Aerobic Bacterial Vaginosis and Lactobacillus Species Associated with Cytomegalovirus in Abortion.

Abortion is a common complication in the life cycle of pregnancy. Based on the American College of Obstetricians and Gynecologists, spontaneous abortion is defined as the expulsion of an embryo or the extraction of a fetus at the age of 20-22 weeks of pregnancy. This study aimed to investigate the relationship between socioeconomic factors and bacterial vaginosis (BV) in women having an abortion. As a secondary aim, it attempted to detect common bacteria that cause vaginosis associated with miscarriage and are related to Cytomegalovirus (CMV) and Lactobacillus species (spp.). A total of 113 high vaginal swabs were taken from women having an abortion. Some variables that have been investigated in this study include age, education, and infection. After the vaginal discharge collection, the smear was prepared. Afterward, one or two drops of normal saline solution were put on the prepared smear with a cover slip, and then, they were examined under a microscope. Gram stain kits (Hi-media, India), were used to differentiate between the shapes of bacterial isolates. The wet mount technique was then utilized for the detection of Trichomonas vaginalis and aerobic BV. All the samples were used for smear gram staining and were cultured on blood agar, chocolate agar, as well as MacConkey agar. Biochemical examinations performed on suspicious cultures included the Urease test, Oxidase test, Coagulase test, and Catalase test. In the present study, the participants' age ranged from 14 to 45 years. Women aged 24-34 years had a high rate of miscarriage, determined at 48 (42.5%), which was considered a high incidence rate. The results showed that 28.6% of the studied population experienced abortion once and 71.4% of them experienced it twice due to aerobic BV. The recorded data also revealed that 50% of the studied population, who were infected with CMV or Trichomonas vaginalis, experienced abortion once and the other 50% experienced it twice. From 102 samples infected with Lactobacillus spp., 45.17% experienced abortion once and 42.2% experienced it twice.

Current practices of management of maternal and congenital Cytomegalovirus infection during pregnancy after a maternal primary infection occurring in first trimester of pregnancy: Systematic review.

INTRODUCTION: Congenital CMV infection is the first worldwide cause of congenital viral infection but systematic screening of pregnant women and newborns for CMV is still debated in many countries. OBJECTIVES: This systematic review aims to provide the state of the art on current practices concerning management of maternal and congenital CMV infection during pregnancy, after maternal primary infection (PI) in first trimester of pregnancy. DATA SOURCES: Electronically searches on databases and hand searches in grey literature. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: Primary outcome was listing biological, imaging, and therapeutic management interventions in two distinct populations: population 1 are pregnant women with PI, before or without amniocentesis; population 2 are pregnant women with congenitally infected fetuses (after positive amniocentesis). Secondary outcome was pregnancy outcome in population 2. RESULTS: Out of 4,134 studies identified, a total of 31 studies were analyzed, with 3,325 pregnant women in population 1 and 1,021 pregnant women in population 2, from 7 countries (Belgium, France, Germany, Israel, Italy, Spain and USA). In population 1, ultrasound (US) examination frequency was 0.75/month, amniocentesis in 82% cases, maternal viremia in 14% and preventive treatment with hyperimmune globulins (HIG) or valaciclovir in respectively 14% and 4% women. In population 2, US examination frequency was 1.5/month, magnetic resonance imaging (MRI) in 44% cases at 32 weeks gestation (WG), fetal blood sampling (FBS) in 24% at 28 WG, and curative treatment with HIG or valaciclovir in respectively 9% and 8% patients. CONCLUSIONS: This systematic review illustrates management of maternal and congenital CMV during pregnancy in published and non-published literature, in absence of international consensus. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019124342.

Human cytomegalovirus blocks canonical TGFß signaling during lytic infection to limit induction of type I interferons.

Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGFß interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.

Co-infection of Pneumocystis jirovecii pneumonia and pulmonary CMV in a infant with X-linked severe combined immunodeficiency.

