Primary Cytomegalovirus Research Articles

Prevalence and timing of prenatal ultrasound findings in cytomegalovirus‐infected pregnancies

AbstractIntroductionTo investigate the prevalence and timing of prenatal neurosonographic abnormalities after primary cytomegalovirus seroconversion by the first trimester of pregnancy. The additional value of magnetic resonance imaging (MRI) and the correlation between cytomegalovirus viral load in amniotic fluid and adverse neonatal outcomes were evaluated.Material and MethodsA retrospective study between 2006 and 2022 examined data from 440 women with amniocentesis for periconceptional and first‐trimester cytomegalovirus seroconversion. Cases with positive amniocentesis and subsequent follow‐up were included. Prenatal neurosonography, MRI, and clinical outcomes were analyzed.ResultsOut of 190 women included, 37% (n = 70) presented with a normal neurosonography. Patients exhibiting abnormal neurosonography findings showed higher viral loads in amniotic fluid compared to those with a normal neurosonography (p = 0.002). In 26% (n = 49) the first abnormal ultrasound sign was already picked up at amniocentesis, and the most common ones were echogenic bowels (49%) and periventricular echogenicity (43%). With increasing gestational age, the likelihood of a new abnormal neurosonography finding decreases. MRI discovered additional abnormalities in 14% (n = 10).ConclusionsThe results highlight the importance of combining diagnostic modalities, from amniocentesis to biweekly ultrasound monitoring and subsequent MRI evaluation, to capture the chronological progression and subsequent outcome of congenital cytomegalovirus.

CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of infectious disease related birth defects worldwide. How the immune response modulates the risk of intrauterine transmission of HCMV after maternal infection remains poorly understood. Maternal T cells likely play a critical role in preventing infection at the maternal-fetal interface and limiting spread across the placenta, but concerns exist that immune responses to infection may also cause placental dysfunction and adverse pregnancy outcomes. This study investigated the role of CD4+ and CD8+ T cells in a guinea pig model of primary cytomegalovirus infection. Monoclonal antibodies specific to guinea pig CD4 and CD8 were used to deplete T cells in non-pregnant and in pregnant guinea pigs after mid-gestation. CD4+ T cell depletion increased the severity of illness, caused significantly elevated viral loads, and increased the rate of congenital guinea pig cytomegalovirus (GPCMV) infection relative to animals treated with control antibody. CD8+ T cell depletion was comparably well tolerated and did not significantly affect the weight of infected guinea pigs or viral loads in their blood or tissue. However, significantly more viral genomes and transcripts were detected in the placenta and decidua of CD8+ T cell depleted dams post-infection. This study corroborates earlier findings made in nonhuman primates that maternal CD4+ T cells play a critical role in limiting the severity of primary CMV infection during pregnancy while also revealing that other innate and adaptive immune responses can compensate for an absent CD8+ T cell response in α-CD8-treated guinea pigs.

Discrimination of primary and chronic cytomegalovirus infection based on humoral immune profiles in pregnancy.

BACKGROUNDMost humans have been infected with cytomegalovirus (CMV) by midlife without clinical signs of disease. However, in settings in which the immune system is undeveloped or compromised, the virus is not adequately controlled and consequently presents a major infectious cause of both congenital disease during pregnancy as well as opportunistic infection in children and adults. With clear evidence that risk to the fetus varies with gestational age at the time of primary maternal infection, further research on humoral responses to primary CMV infection during pregnancy is needed.METHODSHere, systems serology tools were applied to characterize antibody responses to CMV infection in pregnant and nonpregnant women experiencing either primary or chronic infection.RESULTSWhereas strikingly different antibody profiles were observed depending on infection status, limited differences were associated with pregnancy status. Beyond known differences in IgM responses used clinically for identification of primary infection, distinctions observed in IgA and FcγR-binding antibodies and among antigen specificities accurately predicted infection status. Machine learning was used to define the transition from primary to chronic states and predict time since infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection.CONCLUSIONIn sum, this work provides insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics.FUNDINGCYMAF consortium and NIH NIAID.

Cytomegalovirus-Specific Hyperimmune Immunoglobulin Administration for Secondary Prevention after First-Trimester Maternal Primary Infection: A 13-Year Single-Center Cohort Study.

