Tissue-invasive Disease Research Articles

P-2362. Risk Factors for Persistent and Recurrent CMV DNAemia in a Real-World Cohort of SOT and HSCT Patients Receiving Maribavir

Abstract Background Refractory/resistant (R/R) CMV infection, defined by persistent symptoms or DNAemia after at least two weeks of antiviral therapy, is associated with high rates of rejection and mortality in transplant patients. Maribavir (MBV) is a newer agent with demonstrated efficacy in achieving DNAemia clearance without the bone marrow suppression associated with conventional first line therapy. However, there is less data on the risk factors for treatment failure with MBV. We sought to evaluate clinical outcomes of MBV in transplant patients in a real-world patient cohort.Table 1:Demographic Characteristics Methods A retrospective chart review was conducted of adult solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients who received MBV for R/R CMV infection at a high-volume transplant center from 2021-2023. The main treatment outcome was failure (defined as persistence of DNAemia requiring a switch in therapy).Table 2:Risk Factors for Maribavir Failure Results Nineteen patients received MBV for CMV DNAemia or tissue-invasive disease. Overall, 84% were SOT, 63% had high-risk CMV serostatus, and 90% had asymptomatic DNAemia. Twenty-six percent of patients experienced MBV failure. The median absolute lymphocyte count (ALC) was 852 µL at MBV switch in those with successful treatment compared with 262 µL in those with MBV failure, although this did not reach statistical significance. Peak viral load was also not significantly associated with MBV failure. Five patients later developed MBV resistance by commercial genotype sequencing. Conclusion Real world use of MBV demonstrated comparable rates of viral clearance with clinical trial data in SOT and HSCT patients. While not statistically significant, there was a trend towards MBV failure in patients with lower ALC. Future studies may be useful to determine if switching to MBV before onset of worsening lymphopenia related to first line therapy would impact the rate of treatment failure and MBV resistance. The lack of association between VL and virologic response also suggests that MBV may be safely used in patients regardless of viral load. Disclosures Joanna M. Schaenman, MD, PhD, FAST, Eurofins Viracor: Honoraria|F2G: Grant/Research Support|MedCure: Advisor/Consultant|Moderna: Clinical trial support to institution|OneLegacy: Advisor/Consultant

P-2313. Multinational, Retrospective Study Assessing Outcomes and Healthcare Resource Utilization in Hematopoietic Stem Cell Transplant Recipients with Cytomegalovirus Infection and Refractory, Resistance, or Intolerance to Anti-Cytomegalovirus Treatments: Analysis of Impact of Viremia Clearance on Outcomes

Abstract Background Cytomegalovirus (CMV) infection is a risk factor for morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. This real-world analysis describes the impact of viremia clearance on outcomes in HSCT recipients with refractory, resistant or intolerant (RRI) CMV infection to anti-CMV agents. Methods This multicenter, retrospective chart review study included adult HSCT recipients with RRI CMV infection. Data between 2014 and 2021 were collected from 14 centers in Europe and the USA. The analysis descriptively compared demographics, patient characteristics, clinical outcomes, and hospitalizations in patients who did versus did not achieve viremia clearance during the first RRI CMV episode. Results Among 247 patients with a first RRI CMV episode, 145 (59%) achieved viremia clearance and 102 (41%) did not. In patients with vs without viremia clearance, respectively, median age was 53 vs 60 years, and 46% vs 58% were male. Of the 145 and 102 first RRI CMV episodes with vs without viremia clearance, respectively, 52% vs 75% were identified as refractory, 61% vs 31% as intolerant, and 3% vs 9% as resistant (categories not mutually exclusive); 9% vs 15% of patients developed tissue invasive disease. CMV recurrence occurred in 35% vs 37% and graft failure in 3% vs 6% of patients with vs without viremia clearance, respectively (Table). Myelosuppression and nephrotoxicity events during CMV episodes were reported in 54% vs 44% and 26% vs 27% of patients with vs without viremia clearance, respectively (Table). CMV-related hospitalizations with/without emergency department visits occurred in 35% of patients with viremia clearance vs 43% of patients without viremia clearance (Table). Notably, the overall mortality within 1 year of RRI identification in patients without viremia clearance was higher than in those with viremia clearance (68% vs 30%, respectively). Conclusion These results highlight the high disease burden in HSCT recipients with RRI CMV infection. In this difficult-to-treat population, the mortality rate was higher in patients without viremia clearance than in patients with viremia clearance. Disclosures Kimberly Davis, RPh, MS, Takeda: Employee|Takeda: Stocks/Bonds (Public Company) Ines Mendonça, MSBiostats, CTI Clinical Trial & Consulting Services: Employee (paid to provide consulting services including medical writing and statistical analysis) Tien Bo, PharmD, Takeda: Employee|Takeda: Stocks/Bonds (Public Company)

