Clinical characteristics and outcomes in CMV infection in intestinal transplant recipients: A single‐center experience

Cytomegalovirus (CMV) infection is one of the most common posttransplantation infections and has been associated with increased rejection and mortality. Data in intestinal transplants recipients are limited.

mediated immunity guided prophylaxis should be used to prevent infections in this population.

cytomegalovirus, immunosuppression, intestinal transplant, multi-visceral transplant, solid organ transplant INTRODUCTION
Intestinal transplantation has become a lifesaving procedure for patients with irreversible intestinal failure either from short bowel syndrome, or from motility and absorption disorders, in whom total parenteral nutrition causes life threatening complications or liver dysfunction. 1 In the past several decades, the number of intestinal transplants has increased due to advances in the surgical field, postsurgical care, and immunosuppression. 1 Despite these advances, intestinal transplantation remains the least frequently performed procedure because of its high risk of complications, both surgically and medically, including infectious disease complications. 2 Of a total of 386 878 solid organ transplants (SOTs) performed in the United States between 2009 and 2020, only 1486 (0.4%) were intestinal transplants. 3 Due to an increased risk for rejection, higher doses of immunosuppressants are required after intestinal transplantation. This puts recipients at a higher risk of infection, as compared to other SOT recipients. 4,5 Cytomegalovirus (CMV) infection is a common infection in SOT recipients and has been associated with increased morbidity and mortality, directly, and indirectly. 6 In a large cohort of SOT recipients in general, all-cause mortality after CMV infection was 6.4%. 7 Indirect effects due to CMV includes increased risk of rejection, graft loss, 6 as well as other infections, such as invasive fungal disease as shown in a cohort of liver transplant recipients. 6,8 CMV is prevalent worldwide, with 80% of Americans being infected by age 60. 9 After primary infection, latency is established in monocytes, dendritic cells, megakaryocytes, and myeloid progenitor cells in the bone marrow. 10 Cytotoxic T cells are the primary driver of viral replication. However, in SOT recipients, the T-cell function is altered by the use of immunosuppressant therapy, and reactivation could occur. 11 Owing to its potentially devastating effects, there has been much emphasis on finding predisposing factors in transplant patients to find an efficient prevention method to protect them from CMV effects. Even though some studies identified the risk factors for developing CMV infection in this population, including antithymocyte globulin (ATG), [12][13][14]

CMV prevention, testing, and treatment strategy for intestinal transplant recipients
All recipients received prophylaxis for CMV for up to 1 year with (val)ganciclovir if tolerated. The dose of prophylaxis with (val)ganciclovir was renally adjusted regular prophylactic dose. Prophylaxis for CMV was preceded by administration of CMV specific immunoglobulin after 2013 when it was added in the protocol of our institution. We are switching to oral valganciclovir from intravenous ganciclovir when the recipient can achieve targeted tacrolimus level only with oral tacrolimus. CMV testing was performed every 2 weeks regardless of the symptoms for the first 6 months even while on prophylaxis, and also when the treating physicians suspected CMV infection such as when recipients develop fever, cytopenia, and diarrhea. CMV PCR testing was performed using the COBAS Amplicor TA B L E 1 Data presented as absolute number (percentage), unless specified otherwise.

Definition
After collecting the symptoms and PCR testing results, the authors retrospectively categorized each episode of CMV infection based on the criteria published by Ljungman et al. 15 Resistant and refractory CMV infections have been defined elsewhere. 16 Recurrence of CMV infection was defined as any detectable DNAemia requiring treatment after stopping antivirals for initial episode. 17,18

Statistical analysis
Demographic data were analyzed using descriptive statistics.  (val)ganciclovir prophylaxis discontinuation due to leukopenia and developing CMV infection, respectively.

Clinical characteristics of CMV infection
The clinical characteristic of CMV infection was summarized in Table 2.

Risk factor analysis
Risk factor analysis was used to determine this cohort's potential predictors of CMV infection. First, we conducted a univariate analysis. In the univariate analysis, only younger age was identified as risk factor (p = .007). Subsequently, we developed a multivariate model whose p values were less than .2 in univariate analysis. We conducted logistic regression analysis using stepwise backward elimination. Age and rejection within 3-month posttransplant were included in the model.

Treatment and outcomes
The outcome of CMV infection is summarized in Table 2

DISCUSSION
We outlined a single-center retrospective cohort study describing our  To the best of our knowledge, this is one of the most significant reports evaluating CMV infection in intestinal transplant recipients.
In summary, we conducted the retrospective cohort study about CMV infection in small-bowel and multi-visceral transplant recipients.
Only young age was identified as a risk factor for CMV infection in this cohort. Due to high breakthrough infection, we recommend monitoring CMV PCR even while on prophylaxis. Further strategies to monitor CMV specific immunity to guide the prophylaxis and treatment should be developed in this vulnerable population.

AUTHOR CONTRIBUTIONS
Anmary A. Fernandez and Yoichiro Natori conceived the study. Anmary