We herein report a rare case of co-infection of Pneumocystis jirovecii pneumonia and pulmonary CMV in a 3-month-old infant with X-linked severe combined immunodeficiency, in which diagnostic clues were obtained from the bronchoalveolar lavage fluid. We focus on the value of cytological diagnosis of P. jirovecii pneumonia and pulmonary CMV in the bronchoalveolar lavage fluid. Recognizing morphological characteristics of these pathogenic microorganisms is important to get timely diagnosis and treatment for the patients. Furthermore, repeated severe infections in infants should remind us to screen for immunosuppressed states.

Faecal Microbiota Transfer - a new concept for treating cytomegalovirus colitis in children with ulcerative colitis.

INTRODUCTION: Cytomegalovirus (CMV) infection in patients with inflammatory bowel disease (IBD) is reactivated by the use of immunosuppressive drugs. CMV infection may produce IBD flares refractory to standard therapy. OBJECTIVE: The aim of our study was to assess the efficacy and safety of faecal microbiota transplantation (FMT) for the treatment of CMV colitis in patients with ulcerative colitis (UC) flare. MATERIAL AND METHODS: A total of 8 children, with mild to severe UC, positive for CMV PCR in colonic biopsies, received 50-100 ml FMT by nasogastric tube on 5 consecutive days in each of 2 weeks. During the study, the subjects were treated with 5ASA and FMT. Immunosuppressant therapy was withdrawn, when CMV colitis was diagnosed by positive DNA PCR in colonic tissues. The clinical response was defined as a decrease of Paediatric UC Activity Index by ≥20 points. RESULTS: At the 6th week of the study, negative colonic CMV DNA PCR was measured after 10 infusions in 7/8 patients. For one boy, 20 infusions were administered to assess CMV elimination from colonic biopsies. A clinical response was observed in 3/8 patients, with clinical remission in 3/8 patients. Faecal calprotectin decreased significantly in 3 patients. CRP normalized in 2 patients after 6 weeks. No serious adverse effects were observed during and after infusions. CONCLUSIONS: FMT seems to be an effective and safe treatment option for CMV colitis in children with UC. This is the first study to demonstrate the application of FMT as a new therapeutic option for CMV colitis.

Human Cytomegalovirus-Induced Interleukin-10 Production Promotes the Proliferation of Mycobacterium massiliense in Macrophages.

Human cytomegalovirus (HCMV) exploits the interleukin-10 (IL-10) pathway as a part of its infection cycle through the manipulation of the host IL-10 signaling cascade. Based on its immunomodulatory nature, HCMV attenuates the host immune response and facilitates the progression of co-infection with other pathogens in an immune-competent host. To investigate the impact of HCMV infection on the burden of non-tuberculous mycobacteria (NTM), whose prevalence is growing rapidly worldwide, macrophages were infected with HCMV and further challenged with Mycobacterium massiliense in vitro. The results showed that HCMV infection significantly increased host IL-10 synthesis and promoted the proliferation of M. massiliense in an IL-10-dependent manner. Transcriptomic analysis revealed that HCMV infection dampened the regulatory pathways of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 (IL-1), consequently abrogating the immune responses to M. massiliense coinfection in macrophages. These findings provide a mechanistic basis of how HCMV infection may facilitate the development of pathogenic NTM co-infection by upregulating IL-10 expression.

[Comparison of Two Commercial Quantitative Cytomegalovirus (CMV) Polymerase Chain Reaction Tests Calibrated by World Health Organization International CMV Standard]. / Dünya Saglik Örgütü Uluslararasi Sitomegalovirüs (CMV) Standardi ile Kalibre Edilmis Iki Ticari Kantitatif CMV Polimeraz Zincir Reaksiyonu Testinin Karsilastirilmasi.

