Gastrointestinal Cytomegalovirus Disease Research Articles

Clinical characteristics and outcomes of immunocompromised critically ill patients with cytomegalovirus end-organ disease: a multicenter retrospective cohort study

BackgroundCytomegalovirus (CMV) infection in patients with cellular immune deficiencies is associated with significant morbidity and mortality. However, data on CMV end-organ disease (CMV-EOD) in critically ill, immunocompromised patients are scarce. Our objective here was to describe the clinical characteristics and outcomes of CMV-EOD in this population.MethodsWe conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010–December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality.ResultsWe studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15–27.30), CMV pneumonia (OR 2.57; 95% CI 1.13–6.03), lymphocytes < 0.30 × 109/L at diagnosis of CMV-EOD (OR 2.40; 95% CI 1.05–5.69), worse SOFA score at ICU admission (OR 1.18; 95% CI 1.04–1.35), and older age (OR 1.04; 95% CI 1.01–1.07).ConclusionsMortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

Late cytomegalovirus disease after hematopoietic cell transplantation: significance of novel transplantation techniques

AbstractPreemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed.

Comparative Analysis of Cytomegalovirus Gastrointestinal Disease in Immunocompetent and Immunocompromised Patients.

Cytomegalovirus (CMV) gastrointestinal (GI) diseases impact both immunocompromised and immunocompetent individuals, yet comprehensive studies highlighting the differences between these groups are lacking. In this retrospective study (January 2000 to July 2022) of 401 patients with confirmed CMV GI diseases, we categorized them based on immunological status and compared manifestations, treatments, outcomes, and prognostic factors. The immunocompromised patients (n = 193) showed older age, severe illnesses, and higher comorbidity rates. GI bleeding, the predominant manifestation, occurred more in the immunocompetent group (92.6% vs. 63.6%, p = 0.009). Despite longer antiviral therapy, the immunocompromised patients had higher in-hospital (32.2% vs. 18.9%, p = 0.034) and overall mortality rates (91.1% vs. 43.4%, p < 0.001). The independent factors influencing in-hospital mortality in the immunocompromised patients included GI bleeding (OR 5.782, 95% CI 1.257-26.599, p = 0.024) and antiviral therapy ≥ 14 days (OR 0.232, 95% CI 0.059-0.911, p = 0.036). In the immunocompetent patients, age (OR 1.08, 95% CI 1.006-1.159, p = 0.032), GI bleeding (OR 10.036, 95% CI 1.183-85.133, p = 0.035), and time to diagnosis (OR 1.029, 95% CI 1.004-1.055, p = 0.021) were significant prognostic factors, with the age and diagnosis time cut-offs for survival being 70 years and 31.5 days, respectively. GI bleeding is the most common manifestation and prognostic factor in both groups. Early diagnosis and effective antiviral therapy can significantly reduce in-hospital mortality.

Cytomegalovirus Diseases of the Gastrointestinal Tract in Immunocompetent Patients: A Narrative Review.

Cytomegalovirus (CMV) is a potential pathogen that causes gastrointestinal (GI) tract diseases regardless of host immunity. In contrast to immunocompromised individuals, immunocompetent patients lack a comprehensive overview of the gastrointestinal manifestations. This study aims to provide a comprehensive summary of the current evidence regarding presentations, diagnostics, management, risk assessment, and outcomes in immunocompetent patients with CMV GI disease. A thorough literature search of English publications up to April 2022 was conducted across electronic databases to identify relevant articles, with eligible case series selected for detailed analysis. The majority of immunocompetent patients affected by CMV GI disease are typically elderly, critically ill, or burdened with comorbidities that compromise immunity. Clinical presentations range from subtle symptoms to severe surgical conditions, including instances of mortality. Specific clinical presentations, blood test results, or endoscopic features are lacking, necessitating reliance on histopathological tests such as immunohistochemistry staining for diagnosis. While antiviral therapy may offer benefits in improving outcomes, careful individual assessment is warranted due to diverse comorbidities and potential side effects. Mortality rates vary considerably based on underlying medical conditions and therapeutic approaches. It is imperative for clinicians to maintain vigilance for CMV GI disease among high-risk groups, despite their baseline immunocompetence, in order to enhance clinical outcomes.

