CMV Infection In Patients Research Articles

Abundance, diversity and functionality of cytomegalovirus-specific T cells depends on HLA genotype of the donor and hierarchy of the immunodominant epitopes

Abstract Cytomegalovirus (CMV)-specific T-cells from healthy donor are used as a treatment of CMV infection in patients receiving immunosuppressive therapy following transplantation. To choose the optimal donor and to select the best isolation method (MHC-tetramer or IFNy secretion assay) CMV-specific T-cells should be characterized by specificity and functionality. We compared the antigen specificity, diversity and functionality of T-cell responding to CMV pp65 and to three pp65-derived immunodominant epitopes: NLV restricted by HLA-A*02, TPR and RPH restricted by HLA-B*07. 87 healthy donors were divided into 4 groups according to the presence of HLA-A*02 and/or HLA-B*07. CMV-specific response was analyzed by flow cytometry. For 6 donors antigen-specific cells were isolated by MHC-tetramer staining and pp65 IFNγ secretion assay followed by FACS. cDNA libraries of T-cell receptor β-chains were prepared and sequenced by NGS. We found that pp65-specific T-cell response (IFNy-producing T-cell after stimulation with pp65 CMV) was strongly focused on pp65-derived epitopes NLV, TPR and RPH in fixed hierarchy. NLV-specific clones constituted most pp65-specific cells in presence of HLA-A*02 but not when HLA-B*07 was also present. NLV-specific fraction consisted of few large clones, TPR− and RPH-specific cells were more diverse. Many MHC-tetramer+ clones were non-functional as they were not detected in IFNy+ fraction after pp65 stimulation. In summary, HLA-genotype significantly affects magnitude and structure of pp65-specific T-cell response. It should be taken into consideration for choosing a donor of CMV-specific T cells. IFNy secretion assay produces more diverse and more functional cell product.

Prophylaxis vs preemptive therapy in prevention of CMV infection: new insight on prophylactic strategy after allogeneic hematopoietic cell transplantation

AbstractCytomegalovirus (CMV), the beta-human herpesvirus type 5 (HHV-5), is a major cause of morbidity in immunocompromised hosts, especially recipients of allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation. The standard-of-care approach to CMV prevention based on CMV surveillance-guided preemptive therapy is being challenged by the recent approval of letermovir (LMV) for primary prophylaxis. Real-word clinical data show dramatic improvement in the reduction of risk of CMV infection and any CMV viremia in all studies performed so far. LMV is the drug that is breaking the paradigm of preemptive therapy with shift to prophylaxis. A summary of reported data presented in 2019 annual meetings of American Society of Transplantation and Cellular Therapy (ASTCT), European Society for Blood and Marrow Transplantation (EBMT) and American Society of Hematology (ASH), as well as already published results, is presented in this review. A total number of 401 adult high-risk patients on primary prophylaxis after HCT were reported in 11 studies up to January 1, 2020. It was shown that fewer patients in the LMV arms had any CMV reactivation or need for CMV treatment compared with the any other prophylactic or preemptive approaches. In conclusion, LMV is much highly effective than CMV-guided preemptive therapy in preventing CMV infection and CMV disease. The use of LMV in prophylaxis results in an improvement in overall survival during the first 24 and 48 weeks. LMV has a favorable safety profile, as it does not cause myelotoxicity. Current guidelines of European Conference on Infections in Leukemia (ECIL7) recommend LMV for the use in prophylaxis of CMV infection in patients after allogeneic hematopoietic cell transplant.

Ulcerative Colitis and Cytomegalovirus Infection: From A to Z

Despite multiple studies, the role of cytomegalovirus [CMV] infection in exacerbating the severity of inflammation in ulcerative colitis [UC], and its response to treatment, remain debatable. Additionally, the optimal diagnostic tests for CMV infection in the setting of UC relapse, and timing of antiviral treatment initiation, remain unclear. The challenge faced by gastroenterologists is to differentiate between an acute UC flare and true CMV colitis. It seems that the presence of CMV colitis, as defined by the presence of intranuclear or intracellular inclusion bodies on haematoxylin and eosin [H&E] staining and/or positive immunohistochemistry [IHC] assay on histology, is associated with more severe colitis. Patients with CMV infection and acute severe colitis are more resistant to treatment with corticosteroids than non-infected patients. This refractoriness to steroids is related to colonic tissue CMV viral load and number of inclusion bodies [high-grade CMV infection] which may have a pronounced effect on clinical outcomes and colectomy rates. Whereas many studies showed no effect for antiviral treatment on colectomy rates in CMV-infected UC patients, there was a significant difference in colectomy rates of patients with high-grade infection who received anti-viral therapy compared with those who did not receive treatment. It was therefore proposed that high-grade CMV disease indicates that the virus is acting as a pathogen, whereas in those with low-grade CMV disease, the severity of IBD itself is more likely to influence outcome. The different algorithms that have been put forward for the management of patients with UC and concomitant CMV infection are discussed.

