CMV seropositivity is a potential novel risk factor for severe COVID-19 in non-geriatric patients

Background: COVID-19 has so far affected more than 250 million individuals worldwide, causing more than 5 million deaths. Several risk factors for severe disease have been identified, most of which coincide with advanced age. In younger individuals, severe COVID-19 often occurs in the absence of obvious comorbidities. Guided by the finding of cytomegalovirus (CMV)-specific T cells with some cross-reactivity to SARS-CoV-2 in a COVID-19 intensive care unit (ICU) patient, we decided to investigate whether CMV seropositivity is associated with severe or critical COVID-19. Methods: National German COVID-19 bio-sample and data banks were used to retrospectively analyze the CMV serostatus of patients who experienced mild (n=101), moderate (n=130) or severe to critical (n=80) disease by CMV IgG serology. We then investigated the relationship between disease severity and CMV serostatus via statistical models. Results: Non-geriatric patients (< 70 years) with severe COVID-19 were found to have a very high prevalence of CMV-seropositivity, while CMV status distribution in individuals with mild disease was similar to the prevalence in the German population; interestingly, this was not detectable in older patients. Prediction models support the hypothesis that the CMV serostatus might be a strong biomarker in identifying younger individuals with a higher risk of developing severe COVID-19. Conclusions: We identified CMV-seropositivity as a potential novel risk factor for severe COVID-19 in non-geriatric individuals in the studied cohorts. More mechanistic analyses as well as confirmation of similar findings in cohorts representing the currently most relevant SARS-CoV-2 variants should be performed shortly.

Impact of Donor Age and Relationship on Outcomes of Peripheral Blood Haploidentical Hematopoietic Cell Transplantation

Introduction: Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly utilized therapy for a variety of hematologic malignancies. Determining which donor characteristics affect transplant outcomes is of particular interest in haplo-HCT, as there are often multiple donors available for a given patient. A survival benefit with younger donors has been reported in some recent observational studies (DeZern et. al., Blood Advances, March 2021); (Canaani et. al., AJH, Sep. 2017). A decrease in non-relapse mortality (NRM) and increase in relapse with no overall survival difference associated with younger donors has also been observed (Mariotti et. al., Blood Advances, June 2020). These previous studies have utilized populations with bone marrow as the predominant stem cell source. Solomon et al. (BBMT Sep. 2018) observed poorer survival, increased relapse, and worse NRM with parent donors relative to children in a largely peripheral blood population. HLA DR and DP mismatch were noted to be associated with improved survival. Here we describe outcomes in peripheral blood haplo-HCT and their association with potentially selectable donor characteristics including age and relationship to the patient. Patients and Methods: We performed a retrospective review of patients who underwent peripheral blood haplo-HCT with PtCy from July 2009 through May 2021. A total of 323 patients were identified with AML (205), ALL (43), MDS (26), and other (49). Univariate and multivariate analyses (MVA) were conducted examining the effect of donor characteristics on overall survival (OS), NRM, relapse, acute and chronic GVHD. Donor characteristics included age, relationship, ABO status, CMV status, and HLA match grade. We controlled for patient characteristics known to affect outcomes including disease type, DRI, HCT CI, KPS, active disease at transplant, myeloablative conditioning, and prior HCT. Results: Median donor age was 40 (range 15-71) with male predominance (64%). Most were ABO compatible (63%) - 12% had major ABO mismatch, 20% minor, and 4% bidirectional. Donor-recipient CMV status matched in 61% of pairs, 13% were donor positive-recipient negative, 26% donor negative-recipient positive. Most were 5/10 HLA matched (51%) with 20% 6/10 and 13% 7-9/10. Univariate analysis revealed that increasing donor age was associated with higher NRM (HR 2.29, p=0.005 for donors age 30-44; HR 2.06, p=0.012 age &gt; 44) but lower relapse risk (HR 0.56, p=0.012 age 30-44; HR 0.69, p=0.10 age &gt; 44). There were no differences in aGVHD or cGVHD based on donor characteristics in univariate analysis. In MVA, relapse risk was lower in patients with older donors , p=0.046). In contrast, NRM was higher in patients with older donors (HR 1.73 age 30-44, HR 1.69 age &gt; 44, p=0.010). There was no difference in overall survival based on donor age (HR 1.23 age 30-44, HR 1.38 age &gt; 44, p=0.11). We next examined the effect of donor relationship on outcomes while controlling for donor age, patient age, and patient disease risk factors. We found no difference in outcomes between parent, sibling, or child donors. Conclusions: Increasing donor age was associated with lower relapse risk but higher NRM. These competing effects resulted in no difference in OS based on donor age. Other donor factors including relationship (parent / sibling / child), CMV status, ABO mismatch, donor sex, and HLA match grade were not associated with outcomes. Solomon et al. reported better outcomes with child compared to parent donors, a finding not replicated here, however our analysis controlled for donor age which could have been a proxy for relationship in their study. These data suggest that in peripheral blood haplo-HCT, younger donors may be preferred in patients with high risk of transplant related complications. In contrast, older donors may be preferred in patients where relapse risk is high. Data on HLA-DR and DP match is being analyzed and will be presented at the ASH 2021 meeting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A novel Iowa–Mayo validated composite risk assessment tool for allogeneic stem cell transplantation survival outcome prediction