Clinical Characteristics of Cytomegalovirus Disease of the Upper Gastrointestinal Tract: A 10-Year Multicenter Retrospective Study

Objectives: Gastrointestinal cytomegalovirus (CMV) disease is a major contributor to mortality in immunocompromised patients. Few studies have discussed upper gastrointestinal CMV (UGICMV) disease in immunocompetent patients. We compared the clinical outcomes of UGI-CMV between immunocompromised and immunocompetent patients.Methods: This retrospective study included patients with UGI-CMV disease from five tertiary hospitals across Korea (2010– 2022). Patients’ clinical data and outcomes were recorded.Results: UGI-CMV was diagnosed in 54 patients; 27 (50.0%) had esophageal, 24 (44.4%) had gastric, and 3 patients (5.6%) had duodenal involvement. Patients’ median age was 64 years (interquartile range 53–75 years), and the most common comorbidities included hypertension (57.4%) and diabetes (38.9%). The predominant symptom was abdominal pain (46.3%), and the most common endoscopic finding was ulcers (70.4%). Antiviral treatment was administered to 31 patients, and 23 patients underwent observation without treatment. We investigated 32 immunocompromised (59.3%) and 22 immunocompetent (40.7%) patients and observed no intergroup differences in comorbidities and in laboratory and endoscopic findings. Immunocompromised patients had longer length of hospitalization (median 46.2 days vs. 20.0 days, &lt;i&gt;p&lt;/i&gt;=0.001). However, treatment outcomes, including the need for intensive care unit admission and mortality did not significantly differ. The overall mortality rate was 13.0%; one patient from the immunocompromised group died of UGI-CMV disease. The treatment success rate was higher in immunocompromised patients who received antiviral therapy (&lt;i&gt;p&lt;/i&gt;=0.011).Conclusions: UGI-CMV disease is not uncommon in immunocompetent patients, although symptoms are milder than those in immunocompromised patients. Our findings emphasize the importance of clinical vigilance for accurate diagnosis of CMV infection, particularly in susceptible symptomatic patients and highlight the need for active antiviral treatment for management of immunocompromised patients.

Late CMV Disease after Hematopoietic Cell Transplantation: Significance of Post-Transplant Cyclophosphamide, Steroid Treatment and CMV Viral Load

Introduction: Pre-emptive therapy (PET) and letermovir prophylaxis are effective in preventing CMV disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT), and are widely used worldwide. However, both strategies are associated with late-onset CMV disease. The goal of this study was to determine the period of risk, clinical manifestations, risk factors for initial and recurrent late CMV disease at key landmark time points, and its impact on mortality. Patients and Methods: We retrospectively analyzed CMV seropositive allogeneic HCT recipients transplanted between 2001 and 2017 who survived more than 100 days post HCT. All patients underwent PCR monitoring and PET before day 100 and for patients deemed at high risk for late CMV complications continuation of PCR monitoring and PET was recommended. Data were collected via medical record review of CMV disease and viremia, PET, transplant variables such as lymphopenia, corticosteroid use, donor type, stem cell source, type of underlying disease, and outcomes for 2 years post-transplantation. Cumulative incidence curves and Cox proportional hazards models were used to evaluate time to event and risk factors for late CMV disease and mortality. Results: Among 2155 day 100 survivors, 166 episodes of late CMV disease were observed in 144 (6.7%, 95% CI 5.7%-7.8%) patients. Most of the cases were diagnosed between day 100 and 1 year (126 cases), 40 episodes occurred within the second year (1.6% 95%CI 1.2%-2.3%) post HCT (Figure 1). CMV gastrointestinal (GI) disease (3.4%, 95% CI 2.7%-4.2%) was the most common manifestation of late CMV disease, followed by CMV pneumonia (2.9%, 95% CI 2.2%-3.7%), occurring at a median of 196 days after HCT for first GI disease episode (range 104-685) and 211 days (range 105-574) for first late pneumonia. Twenty-nine patients (10.5%, 95% CI 7%-14.7%) developed recurrent CMV disease. Most recurrences involved the same anatomical site as the first episode with a median of 126 days (range 52-444) after the initial event. Five patients developed a third episode, with a median of 145 (range 85-350) days after their second episode. Prolonged CMV surveillance was recommended in 1787 (83%) cases. High risk patients included: cord blood recipients , in vivo T-cell depletion, acute or chronic GvHD requiring steroid treatment, or those who were treated due to CMV infection before day 100. Based on day 100 risk stratification, cumulative incidence of late CMV disease occurred in 7.6% (95% CI 6.4%-8.9%) and 2.8% (95% Ci 1.4%-4.8%) in high and low risk groups, respectively. In a subgroup analysis (HCT 2001-2011), adherence to late CMV surveillance recommendations was reduced: by week 20 post-HCT, approximately 6 weeks post-discharge, only 65% of patients had CMV PCR tests performed. By 1-year post-HCT, only 40% of patients were still being tested. In multivariable analyses, steroid treatment after day 100 at a dose of ≥1mg/kg, post-transplant cyclophosphamide, GvHD prior day 100, and CMV viremia before day 100 were associated with increased risk of late CMV disease. (Figure 2). The only factors contributing to recurrence of CMV disease were HLA mismatched donor status (aHR 2.92, 95% CI 1.03-8.28) and treatment with high dose steroids ≥1mg/kg after day 100 (as time dependent variable) (aHR 7.60, 95% CI 3.32-17.4). In a landmark analysis of 1-year survivors, the risk of late CMV disease was increased in chronic GvHD patients (aHR 2.11, 95% CI 0.99-4.51, p=0.054) and those with a CMV disease episode prior to 1 year (aHR 2.80, 95% CI 1.23-6.40). Among 144 patients with late CMV disease, 32 (22%) died within 6 weeks of diagnosis of the last episode. Patients who developed late CMV pneumonia were at the highest risk of death by year 2 after HCT (aHR 4.08, 95% CI 2.62-6.35), while GI disease was associated with a somewhat lower risk (aHR 1.62, 95% CI 1.05-2.5). Conclusion: In a large cohort for which late surveillance and PET was recommended, late CMV disease occurred frequently, and was associated with the use of high dose steroids, post-transplant cyclophosphamide, and CMV reactivation before day 100. Late CMV pneumonia and GI disease were associated with overall mortality. Improved strategies to prevent late CMV disease are needed in high-risk patients, including continued antiviral prophylaxis or surveillance strategies that are more suitable for the late setting, such as home-based CMV testing.

