Cytomegalovirus Viral Load Research Articles

Risk of New-Onset Diabetes after Transplantation among Kidney Transplant Recipients with Cytomegalovirus Infection: A Retrospective Analysis

Background: New-onset diabetes after transplantation (NODAT) is one of the common complications reported in patients with kidney transplant and is associated with risk of infection, poor allograft and patient survival. There is conflicting research literature regarding the role of cytomegalovirus (CMV) infection in increasing the risk of NODAT development. Objective: To assess the risk of development of NODAT in kidney transplant patients with CMV infection Methods: A total of 59 kidney transplant patients were studied from March 2017 to February 2019. NODAT was defined as two readings of fasting plasma glucose of ≥126 mg/dL at three months post-transplant. CMV viral load was also documented. The 12 months post-transplant allograft and patient survival outcomes were also measured. Results: Mean age was 43.4 ± 6.2 years. Nearly one-fourth, 14 (23.7%), of the patients had NODAT. CMV viral load and viremia were high in NODAT group; however, the result did not reach statistical significance. CMV DNA replication was statistically high during 1-6 months post-transplant for NODAT group (P<0.001). Only 7 (11.9%) recipients advanced to symptomatic CMV infection. Also, we found that high CMV viremia load was associated with poor kidney allograft function at 12 months. Conclusions: In summary, this study showed that infection with CMV may not be a risk factor to develop NODAT in patients transplanted with kidney. An elevated CMV viral load may decrease the post-transplant allograft function at 12 months. The prompt diagnosis and timely management of CMV infection could substantially lessen the risk to develop NODAT subsequent worsening of allograft and patient survival. Keywords: Kidney; Transplant; NODAT; New-onset Diabetes; Cytomegalovirus

Cytomegalovirus infection in liver-transplanted children.

Cytomegalovirus (CMV) infection is a common complication of liver trans-plantation in children. The CMV serostatus of recipients and donors is the primary risk factor, and prophylaxis or pre-emptive strategies are recommended for high-risk patients. Graft rejection, coinfection and Epstein-Bar virus reactivation, which can lead to post-transplant lymphoproliferative disease, are indirect effects of CMV infection. Assessment of CMV infection viral load should be routinely performed upon clinical suspicion. However, tissue-invasive CMV disease is not associated with CMV viraemia and requires confirmation by tissue pathology. Oral valganciclovir and intravenous ganciclovir are equivalent treatments, and the duration of treatment depends on factors including CMV viral load, tissue pathology, and clinical response. Risk stratification by donor and recipient status prior to transplantation and post-transplantation antiviral prophylaxis or pre-emptive therapy are recommended. Adult guidelines have been established but additional study of the effectiveness of the preventive guidelines in children is needed. This review summarizes the burden, risk factors, clinical manifestations, laboratory evaluation, treatment, and prevention of CMV infection in children after liver transplantation.

Evaluation of the sample-to-result, random access NeuMoDx platform for viral load testing of Cytomegalovirus and Epstein Barr virus in clinical specimens

BackgroundThe detection and follow up of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viral loads (VL) are crucial in the management of immunocompromised patients. Recently, molecular CE-IVD assays for detection and quantification of CMV and EBV have been launched for use on the random-access and sample-to-result NeuMoDx 96 and 288 platforms (Qiagen). ObjectiveEvaluating the qualitative and quantitative performance of the NeuMoDx CMV and EBV assays in clinical specimens compared to a lab developed tests (LDT) and the CE-IVD assays on the Abbott m2000 system. MethodBoth a prospective and a retrospective panel, compiled of non-detectable (ND), non-quantifiable (NQ) and quantifiable VLs in plasma samples have been evaluated for both CMV and EBV: NeuMoDx versus LDT and NeuMoDx versus Abbott m2000. Quantitative agreement was determined for samples with a quantifiable VL on both systems. ResultsQualitative and quantitative agreement between the NeuMoDx and LUMC's LDT CMV assays was 88%. Qualitative agreement between the NeuMoDx and Abbott m2000 CMV assays was 92% and quantitative agreement was 87%. Qualitative and quantitative agreement between the NeuMoDx and the LDT EBV assays was 87%. Qualitative agreement between the NeuMoDx and Abbott m2000 EBV assays was 91% and quantitative agreement was 0%. ConclusionThese data show that the NeuMoDx assays are suitable for both detection and quantification of CMV and EBV in a medium- to high throughput diagnostic setting, but that differences in sensitivity and quantification (for EBV, NeuMoDx versus Abbott m2000) warrant an extensive transition period when using the respective assays for following VL in patient samples.

