Incidence and severity of cytomegalovirus infection in seropositive heart transplant recipients.

BACKGROUND: The frequency and significance of cytomegalovirus (CMV) infection in seropositive (R+) heart transplant recipients (HTR) is unclear, with preventative recommendations mostly extrapolated from other groups. We evaluated the incidence and severity of CMV infection in R+ HTR, to identify risk factors and describe outcomes. METHODS: R+ HTR from 2010 to 2019 were included. Antiviral prophylaxis was not routinely used, with clinically guided monitoring the local standard of care. The primary outcome was CMV infection within one-year post-transplant; secondary outcomes included other herpesvirus infections and mortality. RESULTS: CMV infection occurred in 27/155 (17%) R+ HTR. Patients with CMV had a longer hospitalization (27 vs. 20 days, unadjusted HR 1.02, 95% CI 1.00-1.02, p = .01), higher rate of intensive care readmission (26% vs. 9%, unadjusted HR 3.46, 1.46-8.20, p = .005), and increased mortality (33% vs. 8%, unadjusted HR 10.60, 4.52-24.88, p < .001). The association between CMV and death persisted after adjusting for multiple confounders (HR 24.19, 95% CI 7.47-78.30, p < .001). Valganciclovir prophylaxis was used in 35/155 (23%) and was protective against CMV (infection rate 4% vs. 27%, adjusted HR .07, .01-.72, p = .025), even though those receiving it were more likely to have received thymoglobulin (adjusted OR 10.5, 95% CI 2.01-55.0, p = .005). CONCLUSIONS: CMV infection is common in R+ HTR and is associated with a high burden of disease and increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection, despite being at higher risk. These findings support the routine use of antiviral prophylaxis following heart transplantation in all CMV R+ patients.

Female sex and advanced age are associated with invasive cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: Limited data exist to describe sex-based differences in the severity of cytomegalovirus (CMV) infection after solid organ transplant (SOT). We sought to identify if a difference exists in likelihood of tissue-invasive disease between male and female SOT recipients and to understand how age affects this relationship. METHODS: A retrospective cohort of 180 heart, liver, and kidney recipients treated for CMV was examined. A logistic regression model was developed to assess the relationship between female sex and CMV type (noninvasive vs. invasive). A secondary regression analysis looked at the relationship of invasive CMV with a variable combining sex with age above or below 50. RESULTS: There were 37 cases of proven or probable invasive CMV, occurring in 30% of females versus 16% of males. After adjustment for potential confounders, females with CMV infection were significantly more likely to have invasive disease (odds ratio (OR) 2.69, 95% confidence interval (CI) 1.25-5.90, p = .01). Females 50 years or older were at particular risk compared with males under 50 years (adjusted OR 4.54, 95% CI 1.33-18.83, p = .02). CONCLUSION: Female SOT recipients with CMV in our cohort were more likely than males to have tissue-invasive disease, with the highest risk among older females. Further prospective studies are warranted to explore underlying immunologic mechanisms.

Cytomegalovirus in inflammatory bowel disease: a clinical approach.

Cytomegalovirus (CMV) infection can be a challenging clinical problem in patients with inflammatory bowel disease (IBD), particularly ulcerative colitis. Clinical presentation is difficult to distinguish from an underlying disease flare. Several diagnostic modalities are now available and when combined can aid clinicians in the identification of patients who are most likely to benefit from antiviral therapy. The aim of this article is to review the available literature and outline a practical approach to the diagnosis and management of CMV in patients with IBD.

Evaluation of Quantiferon®-Monitor as a biomarker of immunosuppression and predictor of infection in lung transplant recipients.

BACKGROUND: Optimizing immunosuppression in lung transplant recipients (LTR) is crucially important in minimizing the risk of infection and rejection. Quantiferon®-Monitor (QFM) is a candidate immune function biomarker which has not yet been rigorously evaluated in the lung transplant setting. The aim of this prospective cohort study was to explore relationships between QFM results, immunosuppression, and infection/rejection in LTR. METHODS: QFM, which measures interferon-γ after stimulation with innate and adaptive immune antigens, was tested before and at 2, 6, 12, 24 and 52 weeks post-transplant. Immunosuppression relationships were assessed with linear mixed effects models. Clinical outcomes were analyzed based on the preceding QFM result. RESULTS: Eighty LTR were included. Median pre-transplant QFM levels were 171 IU/mL (IQR 45-461), decreasing to 3 IU/mL (IQR 1-8) at 2 weeks post-transplant then progressively recovering toward baseline with time from transplant. Prednisolone was strongly inversely associated with QFM level (0.1 mg/kg dose increase correlating with 88 IU/mL QFM decrease, 95% CI 61-114, P < .001). Patients with QFM values <10 and <60 IU/mL were more likely to develop a serious opportunistic infection between 3 and 6 months (HR 6.38, 95% CI 1.37-29.66, P = .02) and 6-12 months (HR 3.25, 95% CI 1.11-9.49, P = .03) post-transplant, respectively. CONCLUSIONS: QFM values declined significantly post-transplant, with patients recovering at different rates. Prednisolone dose significantly impacted QFM results. Low levels were associated with infection beyond 3 months post-transplant, suggesting that QFM may be able to identify overly immunosuppressed patients who could be targeted for dose reduction. Larger prospective studies are needed to further evaluate this promising assay.