Cytomegalovirus Infections in the Atypical Host: A Case Series of Clinical Conundra.

Background Cytomegalovirus (CMV) reactivation may occur as the shedding of the virus from various body sites or could represent an active disease that might be fatal if untreated. Distinguishing between the two states may prove very difficult. The role of the CMV disease in patients with hematological malignancies or transplant patients is more defined than that in other immunocompromised patients where neither anti-CMV prophylaxis is used nor plasma CMV levels are monitored. Here, we try to examine cases with CMV viremia in the latter group of patients in an attempt to make a distinction between CMV infection and disease to determine which patients would benefit from treatment. Methods Elderly patients, patientswith rheumatological disorders, and patients with inflammatory bowel disease (IBD) and with clinical suspicion of CMV disease who were referred to the infectious diseases service at Sultan Qaboos University Hospital were examined from 1 January 2018 to 31 January 2023. We added a patient we found in our referral log book from2012. Clinical, epidemiological, and laboratory data were retrieved from the hospital information system. Plasma CMV levels and CMV body fluidlevels including pulmonary samples obtained from bronchoalveolar lavage (BAL) in suspected cases of CMV pneumonitis and gastrointestinal (GI) CMV levels obtained from stool and gastrointestinal tissue biopsies in suspected cases of gastrointestinal CMV disease were collected. COBAS® AmpliPrep/COBAS® TaqMan®assay (Roche Molecular Systems, Inc., Branchburg, NJ)was used to measure CMV copies per milliliter. Results A total of 28 patients were considered to have CMV disease, 12 of whom were elderly (≥60 years) and the rest were young and middle aged (Y/M). The most commoncomorbidities of the elderly included chronic kidney disease (CKD), hypertension (HTN), and diabetes mellitus (DM). In the Y/M group, seven patients had systemic lupus erythematosus (SLE), one had antineutrophilcytoplasmic antibody (ANCA) associated vasculitis, four patients had IBD, two had IBD plus primary immunodeficiencies (one patient had agammaglobulinemia and one had combined deficiencies), and one patient had combined immunodeficiency. CKD was a common finding in the SLE patients. Diarrhea was the most commonCMV presentation occurring in 19 patients (67.9%), being bloody in 10 patients. Four patients had pulmonary presentations, and four had hematological presentations in the form of anemia or pancytopenia. Nineteen patients were given CMV antiviral treatment, and one patient received it during the first episode but not in the second episode. Twenty-eight-day mortality in the treated group was 20% versus 55.5% in the untreated group. The majority of the deaths occurred in the SLE and elderly patients. Thrombocytopenia occurred in 60.7%, 70.6% of whom died signaling a potential predictive role for thrombocytopenia in early empirical CMV antiviral treatment and in prognosis. Conclusion The difficulty in distinguishing CMV infection from CMV disease remains a concern in the elderly and SLE patients. In our small study, there was a survival benefit in early screening for CMV and initiating preemptive CMV antiviral therapy in these two groups even before CMV disease is proven. This urgency was not observed for patients with IBD or primary immunodeficiencies. A major common factor for CMV disease was CKD, whereas thrombocytopenia was an indicator of disease and prognosis.