Cytomegalovirus (CMV) viral load quantitation is important in diagnosis, follow-up, and monitoring of antiviral therapy in transplanted patients. In this study, it was aimed to compare the results of the two commercial World Health Organization (WHO) International CMV standard calibrated polymerase chain reaction tests, CMV Cobas Ampliprep/Cobas Taqman (CMV-CAP/CTM) (Roche, Germany) and Artus CMV QIASymphony-Rotorgene (CMV-QS-RGQ) (Qiagen, Germany). Both tests were performed simultaneously on 244 plasma samples. The results were measured in copies/ml and converted to IU/ml by multiplying with 0.91 for CMV-CAP/CTM and 1.64 for CMV-QS-RGQ, as specified by the manufacturers. CMV DNA was detected in 174 (71.3%) and was not detected in 52 (21.3%) of the samples and eighteen (7.4%) samples had discordant results by both of the tests. In 16 out of 18 samples with discordance, the viral load was below the dynamic measuring ranges of both tests. In one sample, CMV DNA could not be detected by CMV-CAP/CTM but detected by CMV-QS-RGQ with 497 copies/ml, and 334 copies/ml CMV DNA was detected by CMV-CAP/CTM in another sample where it could not be detected by CMV-QS-RGQ. A high degree of agreement was found between the qualitative results of the both tests (kappa= 0.80, p< 0.001). For quantitative results in the dynamic measuring range of both assays (n= 129), the median viral load values measured by CMV-CAP/CTM and CMV-QS-RGQ were 1140 copies/ml (range: 151-254000) and 1826 copies/ml (range: 189-551521). When the results were converted to IU/ ml, the median viral load values measured by CMV-CAP/CTM and CMV-QS-RGQ were 1037 IU/ml (range: 137-231140) and 2993 IU/ml (range: 310-904133), respectively. There was a very strong correlation (r= 0.94, p< 0.001; r= 0.94, p< 0.001, respectively) between the log10 values of the quantitative results in the dynamic measuring ranges (n= 129) as copies/ml and IU/ml of both tests. CMV-QS-RGQ values corresponding to 150, 1000, 3000 copies/ml in CMV-CAP/CTM were as 94.5, 1571, 323.5 copies/ml and CMV-QS-RGQ values corresponding to 137, 910, 2730 IU/ml in CMV CAP/CTM were as 154, 2557.6, 6965.9 IU/ml, respectively. A variation of 0.45 log10 was determined between these values. In a total of 131 samples; 129 of them with the result of both tests in the dynamic measuring range and two of them which CMV DNA was not detected in one of the tests; it was found that 112 (85.5%) results for copy/ ml, 73 (56%) results for IU/ml were within the measurement difference of ± 0.5 log10 and 19 (14.5%) results for copy/ml and 58 (44%) results for IU/ml were greater than ± 0.5 log10. Bland-Altman analysis showed that CMV-CAP/CTM test made lower measurements than CMV-QS-RGQ and the average difference for copy/ml and IU/ml results were 0.22 log10 copies/ml and 0.47 log10 IU/ml. In conclusion; when the results were converted to IU/ml, the number of samples with an acceptable measurement difference between the two test results (≤ 0.5 log10) decreased and the number of samples with a measurement difference > 0.5 log10 increased and the difference was found as statistically significant (p< 0.001). Calibrating the Roche CMV CAP/CTM and Artus CMV-QS-RGQ tests with the WHO international CMV standard did not increase comparability between quantitative results in plasma samples, on the contrary, it was found that when the results were converted to IU/ml, a measurement difference indicating biologically significant viral replication was detected between the two test results.

Human cytomegalovirus long noncoding RNA4.9 regulates viral DNA replication.

Viruses are known for their extremely compact genomes composed almost entirely of protein-coding genes. Nonetheless, four long noncoding RNAs (lncRNAs) are encoded by human cytomegalovirus (HCMV). Although these RNAs accumulate to high levels during lytic infection, their functions remain largely unknown. Here, we show that HCMV-encoded lncRNA4.9 localizes to the viral nuclear replication compartment, and that its depletion restricts viral DNA replication and viral growth. RNA4.9 is transcribed from the HCMV origin of replication (oriLyt) and forms an RNA-DNA hybrid (R-loop) through its G+C-rich 5' end, which may be important for the initiation of viral DNA replication. Furthermore, targeting the RNA4.9 promoter with CRISPR-Cas9 or genetic relocalization of oriLyt leads to reduced levels of the viral single-stranded DNA-binding protein (ssDBP), suggesting that the levels of ssDBP are coupled to the oriLyt activity. We further identified a similar, oriLyt-embedded, G+C-rich lncRNA in murine cytomegalovirus (MCMV). These results indicate that HCMV RNA4.9 plays an important role in regulating viral DNA replication, that the levels of ssDBP are coupled to the oriLyt activity, and that these regulatory features may be conserved among betaherpesviruses.