Cytomegalovirus Enterocolitis in a Patient Treated with Methylprednisolone for Amiodarone Hypersensitivity Pneumonitis.

Cytomegalovirus (CMV) is a common cause of infection in immunocompromised individuals, such as patients with hematological malignancies or AIDS, but can also occur in patients with other acquired immunodeficiencies. In tissue-invasive diseases, CMV diagnosis requires CMV DNA in the plasma and the histological confirmation of CMV in a tissue or organ. Evidence of CMV colitis requires a characteristic endoscopic picture with ulcers with a well-defined, convex appearance and CMV viral inclusions in the form of an "owl's eye" on mucosal sections stained with hematoxylin and eosin. CMV-specific immunohistochemistry is the gold standard for identifying CMV in tissue biopsies. It is important to consider a CMV infection in the diagnostic process, as it may delay the diagnosis and the treatment. We present the case of a 78-year-old patient with amiodarone interstitial lung disease who was treated with methylprednisolone. Two weeks after the start of his treatment, he was admitted to the hospital for acute gastroenterocolitis and Addisonian crisis. An examination had confirmed a tissue-invasive CMV disease. He was treated with valganciclovir for a total of six weeks. After the completion of treatment, the patient showed no clinical signs of CMV infection, and both laboratory and histological examinations revealed no residual CMV disease. Tissue-invasive CMV disease can occur in patients with acquired immunodeficiency, which may result from various causes, including glucocorticoid treatment.

Evaluation and comparison of three high throughput assays (Alinity m CMV, Aptima CMV Quant and cobas CMV) for quantifying CMV DNA in plasma samples

BackgroundCytomegalovirus (CMV) can cause symptomatic CMV syndrome or tissue-invasive CMV disease in immunocompromised individuals, including solid-organ transplant and hematopoietic stem cell transplant recipients. In these populations, monitoring of CMV load is essential, assessing both risk of disease and response to antiviral therapy. High throughput commercial assays are currently available for CMV quantitation, but they are often evaluated independently, with few studies comparing these assays. This study evaluated CMV quantitative assays for use with the Roche cobas 6800, Abbott Alinity m and Hologic Panther platforms using stored patient plasma. MethodsAnalytical evaluation was performed using the 1st WHO international standard for human CMV for Nucleic Acid Amplification Techniques (cobas and Alinity m) or the Hologic CMV QC Calibrator 6 (Aptima). Parallel testing of 136 clinical plasma samples was performed across the three platforms. ResultsLinearity for each assay ranged from 98.6 % to 99.96 % and precision and limit of quantitation were as expected with little variation between platforms. 136 clinical plasma samples were evaluated with similar agreement observed between each assay. The greatest positive agreement was between the Aptima Quant and Alinity m assays (95.6 %, 95 % CI 89–98.6 %) and the lowest between the Aptima Quant and cobas assays (94.1 %, 87.4–97.5 %). ConclusionsAll assays were sensitive and accurate when quantifying CMV, and performance across all 3 assays was comparable for monitoring CMV viral loads in patient plasma.