378. Utility of CMV Quantitative PCR in Tissue Biopsy for the Diagnosis of CMV Gastrointestinal Disease among Solid Organ Transplant Recipients

Abstract Background Cytomegalovirus (CMV) infection is an important cause of morbidity after solid organ transplantation (SOT). Rapid and accurate diagnosis of gastrointestinal (GI) CMV disease is central to the early initiation of appropriate therapy. Currently, the diagnosis mainly relies on histopathology on formalin-fixed GI tissue biopsy. CMV diagnosis by quantitative polymerase chain reaction (qPCR) on tissue biopsy is not routinely performed for the diagnosis of tissue invasive disease, but potentially holds many practical advantages over the gold standard including a rapid turnaround time and providing a quantitative objective result. Methods We compared the performance of CMV qPCR on fresh GI biopsy with tissue biopsy histopathology for the diagnosis of GI CMV disease. Results A total of 62 SOT patients with GI symptoms underwent endoscopic assessment with GI biopsy analyses for both histopathology and tissue CMV qPCR. Twelve patients (19.4%) had proven CMV disease on histopathology. Among them, all had a positive qPCR on biopsy (median value of log 7.7 and 5.4 x107 copies/mL), and all had a positive serum CMV PCR (median value of log 4.5 and 3.4 x104 copies/mL). Of the 49 remaining patients with negative histopathology, 26 (53%) had CMV qPCR positive tissue biopsy specimens with a median log 4.3 and 2.0 x104 copies/mL. Of these 26 patients with histopathology negative/CMV qPCR positive tissue biopsies, 10 had positive serum CMV qPCR. Twenty-four patients were negative for all three tests: histopathology, CMV qPCR on tissue biopsy, and CMV viremia. ROC analysis for optimal threshold value for CMV qPCR on tissue biopsy for diagnosis of confirmed CMV GI disease is 104 824 copies/mL (sensitivity 100%, specificity 82%, area under ROC 0.91). Conclusion Our study shows that tissue biopsy CMV qPCR is highly sensitive (sensitivity of 100%) for the diagnosis of CMV GI disease. As such, tissue CMV qPCR may be a useful adjunctive diagnostic tool for the rapid diagnosis of CMV GI disease. Disclosures All Authors: No reported disclosures.

Cytomegalovirus Diseases of the Gastrointestinal Tract.

Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract can be fatal. However, very few studies have provided comprehensive analyses and specified the differences in symptoms observed in different parts of the GI tract. This study aimed to comprehensively analyze clinical manifestations and management of GI CMV disease. This retrospective cohort study enrolled the patients who had CMV diseases of the GI tract proved by CMV immunohistochemistry stain from the pathology database in a 4000-bed tertiary medical center between January 2000 and May 2021. The patient characteristics, clinical manifestations, endoscopic features, treatments, outcomes, and prognostic factors were analyzed. A total of 356 patients were enrolled, including 46 infected in the esophagus, 76 in the stomach, 30 in the small intestine, and 204 in the colon. In total, 49.4% patients were immunocompromised. The overall in-hospital mortality rate was 20.8%: CMV enteritis had the highest rate (23.3%). Sixty percent of patients received antiviral treatment and 16% were administered both intravenous and oral anti-viral drugs (Combo therapy, minimal and mean treatment duration were 14 and 39.9 ± 25 days). Prognostic factors of in-hospital mortality included age, immune status, albumin level, platelet count, GI bleeding, time-to-diagnosis, and Combo therapy. In the survival analysis, immunocompetent patients receiving Combo therapy had the best survival curve, and immunocompromised patients receiving non-Combo therapy had the worst survival curve. Combo therapy ≥14 days resulted in a better outcome for both immunocompromised and immunocompetent patients. In conclusion, CMV GI diseases affect both immunocompromised and immunocompetent hosts, and a complete treatment course should be considered for patients with poor prognostic factors.

Optimal duration of antiviral treatment in patients with gastrointestinal cytomegalovirus disease at a low and high risk of relapse.

