal and Liver Transplant Patients Caused by Genotypically Distinct Strains of Pneumocystis jirovecii

An outbreak of 29 cases of Pneumocystis jirovecii pneumonia (PCP) occurred among renal and liver transplant recipients (RTR and LTR) in the largest Danish transplantation centre between 2007 and 2010, when routine PCP prophylaxis was not used. P. jirovecii isolates from 22 transplant cases, 2 colonized RTRs, and 19 Pneumocystis control samples were genotyped by restriction fragment length polymorphism and multilocus sequence typing analysis. Contact tracing was used to investigate transmission. Potential risk factors were compared between PCP cases and matched non-PCP transplant patients. Three unique Pneumocystis genotypes were shared among 19 of the RTRs, LTRs, and a colonized RTR in three distinct clusters, two of which overlapped temporally. In contrast, Pneumocystis control samples harbored a wide range of genotypes. Evidence of possible nosocomial transmission was observed. Among several potential risk factors, only cytomegalovirus viremia was consistently associated with PCP (P=0.03; P=0.009). Mycophenolate mofetil was associated with PCP risk only in the RTR population (P=0.04). We identified three large groups infected with unique strains of Pneumocystis and provide evidence of an outbreak profile and nosocomial transmission. LTRs may be infected in PCP outbreaks simultaneously with RTRs and by the same strains, most likely by interhuman transmission. Patients are at risk several years after transplantation, but the risk is highest during the first 6 months after transplantation. Because patients at risk cannot be identified clinically and outbreaks cannot be predicted, 6 months of PCP chemoprophylaxis should be considered for all RTRs and LTRs.

Association of cytomegalovirus and other pathogens with frailty and diabetes mellitus, but not with cardiovascular disease and mortality in psycho-geriatric patients; a prospective cohort study

BackgroundStudies about associations of infections with herpes viruses and other pathogens, such as Chlamydia pneumoniae (CP) and Helicobacter pylori (HP) with cardiovascular disease (CVD), diabetes mellitus (DM), frailty and/or mortality are conflicting. Since high levels of antibodies against these pathogens occur in the elderly, the role of these pathogens in morbidity and mortality of vulnerable elderly was explored.ResultsBlood samples of 295 community dwelling psycho-geriatric patients were tested for IgG antibodies to herpes simplex virus type 1 and 2, varicella zoster virus, Epstein Barr virus (EBV), cytomegalovirus (CMV), human herpes virus type 6 (HHV6), CP and HP. Frailty was defined with an easy-to-use previously described frailty risk score. Relative risks (RR) with 95% confidence intervals were calculated to evaluate associations between CVD, DM, frailty and pathogens. Pathogens as a predictor for subsequent mortality were tested using Kaplan Meier analyses and Cox proportional hazard models. The mean age was 78 (SD: 6.7) years, 20% died, 44% were defined as frail, 20% had DM and 49% had CVD. Presence of CMV antibody titers was associated with frailty, as shown by using both qualitative and quantitative tests, RR ratio 1.4 (95% CI: 1.003-2.16) and RR ratio 1.5 (95% CI: 1.06-2.30), respectively. High IgG antibody titers of HHV6 and EBV were associated with DM, RR ratio 3.3 (95% CI: 1.57-6.49). None of the single or combined pathogens were significantly associated with mortality and/or CVD.ConclusionsPrior CMV infection is associated with frailty, which could be in line with the concept that CMV might have an important role in immunosenescence, while high IgG titers of HHV6 and EBV are associated with DM. No association between a high pathogen burden and morbidity and/or mortality could be demonstrated.

Mycobacterium Tuberculosis—Associated Immune Reconstitution Syndrome in Solid-Organ Transplant Recipients

Incidence, characteristics, and risk factors for tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRS) in solid-organ transplant (SOT) recipients are not known. Patients are composed of 64 consecutive SOT recipients with TB followed for 12 months. IRS was defined based on previously proposed criteria. IRS developed in 14% (9/64) of the patients, a median of 47 days after the use of anti-TB therapy. Liver versus other types of organ transplant recipients (adjusted odds ratio [OR], 6.11; 95% confidence interval [CI], 1.08-34.86), prior cytomegalovirus infection (adjusted OR, 5.65; 95% CI, 0.93-34.47), and rifampin use (adjusted OR, 4.56; 95% CI, 0.74-27) were associated with a higher risk of IRS. The presence of more than one factor (liver transplantation, cytomegalovirus infection, and rifampin use) when compared with none of these factors conferred a 19-fold increase in the risk of IRS (P=0.01). Mortality at 1 year after diagnosis was 33.3% in patients with IRS and 17.2% in those without IRS (P=0.31). IRS was documented in 14% of the SOT recipients with TB. We determined clinically identifiable factors that may be useful in assessing the risk of tuberculosis-associated posttransplantation IRS.