Clinical Test Comparison for Improved Diagnosis of Mucormycosis

Abstract Mucormycosis is a rapidly progressive and invasive fungal infection caused by members of the order Mucorales. Proper treatment relies on a timely diagnosis. However, traditional fungal culture takes several days to weeks and has low sensitivity for recovering Mucorales, as these organisms are sensitive to specimen preparation, including tissue homogenization, and low storage temperatures. More rapid and sensitive diagnostic methods are needed to promptly detect infection. Our laboratory previously developed a real-time PCR assay that detects the most common genera associated with mucormycosis to help improve diagnosis. The assay was analytically validated for a variety of specimen types including serum, tissue (both fresh and FFPE), respiratory secretions and body fluids. Little is known about the agreement between our laboratory developed PCR and other detection methods such as culture or sequencing. We reviewed 6 years of laboratory data to assess overall PCR positivity rate, positivity rate across sample types, and agreement with culture and/or pan-fungal sequencing. We also calculated turnaround time to results to gauge the diagnostic value of Mucorales PCR. Test comparisons with fungal culture and/or pan-fungal sequencing were performed if testing was ordered within 30 days of each other. In our study, we reviewed 3,804 total PCR orders for 2,195 patients. The overall positivity rate of Mucorales PCR orders was 3.81% and varied among different sample types, with fresh tissue and body fluid having the highest positivity rates (18.11% total tissue (33.3% lung tissue) and 10.94% all body fluid (12.5% pleural fluid)) and sputum and CSF having the lowest positivity rates (<1% positivity for both). In a cohort of 428 patients with fungal culture and/or sequencing also performed, 29 patients tested positive for Mucorales by at least one method. PCR detected Mucorales on average 7.83 days sooner than fungal culture (average time to positive result: 3.65 vs. 11.47 days). In patients with culture- or sequencing-confirmed Mucorales infection, PCR had a 100% agreement when comparing shared samples from the same source and collection time. Mucorales PCR was also able to detect infection in 10 (34.5%) other patients who were culture-negative for Mucorales. Our findings suggest that PCR could be a valuable diagnostic tool for suspected mucormycosis, especially tissue invasive disease. PCR increased case detection by 34.5% with a faster turnaround time than culture with lesser cost than sequencing. The main limitation of our study was lack of access to patient information to assess pretest probability of Mucormycosis.

CodY controls the SaeR/S two-component system by modulating branched-chain fatty acid synthesis in Staphylococcus aureus.

Staphylococcus aureus is a Gram-positive, opportunistic human pathogen that is a leading cause of skin and soft tissue infections and invasive disease worldwide. Virulence in this bacterium is tightly controlled by a network of regulatory factors. One such factor is the global regulatory protein CodY. CodY links branched-chain amino acid sufficiency to the production of surface-associated and secreted factors that facilitate immune evasion and subversion. Our previous work revealed that CodY regulates virulence factor gene expression indirectly in part by controlling the activity of the SaeRS two-component system (TCS). While this is correlated with an increase in membrane anteiso-15:0 and -17:0 branched-chain fatty acids (BCFAs) derived from isoleucine, the true mechanism of control has remained elusive. Herein, we report that CodY-dependent regulation of SaeS sensor kinase activity requires BCFA synthesis. During periods of nutrient sufficiency, BCFA synthesis and Sae TCS activity are kept relatively low by CodY-dependent repression of the ilv-leu operon and the isoleucine-specific permease gene brnQ2. In a codY null mutant, which simulates extreme nutrient limitation, de-repression of ilv-leu and brnQ2 directs the synthesis of enzymes in redundant de novo and import pathways to upregulate production of BCFA precursors. Overexpression of brnQ2, independent of CodY, is sufficient to increase membrane anteiso BCFAs, Sae-dependent promoter activity, and SaeR ~P levels. Our results further clarify the molecular mechanisms by which CodY controls virulence in S. aureus.IMPORTANCEExpression of bacterial virulence genes often correlates with the exhaustion of nutrients, but how the signaling of nutrient availability and the resulting physiological responses are coordinated is unclear. In S. aureus, CodY controls the activity of two major regulators of virulence-the Agr and Sae two-component systems (TCSs)-by unknown mechanisms. This work identifies a mechanism by which CodY controls the activity of the sensor kinase SaeS by modulating the levels of anteiso branched-chain amino acids that are incorporated into the membrane. Understanding the mechanism adds to our understanding of how bacterial physiology and metabolism are linked to virulence and underscores the role virulence in maintaining homeostasis. Understanding the mechanism also opens potential avenues for targeted therapeutic strategies against S. aureus infections.