Markers of microbial translocation during pregnancy: differences among HIV+ women of African and European provenance.

INTRODUCTION: Microbial translocation (MT) markers are indicators of HIV-related immune activation, but reference values are mostly derived from European or North American populations and could be substantially different in populations living in developing countries. Here we evaluate possible differences in MT markers levels in HIV+ pregnant women of different geographical provenance. METHODOLOGY: This study is nested within an observational study of pregnant women with HIV in Italy. Women were dichotomized on the basis of provenance in two groups of European (n = 14) and African (n = 26) origin. Soluble CD14, lipopolysaccharide-binding protein (LBP) and intestinal-fatty acid binding protein (I-FABP) were measured in plasma samples collected between the first and second trimester of pregnancy. RESULTS: Demographic and viroimmunological characteristics were similar between groups, although European women were more commonly smokers and HCV-coinfected. Irrespective of origin, LBP plasma levels were positively correlated with I-FABP (r = 0.467, p = 0.004) and sCD14 levels (r = 0.312 p = 0.060). Significantly higher levels of sCD14 (1885 vs. 1208 ng/mL, p = 0.005) LBP (28.5 vs. 25.3 µg/mL, p = 0.050) and I-FABP (573.4 vs. 358.2 pg/mL, p = 0.002) were observed in European compared with African women. A multivariable linear regression analysis, adjusted for smoking and HCV coinfection confirmed the association between sCD14 levels and women provenance (p = 0.03). CONCLUSIONS: Our observations indicate significant differences in soluble markers among women of different provenance. In the design and analysis of studies evaluating MT markers, population-specific reference values should be considered.

Metagenomic next-generation sequencing for mixed pulmonary infection diagnosis.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is emerging as a promising technique for pathogens detection. However, reports on the application of mNGS in mixed pulmonary infection remain scarce. METHODS: From July 2018 to March 2019, 55 cases were enrolled in this retrospective analysis. Cases were classified into mixed pulmonary infection (36 [65.5%]) and non-mixed pulmonary infection (19 [34.5%]) according to primary diagnoses. The performances of mNGS and conventional test on mixed pulmonary infection diagnosis and pathogen identification were compared. RESULTS: The sensitivity of mNGS in mixed pulmonary infection diagnosis was much higher than that of conventional test (97.2% vs 13.9%; P < 0.01), but the specificity was the opposite (63.2% vs 94.7%; P = 0.07). The positive predictive value of mNGS was 83.3% (95% CI, 68.0-92.5%), and the negative predictive value was 92.3% (95% CI, 62.1-99.6%). A total of 5 (9.1%) cases were identified as mixed pulmonary infection by both conventional tests and mNGS, however, the pathogens identification results were consistent between these two methods in only 1 (1.8%) case. In summary, the pathogens detected by mNGS in 3 (5.5%) cases were consistent with those by conventional test, and only 1 (1.8%) case was mixed pulmonary infection. According to our data, mNGS had a broader spectrum for pathogen detection than conventional tests. In particular, application of mNGS improved the diagnosis of pulmonary fungal infections. Within the 55 cases, mNGS detected and identified fungi in 31 (56.4%) cases, of which only 10 (18.2%) cases were positive for the same fungi by conventional test. The most common pathogen detected by mNGS was Human cytomegalovirus in our study, which was identified in 19 (34.5%) cases of mixed pulmonary infection. Human cytomegalovirus and Pneumocystis jirovecii, which were detected in 7 (12.7%) cases, were the most common co-pathogens in the group of mixed pulmonary infection. CONCLUSIONS: mNGS is a promising technique to detect co-pathogens in mixed pulmonary infection, with potential benefits in speed and sensitivity. TRIAL REGISTRATION: (retrospectively registered): ChiCTR1900023727. Registrated 9 JUNE 2019.

Use of mTOR inhibitor as prophylaxis for cytomegalovirus disease after kidney transplantation: A natural experiment.