We evaluated the association between antiviral treatment duration and relapse of gastrointestinal (GI) cytomegalovirus (CMV) disease by analyzing the risk factors for relapse.Patients who were diagnosed with GI CMV disease at a tertiary hospital from January 2008 to April 2019 were retrospectively enrolled. Patients with relapsed disease were those with a recurrence of GI CMV disease at least 4 weeks after the initial antiviral treatment.Of 238 participants, including 145 (51.9%) with upper and 93 (48.1%) with lower GI CMV diseases, 27 (11.3%) had experienced relapses. The difference in antiviral treatment duration between the relapsed and nonrelapsed GI CMV groups was not significant (median days, 21.0 vs 17.0, P = .13). Multivariate analysis revealed that hematologic malignancy (odds ratio, 3.73; P = .026) and ulcerative colitis (odds ratio, 4.61; P = .003) were independent risk factors for relapse. Participants with at least one of these risk factors and those with no independent risk factors were classified under the high- (relapse rate, 25.9%) and low-risk of relapse groups (relapse rate, 6.7%), respectively. Accordingly, we further stratified 180 (75.6%) and 58 (24.4%) participants under the low- and high-risk of relapse groups, respectively. There was no significant difference in relapse rates between the high- and low-risk groups according to antiviral treatment duration.Approximately 10% of the participants experienced relapses after antiviral treatment, with hematologic malignancy and ulcerative colitis featuring as risk factors. Therefore, prolonged antiviral treatment might not be helpful in preventing GI CMV disease relapse.

Clinical characteristics and viral load patterns in children with cytomegalovirus gastrointestinal disease after allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) reactivation in allogeneic hematopoietic stem cell transplantation (allo-HSCT) causes significant morbidity and mortality. This study aimed to investigate the clinical characteristics of children diagnosed with CMV GI disease after allo-HSCT. This was a retrospective cohort study of patients <19 years old that underwent allo-HSCT during an 11-year period. Of the 756 patients, 55.5% (n = 420) experienced post-transplant CMV DNAemia, 2.9% (n = 22) were diagnosed with proven CMV GI diseases, and the highest incidence wasfound in familial mismatched donors (5.6%, P = 0.029). CMV GI disease was diagnosed <100 days of transplant in 68.2% (n = 15/22), and 13.6% (n = 3/22) did not have concurrent CMV DNAemia. Patients were divided into five groups based on the patterns of CMV viremia initiation and duration post-HSCT. At 3 months post-transplant, lower CD4+ (P = 0.006) and CD8+ (P = 0.011) T-cell counts were observed in patients with waxing and waning CMV viral load titers >100 days post-transplant (groups 1-3) compared to those with CMV DNAemia only prior to 100 days post-transplant and those without concurrent CMV DNAemia (groups 4-5). A higher 1-year all-cause mortality was observed in groups 1-3 compared to groups 4-5 (42.8% vs. 0%; P = 0.051). Active surveillance and aggressive management of CMV reactivation is crucial, especially in children with delayed CD4+ and CD8+ T-cell reconstitution after allo-HSCT.

Gastrointestinal cytomegalovirus disease secondary to measles in an immunocompetent infant.

Yang et al reported an immunocompetent infant with gastrointestinal cytomegalovirus disease secondary to measles infection. We express our opinion about the diagnosis and treatment of this rare disease.

#50: Cytomegalovirus Retinitis Among Pediatric Hematopoietic Stem Cell and Solid Organ Transplantation Recipients: A Contemporary Review

Abstract Background Cytomegalovirus infection can cause significant morbidity and mortality after transplantation. Cytomegalovirus retinitis (CMVR) can be a major complication of tissue invasive CMV disease in transplant recipients. There are little data regarding the contemporary incidence and outcomes of CMVR among pediatric transplant recipients. Methods We performed a retrospective cohort analysis of allogeneic hematopoietic (allo-HCT) and solid organ transplant (SOT) recipients who received medical care at Nationwide Children’s Hospital (NCH) from 1/1/10–11/30/20 and had a diagnosis of CMVR to describe the incidence, timing post-transplant, ocular manifestations, management, and outcomes. Basic demographic and clinical data, pre-transplant donor/recipient CMV serostatus, and post-transplant CMV infection data were collected. Graft-specific CMV surveillance and prophylaxis strategies were performed according to NCH hospital guidelines. During the study period, quantitative plasma CMV PCR assays included copies/mL (2010–2013) and WHO international standard IU/mL (2013–2020). Results During the 10-year study period, 347 patients underwent allo-HCT (N=214) or SOT (N=133; heart N=46, liver N=36, kidney N= 52; 1 patient had concomitant kidney and liver transplantation); median age was 8.6 years [range 0.1–25.9] and 198 (56.5%) were male. In total, 98 patients had CMV DNAemia post-transplant, and CMVR was diagnosed in 3 (HCT=2, SOT=1), for an overall CMVR incidence of 0.86% among all transplant recipients and occurring in 3% of patients with CMV DNAemia. No CMVR was diagnosed in patients without CMV DNAemia. An ophthalmologic examination was performed in 58 (59%) of patients with any DNAemia compared with 67 (27%) of patients without DNAemia. CMVR was diagnosed on funduscopic examination a median of 183 days [range 34–512] post-transplant based on visual symptomatology (N=2) or by routine eye screening prompted by DNAemia (N=1). CMV DNAemia at the time of CMVR was 1,463 copies/mL, 3,000, and 14,204 IU/mL; all patients had prolonged (&amp;gt;3 months) CMV detection before CMVR. One SOT recipient had concomitant pathology confirming CMV gastrointestinal tract disease. Two of the 3 CMVR cases occurred in the setting of genotypic UL94 CMV resistance mutations (A594V, H520Q)(Figure 1). Two patients were already receiving CMV antiviral therapy (maribavir N=1; valganciclovir=1) at the time of CMVR diagnosis. After the CMVR diagnosis, all patients were prescribed systemic foscarnet. Adjunctive therapies included concurrent intravitreal antiviral therapy (ganciclovir N=1; foscarnet N=1) and adoptive immunotherapy with CMV antiviral specific T-cells (N=1, HCT). Improvement of ocular symptoms occurred in 2 patients at 15 and 20 days after starting targeted CMV antiviral therapy; one patient developed permanently impaired vision. Conclusion CMVR remains as an important complication in transplant recipients. Although CMVR incidence was low in our cohort of transplant recipients, it occurred most frequently in cases of CMV resistance, prolonged DNAemia, and led to permanent visual impairment in 1 of 3 patients. The development of resistant CMV may have a role in the occurrence, progression, and severity of CMVR. Additional pediatric-specific data are needed to better characterize CMVR and inform optimal prevention strategies.