Commentary: Understanding the pathophysiology of poverty

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Cytomegalovirus Infections among African-Americans

BackgroundSince African-Americans have twice the prevalence of cytomegalovirus (CMV) infections as age-matched Caucasians we sought to determine the ages and possible sources of infection of African-American children.MethodsSubjects were 157 African-American healthy children and adolescents and their 113 household adults in Richmond VA. Families completed a questionnaire, provided saliva for antibody testing, and adolescents were interviewed regarding sexual activity.ResultsRegardless of age CMV seropositivity was not associated with gender, breast feeding, health insurance, sexual activity, or household income, education, or size. In the final regression model, prior CMV infection in adults was over two-fold higher than in children (chi-square = 18.8, p < 0.0001). At one year of age the CMV seropositivity rate was 11% (95%CI = 4% – 24%) and increased 1.8% each year until age 13 years. Between ages 13 and 20 years the CMV seropositivity rate remained between 22% and 33%. For adults, the CMV seropositivity rate was 84% in 21 year olds (95%CI = 69%–.92%). There was no association between CMV infections of the children and their mothers but CMV infections among siblings were associated.ConclusionWe observed that African-American children had CMV seroprevalence rates by age 20 years at less than one-half of that of their adult mothers and caregivers. Sibling-to-sibling transmission was a likely source of CMV infections for the children. The next generation of African-American women may be highly susceptible to a primary CMV infection during pregnancy and may benefit from a CMV vaccine.

The association of prior cytomegalovirus infection with neovascular age-related macular degeneration

Purpose To determine if prior exposure to pathogens associated with vascular disease, cytomegalovirus, Chlamydia pneumoniae, and Helicobacter pylori correlates with neovascular age-related macular degeneration (AMD). Design An experimental study. Methods Setting Institutional. Bascom Palmer Eye Institute, October 2001 to December 2002. Patient population 150 patients (47 neovascular amd, 36 dry amd, and 67 non-amd controls) were included in the study. exclusion criteria included hiv infection, malignancy, recent acute illness requiring hospitalization within 6 months, or immunosuppressive illness. Procedure Serum samples were obtained for analysis of cytomegalovirus, chlamydia pneumoniae, and helicobacter pylori igg antibody titers by elisa. Main outcome measure Comparison of the distribution of igg titers between patients with wet amd, dry amd, and controls. Results The average cytomegalovirus IgG titer was higher in patients with wet AMD versus controls (p = 0.02, Student t-test, two-tailed) and patients with dry AMD (p = 0.06). Twenty-six (55%) of 47 subjects with wet AMD had high cytomegalovirus IgG titers compared with 14 (39%) of 36 patients with dry AMD (odds ratio [OR] = 2.23, 95% confidence interval [CI] = 0.77 to 6.44) and 23 (34%) of 67 control patients (OR = 2.49, 95% CI = 0.98 to 6.33). There was no major difference in the distribution of titers for Chlamydia pneumoniae IgG and Helicobacter pylori IgG in wet and dry AMD patients. Five of 47 patients with wet AMD (11%) had high antibody titers to all three pathogens, compared with only 1 of 36 patients with dry AMD (3%) (OR = 4.17, 95% CI = 0.46 to 37.36). Conclusions There was a significant association of high cytomegalovirus IgG titer with neovascular AMD compared with dry AMD and control patients. Chronic infection with cytomegalovirus may be a novel risk factor for the progression from dry to neovascular AMD.

Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection

The nature of the immune response in coronary artery disease (CAD) is not fully defined. One pathogen that has been linked to atherogenesis, cytomegalovirus (CMV), is known to exert strong and long-lasting effects on peripheral T cells. In the present study, we investigated the effect of prior CMV infection on the immune system in CAD patients. Patients with stable angina and angiographically verified CAD (n=43) and clinically healthy controls (n=69) were included. The expression of CD57 and CD28 on peripheral CD4+ and CD8+ T cells was evaluated with three-colour flow cytometry. The findings were related to serological markers of inflammation, T-cell activation and CMV seropositivity. An expansion of CD8+ T cells expressing CD57 but lacking CD28 was seen in the patient group. The numbers of CD8+ CD57+ and CD8+ CD28-T-cell subsets were independently related to CMV seropositivity (P<0.001) but also to CAD per se (P<0.05). Serum concentrations of C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were elevated in the patients but not related to CMV or CD8+ T-cell subsets. A pronounced shift in peripheral T-cell homeostasis was observed in CAD patients. Primarily CMV infection but also CAD per se contributed to the expansion of CD8+ T-cell subsets. The T-cell changes were not related to a systemic inflammatory response but should rather be considered as markers of a chronic antigen exposure and/or immunosenescence in CAD.

Previous cytomegalovirus infection and restenosis after aggressive angioplasty with provisional stenting.

The aim of this study was to determine the impact of previous with cytomegalovirus (CMV) on restenosis after aggressive angioplasty with provisional stenting. We prospectively studied 78 consecutive patients scheduled for 6-month follow-up coronary angiography as part of the SIPS study. Anti-CMV IgG and IgM antibodies were measured on admission. Anti-CMV IgG positive and anti-CMV IgG negative patients had similar minimal lumen diameter (MLD) in the target vessel before (0.68 +/- 0.49 mm vs 0.71 +/- 0.52 mm, P = 0.84) and directly after the intervention (2.50 +/- 0.60 mm vs 2.57 +/- 0.52 mm, P = 0.58). After 6 months, however, the MLD was significantly smaller in CMV-positive as compared to CMV-negative patients (1.57 +/- 0.82 mm vs 2.00 +/- 0.83 mm, P < 0.03). Net lumen gain at 6 months was significantly lower in CMV-positive patients (0.89 +/- 0.79 mm vs 1.30 +/- 0.87 mm, P < 0.04) and the rate of clinically relevant restenosis was significantly higher (31% vs 7%, P < 0.02). In a multivariate logistic regression model, CMV seropositivity was an independent predictor of restenosis (odds ratio 5.7 (95% CI 1.2-30.3, P = 0.04). Six months after aggressive coronary angioplasty with provisional stenting, patients with prior CMV infection had a smaller MLD and a higher restenosis rate. CMV seropositivity was a strong independent predictor of restenosis.