Are the Patterns of Cytomegalovirus Viral Load Seen After Solid Organ Transplantation Affected by Circadian Rhythm?

BackgroundCytomegalovirus (CMV) is an important opportunistic pathogen after transplantation. Some virological variation in transplant recipients is explained by donor and recipient CMV serostatus, but not all. Circadian variability of herpesviruses has been described, so we investigated the effect of time of day of transplantation on posttransplant CMV viremia.MethodsWe performed a retrospective analysis of 1517 patients receiving liver or kidney allografts at a single center from 2002 to 2018. All patients were given preemptive therapy with CMV viremia monitoring after transplantation. Circulatory arrest and reperfusion time of donor organ were categorized into 4 periods. Patients were divided into serostatus groups based on previous CMV infection in donor and recipient. CMV viremia parameters were compared between time categories for each group. Factor analysis of mixed data was used to interrogate this complex data set.ResultsLive-donor transplant recipients were less likely to develop viremia than recipients of deceased-donor organs (48% vs 61%; P < .001). After controlling for this, there was no evidence of time of day of transplantation affecting CMV parameters in any serostatus group, by logistic regression or factor analysis of mixed data.DiscussionWe found no evidence for a circadian effect of transplantation on CMV viremia, but these novel results warrant confirmation by other centers.

The Prevalence of Cytomegalovirus (CMV) Infection among Infants and Correlation between CMV PCR with Clinical Outcomes in a Tertiary Teaching Hospital in Malaysia

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of congenital hearing loss and neurodevelopmental disability. This study aimed to describe the prevalence and clinical manifestations of infants age 12 months and below with CMV infection in Hospital Universiti Sains Malaysia (Hospital USM) and to determine the correlation between CMV PCR with clinical outcomes. A total of 648 hospitalized infants with clinically suspected cases of cytomegalovirus infection admitted to Hospital USM from January 2018 to December 2018 were tested for anti-CMV IgM and IgG by electrochemiluminescence immunoassay method. The results suggestive of CMV infection were requested for the second serum sample at 2-4 weeks’ interval together with plasma samples for CMV DNA viral load quantification by real-time PCR and maternal sample for serological analysis. Correlation of CMV viral load with clinical outcomes was analyzed using the point- biserial correlation. The results showed that the prevalence of acute CMV infection was 6.48 % (42/648) and cCMV infection was 0.3% (n=2/648). The findings were as follows: acute CMV infection (n = 42), passive immunity (n = 113) and inconclusive (n =41).) CMV hepatitis (p-value= 0.018), rash (p-value= 0.043), presumed sepsis (p-value=0.044) and abnormal hearing (p-value 0.031) were significantly associated with CMV status. Significant moderate correlation between CMV viral load and abnormal hearing assessment was observed. As a conclusion, CMV hepatitis, presumed sepsis, rash, and abnormal hearing were associated with the infant's CMV status. A significant correlation was found between CMV viral load and abnormal hearing.

Cytomegalovirus Exposure and the Risk of Overall Infection After Kidney Transplantation: A Cohort Study on the Indirect Effects Attributable to Viral Replication.

Previous reports hypothesized that cytomegalovirus (CMV) may predispose to non-CMV infection after kidney transplantation (KT). We analysed the incidence of non-CMV infection (overall, bacterial and opportunistic) in 291 KT recipients according to the previous development of any level or high-level (≥1,000 IU/ml) CMV viremia. Exposure to CMV replication was assessed throughout fixed intervals covering first the 30, 90, 180 and 360 post-transplant days (cumulative exposure) and non-overlapping preceding periods (recent exposure). Adjusted Cox models were constructed for each landmark analysis. Overall, 67.7 and 50.5% patients experienced non-CMV and CMV infection, respectively. Patients with cumulative CMV exposure had higher incidence of non-CMV infection beyond days 30 (p-value = 0.002) and 90 (p-value = 0.068), although these associations did not remain after multivariable adjustment. No significant associations were observed for the remaining landmark models (including those based on high-level viremia or recent CMV exposure), or when bacterial and opportunistic infection were separately analysed. There were no differences in viral kinetics (peak CMV viremia and area under curve of CMV viral load) either. Our findings do not support the existence of an independent association between previous CMV exposure and the overall risk of post-transplant infection, although results might be affected by power limitations.

Immune Modulation and Cytomegalovirus Reactivation in Sepsis-induced Immunosuppression: A Pilot Study.