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool. Using a lasso-penalized Cox regression model (n = 273), performance status, HCT-CI, refined disease-risk index (rDRI), donor and recipient CMV status, and donor age were identified as predictors of disease-free survival (DFS). The results for overall survival (OS) were similar except for recipient CMV status not being included in the model. Models were validated in an external dataset (n = 378) and resulted in a c-statistic of 0.61 and 0.62 for DFS and OS, respectively. Importantly, this tool incorporates donor age as a variable, which has an important role in HSCT outcomes. This needs to be further studied in prospective models. An easy-to-use and a web-based nomogram can be accessed here: https://allohsctsurvivalcalc.iowa.uiowa.edu/.

Prognosis of Biliary Atresia Associated With Cytomegalovirus: A Meta-Analysis

Objective: The etiology of biliary atresia is unclear, but viral infection has been implicated. The aim of the current meta-analysis was to investigate relationships between cytomegalovirus (CMV) and the prognosis of biliary atresia.Methods: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, and Wanfang Data electronic databases were searched for eligible studies. Each relevant text was thoroughly reviewed and examined, including related papers in their reference lists.Results: A total of nine studies including 784 patients were included in the analysis. Biliary atresia patients with CMV exhibited significantly lower jaundice clearance (odds ratio: 0.46, p &lt; 0.0001; I2 = 15%, p = 0.31). There were no significant differences in the rates of cholangitis or native liver survival. CMV-pp65-positive biliary atresia patients had a significantly lower rate of jaundice clearance (odds ratio: 5.87, p = 0.003; I2 = 0%, p = 0.71) and a significantly higher rate of cholangitis (odds ratio: 0.21, p = 0.01; I2 = 0%, p = 0.43) than CMV antibody-positive biliary atresia patients.Conclusion: Biliary atresia patients who were also infected with CMV had a poorer prognosis, particularly with respect to jaundice clearance. CMV status may influence the prognosis of biliary atresia. Clinicians should be able to routinely identify the subset of biliary atresia patients who are also CMV-positive, in order to improve native liver survival.

#76: Epidemiology of Cytomegalovirus (CMV) in Pediatric Solid-Organ Transplant Recipients (SOTR) at Texas Children’s Hospital (TCH)