Incidence and Impact of Non-CMV Herpes Viral Infection in Haploidentical and Matched Sibling Donors Receiving Post-Transplant Cyclophosphamide (PTCy): A CIBMTR Analysis

Single-center studies have reported increased risk of CMV infection in patients undergoing allogeneic transplant using haploidentical graft with post-transplant cyclophosphamide (HaploCy), however limited data exists regarding the impact of this transplant platform on the incidence of non-CMV herpes viruses (NCHV) infection (viremia/disease). Furthermore, it is unclear if the donor type or altered immune reconstitution resulting from the use of PTCy contributes to this infection risk. To study this, patients reported to the CIBMTR with AML/ALL/MDS transplanted between 2012 and 2017 receiving HaploCy (n = 757), matched-sibling donors receiving PTCy (SibCy, n=403), or matched sibling with calcineurin inhibitor and methotrexate/mycophenolate mofetil (SibCNI, n=1605) with either marrow or peripheral blood grafts were examined (Table 1). Too few matched unrelated donors (MUD) receiving PTCY reported to CIBMTR resulted in exclusion of MUD transplants. The cumulative incidence of NCHV in the HaploCy, SibCy and SibCNI were 6.9% (99% CI, 4.7-9.4), 3.2% (1.3-5.9), and 1.7% (1-2.6) respectively by day 30 [p<0.001] and increased to 13.9% (10.8 – 17.3), 10.7 % (7.1 – 15), and 5.7% (4.3 – 7.3) by 6 months after transplant [p<0.001] [Figure 1]. Notably, this is driven by a higher frequency of HHV-6 viremia [HaploCy = 9.3%; SibCy = 5.7%; SibCNI = 1.9%]. Figure 2 shows the multivariable models of survival, relapse, transplant related mortality, and chronic GVHD with a reference group of SibCNI without NCHV infection for the main effect variable of donor and infection. The model examines through the first 2 years after transplant and there was a center effect. Our results suggest that HaploCY is associated with an increased incidence of NCHV infection and HHV-6 viremia predominates. The SibCy cohort experienced an increased incidence of NCHV infections as well. However, only in the HaploCy group is this independently associated with increased TRM and decreased survival. Improved surveillance and preemptive treatment may mitigate the mortality associated with NCHV infections in HaploCy recipients.

Incidence and Impact of Cytomegalovirus Infection in Haploidentical and Matched-Related Donors Receiving Post-Transplant Cyclophosphamide (PTCy): A CIBMTR Analysis

Single-institution studies suggest increased incidence of CMV infection (DNAemia/organ disease) in recipients of haploidentical grafts with PTCy (HaploCy). It is unclear what factors confer the increased risk. Given increased use of PTCy in matched-sibling donor transplant (SibCy), we examined the impact of donor type and PTCy on transplant outcomes by donor(D)/recipient(R) CMV serostatus and reported CMV DNAemia by day 180. Patients reported to the CIBMTR with AML/ALL/MDS receiving HaploCy (n = 757), SibCy (n=403), or Sib with calcineurin inhibitor and methotrexate/mycophenolate mofetil (SibCNI, n=1605) between 2012 and 2017 were examined (Table 1). Too few MUD with PTCy were reported to include MUD cohorts. Cumulative incidences of CMV DNAemia by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26) for HaploCy, SibCy, and SibCNI respectively [p<0.001]. CMV organ disease was similar [HaploCy, 4% (2-6); SibCy, 4% (2-7); SibCNI, 2% (1-3); p=0.115]. Median onset (days) of CMV infection differed [HaploCy: 38 (range, 2 – 176); SibCy, 32 (5 – 136); SibCNI: 42 (4 – 176), p<0.001]. Figures 1 and 2 show the multivariable analyses for survival, relapse, transplant related mortality, and chronic GVHD examining the effect of D/R CMV serostatus and by CMV DNAemia by day 180. Reference groups were D-/R- SibCNI and SibCNI without CMV DNAemia, respectively. The risk of CMV infection was greatest for CMV Seropositive recipients (R+) with the greatest risk in PTCy recipients regardless of donor [HaploCy: RR 50.3 (14.4 – 175.2); SibCy: RR 47.7 (13.3 – 171.4); SibCNI: RR 24.4 (7.2 – 83.1); p<0.001]. The D+/R- groups also have increased risk for CMV infection [HaploCy: RR 16.3 (4 – 70.5); SibCy: RR 10.1 (2.3 – 43.9); SibCNI: 8.4 (2.4 – 29.2)]. Our study shows that PTCy is associated with higher incidence of CMV infection among both Haplo and Sib transplants. Among seropositive and CMV-infected patients, HaploCy had worse OS and TRM, whereas differences between SibCy and SibCNI were not significant. Neither CMV infection nor serostatus affect relapse. This study supports use of more aggressive prevention strategies in patients receiving PTCy and at risk for CMV infection.