IntroductionSepsis is a life-threatening condition caused due to dysregulated immune response to an infection and progressive immunosuppression. Reactivation of cytomegalovirus (CMV) occurs frequently in sepsis and is found associated with adverse outcomes. The study objective was to evaluate the association between incidence of CMV reactivation and immune alteration in sepsis-induced immunosuppression in patients with prolonged sepsis.Patients and methodsPatients admitted to intensive care unit (ICU), with severe sepsis and CMV immunoglobulin G (IgG) seropositivity, were prospectively enrolled. Other manifest immune suppression causes were excluded. Samples were collected on enrolment and further once a week until day 21 or death/discharge. CMV viral load was quantified using qPCR. Lymphocyte subset analysis (CD3+, CD4+, CD8+, CD19+, CD16+/CD56+, and CD25+CD127− regulatory T cells), human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes, programmed death-1 (PD-1) expression on T lymphocytes, and proinflammatory (interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)), anti-inflammatory cytokines levels (IL-2, IL-4, and IL-10) were analyzed by flow cytometry as markers for immunosuppression.ResultsA total of 25 CMV IgG-positive patients and 11 healthy controls were included. CMV reactivation occurred in 20 patients. Patients with CMV reactivation had T-cell lymphopenia. PD-1 expression on CD4+ and CD8+ T cells was markedly elevated (p <0.02) in CMV-reactivated patients compared to nonreactivated patients. HLA-DR expression was significantly low on monocytes in all septic patients (p <0.01) compared to healthy controls. IL-6 levels showed elevation at day 7, whereas IL-10 was found to be significantly higher from day 0 in CMV-reactivated group.ConclusionOur study concluded that immune suppression markers and cytokine levels in patients with severe sepsis were found to be significantly associated with the incidence of CMV reactivation.How to cite this articleLambe G, Mansukhani D, Khodaiji S, Shetty A, Rodrigues C, Kapadia F. Immune Modulation and Cytomegalovirus Reactivation in Sepsis-induced Immunosuppression: A Pilot Study. Indian J Crit Care Med 2022;26(1):53–61.

Role of Cytomegalovirus in the Development of Posttransplant Lymphoproliferative Disorders With or Without Epstein-Barr Virus Infection.

Many studies have revealed the role of Epstein-Barr virus infection, in combination with chronic immunosuppression, as the main factor in the development of posttransplant lymphoproliferative disorder malignancy. Although many studies have been published on other confounding factors involved in posttransplant lymphoproliferative disorders, the role of coinfection with both cytomegalovirus and Epstein-Barr virus has not been investigated. We evaluated the role of cytomegalovirus infection as a risk factor in transplant recipients who were simultaneously infected with Epstein-Barr virus. In the current retrospective study, 143 recipients of various solid-organ transplants at Namazi Hospital from April 2018 to March 2019 were assessed for coinfection with cytomegalovirus and Epstein-Barr virus with the TaqMan real-time polymerase chain reaction assay. We collected clinical and pathology details from their medical records. Of the 143 patients, 81 (57%) were male. Children under 5 years old were the largest group with 32% prevalence, and the most common organ transplant in this study was liver transplant. The prevalence of cytomegalovirus and Epstein-Barr virus coinfection was 12.6% (18/143 patients), of whom 50% experienced posttransplant lymphoproliferative disorder (9/18 patients) during 18 months after transplant. The incidence of posttransplant lymphoproliferative disorder was significantly higher among patients coinfected with cytomegalovirus and Epstein-Barr virus than among patients without coinfection. We observed a significant correlation between cytomegalovirus viral loads, as well as Epstein-Barr virus genome load, in posttransplant lymphoproliferative disorder development. Coinfection with cytomegalovirus and Epstein-Barr virus, as well as the genome load of each virus, can serve as a strong predictive factor of posttransplant lymphoproliferative disorder in solidorgan transplant recipients.

Characterization of Cytomegalovirus Viremia in Renal Transplant Recipients.