OBJECTIVES: To describe the incidence of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving an mTOR-inhibitor-containing immunosuppressive regimen without prophylactic CMV treatment. METHODS: This single-center retrospective cohort analysis included all de novo kidney transplant recipients (09/15/2015-07/31/2017) receiving 3 mg/kg single dose of rabbit antithymocyte globulin induction, tacrolimus, everolimus, and prednisone. Preemptive therapy was initiated only in patients deemed at higher risk for CMV infection: (a) D+/R- CMV patients; (b) after treatment for acute rejection (ARt); and (c) after everolimus discontinuation (EVRd). RESULTS: Of 230 patients, there were no episodes of CMV disease among 217 (94%) without criteria to initiate preemptive therapy. Of 77 (33.5%) patients initiating preemptive therapy, 13 were D+/R-, 30 were ARt, and 34 were EVRd. The overall incidence of first CMV infection/disease was 6% (46.1% in D+/R-, 13.3% ARt [all patients had also discontinued everolimus], and 11.8% after early [<90 days] EVRd). The incidence of biopsy-proven acute rejection was 5.6%, and median glomerular filtration rate at month 12 was 47 mL/min/1.73m2 . One-year patient and death-censored graft survivals were 97.4% and 98.1%. CONCLUSION: This study suggests that everolimus-containing immunosuppressive regimen reduces the need for preventive strategies for CMV infection in the majority of kidney transplant recipients, reducing antiviral drug-associated toxicities and healthcare-related expenditures.

Multiple infections by EBV, HCMV and Helicobacter pylori are highly frequent in patients with chronic gastritis and gastric cancer from Southwest Mexico: An observational study.

The chronic inflammation and damage to the gastric epithelium induced by Helicobacter pylori (H. pylori) are the main risk factors for gastric cancer development. Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) induce chronic inflammation and have been found in gastric tumors. The objectives this observational study were to determine the frequency of multiple infections by Helicobacter pylori, Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) and to relate the infection by EBV and HCMV with H. pylori vacA/cagA genotypes in patients with chronic gastritis or gastric cancer. DNA from H. pylori, EBV and HCMV was detected by PCR in biopsies from 106 Mexican patients with chronic gastritis and 32 from gastric cancer. The cagA status and the vacA genotypes of H. pylori were determined by PCR. In chronic gastritis and gastric cancer EBV was found in 69.8% and 87.5%, HCMV in 52.8% and 53.1%, and H. pylori in 48.1% and 40.6%, respectively. In chronic gastritis, 53% of H. pylori patients were EBV and 33% were both EBV/HCMV; in gastric cancer, 92.3% of H. pylori-infected individuals were EBV and 46.1% were EVB/HCMV. All the intestinal- and mixed-type tumors and the 83.3% of diffuse-type tumors were EBV. No significant differences were found between single infections or coinfections with the diagnosis or the cancer type. The H. pylori genotypes were not related to EBV or HCMV infection. The frequency of dual infections by H. pylori, EBV and HCMV is higher in patients from southwest Mexico than other populations. It is likely that these pathogens act synergistically to induce inflammation and gastric cancer.

Hemophagocytic syndrome in patients living with HIV: a retrospective study.

Various infectious diseases can hyper-stimulate the immune system, causing hemophagocytic syndrome (HPS). Little is known regarding the accuracy of diagnostic criteria and epidemiological triggering factors in the acquired immunodeficiency syndrome (AIDS) setting. We investigated the major infectious disease triggers of HPS in patients living with human immunodeficiency virus (HIV)/AIDS and determined the accuracy of bone marrow aspiration (BMA). The inclusion criteria were (i) confirmed HIV diagnosis, (ii) bone marrow aspiration, and (iii) a minimum of four HPS criteria. Patients were further classified into those with four presumed HPS criteria, or ≥ 5 confirmed criteria. The disease triggers, accuracy of bone marrow aspiration, and prognosis markers were examined. Presumed HPS was observed in 15/36 patients (41%), and confirmed HPS in 58% (n = 21). The major etiological triggers were infection with Mycobacterium (34%), Cytomegalovirus (14%), Cryptococcus neoformans (11%), and hematological or tumoral disease (11%). BMA demonstrated 93% specificity on screening diagnosis (odds ratio [OR] 12.7, 95% confidence interval [CI] 1.4-115.1, P = 0.01). Ferritin > 5000 ng/mL correlated with probability of death in univariate analysis (OR 6.00, 95% CI 1.33-27.05, P = 0.02). Ferritin performance as test of death probability presented area under the curve as 0.74 (95% CI 0.56-0.91, P = 0.016). However, neither cluster of differentiation for lymphocyte count nor HIV viral load correlated with patient deaths. Mycobacterium spp. and Cytomegalovirus were the main factors triggering HPS, followed by Cryptococcus neoformans, and hematological and tumoral diseases. High ferritin levels were associated with increased death probability. High specificity was noted with BMA.