Cytomegalovirus Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted WomenDalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq

Atherosclerosis is a form of the cardiovascular diseases which may occur due to a chronic inflammatory reaction to endothelial damage caused by multiple causes which include infection by microorganisms like (CMV). The present study aims to evaluate the effect of cytomegalovirus infection in patients and its relation to atherosclerosis and to measure the monocyte chemoattractant protein-1 (MCP-1) as a predictive marker for inflammatory process. A total of 30 women who were attending the Gynecology outpatient clinics and were suffering from abortion for first time or with recurrent abortion due to CMV infection were enrolled in the current study. For comparison, twenty blood samples were collected from healthy apparent women as a control group in this study. Serum MCP-1, IL-6 and CMV-IgM were measured by using ELISA technique. Lipid profile which includes total cholesterol, triglycerides, high density lipoprotein (HDL), and low density lipoprotein (LDL) was measured by spectrophotometer. The results of this study showed a significant difference in mean of IL-6 in patients was (570.67 ± 199.27) when compared to control group (pEƒ0.0001). While there is no significant difference of MCP-1 level between patients and control group (P=0.134). And the results showed a significant elevation of cholesterol (P<0.05) and a highly significant elevation of triglyceride and LDL in CMV infected patients (P<0.01), while no elevation occurred in HDL values (P=0.977), according to the present data there is a correlation between CMV infection and atherosclerosis. How to Cite this Article Pubmed Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq. Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted SRP. 2020; 11(3): 320-323. doi:10.5530/srp.2020.3.37 Web Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq. Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted http://www.sysrevpharm.org/?mno=92947 [Access: March 30, 2021]. doi:10.5530/srp.2020.3.37 AMA (American Medical Association) Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq. Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted SRP. 2020; 11(3): 320-323. doi:10.5530/srp.2020.3.37 Vancouver/ICMJE Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq. Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted SRP. (2020), [cited March 30, 2021]; 11(3): 320-323. doi:10.5530/srp.2020.3.37 Harvard Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq (2020) Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted SRP, 11 (3), 320-323. doi:10.5530/srp.2020.3.37 Turabian Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq. 2020. Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted Systematic Reviews in Pharmacy, 11 (3), 320-323. doi:10.5530/srp.2020.3.37 Chicago Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq. Cytomegalovirus Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted Women. Systematic Reviews in Pharmacy 11 (2020), 320-323. doi:10.5530/srp.2020.3.37 MLA (The Modern Language Association) Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq. Cytomegalovirus Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted Women. Systematic Reviews in Pharmacy 11.3 (2020), 320-323. Print. doi:10.5530/srp.2020.3.37 APA (American Psychological Association) Style Dalya Basil Hanna, Huda Jaber Waheed, Zahraa Qasim Ali, Maysaa Ali Abdul Khaleq (2020) Infection as Risk of Atherogenic Lipid Profile in Iraqi Aborted Systematic Reviews in Pharmacy, 11 (3), 320-323. doi:10.5530/srp.2020.3.37

Cytomegalovirus Humoral Response Against Epithelial Cell Entry-Mediated Infection in the Primary Infection Setting After Hematopoietic Cell Transplantation.