Role of highly sensitive nucleic acid amplification testing for plasma cytomegalovirus DNA load in diagnosis of cytomegalovirus gastrointestinal disease among kidney transplant recipients.

High plasma cytomegalovirus (CMV) DNA load is generally associated with CMV tissue-invasive disease in solid organ transplant recipients. However, some tissue-invasive diseases, especially CMV gastrointestinal (GI) disease, have undetectable to very low plasma CMV DNA loads. Highly sensitive nucleic acid amplification testing (NAAT) has been increasingly used to quantify low-level CMV DNA loads. Our primary objective was to investigate the epidemiology of CMV GI disease and evaluate the validity of plasma CMV NAAT for the diagnosis of CMV GI disease in kidney transplant (KT) recipients. We conducted a retrospective study of all KT recipients who developed CMV GI disease from January 2016 to December 2018. Plasma CMV DNA load was measured using real-time PCR. The cut-off value of plasma CMV DNA load for diagnosing and risk factors of CMV GI disease were analyzed. A total 17 (3.4%) cases of CMV GI disease occurred in 494 KT recipients. Fifteen (88%) patients had CMV D + /R + serostatus. Fourteen (82%) patients developed CMV GI disease within 6months after KT. Plasma CMV DNA loads were detectable in all (100%) patients with a median load 11,102 (IQR 2,935-107,160) IU/ml. A plasma CMV DNA load of 4,063IU/ml was established as al cut-off for diagnosing CMV GI disease (AUC 0.74, sensitivity 76.5%, specificity 70%, PPV 68, NPV 78). In multivariate analysis, prolonged cold ischemic time (HR 1.14, 95% CI 1.05-1.23, P=.002) and CMV D + /R - serostatus (HR 9.31, 95% CI 2.12-40.74, P=.003) were associated with CMV GI disease. Using highly sensitive NAAT could potentially assist in the diagnosis of CMV GI disease in a CMV D + /R + serostatus setting. KT recipients with CMV seromismatch and prolonged cold ischemic time are at higher risk of CMV GI disease.

Gastrointestinal cytomegalovirus disease secondary to measles in an immunocompetent infant: A case report

BACKGROUNDGastrointestinal cytomegalovirus (CMV) disease occurs commonly in immunocompromised/immunodeficient patients with advanced human immunodeficiency virus infection, neoplasm, solid organ transplantation, hematopoietic stem cell transplantation, or treatment with immunosuppressants, but is rarely reported in association with measles infection.CASE SUMMARYWe describe a case of extensive gastrointestinal CMV disease secondary to measles infection in a 9-mo-old boy who presented with persistent fever and bloody diarrhea. His condition was improved after ganciclovir treatment. Serological analysis of CMV showed negative immunoglobulin (Ig) M and positive IgG. Blood CMV-DNA was 9.26 × 103 copies/mL. The diagnosis of gastrointestinal CMV disease was confirmed by histopathological findings of intranuclear and intracytoplasmic inclusions and Owl’s eye inclusion. This case highlights the differential diagnosis and histopathological characteristics of gastrointestinal CMV infection and laboratory tests.CONCLUSIONExtensive gastrointestinal CMV lesions can be induced by the immune suppression secondary to measles infection. Rational, fast, and effective laboratory examinations are essential for suspected patients.