Kidney transplantation, while improving outcomes for patients with end-stage renal disease, comes with a risk of potentially life-threatening infections such as infection with cytomegalovirus (CMV), a virus associated with allograft rejection, organ dysfunction, and increased mortality. To characterize whether the choice and dose of immunosuppressant therapy and the duration of antiviral prophylaxis after transplant are associated with the incidence of CMV viremia. This study was a retrospective review of all kidney-only transplant recipients at the authors' centre from 2012 to 2016, with a minimum 1 year of follow-up. Patients with CMV viremia (defined as serum CMV viral load greater than 1000 IU/mL) were compared with patients who did not have viremia to investigate potential demographic and treatment-related risk factors. A total of 653 patients were included in the study, of whom 161 (25%) met the criteria for CMV viremia. In univariate analysis, patients with CMV viremia had older age (55 versus 53 years, p = 0.038) and lower mean body weight (75 versus 79 kg, p = 0.015); in addition, the CMV viremia group included larger proportions of patients with Asian descent (40% [64/161] versus 21% [104/492]) and donor-positive/recipient-negative CMV serostatus (29% [47/161] versus 14% [70/492]). With respect to immunosuppressant therapy, patients with CMV viremia more frequently received antithymocyte globulin (ATG) induction (50% [80/161] versus 28% [138/492], p < 0.001) and received a higher weight-based cumulative ATG dose (mean 4.5 versus 4.1 mg/kg, p = 0.038). The multivariate analysis retained use of ATG, cumulative dose of ATG, Asian descent, and CMV serostatus as risk factors for CMV viremia. No statistically significant differences were found for the maintenance immunosuppressant dosing or duration of antiviral prophylaxis. Use of ATG for induction and higher weight-based dose of ATG were associated with an increased risk of CMV viremia. In addition, a component of race may also be involved, with patients of Asian descent being at higher risk. No differences were found in the maintenance dose of immunosuppression or the duration of antiviral prophylaxis.

Immunosuppressive regimens on conversion of cytomegalovirus infection to disease in liver transplant recipients.

Cytomegalovirus (CMV) disease is one of the most common infectious complications after liver transplantation. It is the cause of numerous morbidity and mortalities. Intensity of immunosuppression defined as overall immunosuppressive drug dosage seems to affect infectious complications. The main purpose of this study is to investigate the intensity of immunosuppression on conversion of CMV infection to disease in this population. In this cross-sectional study, we retrospectively evaluated and analyzed the data of all recipients who underwent orthotopic liver transplantation (OLT) between March 2014 and March 2016 and had positive serum PCR for CMV after transplantation in follow- up course. Of 134 recipients, only 66 adult liver transplant recipients were eligible to be studied. Multiple variables such as MELD score, cold ischemic time, warm ischemic time, operative data, immunosuppressive drugs and regimen, plasma CMV viral load, donor and recipient CMV IgG serostatus were recorded and analyzed. of the 66 patients, 50 (76%) had CMV infection and 16 (24%) had disease. There was significant association between donor CMV IgG serostatus, extra corticosteroid pulse therapy, acute cellular rejection, serum tacrolimus level and conversion of CMV infection to CMV disease (P=0.005, 0.001, 0.031, 0.031). It seems that the intensity of immunosuppression has influence on conversion rate of CMV infection to disease in liver recipients.

Cytomegalovirus viremia is associated with poor outcomes in AIDS patients with disseminated nontuberculous mycobacterial disease.

Both cytomegalovirus (CMV) viremia and disseminated nontuberculous mycobacterial (NTM) disease are common opportunistic infections in AIDS patients. Whether concurrent CMV viremia is associated with mortality in patients with AIDS and disseminated NTM disease is unknown. Subjects were patients with AIDS and disseminated NTM disease seen at a single center from January 2015 to April 2021. Data were retrospectively collected. Differences in demographics and clinical characteristics and hospitalization survival rates were compared between patients with disseminated NTM and with CMV viremia or not. Subjects were 113 AIDS patients with disseminated NTM who were seen at this Hospital from January 2015 to April 2021. Twenty-six of the patients had CMV viremia and 87 did not. The median age was 36 years (interquartile range [IQR] 29-42) and 108 patients were male (96%). The median CD4 count was 7 cells/µL (IQR 3-17). The median plasma CMV viral load was 9,245 IU/mL (IQR 3147-45725). The serum albumin of patients with CMV viremia was significantly lower than that of patients without CMV viremia (P = 0.03). Compared to patients without CMV viremia (81.6%), patients with CMV viremia had a significantly poorer prognosis (P = 0.01). Cox regression analysis indicated that the risk of a poor prognosis in patients with CMV viremia was 4.7 times higher than that in patients without CMV viremia (P = 0.003), and patients with CD8 more than 250/μL had a better prognosis (P = 0.02). CMV viremia increases the risk of a poor prognosis in patients with AIDS and a disseminated NTM infection. A routine CMV DNA test should be performed on patients with AIDS and disseminated NTM disease in order to reduce the risk of death.