The influence of humoral immunity on the prevention of primary cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) is poorly understood. To determine whether neutralizing antibodies (nAbs) against CMV pentameric complex (PC)-mediated epithelial cell entry decrease CMV infection after HCT, samples were analyzed from a randomized controlled trial of CMV intravenous immunoglobulin (IVIG) prophylaxis. Weekly serum from 61 CMV donor-positive/recipient-negative (D+/R-) HCT patients (33 control, 28 CMV IVIG) was tested using a PC-entry nAb assay and quantitative CMV polymerase chain reaction (PCR). There was a trend toward higher weekly PC-entry nAb titers (P = .07) and decreased CMV infection by PCR at viral load cutoffs of ≥1000 and ≥10 000 IU/mL in the CMV IVIG arm. High nAb titers were not significantly protective against CMV infection later after HCT in both study arms. Among CMV-infected patients, each log2 increase in nAb titer was associated with an average 0.2 log10 decrease in concurrent CMV viral load after infection (P = .001; adjusted for study arm). This study provides initial support that CMV IVIG prophylaxis moderately enhances PC-entry nAB activity in D+/R- HCT recipients.

2323. Clinical Characteristics and Disease Burden of Epstein–Barr Virus and Four β-Herpes Viruses Infections in Children Visiting Emergency Room

BackgroundIt is well known that most of infants and young children with primary EBV and CMV infection are inapparent, and primary HHV-6B and HHV-7 infection cause exanthema subitum (ES). However, the precise incidence of apparent infection of these viruses remains unclear. Therefore, we sought to elucidate clinical features and disease burdens of these viral infections in febrile children visiting emergency room (ER).MethodsBetween June 2015 and December 2017, febrile children under 5 years old, who visited ER and received hematological examination, were enrolled in this study. Detection of serum viral DNAs using real-time PCR and measurement of antibody titers in acute-phase serum were carried out. Clinical information was collected from the medical records.ResultsIn total of the 905 cases, EBV, CMV, HHV-6B and HHV-7 were detected in 18 cases (2%), 12 cases (1.3%), 104 cases (11.5%) and 23 cases (2.5%), respectively. No HHV-6A DNA was detected. Primary infection rates among EBV, CMV, HHV-6B and HHV-7-infected patients accounted for 44%, 25%, 91% and 57%, respectively. Admission rates of the primary-infected patients were 88% of EBV, 68% of CMV, 66% of HHV-6B and 42% of HHV-7, respectively. Five of the 8 cases (62.5%) of primary EBV-infected patients demonstrated typical clinical course of infectious mononucleosis (IM); however, no IM patient was seen in 9 patients with viral reactivation. No IM case was observed in CMV-infected patients, regardless of primary infection or reactivation. Clinical characteristics were compared between patients with primary HHV-6B and HHV-7 infections because of similarity of clinical features. Average age (1.5 vs. 2.8 years old; P < 0.001), duration of fever (4.5 vs. 2.9 days; P < 0.001), the highest body temperature (40.2 vs. 39.6°C; P < 0.001), and the frequency of typical skin rash (ES) (87% vs. 54%; P < 0.001) were statistically different between the two viral infections. The main reason for admission due to primary HHV-6B and HHV-7 infection was complex-type febrile seizure (58.7 vs. 66.7%; P = 0.705).ConclusionThe clinical features and disease burden of the 5 human herpesviruses infections were elucidated in the febrile children visiting ER.Disclosures All authors: No reported disclosures.

2591. The Role of Neutralizing Antibodies (nAb) Against Cytomegalovirus (CMV) Epithelial Cell-entry in Patients with Self-limited (SL) CMV infection after Hematopoietic Cell Transplantation (HCT)