Clinical Features, Endoscopic Findings, and Predictive Factors for Mortality in Tissue-Invasive Gastrointestinal Cytomegalovirus Disease between Immunocompetent and Immunocompromised Patients.

Background and Aims Tissue-invasive gastrointestinal cytomegalovirus (TI-GI CMV) disease is common in immunocompromised patients, but the increasing prevalence in immunocompetent patients has been reported. This study compared the clinical manifestations, endoscopic features, treatment outcomes, and predictors for inhospital mortality of TI-GI CMV between immunocompromised and immunocompetent patients. Methods Patients with HIV infection, malignancy, or receiving immunosuppressive agents (chemotherapy, high dose, or long-term corticosteroids) were defined as the immunocompromised group. Demographic and inhospital mortality data were obtained and retrospectively analyzed. Results A total of 213 patients (89 immunocompetent) with histologically confirmed TI-GI CMV were enrolled. Immunocompetent patients were older (70 vs. 52 years; p < 0.001), had more GI bleeding as a presenting symptom (47.2% vs. 29.0%; p = 0.010), and shorter symptom onset (2 vs. 14 days, p = 0.018). Concomitant extra-GI involvement was only seen in the immunocompromised group (6.5% vs. 0%; p = 0.02). Diffuse GI tract (14.5% vs. 4.5%; p = 0.032) and esophageal involvement (14.5% vs. 5.6%; p = 0.046) were more frequent in the immunocompromised, while small bowel involvement was more frequent in the immunocompetent group (19.1% vs. 8.1%; p = 0.029). An overall inhospital mortality was 27.7%. There was no significant difference in inhospital survival probability between the two groups (Peto-Peto test, p = 0.65). ICU admission (hazard ratio [HR] 7.21; 95% CI 2.55-20.36), sepsis or shock (HR 1.98; 95% CI 1.08-3.66), malnutrition (HR 2.62; 95% CI 1.05-7.01), and receiving chemotherapy (HR 5.2; 95% CI 1.89-14.29) were independent factors for inhospital mortality. Antiviral treatment for more than 14 days was the only protective factor to improve survival (Peto-Peto test, p < 0.001). Conclusions Immunocompetent and immunocompromised patients with TI-GI CMV disease had distinct clinical and endoscopic characteristics. There was no significant difference in the inhospital mortality between the two groups. The factors for mortality were ICU admission, sepsis/shock, malnutrition, and receiving chemotherapy. Early diagnosis and initiation of antiviral treatment might improve the survival probability.

Advances in Diagnosis and Treatment of Cytomegalovirus Gastrointestinal Infection in Immunocompetent Adults

Cytomegalovirus (CMV), a kind of human herpes virus, is highly prevalent globally. It was believed that CMV posed a considerable risk only in newborns and immunocompromised individuals in the past, but there are increasing reports that CMV caused adverse outcomes in immunocompetent adults. The gastrointestinal canal (especially colon) is one of the usual sites of cytomegalovirus infection. Moreover, severe CMV gastrointestinal disease can lead to considerable mortality. Male, age ≥55 years, immunomodulatory comorbidities (such as kidney failure, pregnancy, diabetes mellitus, or non-hematological malignancies without treatment) and the need for surgical intervention are factors that are not favorable to survival. When patients have unfavorable risk factors for survival or serious complications, antiviral treatment should be administered. Targeted antiviral therapy with intravenous ganciclovir or valganciclovir was suitable for severe CMV disease in immunocompetent adults before the advent of new and safer anti-herpesvirus drugs. Although there are many simple ways to detect the presence of CMV, most of them cannot distinguish between latent infection and active disease, which makes clinical decision-making difficult. CMV gastrointestinal disease has no specific clinical and endoscopic manifestations, and the diagnosis is to a large extent dependent on histopathology and tissue CMV polymerase chain reaction technology. Quantitative testing of tissue CMV DNA is a useful diagnostic tool, but further research is needed to explain the quantitative value, such as obtaining a viral load cutoff to decide whether to apply antiviral therapy.

Diagnostic significance of cytomegalovirus DNA quantitation in gastrointestinal biopsies: comparison with histopathological data and blood cytomegalovirus DNA.