Background Despite the widespread use of prevention strategies, CMV remains a common opportunistic infection in SOTR. Contemporary data regarding CMV in pediatric SOTR are limited. We sought to determine the frequency of and risk factors for CMV infection and disease in a large single-center cohort of pediatric SOTR. Methods A retrospective cohort study of patients &lt;22 years of age who received lung, heart, liver, kidney, or multi-organ transplants at TCH between 2010 and 2018 was completed. Universal CMV prophylaxis was used based on risk status (Figure 1). The primary outcome was quantifiable CMV DNAemia. Associations with CMV DNAemia were measured using Fisher exact, Kruskal–Wallis, and multivariate logistic regression. Survival analysis and time to CMV infection were assessed using Kaplan–Meier plots. Results Among 788 SOTR, 132 (17%) had quantifiable CMV DNAemia; this included 20/105 (19%) lung, 69/290 (24%) liver, 28/178 (16%) heart, 2/15 (13%) multi-organ, and 13/200 (7%) kidney recipients. Fifty-one (6%) SOTR had CMV DNAemia while on antiviral prophylaxis. Post-prophylaxis, 69 (9%) SOTR had CMV reactivation and 12 (2%) had primary infection. The median time to quantifiable DNAemia for patients that developed CMV was 290 days post-transplant for lung, 162 for liver, 186 for heart, and 294 for kidney (P &lt; 0.01), reflecting differences in prophylaxis strategies. High-risk CMV status (D+/R– for heart, liver, kidney, and D+ and/or R+ for lung) was associated with CMV DNAemia (P &lt; 0.01). Type of organ transplanted also showed an association with CMV DNAemia (P = 0.02) with liver transplant recipients more being more likely to have a positive CMV PCR. DNAemia was not associated with age at transplantation, type of organ, or the use of induction immunosuppression. There was no difference in survival during the study follow-up period (1–9 yr) for SOTR with vs. without DNAemia (P = 0.48). Overall, 22/788 (3%) SOTR had CMV disease, 3 (3%) lung, 4 (2%) heart, 8 (3%) liver, 1 (6%) multi-organ, and 6 (3%) kidney recipients. Twenty had CMV syndrome and 2 had tissue invasive disease. Median (range) maximum viral loads were 27700 IU/mL (233-3912694) for SOTR with vs. 900 IU/mL (26-112000) for SOTR without CMV disease (P &lt; 0.01). Conclusion This large contemporary cohort of pediatric SOTR on universal prophylaxis demonstrates low overall rates of CMV DNAemia and CMV disease. High-risk CMV status remains associated with CMV DNAemia, suggesting that further interventions targeting this group may be warranted.

Abstract 16993: Impact of Donor and Recipient Cytomegalovirus Immune Status on Long-Term Graft Survival in Pediatric Heart Transplantation

Introduction: While CMV infection has been associated with graft loss in adult heart transplants, its role in children is less understood. We aim to better understand the effect of donor and recipient CMV immune status at transplant on survival in pediatric recipients. Methods: We analyzed 6,951 pediatric heart-only transplants in the Scientific Registry of Transplant Recipients (1987-2019). Patients were stratified by recipient and donor CMV status at transplant. The primary endpoint was freedom from graft loss. Results: Of the various donor and recipient CMV statuses, only CMV-positive recipients had decreased graft survival compared to CMV-negative ones (at 15-yrs: 47% vs. 53%, HR 1.14). However, when fully adjusted by Cox regression, recipient status was no longer a risk factor ( p = 0.12). In this model, anti-CMV treatment with ganciclovir or valganciclovir was associated with a lower risk of graft loss (HR 0.80, CI 0.71 - 0.90, p < 0.005). When stratified by the four donor-recipient CMV status combinations, antiviral use was associated with improved survival in both donor-positive groups: most strongly in donor-positive/recipient-positive transplants (at 15-yrs: 51% vs. 39%, p < 0.005) and to a lesser extent in donor-positive/recipient-negative transplants (at 15-yrs: 53% vs. 51%, p < 0.005). The association is maintained when examined by era, such as with more frequent use of anti-CMV therapy after 1995. No association with antiviral use was observed in either donor-negative transplant group. Conclusion: CMV-positive recipients had greater long-term graft loss, although this may be confounded by other transplant characteristics. Anti-CMV therapy is associated with improved long-term graft survival in transplants with CMV-positive donors. This finding may explain the lack of association between donor CMV status and graft loss in that an association may be masked by antiviral use. Further investigation of anti-CMV therapy may mitigate risk of graft loss.