A Retrospective Review of Calcineurin Inhibitors’ Impact on Cytomegalovirus Infections in Lung Transplant Recipients

Immunosuppressive therapy reduces the risk for allograft rejection but leaves recipients susceptible to infections. Cytomegalovirus (CMV) is one of the most frequent causes for infection after transplantation and increases the risk for allograft rejection. As lung transplant recipients (LTRs) need to be under immunosuppression for life, they are a vulnerable group. To determine the potential association between the development of CMV infection and the calcineurin inhibitor (CNI) blood levels within previous 90 days, a retrospective review of LTRs was performed. Data from recipients who underwent a lung transplantation (LTx) at our center from January 2011 to December 2018 were collected. The studied recipients, after case/control matching, included 128 CMV-infection cases. The median time from the transplant to the first positive CMV viral load was 291.5 days. In our study, more patients were treated with tacrolimus (91.9%) than with cyclosporine (8.1%). Drug blood levels at selected timepoints showed no statistically significant difference between cases and controls. However, we found that CMV infection was more frequent in the donor-seropositive/recipient-seronegative group, interstitial lung disease (ILD) recipients, LTRs who underwent basiliximab induction, cyclosporine treated recipients, and LTRs with lymphopenia (at the time of CMV infection and 90 days before). In this review of LTRs, no association between the CNI blood level and CMV infection was seen, although other immunity-related factors were found to be influencing, i.e., basiliximab induction, cyclosporine treatment, and lymphopenia.

Cytomegalovirus specific polyfunctional T-cell responses expressing CD107a predict control of CMV infection after liver transplantation

Cytomegalovirus (CMV) viral load after liver transplantation (LT) is controlled by cell mediated immune responses (CMI). Quantification of CMV-specific T-cells may identify patients who control CMV spontaneously and avoid expensive and potentially toxic antiviral therapies. Prospective post-LT clinical, virological and immunological monitoring was carried out up to 1-year post-LT in a cohort of adult recipients. The CMV-specific T-cell response was characterized using flow cytometry intracellular cytokine staining in 49 LT recipients-R (79.6% R+, 20.4% R−). CMV infection occurred in 24 patients (18 D+/R+ and 6 D+/R−). Only patients with undetectable polyfunctional CMV-specific CD4+ T-cells developed CMV infection. Predictive models showed that polyfunctional CMV-specific CD4+ T-cells pre-existing before LT are protective for CMV reactivation posttransplantation. Quantitation of CD4+ T-cell responses to CMV may be a useful marker for spontaneous control of viral replication to tailor antiviral prophylaxis after LT.

Clinical Application of Metagenomic Next-Generation Sequencing in Patients with Hematologic Malignancies Suffering from Sepsis

Background: Sepsis remains a common but fatal complication among patients with immune suppression. We aimed to investigate the performance of metagenomic next-generation sequencing (mNGS) compared with standard microbiological diagnostics in patients with hematologic malignancies. Methods: We performed a prospective study from June 2019 to December 2019. Adult patients with hematologic malignancies and a clinical diagnosis of sepsis were enrolled. Conventional diagnostic methods included blood cultures, serum galactomannan for Aspergillus, cryptococcal antigen and cytomegalovirus (CMV) viral loads. Blood samples for mNGS were collected within 24 h after hypotension developed. Results: Of 24 patients enrolled, mNGS and conventional diagnostic methods (blood cultures, serology testing and virus RT-PCR) reached comparable positive results in 9 cases. Of ten patients, mNGS was able to identify additional pathogens compared with conventional methods; most of the pathogens were virus. Conclusion: Our results show that mNGS may serve as adjunctive diagnostic tool for the identification of pathogens of hematologic patients with clinically sepsis.