This study aims to improve the diagnosis of gastrointestinal (GI) cytomegalovirus (CMV) disease. It presents the results of a novel study in which CMV blood viral load (BVL), tissue viral load (TVL) determined by PCR and hematoxylin-eosin (HE)/immunohistochemistry (IHC) results of GI biopsies are examined comparatively. CMV DNA was investigated by quantitative real-time PCR in blood and GI biopsy specimens of 76 patients suspected of CMV disease. Biopsies were also performed HE/IHC stainings in the pathology laboratory. This study included 76 patients whose median age was 34.5 years and 58% (44) were male. Tissue CMV PCR positivity was detected in the highest colon (40/53;75.5%) samples. HE, IHC, blood and tissue CMV PCR positivity rates of all samples were 15.8, 25, 50 and 71.1%, respectively. When IHC was used as the gold standard test for ROC analysis, the optimal cutoff values for the maximum sensitivity and specificity for BVL and TVL were 1.91 log10 copies/ml and 3.82 log10 copies/mg, respectively. Sensitivity and specificity for the cutoff value of tissue CMV DNA were 78.9 and 74.3%, respectively (P < 0.001). In this study, CMV DNA was detected in 71.1% of the tissue samples of the cases by PCR. Since the sensitivity of the histopathological examinations accepted as the gold standard is low, simultaneous with the histopathological examinations, determination of BVL, TVL and the identification of optimal cutoff values have been shown to support the diagnosis of GI CMV disease.

Quantitative PCR Is Faster, More Objective, and More Reliable Than Immunohistochemistry for the Diagnosis of Cytomegalovirus Gastrointestinal Disease in Allogeneic Stem Cell Transplantation

Diagnosis of gastrointestinal (GI) cytomegalovirus (CMV) disease relies on the presence of GI symptoms and detection of CMV, mainly by immunohistochemistry (IHC), in GI biopsy specimens. Thus, in a symptomatic patient, a positive CMV-IHC result is accepted as a diagnosis of CMV disease. However, a positive CMV-PCR in GI tissue is considered "possible" CMV disease. Therefore, it would be very useful if, in practice, both techniques showed equal sensitivity and reliability. This is because PCR has many practical advantages over IHC for detecting CMV. The aim of this study was to compare quantitative PCR with IHC for the diagnosis of GI CMV disease. A total of 186 endoscopic GI biopsy specimens from 123 patients with GI symptoms after an allogeneic stem cell transplantation (allo-SCT; 2004-2017) were analyzed by IHC and PCR on 113 paraffin-embedded and 73 fresh samples. The results were then compared. Of the patients with macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, "proven" CMV disease, n = 28), all but 1 were CMV-PCR positive. Of the patients without macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, probable CMV disease, n = 4), only 1 was CMV-PCR positive. Eight patients had CMV-IHC-negative/CMV-PCR-positive gut biopsy specimens. These cases fall within the current definition of possible CMV disease. In 6 of these 8 cases (75%), the viral load in GI tissue was very high (>10,000 copies/µg). Taken together, the results from the proven and probable cases revealed that CMV-PCR shows the same sensitivity (100%), specificity (98%), and positive (93%) and negative predictive value (100%) as CMV-IHC. Detection of CMV in fresh GI mucosa by quantitative PCR is as useful as IHC for the diagnosis of GI CMV disease. The results show that quantitative PCR has the same sensitivity, specificity, and positive/negative predictive value as IHC.

Real-time quantitative PCR analysis of endoscopic biopsies for diagnosing CMV gastrointestinal disease in non-HIV immunocompromised patients: a diagnostic accuracy study.

Cytomegalovirus gastrointestinal diseases (CMV-GIDs) are end-organ diseases of the gastrointestinal (GI) tract caused by CMV in immunocompromised patients. We aimed to evaluate the performance of quantitative polymerase chain reaction (qPCR) on endoscopic biopsies. We retrospectively reviewed the qPCR data on endoscopic biopsies in nonhuman immunodeficiency virus (HIV) immunocompromised patients between January 2009 and May 2015. The performance of the qPCR for CMV-GID was evaluated with the sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). A total of 195 patients were included, and 28 patients with confirmed CMV-GID were identified. The AUROC of the qPCR was 0.935 (95% confidence interval [CI], 0.885 to 0.985), the sensitivity was 89.3% (95% CI, 71.8 to 97.7%), and the specificity was 85.6% (95% CI, 79.4 to 97.6%) with a cutoff value of 180 copies/μg DNA. The proportion of patients with inflammatory bowel disease in the histopathology-negative, PCR-positive group was smaller than that in the histopathology-positive group (10.7 vs 35.0%, p = 0.026), but other characteristics were not significantly different. The use of qPCR on endoscopic biopsies demonstrated good diagnostic performance for detecting CMV in non-HIV immunocompromised patients. It may increase the diagnostic yield when combined with a conventional histopathology.