Gastrointestinal Cytomegalovirus Infection in a Transplantation Recipient With a Negative Serum Viral Load: Case Report

Kidney transplant recipients are vulnerable to infections, especially cytomegalovirus (CMV) disease. It is recommended that clinicians plan their prophylaxis and therapeutic regimens based on viral load testing. CMV viral load monitoring testing provides useful information for identifying virologic response and possible antiviral resistance. Due to the paucity of medical literature on guiding viral therapy in cases of CMV tissue disease with nondetectable serum viral load, we intend to provide physicians with evidence on how to guide medical therapy in these cases. A 49-year-old Hispanic male recipient of a kidney transplant from a cadaver donor presented to the emergency department with anorexia, asthenia, diarrhea, weight loss, and supraclavicular and mediastinal adenomegalies at 2 months post-transplantation. Both patients were serum IgG- and IgM-positive for CMV, which classified them as intermediate risk for developing CMV disease or tissue-invasive disease (donor-positive/recipient-positive [D+/R+]). The patient was induced with basiliximab and methylprednisolone and received maintenance therapy with tacrolimus, mycophenolic acid, and prednisone. Real-time polymerase chain reaction analyses were performed due to suspicion for BK virus, B19 parvovirus, Epstein-Barr virus, and CMV, with an undetectable viral load for all. A biopsy specimen taken from the gastrointestinal tract confirmed CMV infection, which was corroborated through immunocytochemistry. Histopathologic testing is a possible option for patients with CMV tissue disease symptoms but no detectable serum viral load. Clinical observation is fundamental when viral monitoring is difficult.

#1731 Clinico-epidemiological characteristics of early versus late onset cytomegalovirus disease among renal transplant recipients: two decade experience

Abstract Background and Aims The epidemiology of the Cytomegalo virus (CMV) disease among renal transplant recipients has changed with the advent of effective antiviral prophylaxis usually occurs in the later part of the post transplant period. To study the difference between CMV infections occurring in early versus late post renal transplant period with respect to nature of immunosuppressive medications (induction agents, maintenance agents and heightening of immunosuppression), type of CMV infection and occurrence of biopsy proven rejection post CMV infection. Method A single centre retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between 1st January, 2002 and 31st December, 2021. CMV disease was classified as early or late depending on detection before or after 90 days post transplant. The differences in clinical presentation between early and late onset CMV disease, use of immunosuppression, and the impact on graft outcomes were studied. Results Total number of recipients with CMV disease was 156 (7.2%) out of total 2164 renal transplant recipients. Twenty-five (16%) patients had early CMV while one hundred and thirty one (84%) had late CMV. The two groups did not differ with respect to induction or use of maintenance immunosuppressive agents. Proportion of CMV syndrome was more among early CMV group (56.0% vs 26.7%, p = 0.01) while tissue invasive disease was more frequent among late CMV group (44.0% vs. 73.3%, p = 0.01). Diarrhoea was more frequent in late (63.4%) versus early CMV (36%) (p = 0.01). Graft loss occurred in 4.0% of early and 25.2% of late CMV cases (p = 0.03). However, both groups did not differ with respect to occurrence of biopsy proven rejection post infection. Conclusion Early CMV presents more frequently as CMV syndrome while late CMV usually manifests as tissue invasive disease. Graft loss is more common in patients with late onset disease.

CMV: 100 days after Kidney Transplantation

Cytomegalovirus (CMV) infection is frequent after kidney transplantation, typically occurring within the first 100 days post-transplant. This prospective, multicenter study aimed to estimate the frequency of CMV disease beyond 100 days post-transplant and demonstrate the usefulness of virological diagnosis during this period. Of 48 kidney transplant recipients with suspected CMV disease, 17% had positive CMV viremia, and 6% had confirmed CMV disease. The 3 cases of CMV disease presented with high viral loads, viral syndrome associated with tissue-invasive disease. For the 45 patients without confirmed disease, virological diagnosis allowed the identification of other etiologies, mainly infectious or iatrogenic. Although infrequent beyond 100 days, CMV disease can occur and be severe, justifying virological screening in the presence of suggestive signs. Differential diagnosis with other causes remains paramount.

Cytomegalovirus surveillance after antiviral prophylaxis in CMV mismatched transplant patients: Does recurrent cytomegalovirus DNAemia impact patient survival?