BackgroundCMV transmission after HCT occurs in 20–30% of CMV-seronegative recipients with CMV-seropositive donors (i.e., CMV D+/R−) and a distinct subset develop transient CMV DNAemia without progression to culture positivity in the absence of antivirals (BMT 1992; 9:221; J Med Virol 2019; 91:1128). The mechanism of SL CMV infection is unknown but may involve nAb, which have been implicated in primary viral clearance, including nAb that inhibit viral epithelial and endothelial cell-entry via CMV pentameric complex (PC). We aimed to describe viral kinetics and the influence of nAb on CMV infection progression in SL CMV-infected patients and controls within a unique cohort from the pre-antiviral era.MethodsWeekly serum samples from 456 CMV D+/R− allogeneic HCT patients collected between 1978–95 were screened using quantitative CMV DNA PCR. Patients with CMV DNAemia in the first 100 days after HCT followed by a sustained return to undetectable levels without positive surveillance CMV cultures were defined as having SL CMV infection. SL CMV-infected patients were matched 1:1:1 to CMV-infected controls (patients with CMV infection by culture in the same period after HCT ± 14 days) and non-infected controls (patients without CMV DNA or culture positivity) to compare viral kinetics and nAb. A modified nAb assay was used to evaluate serum nAb activity against CMV PC-mediated cell entry (Vaccine 2008; 26:5760; JID 2019; in press).ResultsWe identified 9 patients with SL CMV infection and baseline demographics are shown (Table 1). SL CMV-infected patients had a median of 21 days (range 7–54 days) until first positive CMV DNAemia. The median peak CMV DNAemia was 94.2 IU/mL (range 40.2–225.9 IU/mL) and 46,118 IU/mL (range 1,132–284,362 IU/mL) in SL CMV-infected and CMV-infected controls respectively. There was no difference in nAb titers between groups at infection day 0 or in the preceding 4 weeks (Figure 1, Figure 2).ConclusionnAb against CMV PC-mediated cell entry did not appear to play a critical role in viral clearance in SL CMV infection after CMV D+/R- allogeneic HCT. Our study illustrates the potential for clearance of relatively low CMV DNAemia after HCT without the addition of antivirals. CMV-specific T-cell immunity or innate immune mechanisms may be more important in early viral control. Disclosures All authors: No reported disclosures.

Should You Follow the Better-Hearing Ear for Congenital Cytomegalovirus Infection and Isolated Sensorineural Hearing Loss?

To describe the progression of sensorineural hearing loss (SNHL) in the better- and poorer-hearing ears in children with asymptomatic congenital cytomegalovirus (CMV) infection with isolated SNHL. Longitudinal prospective cohort study. Tertiary medical center. We analyzed hearing thresholds of the better- and poorer-hearing ears of 16 CMV-infected patients with isolated congenital/early-onset or delayed-onset SNHL identified through hospital-based CMV screening of >30,000 newborns from 1982 to 1992. By 12 months of age, 4 of 7 patients with congenital/early-onset SNHL developed worsening thresholds in the poorer-hearing ear, and 1 had an improvement in the better-hearing ear. By 18 years of age, all 7 patients had worsening thresholds in the poorer-hearing ear and 3 patients had worsening thresholds in the better-hearing ear. Hearing loss first worsened at a mean age of 2 and 6 years in the poorer- and better-hearing ears, respectively. Nine patients were diagnosed with delayed-onset SNHL (mean age of 9 years vs 12 years for the poorer- and better-hearing ears), 6 of whom had worsening thresholds in the poorer-hearing ear and 1 in both ears. In most children with congenital CMV infection and isolated SNHL, the poorer-hearing ear worsened earlier and more precipitously than the better-hearing ear. This study suggests that monitoring individual hearing thresholds in both ears is important for appropriate interventions and future evaluation of efficacy of antiviral treatment.

2087 Severe CMV Proctitis as the Initial Presentation of Ulcerative Proctitis

INTRODUCTION: CMV colitis is seen in patients with IBD on long term immunosuppressive therapy; studies show the rate of seropositivity in IBD patients is the same as the general population (∼70%). Due to this there is a concern for reactivation when long term immunosuppressive therapy is initiated. Here we present the case of a patient who presented with CMV colitis prior to initiation of any therapy or diagnosis of IBD; CMV colitis in immunocompetent patients remains fairly rare. CASE DESCRIPTION/METHODS: A 30-year-old male with a history of EoE and PUD presented with seven days of painful hematochezia and constipation; he denied any fevers, however did have chills and cold sweats. He had no history of IVDA, intranasal drug use, anal sex, or risky sexual behaviors. His EoE symptoms were well controlled on PPI. Temperature was 103.2 F, he was tachycardic and tachypneic on presentation. CT revealed fecalization of the small bowel, significant stool burden, and rectal stool ball. He was started on lubiprostone and a bowel regimen with PEG-3350, he passed stool with significant decrease in abdominal distention, however he continued to have rectal pain and hematochezia. Colonoscopy was performed and showed diffuse severe inflammation with erythematous, granular, and friable mucosa in the rectum. He was started on rectal mesalamine and corticosteroid therapy. Biopsies returned showing CMV associated severe ulcerative proctitis without evidence of dysplasia. He was then started on ganciclovir and PICC was placed for 2 weeks of treatment. Repeat HIV and HIV viral load testing were done, both returning negative. On follow up in clinic he reported good control of his symptoms with oral and rectal mesalamine. Flexible sigmoidoscopy showed a rectal scar and significantly improved inflammation, biopsy revealed ulcerative proctitis. DISCUSSION: CMV colitis has been commonly associated with UC patients on immunosuppressive therapy. An increasing body of literature shows the presence of colonic CMV infection in patients with UC on therapy has been associated with decreased response to steroids and other immunosuppressive therapies. Prognosis is poor unless the infection is promptly identified and anti-viral therapy is started. It still remains a rare entity in immunocompetent patients. This raises the question if CMV testing should be done prior to initiation of immunosuppressive therapy in these patients and if CMV testing should be done regularly in patients with refractive UC flares.