The Effect of Cytomegalovirus on Pediatric Acute Lymphoblastic Leukemia

Background: Recent evidence supports the role of cytomegalovirus (CMV) in the development of childhood ALL. The underlying mechanism and CMV's role in the leukemic cell phenotype is unknown, but CMV typically interacts with the host immune system allowing the virus to survive in a latent state; it may be that this immune dysregulation affects the risk of ALL. This study aims to explore the association of CMV and ALL at the time of leukemia diagnosis, using AML cases as a control and further, to determine whether CMV affects certain subgroups of ALL patients such as specific ethnicities, age groups, or cytogenetic subtypes.Methods: Pediatric diagnostic leukemia bone marrow samples obtained from the California Childhood Leukemia Study were screened for the presence of CMV DNA using a custom-designed droplet digital PCR assay. A total of 869 cases were analyzed including 125 AML cases and 744 ALL cases. Demographic and clinical features were compared between patients found to be CMV positive (cases with any detectable CMV positive droplets) and those who were CMV negative (cases with no detectable CMV positive droplets). The effect of the level of CMV viral DNA load was also assessed. For a subset of cases (n=61), Affymetrix Array gene expression data were available and differential gene expression performed to compare CMV positive cases with high viral load to CMV negative cases. Odds ratios and confidence intervals were estimated using logistic regression.Results: ALL cases were more likely to be CMV positive compared to AML (OR: 2.50; CI 1.00, 5.47, p = 0.039 for CMV highest quintile vs. CMV negative). Within ALL cases, B-cell ALL (B-ALL) was significantly associated with CMV positivity compared to T-cell ALL (T-ALL) (OR: 2.93; CI: 1.01, 8.52, p = 0.048 for CMV highest tertile vs. CMV negative). Further subtype analysis of B-ALL cases revealed CMV positivity to be significantly associated with high hyperdiploidy, one of the most common ALL subtypes, when compared to ETV6-RUNX1 (OR: 2.52; CI:1.34, 4.73, p = 0.004 for highest CMV tertile vs. CMV negative). CMV positive B-ALL cases were also more likely to harbor deletions of EBF1, a B-cell development gene, compared to CMV negative cases (OR: 6.10; CI: 1.09, 34.06, p = 0.04 for CMV 2 nd tertile vs. CMV negative; OR: 5.54; CI: 1.13, 27.18, p = 0.03 for CMV highest tertile vs. CMV negative). Differential gene expression analysis revealed 830 genes to be significantly differentially expressed between the highest quintile of CMV positive cases and CMV negative cases, and gene ontology analysis revealed upregulation of processes involved in viral infection and replication. Specifically, cytokine signaling pathways including IL-1, IL-8, and IL-7 were upregulated in CMV positive cases while Th1 and the pathway facilitating crosstalk between dendritic cells and natural killer cells were downregulated. Interestingly, B-cell receptor signaling was also upregulated in CMV positive cases.Conclusion: Our results support the hypothesis that CMV plays an enhanced role in leukemia development in specific subtypes of ALL, and not in AML development. The ability of CMV to interact with the host immune system, highlights immune dysregulation as a potential mechanism by which CMV contributes to risk of ALL. Gene expression analysis on a subset of cases revealed differentially expressed genes to be enriched in pathways involved in immune response, suggesting a potential role for active CMV infection in the leukemic phenotype. The patterns of up- and downregulation in these pathways were consistent with the host response to CMV. Additionally, acute CMV infection has been shown to promote B-cell activation and proliferation. Further, CMV seropositive individuals have been reported to have altered immune responses even with the virus in a latent state highlighting the virus's effect on B-cells. In our study we also found B-cell receptor signaling to be upregulated in CMV positive cases. This is consistent with the known effects of CMV in a typical host, but in patients with leukemia it provides an interesting potential link between CMV infection and development of pediatric ALL. These intriguing results require validation and warrant continued investigation of the role of CMV in pediatric leukemia development. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Single Center Retrospective Analysis of Letermovir for Cytomegalovirus Prophylaxis after Allogeneic Stem Cell Transplant in Cytomegalovirus Seropositive Recipients or Donors