Role of CMV-serostatus and CX3CR1 on lymphocyte kinetics and left ventricular remodelling in patients with acute myocardial infarction

Background Patients with latent cytomegalovirus (CMV) infection have higher rates of adverse cardiovascular outcomes, but the reasons for this remain elusive. CMV-induced changes to T-lymphocyte populations, with a proliferation of CMV-specific, CX3CR1+ effector memory cells, may contribute. Effector T-cells are associated with cardiovascular mortality in CMV positive patients, and ischaemia-reperfusion injury after ST-elevation myocardial infarction (STEMI) and primary percutaneous coronary intervention (pPCI). Purpose To investigate the effect of CMV status on lymphocyte kinetics and cardiac MRI (cMRI) parameters in 52 STEMI patients receiving pPCI, and examine the prognostic relevance of pre-reperfusion lymphocyte count in a large cohort. Methods We retrospectively analysed the association between pre-reperfusion lymphocyte count, troponin, and long-term survival in 4874 consecutive STEMI patients. Using flow cytometry, we analysed lymphocyte kinetics in 52 STEMI patients, of known CMV status, during and after pPCI. We assessed the impact of CMV status on infarct size, left-ventricular (LV) function and microvascular obstruction with cMRI in the first week after reperfusion in 101 patients. Repeat cMRI at 12 weeks, to assess LV remodelling, was obtained in 48 patients. Results Pre-reperfusion lymphopenia is an independent predictor of mortality over 7.5 years (hazard ratio for lowest vs highest quartile: 2.0; 95% CI 1.7–2.4; p&lt;0.001), and is associated with higher admission troponins (p&lt;0.001 for lowest vs second-lowest quartile), suggesting lymphocyte count falls prior to reperfusion in response to myocardial injury. CMV positive patients had more cytotoxic T-cells, strongly expressing the fractalkine receptor, CX3CR1. In CMV positive patients these cells fell dramatically by 90 minutes post-reperfusion, and dropped more sharply in patients with extensive microvascular obstruction on cMRI (p≤0.05 in all effector subsets). CX3CR1 expression was lower at 90 minutes post-reperfusion than at 24 hours (return to physiological expression) in all effector T-cell subsets. All subsets lost a similar proportion of their 24-hour value, but consistently lost a larger proportion in CMV positive patients (−27% in CMV+, −18% in CMV−; p=0.007). CX3CR1 expression falls in the presence of fractalkine, and we hypothesise that membrane-bound fractalkine is induced more strongly in CMV positive patients, as soluble fractalkine levels were similar. At 12 weeks, LV remodeling was worse in CMV positive patients (change in end-diastolic volume: +10.7ml vs −6.1ml; p=0.02). Conclusions Lymphopenia occurs prior to reperfusion in STEMI, and predicts long-term mortality. Effector T-cells drop substantially after reperfusion only in CMV positive patients, likely mediated by CX3CR1-fractalkine interaction, and this is associated with adverse cMRI findings. Remodeling is worse in CMV positive patients at 12 weeks post-STEMI. Lymphocytes, troponin and survival Funding Acknowledgement Type of funding source: Public Institution(s)

Child HIV Exposure and CMV Seroprevalence in Botswana: No Associations With 24-Month Growth and Neurodevelopment

Background We sought to identify predictors of child cytomegalovirus (CMV) infection overall and by maternal HIV status and to assess associations of child CMV status with growth and neurodevelopmental outcomes at 24 months of age in Botswana. Methods Data and samples were used from the Botswana-based observational Tshipidi study (2010–2014), enrolling pregnant women living with and without HIV and following their infants through 2 years of age. Child plasma samples were tested at 18 months of age for anti-CMV immunoglobulin G (IgG). Associations were assessed between detectable anti-CMV IgG and growth (using the World Health Organization Child Growth Standards) and neurodevelopment (using the Bayley Scales of Infant and Toddler Development III and the Developmental Milestones Checklist) at 24 months of age. Results Of 317 children, 215 (68%) had detectable anti-CMV IgG at 18 months of age. Comparatively, 83% (n = 178) of HIV-unexposed uninfected (HUU) children had positive CMV serology vs 47% (n = 139) of HIV-exposed uninfected (HEU) children (P &lt; .01); 100% of HUU vs 10.5% of HEU children breastfed. Child CMV infection was not associated with weight-for-age, weight-for-length, or length-for-age z-scores at 24 months. In HUU children, CMV infection was associated with smaller head circumference (P &lt; .01). No difference was observed by child CMV status in any neurodevelopmental domain at 24 months. Conclusions We observed high CMV seropositivity in 18-month-old children in Botswana, with higher seropositivity among breastfed (HUU) children. Positive CMV serostatus was not associated with 24-month child growth or neurodevelopmental outcomes, with the exception of smaller head circumference among HUU CMV-positive children.