Association between lymphocyte subsets and cytomegalovirus infection status among patients with systemic lupus erythematosus: A pilot study.

This study aimed to determine the association between different lymphocyte subsets and cytomegalovirus (CMV) infection status in patients with systemic lupus erythematosus (SLE). We performed a retrospective study among SLE patients with CMV infection and collected patient socio-demographic and clinical characteristics, as well as their recorded circulating lymphocyte subsets. Univariate and multivariable logistic regression analyses examined the relationship between CMV infection status and lymphocyte subset counts. We included 125 hospitalized patients with SLE, consisting of 88 with documented CMV infection and 37 without any evidence of CMV or other infections. Among the 88 CMV-infected patients, 65 (73.8%) patients developed CMV disease and 23 (26.2%) presented as CMV viremia. Compared to uninfected patients (1520 ± 101 cells/μL), lymphocytes remained stable among those with CMV viremia (1305 ± 272 cells/μL, P = .995). However, compared to their uninfected counterparts, there was a marked decrease in lymphocytes among patients with CMV disease (680 ± 513 cells/μL, P < .001). Analysis of lymphocyte subsets via flow cytometry showed that CD4+ T cell, CD8+ T cell, and natural killer cell counts were lower among those with CMV disease compared to those with CMV viremia and those without infection. Further, multivariable analysis showed that total lymphocyte (odds ratio [OR] 0.999, 95% confidence interval [CI] 0.998–1.000, P = .007) and CD4+ T cell counts (OR 0.99, 95% CI 0.992–0.998, P = .003) were negatively associated with CMV disease. Our findings support a potential inverse relationship between lymphopenia, specifically CD4+ T-cell lymphopenia, and CMV disease among hospitalized SLE patients.

Triplex Vaccine in Preventing CMV Infection in Patients Undergoing Hematopoietic Stem Cell Transplantation

Triplex Vaccine in Preventing CMV Infection in Patients Undergoing Hematopoietic Stem Cell Transplantation

Risk factors for cytomegalovirus infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

AimsCytomegalovirus (CMV) infection under immunosuppression sometimes causes death. This study aimed to elucidate risk factors for CMV infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).MethodsPatients with AAV who underwent remission induction treatment at Okayama University Hospital between 2006 and 2016 were retrospectively analyzed. The primary outcome was the development of CMV infection within 3 months.ResultsOf the 111 patients, 13 (11.7%) patients developed CMV infection. Patients with CMV infection were older (p = 0.030) and had a higher body mass index (p = 0.029) in comparison to those without CMV infection. A higher proportion had a severe form (p = 0.001) and granulomatosis with polyangiitis (GPA) (p = 0.001), as well as a higher Birmingham Vasculitis Activity Score (p = 0.018) and C-reactive protein (p = 0.018) levels at baseline. Using logistic regression analysis, severe form and GPA were independent risk factors (odds ratio [OR] = 9.68, 95% confidence interval [CI] = 1.92–60.23, and OR = 7.46, 95% CI = 1.46–47.60, respectively). In addition, patients with CMV infection were more likely than those without infection to be glucocorticoid-related diabetes mellitus (p = 0.025).ConclusionOur study highlights disease severity and subgroups of AAV as risk factors for CMV infection.