Primary cytomegalovirus infection during pregnancy has a high risk of vertical transmission, with severe fetal sequelae mainly associated with first-trimester infections. We conducted a retrospective analysis of 200 IU/kg cytomegalovirus-specific hyperimmune globulin (HIG), used in first-trimester maternal primary infections for congenital infection prevention. The primary outcome was vertical transmission, defined as neonatal viruria or positive amniocentesis if pregnancy was discontinued. HIG, initially administered monthly and since 2019 biweekly, was discontinued in negative amniocentesis cases. Women declining amniocentesis and positive amniocentesis cases with normal sonography were offered monthly HIG until delivery as a treatment strategy. The total transmission rate was 29.9% (32/107; 10 pregnancy terminations with positive amniocentesis, 18 completed pregnancies with positive amniocentesis and 4 declining amniocentesis). Maternal viremia was the only factor associated with fetal transmission (OR 4.62, 95% CI 1.55-13.74). The transmission rate was not significantly different whether HIG was started during the first or second trimester (28.2% vs. 33.3%; p = 0.58), or between monthly and biweekly subgroups (25.7% vs. 37.8%, p = 0.193). Pre-treatment maternal viremia could inform decisions as a predictor of congenital infection.

EE73 Direct Healthcare Costs Associated With Primary Symptomatic Cytomegalovirus in the United States

EE73 Direct Healthcare Costs Associated With Primary Symptomatic Cytomegalovirus in the United States

Human cytomegalovirus UL23 exploits PD-L1 inhibitory signaling pathway to evade T cell-mediated cytotoxicity.

T cell immunity is pivotal in controlling primary human cytomegalovirus (HCMV) infection, restricting periodic reactivation, and preventing HCMV-associated diseases. Despite inducing a robust T cell immune response, HCMV has developed sophisticated immune evasion mechanisms that specifically target T cell responses. Although numerous studies have been conducted on HCMV-specific T cells, the primary focus has been on the impact of HCMV on T cell recognition via major histocompatibility complex molecules. Our studies show for the first time that HCMV exploits the programmed death ligand 1 (PD-L1) inhibitory signaling pathway to evade T cell immunity by modulating the activities of T cells and thereby blocking the secretion of IFN-γ, which is directly mediated by HCMV-encoded tegument protein UL23. While PD-L1 has been extensively studied in the context of tumors and viruses, its involvement in HCMV infection and viral immune evasion is rarely reported. We observed an upregulation of PD-L1 in normal cells during HCMV infection and provided strong evidence supporting its critical role in UL23-induced inhibition of T cell-mediated cytotoxicity. The novel strategy employed by HCMV to manipulate the inhibitory signaling pathway of T cell immune activation for viral evasion through its encoded protein offers valuable insights for the understanding of HCMV-mediated T cell immunomodulation and developing innovative antiviral treatment strategies.

Letermovir Primary Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: Real-Life Data from a University Hospital in Argentina.

Cytomegalovirus (CMV) infection remains the most common clinically significant infection after allogeneic hematopoietic stem cell transplantation (allo-HCT) and is associated with considerable morbidity and mortality. The present study was designed to describe and compare the incidence of untreated CMV reactivation (uCMVr), clinically significant infection (cs-CMVi) and disease (CMVd), as well as CMV-related hospitalization and outcome of allo-HCT patients, either treated with letermovir (LET) primary prophylaxis or managed with preemptive therapy (PET). This is a prospective observational cohort study of adult CMV seropositive allo-HCT patients who either received primary prophylaxis with LET within the first 100 days after HCT or were managed with PET. The study population comprised 105 patients (28 in the LET group and 77 in the PET group). Compared to the PET group, patients in the LET group received more allo-HCT from alternative donors (54.5% vs. 82.14%, P=0.012). More than half of the patients in both groups were classified as high risk for CMVd. In the LET vs. PET group, cs-CMVi and CMVd developed respectively in 0 vs. 50 (64.94%), P=<0.0001, and 0 vs. 6 (7.79%), P=0.18. In the LET group, uCMVr occurred in 5 (17.8%) and were all considered blips. Hospital admissions related to cs-CMVi or CMVd in the PET group vs. LET group were 47 (61.04%) vs. 0, respectively, P=<0.0001. No differences were observed in 100-day mortality. LET primary prophylaxis proved effective in preventing cs-CMVi and CMVd and reducing hospitalizations in allo-HCT adults. Blips can occur during prophylaxis and do not require LET discontinuation.

Indirect impact of SARS-CoV-2 pandemic on incidence of maternal primary cytomegalovirus and Toxoplasma gondii infection in pregnancy.