Cytomegalovirus (CMV) mismatched, donor IgG-positive/recipient IgG-negative, solid organ transplant recipients (SOTRs) are at high risk of CMV invasive disease. Post-prophylaxis disease is an issue in this population. Some programs employ surveillance after prophylaxis (SAP) to limit the incidence of post-prophylaxis disease. This was a single-center retrospective cohort study that included all CMV mismatched SOTRs from 2003 to 2017. Patients underwent SAP with weekly CMV plasma viral load for 12 weeks. The subjects were classified into three post-prophylaxis DNAemia patterns: no DNAemia, one episode of DNAemia, and multiple episodes of DNAemia. We calculated the cumulative incidence of each DNAemia pattern. We also determined 5-year mortality based on DNAemia pattern stratified by organ transplant type. Post-prophylaxis recurrent DNAemia occurred in 63% of lung recipients and 32% of non-lung recipients (p = .003). Tissue invasive CMV disease was diagnosed in 3% of the population and CMV syndrome was diagnosed in 33%. Recurrent DNAemia was not associated with 5-year mortality. In this cohort, undergoing SAP tissue invasive disease was uncommon and CMV DNAemia recurrence did not have an impact on long-term mortality.

Clinico-epidemiological characteristics of early- versus late-onset cytomegalovirus disease among renal transplant recipients: A two-decade experience

BackgroundReactivation of cytomegalovirus (CMV) infection in transplant patients is high because of immunosuppression. We have evaluated the clinical and epidemiological characteristics of early versus late onset of CMV infection among renal transplant recipients. MethodsA single center retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between January 2002 and December 2021. CMV disease was classified as early or late depending on its detection prior to or after 90 days post-transplantation. Herein, we reported the differences between early and late onset of CMV disease with respect to clinical symptoms, the use of immunosuppression and the impact on graft outcomes. ResultsOut of total 2164 renal transplant recipients, 156 patients (7.2%) were diagnosed with CMV disease. Among these 156 patients, 25 patients (16%) had early CMV while 131 patients (84%) had late CMV. Overall, the two groups did not differ with respect to the induction or maintenance of immunosuppressive agents. However, the proportion of CMV syndrome was greater among early (56.0%) than late (26.7%) CMV groups (p = 0.01). In contrast, tissue invasive disease was more frequent among late (73.3%) in comparison to early (44.0%) CMV groups (p = 0.01). Among clinical symptoms, diarrhea was more frequent in late (63.4%) vs. early (36%) CMV-affected patients (p = 0.01). Graft loss occurred in 4.0% of early CMV group vs. 25.2% of late CMV group (p = 0.03). Neither of the clinical groups differed with respect to occurrence of biopsy-proven allograft rejection post-infection. ConclusionsEarly CMV disease presents more frequently as CMV syndrome while late CMV disease usually manifests itself as tissue invasive disease. Graft loss is more common in patients with late onset of CMV disease.

Safety and efficacy of a reduced frequency viral monitoring strategy for Epstein-Barr virus, cytomegalovirus, and BK polyomavirus post-kidney transplant: A quality assurance initiative.

There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19 pandemic, the Transplant Manitoba Adult Kidney Program updated its monitoring protocols for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) to a reduced frequency. This single-center nested case-control study evaluated 252 adult kidney transplant recipients transplanted from 2015 to 2021, with the updated protocols effective on March 19th 2020. Cases included recipients transplanted after the protocol update who developed CMV, EBV, and BKV DNAemia and were matched to controls with DNAemia transplanted prior to the protocol update. The primary outcome was the difference in maximum DNA load titers between cases and matched controls. Secondary outcomes included time to initial DNAemia detection and DNAemia clearance. Safety outcomes of tissue-invasive viral disease were described. There were 216 recipients transplanted preupdate and 36 recipients postupdate. There was no difference between cases and controls in maximum or first DNA load titers for EBV, CMV, or BKV. Cases experienced earlier EBV DNAemia detection (26 (IQR 8, 32) vs. 434 (IQR 96, 1184) days, p=.005). Median follow-up was significantly longer for recipients transplanted preupdate (4.3vs. 1.3 years, p<.0001). After adjusting for follow-up time, there was no difference in DNAemia clearance or tissue-invasive viral disease. Our findings suggest that reduced frequency viral monitoring protocols may be safe and cost-effective. This quality assurance initiative should be extended to detect longer-term and tissue-invasive disease outcomes.