Immunological damage effects of cytomegalovirus infection on bone marrow hematopoietic cells

Objective: Toobserve the damage effects of cytomegalovirus (CMV) infection on hematopoietic cells and to investigate the clinical significance. Methods: (1) ELISA assay wasused to detect IL-17 and IFN-γ levels in the peripheral blood serum of 36 patients on pretherapy and posttherapy. (2) Changes of peripheral blood lymphocyte subsets were detected by FACS. (3) Cytological observation of cervical lymph nodes was executed by needle aspiration cytology. (4) Cellular immunochemistry and immunofluorescence staining were performed to observe the POX release, HLA-DR expression, IL-17A and IFN-γ secretion-like expression status of activated immune cells in the bone marrow hematopoietic microenvironment. Serum samples from healthy individuals were used as controls. Bone marrow smears from patients without iron deficiency anemia were compared as bone marrow immunostaining. Results: (1) Serum levels of IL-17 and IFN-γ were significantly increased in CMV-infected patients [IL-17 (48.23±3.86) ng/L vs (20.16±1.05) ng/L,respectively; IFN-γ (40.16±3.11) vs (8.17±1.92) ng/L,P<0.01]. (2) The proportion of CD16+/CD56+NK cells was significantly increased in patients [(43.54±6.01)% vs (14.01±3.25)%, P<0.01]. The proportion of CD3+CD4+T and CD3+CD8+T cells decreased,(20.91±53.15)% vs (35.10±4.88)%, and (15.41±5.13)% vs (25.11±3.92)%,respectively,P<0.05. (3) Large numbers of abnormal lymphocytes and macrophages (MΦ) that engulf large quantities of CMV inclusion bodies were observed in bone marrow and lymph nodes. CMV infected and destroied the hematopoietic cells of various lines in the bone marrow. The activated MΦ phagocytizedthe CMV inclusion bodies and also phagocytosed CMV-infected blood cells. (4) Activated MΦ in bone marrow hematopoietic microenvironment released POX strongly positive, highly expressed class Ⅱ HLA-DR, and highly expressed inflammatory factors IL-17A and IFN-γ. (5) Twenty-twopatients with elevated WBC were treated with ganciclovir combined with antibiotics for 2 weeks after the disappearance of the foci, WBC counts and CMV-IgM levels of 16 cases were reduced to normal.Six patients with CMV who were not turned negative were tprolonged,and the granulocyte and/or platelet counts fell below normal range. Fourteenpatients withreduced granulocyte or platelet count, CMV-IgM levels were slow descend,and the ganciclovir treated more than 4 weeks. Conclusions: CMV can infect hematopoietic bone marrow nucleated blood cells and destroy hematopoiesis. NK and MΦ cells are important effector cells against CMV infection. Activated macrophages are dual in nature, they can engulf CMV virus and virus-infected blood cells,and also aggravate bone marrow immune damage by releasing inflammatory factors such as POX and IL-17A and IFN-γ.

Elevated Cytomegalovirus and Epstein-Barr virus burden in rheumatoid arthritis: A true pathogenic role or just a coincidence

BackgroundCytomegalovirus (CMV) and Epstein-Barr virus (EBV) have created great interest as their immunomodulatory action and latent forms could play a role in the advance of autoimmune diseases. Aim of the workTo investigate the viral load of CMV and EBV in the serum of rheumatoid arthritis (RA) patients’ and study their association with the clinical and laboratory profiles. Patients and methodsThe study included 50 RA patients and 32 healthy controls. Disease activity score (DAS28) was assessed and the medications received reported. Quantitation of CMV and EBV DNA in serum of all subjects was achieved by real-time polymerase chain reaction. ResultsPatients were 38 females and 12 males with mean age of 43.1 ± 12 years, disease duration of 6.5 ± 5.7 years; age of onset 36.6 ± 12.8 years. CMV DNA was detected in serum of 68% (34\\50) patients, while EBV DNA was detected in 40% (20\\50). Fourteen (28%) patients had both EBV and CMV DNA detected in serum. No viruses were detected in serum of 10/50 (20%) patients or in healthy controls. The mean viral load of CMV and EBV detected were 42005 ± 24805 copies/ml and 18756 ± 24937 copies/ml respectively. A significant increased frequency of anemia (p < 0.0001), Raynaud's (p < 0.0001), oral ulcers (p = 0.014) and arthritis (p < 0.0001) was detected in those infected with CMV versus those infected with EBV. ConclusionsA high incidence of CMV and EBV was detected in RA patients with increased viral load than described previously. Frequencies of RA disease manifestations are significantly higher in CMV infected patients compared to those infected with EBV.