Public health interventions promoted during the SARS-CoV-2 pandemic to control viral spread have impacted the occurrence of other communicable disease. Yet no studies have focused on perinatal infections with the potential for neonatal sequelae, including cytomegalovirus (CMV) and Toxoplasma gondii (TG). Here we investigate whether incidence rates of maternal primary CMV and TG infection in pregnancy were affected by the implementation of pandemic-related public health measures. A retrospective study including all pregnant women with confirmed primary CMV or TG infection in pregnancy, managed between 2018 and 2021 at two university centers. The incidence rate was calculated as the number of CMV and TG infections per 100 consultations with a 95% confidence interval (CI). Data were compared between pre-pandemic (2018-2019) and pandemic (2020 and 2021) years. The Newcombe Wilson with Continuity Correction method was employed to compare incidence rates. The study population included 215 maternal primary CMV and 192 TG infections. Rate of maternal primary CMV infection decreased in 2021 compared with 2018-2019 (4.49% vs 6.40%, attributable risk [AR] 1.92, P = 0.019). By contrast, the rate of TG infection substantially increased in 2020 (6.95% vs 4.61%, AR 2.34, P = 0.006). Close contact with cats was more common among patients with TG infection in 2020 and 2021 than among pre-pandemic TG-infected women (26.3% and 24.4% vs 13.3%, P = 0.013). Pandemic-related public health interventions and associated behavioral and lifestyle changes exerted a divergent effect on the incidence of primary CMV and TG infection in pregnancy, likely due to modulation of exposure to risk factors for these infections.

(35) - Tolerability and Clinical Efficacy of Letermovir for Primary Cytomegalovirus Prophylaxis After Heart Transplantation

(35) - Tolerability and Clinical Efficacy of Letermovir for Primary Cytomegalovirus Prophylaxis After Heart Transplantation

Immune thrombocytopenia secondary to primary cytomegalovirus infection after renal transplantation treated with a thrombopoietin receptor agonist: a case report

BackgroundImmune thrombocytopenia (ITP) is an acquired disorder characterised by a low platelet count due to immune-mediated destruction and impaired platelet production. Here we report a rare case of primary cytomegalovirus (CMV) infection followed by thrombocytopenia after renal transplantation (RT).Case presentationA 24-year-old male patient with end-stage kidney disease secondary to hereditary focal segmental glomerulosclerosis was treated with peritoneal dialysis and received ABO-compatible living-related RT from his aunt. Nine months after the RT, the patient was diagnosed with primary CMV infection. After initiating treatment for primary CMV infection, the patient developed thrombocytopenia. After excluding other diseases or drugs that may cause thrombocytopenia, the patient was finally diagnosed with ITP, administered prednisolone (PSL), and started on Helicobacter pylori eradication therapy. Tapering the PSL dose was difficult, but thrombopoietin receptor agonists (TPO-RAs) were effective.ConclusionsIn this case, the patient was diagnosed with ITP, and other causes of thrombocytopenia after RT were successfully ruled out. This case report demonstrates that RT recipients can develop ITP after CMV infection, and, in such cases, TPO-RAs may be an attractive option as a second-line therapy.

Acute cytomegalovirus proctitis and epididymitis acquired via sexual transmission in an immunocompetent patient: a case report

BackgroundWe present a case report of an immunocompetent host with presumed sexually transmitted cytomegalovirus proctitis and epididymitis, where there currently is a sparsity of published data.Case presentationA 21-year-old previously healthy Caucasian individual was admitted for severe rectal and testicular pain in the setting of proctitis and epididymitis. Serology and rectal pathology confirmed acute primary cytomegalovirus infection.ConclusionsThis report details his diagnostic workup and highlights cytomegalovirus as a rare cause of sexually transmitted disease among immunocompetent persons.

Biweekly Versus Monthly Hyperimmune Globulin Therapy for Primary Cytomegalovirus Infection in Pregnancy.

Primary cytomegalovirus (CMV) infection during pregnancy is associated with an increased risk of congenital CMV (cCMV). Hyperimmune globulin (HIG) therapy has been proposed as a potential prophylaxis to reduce maternal-fetal transmission. Data on whether the administration of HIG every 2 weeks offers benefits over HIG administration every 4 weeks are lacking. This was a retrospective analysis including pregnant women with primary CMV infection diagnosed in the first or early second trimester between 2010 and 2022 treated with HIG every 4 weeks (300 IE HIG per kg) or every 2 weeks (200 IE HIG per kg), respectively. In total, 36 women (4 weeks: n = 26; 2 weeks: n = 10) and 39 newborns (4 weeks: n = 29; 2 weeks: n = 10) were included. The median gestational age at the first HIG administration was 13.1 weeks. There was no significant difference in the cCMV rates between the women who received HIG every 4 versus every 2 weeks (n = 8/24 [33.3%] vs. 3/10 [30.0%]; p = 0.850). An abnormal fetal ultrasound was present in three fetuses and fetal magnetic resonance imaging (MRI) anomalies in four fetuses were related to cCMV infection, with no significant difference in the frequency between the two groups. A larger study will be needed to determine whether HIG administration every 2 instead of every 4 weeks improves the maternal-fetal transmission rates.