Background: Up to 70% of allogeneic stem cell transplant (alloSCT) recipients who are cytomegalovirus (CMV) seropositive experience CMV reactivation and up to a third are complicated by end-organ disease. Letermovir, an antiviral agent targeting CMV, is FDA-approved for prophylaxis of CMV reactivation in CMV seropositive recipients of alloSCT. 1-4 In CMV seropositive recipients, letermovir use up to week 14 after alloSCT has demonstrated a significantly lower incidence of clinically significant CMV infection (csCMVi) and an overall mortality benefit as far as 24 weeks after transplant. 5-8 However, data on csCMVi beyond 24 weeks is lacking. Additionally, more information is needed on letermovir use in patients who had prior alloSCT, are CMV seronegative, have a detectable CMV viral load but without csCMVi, and/or are high risk*.Methods: This is a single-center, retrospective, comparative cohort analysis of 524 patients who received alloSCT at Barnes-Jewish Hospital from January 2016 to June 2019. Of those, 191 patients were excluded because both the recipient and donor were seronegative for CMV. Patient information was obtained from the electronic medical record systems after IRB approval of the protocol. Gray's sub-distribution methods (while account for death as competing risk) were used to calculate the incidence of csCMVi and to assess the effect of letermovir on csCMVi. Univariate and multivariate Cox proportional hazards models were fitted for the effect of letermovir on overall survival (OS), and time-dependent Cox model was used to determine the effect of csCMVi on OS.Results: Out of 333 patients, 149 received letermovir. The median follow-up period was 13.38 months (0.033 to 63.8 months). A univariate analysis demonstrated that csCMVi was associated with worse OS (HR 2.173, 95% CI 1.602-2.948). Among those who received letermovir, there were reductions in csCMVi for the overall cohort and for high-risk patients at 100 days, 180 days, and 365 days after alloSCT. In seropositive recipients receiving seropositive alloSCT (CMV +/+), there were reductions in csCMVi at days 100, 180, and 365 after transplant. In seropositive recipients receiving seronegative alloSCT (CMV +/-), there was a reduction in csCMVi at 100 days after transplant. There was a reduction in CMV-related mortality at day 180 post-transplant (p=0.03) but not at day 365 (p=0.46). Additionally, for the overall cohort, the letermovir group showed worse OS from days 180-365 (HR 1.938, 95% CI 1.143-3.285). In CMV seronegative patients receiving seropositive SCT (CMV -/+), no difference in csCMVi was detected at days 100, 180, and 365. A landmark analysis of Day 100 IgG level effect on csCMVi incidence demonstrated that lower IgG level (<485) is associated with higher csCMVi rates after Day 100 (p=0.004). Day 100 CD4 level was not found to be predictive of csCMVi (p=0.744).Conclusion: Letermovir prophylaxis reduces csCMVi overall and in high risk and CMV seropositive patients. We observed a reduction in CMV-related mortality at 180 days after transplant with letermovir prophylaxis. A worsening of OS after day 180 and a trend towards worse non-relapse mortality was surprising and may be related to a higher degree of immunosuppression associated with post-transplant cyclophosphamide (PTCy) use, haploidentical SCT, thymoglobulin use, prior SCTs, and CMV high-risk* patients. Additionally, letermovir was stopped at day 100 at which point survival worsens and the incidence of csCMVi precipitously increases. Our results suggest that there may be additional benefit to extending letermovir therapy past day 100 in the high-risk groups, haploidentical SCT group, patients with low IgG levels at day 100, and subclinical CMV viremia.*High risk patients were defined as those receiving haploidentical, mismatched related, mismatched unrelated, umbilical cord blood, T-cell depleted graft stem cell transplants or immunosuppression with methylprednisolone > 1 mg/kg or 2 or more immunosuppressants. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Factors Associated With Cytomegalovirus Infection in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Prospective Single-Center Study.

The human cytomegalovirus is a notorious pathogen in the pediatric transplant setting. Although studies on factors in complicity with cytomegalovirus infection abound, the roles of age, sex, allogeneic hematopoietic stem cell transplant modality, and type of underlying disease (malignant vs nonmalignant) with regard to cytomegalovirus infection and viral load in children are seldom explored. Our aim was to examine the significance of these factors on cytomegalovirus infection and viral load in Serbian pediatric recipients of allogeneic hematopoietic stem cell transplant. Thirty-two pediatric recipients of allogeneic hematopoietic stem cell transplant to treat various malignant and nonmalignant disorders were prospectively monitored for cytomegalovirus infection. The real-time quantitative polymerase chain reaction was used for pathogen detection and quantitation. Demographic and virologic parameters were statistically analyzed with SPSS statistics software (version 20). Cytomegalovirus DNA was detected in 23 patients (71.9%). Infection occurred significantly more often (P = .015) in patients with haploidentical donors. The opposite was noted for matched sibling grafts (P = .006). Viral load was higher in female patients (P = .041) and children with malignant diseases (P = .019).There was no significant relationship between viral infection or load and medical complications. Transplant recipients presented with a high incidence of cytomegalovirus viremia. The modality of allogeneic hematopoietic stem cell transplant was associated with the frequency of cytomegalovirus infection. Age, sex, type of underlying disease, and medically relevant events were not conducive to occurrences of viremia. Notably, we observed substantial viral loads in female patients and patients with neoplastic diseases. Studies comprising larger populations are needed to better understand these results.