Typical hemophagocytic syndrome associated with cytomegalovirus infection in an immunocompetent patient: a case report and literature review.

Cytomegalovirus (CMV) infection is currently prevalent in populations throughout the world, and 56%‍-94% of the global population is seropositive for CMV. CMV infection mainly affects immunocompromised hosts. In these cases, it can cause significant symptoms, tissue-invasive disease, and many sequelae including death (Dioverti and Razonable, 2016). The vast majority of healthy adults with CMV infection experience an asymptomatic course; when symptomatic, it manifests as a mononucleosis-like syndrome in approximately 10% of patients (Sridhar et al., 2018). The gastrointestinal tract and central nervous system appear to be the most frequent sites of severe CMV infection in immunocompetent individuals (Rafailidis et al., 2008). However, CMV infection is relatively rarely recorded in immunocompetent hosts.

Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy

Introduction: Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, the incidence and outcomes of CMV reactivation in patients undergoing chimeric antigen receptor T (CAR T) cell therapy remain poorly understood. Methods: Single-center retrospective study of 109 adult CMV seropositive patients who received CAR T cell therapy between February 2018 and February 2023. CMV viral load was monitored at the discretion of the treating physician. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV (viremia or tissue invasive disease requiring antiviral treatment). The study was approved by our institutional review board and conducted consistent with the principles in the Declaration of Helsinki. A p-value of &amp;lt;0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism Software, version 10.0.0. Results: During the study period, there were a total of 148 patients who received CAR T cell therapy. Patients who were CMV seronegative, had history of previous allogeneic HCT, or those who received letermovir prophylaxis were excluded. In total, 109 patients who were CMV seropositive met the inclusion criteria. The patient characteristics are presented in Table 1. Of the 109 patients, 69% received Axicabtagene Ciloleucel (Yescarta), 15% received Brexucabtagene Autoleucel (Tecartus), 8% received Tisagenlecleucel (Kymriah), 5% received Idecabtagene Vicleucel (ABECMA), and 3% received Lisocabtagene Maraleucel (Breyanzi). Eighty-four patients (77%) developed any grade of CRS with the median day of CRS onset being 4 days (IQR, 2 to 6). Forty-six patients (42%) developed any grade of ICANS. Among patients who developed CRS, 74 (88%) received tocilizumab, 58 (69%) received dexamethasone, and 9 (11%) received anakinra. For dexamethasone group, the median dosage was 103 mg (IQR, 45 to 160). In those receiving tocilizumab, the median number of doses was 2.5 (IQR, 1 to 4) and the dosage was standard 8 mg/kg. 31 patients (28%) had evidence of CMV reactivation (any viremia) and 10 patients (9%) had clinically significant CMV reactivation requiring treatment. The median time from CAR T cell infusion to CMV reactivation was 19 days (IQR, 9 to 31). Among those with clinically significant CMV reactivation, the median peak viremia was 2388 IU/mL; six of these patients (60%) developed CMV syndrome with none having tissue invasive disease; and 9 (90%) had documented clearance of the virus in response to antiviral therapy. In this group, there were 2 deaths but were not attributed to CMV reactivation. One was due to fungemia while the other patient's death was attributed to CAR T therapy related toxicities causing multiorgan failure. Among those who didn't reactivate CMV, 37 patients (47%) received dexamethasone, at a median dose of 90 mg (IQR, 25 to 145), whereas in the 10 patients with clinically significant CMV reactivation, 100% received dexamethasone (P=0.001) with a median dose of 130 mg (IQR, 74 to 263). Additionally, those who received tocilizumab and anakinra were also at a significantly higher risk for clinically significant CMV reactivation (p=0.027 and p=0.03, respectively). Conclusions: CMV reactivation is a common complication of CAR T cell therapy in CMV seropositive individuals. Although confirmatory studies are needed, our data shows that administration of immunosuppression, in particular steroids, for management of CAR T cell toxicities is a major risk factor for CMV reactivation, and close monitoring for preemptive therapy or antiviral prophylaxis might be indicated in this setting.