OP02.01: Effectiveness of valaciclovir for prevention of fetal infection following early gestational primary maternal cytomegalovirus infection

OP02.01: Effectiveness of valaciclovir for prevention of fetal infection following early gestational primary maternal cytomegalovirus infection

Cytomegalovirus-related Guillain-Barre syndrome in an adult liver transplant recipient: a case report

Guillain-Barré syndrome (GBS) is an immune-mediated condition affecting both the motor and sensory spinal roots and peripheric nerves. GBS is a rare entity, with its global incidence being as low as 0.81 to 1.89 cases per 100.000 person-year. Despite its low incidence, GBS have an important morbidity and lethal potential. This syndrome is usually triggered by infections. Due to its clinical presentation heterogeneity and its disease natural history, there is scarse availability of international clinical practice guidelines for the management of this entity. In this report, we present the case of a 67 years-old man on his fifth month after liver transplant (LT), who developed acute non-inflammatory diarrhea followed by sudden ascending symmetric paresia and soles paresthesias. Electrophysiologic studies reported a demyelinating inflammatory polyradiculoneuropathy compatible with GBS, acute severe inflammatory demyelinating polyneuropathy (AIDP) subtype. His neurolo¬gy deficit was associated with a simultaneous primary Cytomegalovirus (CMV) infection, one of the most common GBS-related infectious agents.

Fibroblasts are a site of murine cytomegalovirus lytic replication and Stat1-dependent latent persistence in vivo

To date, no herpesvirus has been shown to latently persist in fibroblastic cells. Here, we show that murine cytomegalovirus, a β-herpesvirus, persists for the long term and across organs in PDGFRα-positive fibroblastic cells, with similar or higher genome loads than in the previously known sites of murine cytomegalovirus latency. Whereas murine cytomegalovirus gene transcription in PDGFRα-positive fibroblastic cells is almost completely silenced at 5 months post-infection, these cells give rise to reactivated virus ex vivo, arguing that they support latent murine cytomegalovirus infection. Notably, PDGFRα-positive fibroblastic cells also support productive virus replication during primary murine cytomegalovirus infection. Mechanistically, Stat1-deficiency promotes lytic infection but abolishes latent persistence of murine cytomegalovirus in PDGFRα-positive fibroblastic cells in vivo. In sum, fibroblastic cells have a dual role as a site of lytic murine cytomegalovirus replication and a reservoir of latent murine cytomegalovirus in vivo and STAT1 is required for murine cytomegalovirus latent persistence in vivo.

The Case | Crescentic glomerulonephritis in a kidney transplant recipient

A 55-year-old man was referred for acute kidney failure. He had undergone a kidney transplantation for focal segmental glomerulosclerosis 6 months before admission. Medical history consisted of hypertension, hypercholesterolemia, monoclonal gammopathy of unknown significance (IgM λ), and tertiary hyperparathyroidism secondary to chronic kidney disease. After anti-thymocyte globulin induction, the maintenance regimen consisted of azathioprine, tacrolimus, and corticosteroids. His baseline creatinine level was around 150 μmol/L, no proteinuria was detected, and a 3-month protocol graft biopsy was unremarkable. Three months after kidney transplantation, the patient developed primary cytomegalovirus infection despite valganciclovir prophylactic treatment in the setting of donor cytomegalovirus positive and recipient negative. No specific organ involvement was detected, and a ganciclovir-based regimen was started. Because of persistent viremia, 2 months after ganciclovir treatment, cytomegalovirus antiviral resistance testing was performed and a UL97 ganciclovir resistance mutation was detected. I.v. foscarnet treatment was initiated at 100 mg/kg per day.

Transient Decrease in Incidence Rate of Maternal Primary Cytomegalovirus Infection during the COVID-19 Pandemic in Japan.

This study evaluated the impact of the coronavirus disease 2019 (COVID-19) pandemic on the occurrence of maternal primary cytomegalovirus (CMV) infection in Japan. We performed a nested case-control study using data from maternal CMV antibody screening under the Cytomegalovirus in Mother and infant-engaged Virus serology (CMieV) program in Mie, Japan. Pregnant women with negative IgG antibodies at ≤20 weeks of gestation who were retested at ≥28 weeks were enrolled. The study period was divided into 2015-2019 as the pre-pandemic and 2020-2022 as the pandemic period, and the study site included 26 institutions conducting the CMieV program. The incidence rate of maternal IgG seroconversion was compared between the pre-pandemic (7008 women enrolled) and pandemic (2020, 1283 women enrolled; 2021, 1100 women; and 2022, 398 women) periods. Sixty-one women in the pre-pandemic period and five, four, and five women during 2020, 2021, and 2022, respectively, showed IgG seroconversion. The incidence rates in 2020 and 2021 were lower (p < 0.05) than that in the pre-pandemic period. Our data suggest a transient decrease in the incidence of maternal primary CMV infection in Japan during the COVID-19 pandemic, which could be due to prevention and hygiene measures taken at the population level.