S3558 Esophageal Candidiasis Leading to Spontaneous Esophageal Rupture

Introduction: Spontaneous esophageal perforation (SEP) is a rare and potentially life-threatening condition usually caused by esophageal trauma due to instrumentation or prolonged vomiting and retching. SEP due to esophageal candidiasis (EC) is extremely rare. We present a case of SEP in a patient with EC despite treatment with systemic antifungals. Case Description/Methods: A 53-year-old woman with a history of stage IV lung adenocarcinoma treated with chemoradiotherapy and immunotherapy presented with fever, abdominal pain, diarrhea and hematochezia. Her symptoms were consistent with immune-checkpoint inhibitor colitis, similar to a recent episode that improved with corticosteroids. She has a history of radiation esophagitis in the form of superficial ulceration and stenosis affecting the proximal esophagus. High-dose intravenous corticosteroids were initiated. Due to minimal response, infliximab was administered. Colonoscopy was unremarkable and random biopsies were negative for cytomegalovirus (CMV). Upper endoscopy (EGD) revealed resolution of the initially seen ulceration and no evidence of stricture or stenosis. However, a new distal superficial esophageal CMV ulcer was found. CMV viral load was 6,810 IU/mL and was successfully treated with intravenous ganciclovir leading to viral clearance. EGD for ongoing hematochezia revealed severe esophageal candidiasis (EC) confirmed with histopathology (Figure 1). Despite completing a 14-day course of intravenous fluconazole was, she developed septic shock due to SEP leading to a hydropneumothorax (Figure 2 and 3). Pleural fluid culture was positive for C. albicans. At that stage, family decided to enroll her in home hospice where she died a few days later. Discussion: Although, EC is not uncommon in immunocompromised patients, it is usually treated successfully with antifungal agents in 80-90% of cases. Transmural invasive Candida infection, however, is exceptionally rare with only 4 confirmed cases in the literature. It may lead to esophageal perforation and esophageal-pleural fistula formation. A second-look EGD with culture and sensitivity is recommend in symptomatic patients with EC who fail to improve with treatment. However, there are no guidelines recommending a repeat EGD in immunocompromised patients who initially had minimal symptoms. Our case suggests that for those patients a repeat EGD should be done to ensure resolution of EC and discontinuation of immunosuppressive therapy should be considered.Figure 1.: Endoscopic picture showing mucosal yellow-white plaques throughout entire esophagus, consistent with candidiasis.Figure 2.: Non-enhanced CT (axial view) demonstrating right hydropneumothorax with loculated fluid components.Figure 3.: Esophagram with extravasation of contrast from superior upper esophagus extending into right upper chest.

S2858 An Unusual Case of Donor-related Disseminated Histoplasmosis with Systemic Complications Due to Patient Noncompliance

Introduction: Disseminated histoplasmosis is a mycosis that often occurs in immunosuppressed settings, such as following solid organ transplants. We present the case of a 61-year-old man with a history of liver transplantation resulting in donor-related disseminated histoplasmosis complicated by Cytomegalovirus viremia and C-difficile infection. This case was also complicated by the patient’s voluntary discontinuation of prophylactic therapy, precipitating disseminated histoplasmosis. Case Description/Methods: A 61-year-old man with a history of liver cirrhosis secondary to non-alcoholic steatohepatitis received a deceased-donor liver transplant. He was given induction immunosuppression with thymoglobulin and subsequently initiated on tacrolimus, prednisone, and mycophenolate. Following the transplant, pathologic evidence of histoplasmosis was identified on the donor spleen. The recipient was placed on prophylactic itraconazole with monthly Histoplasmosis Antigen (Histo Ag) checks. The patient voluntarily discontinued itraconazole after 3 months due to headaches, while still monitoring Histo Ag levels. Three months later, he presented with right lower quadrant abdominal pain, fever, and diarrhea. AST levels were elevated at 240 IU/L ( > 35 IU/L) and ALT levels at 261 IU/L ( > 78 IU/L). A liver biopsy showed granulomatous hepatitis suggestive of histoplasmosis. A CT guided biopsy of a subpleural lung nodule showed similar granulomas. Urine Histo Ag was positive at 13.9 ng/mL (negative: < 0.10 ng/mL). The patient was also found to have cytomegalovirus (CMV) viremia despite taking prophylactic ganciclovir. He concurrently developed C. difficile colitis which resolved with vancomycin. The patient was reinitiated on itraconazole with successful suppression of Histo Ag levels, along with CMV viral load and liver enzymes. He remained on itraconazole for the following 4 years with continued stability. Discussion: Immunodeficient hosts, such as those on post-transplant immunosuppressive therapy, are at an increased risk of developing disseminated histoplasmosis when infected with Histoplasma capsulatum, as with this case. Here, we recognize the value of frequent Histo Ag monitoring and the rapid histoplasmosis progression that can occur if prophylaxis is discontinued. While early monitoring and antifungal treatment can improve outcomes, it is also important to manage treatment noncompliance. This case emphasizes the need for early discussions with patients about prophylactic therapy compliance to avoid complications.

Neonatal Hyperbilirubinemia and Cholestasis.

Neonatal Hyperbilirubinemia and Cholestasis.