Infections of the esophagus: an update on risk factors, diagnosis, and management.

Infectious esophagitis is a leading cause of esophagitis worldwide. While esophageal infections have traditionally been associated with immunocompromised patients, these disorders are becoming increasingly recognized in immunocompetent individuals. The three most common etiologies of infectious esophagitis are Candida, herpes simplex virus, and cytomegalovirus. Human papilloma virus infection can also involve the esophagus in the form of ulcerative lesions and papillomas. Less common etiologies include various other fungal, bacterial, and viral organisms. This review provides a comprehensive update on risk factors, diagnosis, and management of both common and less common infections of the esophagus.

Cytomegalovirus infection and graft rejection as risk factors for pneumocystis pneumonia in solid organ transplant recipients: A systematic review and meta-analysis.

A growing number of publications have reported the outbreaks of post-transplant pneumocystis pneumonia (PJP). In most studies, the onset of PJP was beyond 6-12 months of prophylaxis. Cytomegalovirus (CMV) infection and allograft rejection have been repeatedly reported as probable risk factors for post-transplant PJP. In this systematic review and meta-analysis, we determined the pooled effect estimates of these 2 variables as risk factors. Data sources included PUBMED, MEDLINE-OVID, EMBASE-OVID, Cochrane Library, Networked Digital Library of Theses and Dissertations, World Health Organization, and Web of Science. We excluded publications related to hematopoietic stem cell transplantation (HSCT) or Human Immunodeficiency Virus (HIV) patients. Eventually, 15 studies remained for the final stage of screening. Cytomegalovirus infection (OR: 3.30, CI 95%: 2.07-5.26, I2 : 57%, P = 0.006) and allograft rejection (OR:2.36, CI95%: 1.54-3.62, I2: 45.5%, P = 0.05) significantly increased the risk of post-transplant PJP. Extended prophylaxis targeting recipients with allograft rejection or CMV infection may reduce the risk of PJP.

Unique causes of esophageal inflammation: a histopathologic perspective.

Gastroenterologists frequently perform endoscopic esophageal mucosal biopsies for pathologic diagnosis in patients experiencing symptoms of esophagitis. The more common causes of esophagitis diagnosed on esophageal mucosal biopsy include reflux esophagitis, eosinophilic esophagitis, and infectious esophagitis caused by Candida albicans, herpes simplex virus, and/or cytomegalovirus. However, there are several causes of esophagitis seen less frequently by pathologists that are very important to recognize. We discuss unique types of esophageal inflammation, including acute bacterial esophagitis, esophageal manifestations of dermatologic diseases, medication-induced esophageal injury, and sloughing esophagitis; and we review their clinical and histopathologic features.

Sirolimus exposure and the occurrence of cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation.

Sirolimus appears to protect against cytomegalovirus (CMV) in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation recipients remains unexplored. By means of multivariate continuous-time Markov model analyses, we identified 3 independent covariates that significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure, and sirolimus exposure. CMV-seropositive recipients with CMV-seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by 40% (from 40% to 80%), whereas this probability decreased by 25% (from 40% to 15%) when trough concentrations of sirolimus increased from 0 to 16 ng/mL. Sensitivity analysis showed that sirolimus exposure between 0 and 6 ng/mL has no or negligible effect on CMV DNAemia, but levels >8 ng/mL significantly decreased the number of detectable CMV DNAemia cases (the risk ratios decreased from 0.68 to 0.21 when whole blood sirolimus concentrations changed from 8 to 18 ng/mL, P < .01). In conclusion, we used a pharmacometric statistical tool to provide the first clinical evidence that fewer CMV DNAemia events become detectable as sirolimus exposure increases.