Cytomegalovirus seronegativity rate in pregnant women and primary cytomegalovirus infection during pregnancy in rural Germany

BackgroundCongenital cytomegalovirus (CMV) infection is the most common congenital infection worldwide and one of the leading causes of congenital hearing loss in newborns. The aim of this study was to determine the seroprevalence rate for cytomegalovirus in pregnant women and the rate of CMV serological testing utilised during pregnancy in a rural region in Germany.MethodsRetrospective data on the prevalence of CMV IgG and IgM antibodies were obtained from 3,800 women, identified in the study group of 19,511 pregnant women from outpatient settings whose samples were collected between 1 and 2014 and 30 April 2018. In addition, the serological CMV status in regards to various billing methods was further analyzed.ResultsSerological CMV tests were performed in 3,800 (19.5%) out of 19,511 pregnant women. 2,081 (54.8%) of these women were CMV seronegative. Among those, seroconversion rate of 0.37–1.42% was identified. A proportion of 2,710 (14.7%) of all 18,460 women with statutory health insurance made use of the CMV testing as an individual health service.ConclusionsThe low uptake of CMV serological testing in the study population covered indicates low risk awareness among pregnant women and their healthcare professionals. Presented seronegativity rates and routine seroconversion rate, demonstrate importance to improve intervention strategy to prevent feto-maternal CMV transmission.

Guillain-Barré Syndrome Following Primary Cytomegalovirus Infection in a Patient with Liver Transplantation: a Case Report (P10-5.002)

<h3>Objective:</h3> To report the case of a patient who underwent liver transplantation and developed Guillain-Barré syndrome (GBS) as a result of primary cytomegalovirus (CMV) infection. <h3>Background:</h3> GBS is the most common etiology of paralysis worldwide and it is an autoimmune-mediated neuropathy that is frequently caused by a preceding infection. Although the relationship between CMV and GBS is well known, only about 4% of cases are specifically attributable to this infection. Likewise, few cases of GBS have been reported in the context of liver transplant recipients, and in the majority of cases, it is not ascribable to the CMV infection. <h3>Design/Methods:</h3> Not applicable. <h3>Results:</h3> A 66-year-old male patient with a 5-month medical history of liver transplantation secondary to hepatocellular carcinoma, is seen in the emergency room with a progressive ascending limb weakness and foot dysesthesias for the past eight days. Interestingly, three days before the onset of the symptoms, he presented a self-resolved gastrointestinal infection. Neurological examination revealed decreased strength and areflexia in all extremities, especially in the lower limbs. Nerve conduction studies and electromyography showed an acute inflammatory demyelinating polyneuropathy (AIDP) consistent with the diagnosis of GBS. Lumbar puncture ruled out any potential neuro infections and revealed the typical albuminocytologic dissociation. Additionally, a FilmArray panel was negative for other gastrointestinal pathogens. However, a significant CMV serum viral load indicated an active infection. Therapy with IV immunoglobulin and valganciclovir was started, with symptoms considerably improving after five days. <h3>Conclusions:</h3> GBS can be a rare complication after solid organ transplantation. Although post-transplant immunosuppression is known to increase the likelihood of contracting CMV opportunistic infections, GBS has not been frequently linked to this condition. Also, to our knowledge, this is one of few reports where it occurs after a primary CMV infection in the context of a liver transplant recipient, while other frequent etiologies were ruled out. <b>Disclosure:</b> Dr. Toro has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Watch Neurology . Dr. Gaitan Alfonso has nothing to disclose. Thomas Medina has nothing to disclose. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BIIB. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Merck. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Novartis. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen.

CMV Infection After Letermovir Primary Prophylaxis Discontinuation in Allogeneic Hematopoietic Cell Transplant Recipients.

In this single-center study of 61 allogeneic hematopoietic cell transplant (HCT) recipients receiving letermovir primary cytomegalovirus (CMV) prophylaxis for the first 100 days, we report 23% incidence of clinically significant CMV infection during the first 100 days after letermovir discontinuation, predominately in haploidentical HCT recipients, without any associations with CMV-DNAemia under letermovir.