Does Thymoglobulin Induction Lead to Increased CMV Infection after Heart Transplantation in the Current Tacrolimus Era

Purpose Thymoglobulin (ATG) is commonly used as induction therapy immediately after heart transplantation (HTx). ATG has been associated with an increase in CMV infection when used with maintenance cyclosporine. In the current era, tacrolimus has replaced cyclosporine as the main maintenance immunosuppressive agent. It is not clear whether ATG induction does indeed lead to more CMV infection in the tacrolimus era. Methods Between 2010 and 2016, we assessed 342 patients who received ATG induction therapy and compared them with HTx patients who did not receive ATG (n=312). ATG is routinely administered to patients with renal insufficiency to delay tacrolimus initiation and to sensitized patients (PRA ≥ 10%). Patients treated with ATG were then divided into their donor/recipient CMV serology matching (D+R-, D+R+, D-R+ and D-R-) and analyzed for the development of CMV infection defined as patients presenting with clinical symptoms and detected CMV virus via PCR. Incidence of rejection was also evaluated. Valcyte is routinely administered for CMV prophylaxis. Results There was a trend towards an increase in CMV infection in patients who received ATG induction therapy after HTx (see table). When the ATG population was analyzed by CMV serology, CMV mismatch (D+R-) had a numerical increase in CMV infection but this result was not statistically significant. When compared to the D-R- group on pairwise analysis, there was a trend towards increase in CMV infection and any-treated rejection in the CMV mismatch group (D+R-). (see table). Of note, valcyte induction was similar between groups per the transplant protocol. Conclusion ATG therapy trends towards increased CMV infection post-transplant in the tacrolimus era. Patients who have been treated with ATG and have CMV mismatch (D+R-) may have increased CMV infection risk as well as rejection risk by 2-years after HTx. Larger numbers are needed to confirm these findings.

Cytomegalovirus Infection in Cardiovascular Diseases.

Atherosclerosis underlies the development of many cardiovascular diseases that continue to hold a leading place among the causes of death in developed countries. The role of activated immune cells in atherosclerosis progression has been convincingly demonstrated, but the mechanism of their action remains poorly investigated. Since atherosclerosis is associated with chronic inflammatory response, involvement of viral and bacterial infections in atherogenesis has been examined. A special place among the infectious agents is held by human herpesviruses as the most common persistent viruses in human population coupled to chronic inflammation during atherosclerosis. We found that activation of cytomegalovirus (CMV, human herpesvirus 5) infection is associated with the emergence of acute coronary syndrome, which is in a good agreement with the data on productive CMV infection published elsewhere. In this review, we discuss the data obtained by us and other researchers regarding the role of cytomegalovirus infection and related potential mechanisms resulting in the expansion of atherosclerotic plaques during ischemic heart disease and stroke, including virus transfer to immune and endothelial cells via extracellular vesicles. In particular, the data presented in the review demonstrate that virus spreading in the vascular wall triggers immune system activation in atherosclerotic plaques and causes endothelial dysfunction. Moreover, productive CMV infection in patients with acute myocardial infarction correlates with the extent of endothelial dysfunction. The mechanisms described by us and other researchers may explain the role of CMV infection in atherosclerosis and development of ischemic heart disease.

CMV Infection in Patients with Profound Hearing Loss

CMV Infection in Patients with Profound Hearing Loss

Prevalence of multiple infections and the risk of gastric adenocarcinoma development at earlier age

Helicobacter pylori and Epstein–Barr virus are well established infections for gastric cancer development. However, the role of cytomegalovirus alone or in combination with other infections is unclear. In this case-control study, the prevalence of different infections was evaluated, and their frequency was compared with clinicopathologic features among gastric cancer patients and normal volunteers from 2012 to 2017. Approximately two-thirds (61.9%) of the gastric cancer patients had at least 1 viral infection, while viral infection prevalence in normal volunteers was only 4.7% (P = 0.021). The higher infection frequency in gastric cancer patients was observed for EBV (49.2%). No CMV DNA was detected in normal volunteers. In contrast, one-fourth of the gastric cancer patients were infected with CMV. Furthermore, CMV frequency in tumoral tissues (68.75%) was significantly higher than in nontumoral tissues (12.5%) (P = 0.0311). Although H. pylori infection was significantly lower in tumoral tissues than in nontumoral tissues (P = 0.0136), all tumoral tissues had cagA, while only 61.5% of nontumoral tissues were cagA positive. CMV-infected patients were affected 14 years earlier than uninfected, and CMV-negative patients (mean age = 56 vs. 69 and 70 years; P= 7.6×10−3 and P = 2.7×10−4, respectively). Also, EBV viral load in earlier grades and stages was more than 100-fold higher than advanced grades and stages. Our results show a high level of infections in gastric cancer. The association of these infections especially with CMV contributes to gastric adenocarcinoma development at earlier age.