Severe gastrointestinal cytomegalovirus infection with underlying common variable immunodeficiency in a middle aged lady

Cytomegalovirus is a common herpes virus infection found worldwide and by adulthood majority become seropositive. In immunosuppressed state it may reactivate to cause tissue invasive disease in gastro intestinal tract, liver, lungs, brain and retina with or without viremia. It is commonly seen in bone marrow transplant, organ transplant, AIDS and autoimmune disease requiring intense immunosuppressive therapy. Common variable immunodeficiency is a condition that affects both arms of the immune system and can lead to opportunistic infections. Chance is more when CD4 counts falls below 50 cells/microlt.

Clinical next-generation sequencing assay combining full-length gene amplification and shotgun sequencing for the detection of CMV drug resistance mutations

Cytomegalovirus (CMV) causes severe systemic and tissue-invasive disease in immunocompromised patients, particularly solid organ and hematopoietic stem cell transplant recipients. While antiviral drugs offer promising efficacy, clinical management is complicated by the high frequency of drug resistance-associated mutations. The most commonly encountered mutations occur in the genes encoding for the drug targets: UL54 (DNA polymerase), UL56 (terminase complex), and UL97 (phosphotransferase), conferring resistance to ganciclovir/cidofovir/foscarnet, letermovir, and ganciclovir/maribavir, respectively. Currently, standard practice for detecting drug resistance is sequencing-based genotypic analysis by commercial reference laboratories with strictly prescribed sample requirements and reporting parameters that can often restrict testing in a highly vulnerable population. In order to circumvent these limitations, we developed a dual-step next-generation sequencing (NGS)-based clinical assay that utilizes full-length gene amplification by long-range PCR followed by shotgun sequencing for mutation analysis. This laboratory-developed test (LDT) achieved satisfactory performance with 96.4% accuracy, 100% precision, and an analytical sensitivity of 300IU/mL with 20% allele frequency. Highlighted by two clinical cases, our NGS LDT was able to provide critical results from patient specimens with viral loads <500IU/mL and volumes <0.5 mL - conditions otherwise unacceptable by reference laboratories. Here, we describe the development and implementation of a robust NGS LDT that offers greater testing flexibility and sensitivity to accommodate a more diverse patient population.

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Cather-related Aspergillus Fungemia: Case Report and Literature Review.

Aspergillus fungemia is encountered infrequently in clinical practice, even in the setting of invasive and disseminated disease. Prolonged Aspergillus fungemia secondary to a central venous catheter is notably rarer. We describe the case of a 13-year-old boy with Aspergillus fungemia in the setting of a central venous catheter who was found to have pulmonary aspergillosis upon evaluation. We reviewed the literature for published cases of catheter-related Aspergillus fungemia and summarized the findings. We also sought to differentiate true fungemia from pseudofungemia and explored the clinical significance of aspergillemia. We found 6 published cases of catheter-related Aspergillus fungemia in addition to the 1 discussed in this report. Based on the review of case findings, we propose an algorithm for an approach to a patient with a positive blood culture for Aspergillus spp. True aspergillemia is infrequent even in the setting of disseminated aspergillosis among immunocompromised patients and the presence of aspergillemia does not necessarily portend more severe clinical disease course. The management of aspergillemia should involve a determination of the possibility of contamination, and if deemed genuine, a thorough workup to define the extent of the disease process. Treatment durations should be based on tissue sites of involvement and could be shorter in the absence of tissue-invasive disease.

Cytomegalovirus antigen-specific T cell immune responses in patients with autoimmune diseases under different cytomegalovirus infection status.

Cytomegalovirus antigen-specific T cell immune responses in patients with autoimmune diseases under different cytomegalovirus infection status.

Prevention and management of CMV infection in pediatric solid organ transplant recipients.

Human cytomegalovirus (CMV) remains one of the most common opportunistic infections following solid organ transplantation in children. CMV causes morbidity and mortality through direct tissue-invasive disease and indirect immunomodulatory effects. In recent years, several new agents have emerged for the prevention and treatment of CMV disease in solid organ transplant recipients. However, pediatric data remain scarce, and many of the treatments are extrapolated from the adult literature. Controversies exist about the type and duration of prophylactic therapies and the optimal dosing of antiviral agents. This review provides an up-to-date overview of treatment modalities used to prevent and treat CMV disease in solid organ transplant (SOT) recipients.