The impact of recurrent cytomegalovirus infection on long-term survival in solid organ transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) remains a significant contributor to morbidity and mortality following solid organ transplantation (SOT). While recurrent infection occurs in up to 30% of patients, its impact on mortality is unclear. The aim of this study was to explore the relationship between recurrent CMV infection and long-term survival in SOT recipients. METHODS: We performed a retrospective cohort study of SOT recipients who completed treatment for an episode of CMV infection. Patients were followed until death, loss to follow-up or 10 years following CMV treatment completion. Univariable and multivariable hazard ratios (HR) were calculated, treating relapse and rejection following CMV as time-varying. RESULTS: About 79 kidney, 52 heart, 34 liver, and 5 liver-kidney transplant recipients were included. About 62/170 died, at a median of 3.8 years (IQR 0.8-6.6 years). Median follow-up among the 108 survivors was 7.4 years (IQR 3.7-10 years). Recurrent CMV infection occurred in 49/170 (29%), 67% within 6 months of treatment completion. Mortality among those who relapsed was 39% (19/49) vs 36% (43/121) in those who remained relapse-free (unadjusted HR 1.59, 95% CI 0.92-2.75, P = .10). After adjusting for age and transplanted organ, findings were similar (HR 1.68, 95% CI 0.93-3.04, P = .09). CONCLUSIONS: Mortality following CMV remains high even in the valganciclovir era. Although our findings suggest a possible increased risk of death among patients with recurrent CMV, these did not reach statistical significance. The complex nature of these patients, multiple potential confounders, and limited statistical power made detection of small effects difficult. Larger prospective studies evaluating the clinical impact of strategies to reduce recurrence are needed.

Reactivation of latent cytomegalovirus infection in patients with rheumatologic disease: a case-control study.

The disease burden, risk factors and clinical sequelae of CMV reactivation in patients with rheumatologic conditions is poorly understood. We have described a cohort with underlying rheumatic disease and CMV, and compared a subgroup with systemic lupus erythematosus (SLE) to controls to identify potential risk factors for CMV reactivation. Adults with rheumatic disease and CMV infection from 2000-2015 were identified. SLE cases were matched 3:1 with controls based on age, sex and year of admission, and compared. Fourteen patients were included (6 SLE, 4 rheumatoid arthritis, 2 sarcoidosis, 1 psoriatic arthritis, 1 microscopic polyangiitis). Seven had viremia alone, the remainder tissue-invasive disease. Thirteen received glucocorticoids prior to CMV reactivation. Fever was the most common symptom, and coinfections were seen in eight including four with bacteremia. Thirteen received antiviral therapy (median 33 days), four died during hospitalization. Six patients with underlying SLE and CMV reactivation were compared to 18 SLE controls. Cases received more glucocorticoids prior to admission (median 36.5 vs. 2.5 mg/day, p = 0.006), had longer hospitalizations (median 47 vs. 7 days, p = 0.006) and more coinfections (67% vs. 17%, p = 0.04). There were no significant differences in symptoms at presentation. CMV reactivation occurs in patients with rheumatologic disease, can result in severe clinical sequelae, and is difficult to distinguish from a flare of the underlying disease. Patients with CMV received higher doses of glucocorticoids and developed more co-infections. CMV should be considered during the evaluation of a febrile illness in this complex patient population.

The effect of respiratory viral assay panel on antibiotic prescription patterns at discharge in adults admitted with mild to moderate acute exacerbation of COPD: a retrospective before- after study.

BACKGROUND: Despite well-defined criteria for use of antibiotics in patients presenting with mild to moderate Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD), their overuse is widespread. We hypothesized that following implementation of a molecular multiplex respiratory viral panel (RVP), AECOPD patients with viral infections would be more easily identified, limiting antibiotic use in this population. The primary objective of our study was to investigate if availability of the RVP decreased antibiotic prescription at discharge among patients with AECOPD. METHODS: This is a single center, retrospective, before (pre-RVP) - after (post-RVP) study of patients admitted to a tertiary medical center from January 2013 to March 2016. The primary outcome was antibiotic prescription at discharge. Groups were compared using univariable and multivariable logistic-regression. RESULTS: A total of 232 patient-episodes were identified, 133 following RVP introduction. Mean age was 68.1 (pre-RVP) and 68.3 (post-RVP) years respectively (p = 0.88). Patients in pre-RVP group were similar to the post-RVP group with respect to gender (p = 0.54), proportion of patients with BMI < 21(p = 0.23), positive smoking status (p = 0.19) and diagnoses of obstructive sleep apnea (OSA, p = 0.16). We found a significant reduction in antibiotic prescription rate at discharge in patients admitted with AECOPD after introduction of the respiratory viral assay (pre-RVP 77.8% vs. post-RVP 63.2%, p = 0.01). In adjusted analyses, patients in the pre-RVP group [OR 2.11 (CI: 1.13-3.96), p = 0.019] with positive gram stain in sputum [OR 4.02 (CI: 1.61-10.06), p = 0.003] had the highest odds of antibiotic prescription at discharge. CONCLUSIONS: In patients presenting with mild to moderate Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD), utilization of a comprehensive respiratory viral panel can significantly decrease the rate of antibiotic prescription at discharge.

Absolute Lymphocyte Count: A Predictor of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients.

Background: Recurrent cytomegalovirus (CMV) disease in solid organ transplant recipients frequently occurs despite effective antiviral therapy. We previously demonstrated that patients with lymphopenia before liver transplantation are more likely to develop posttransplant infectious complications including CMV. The aim of this study was to explore absolute lymphocyte count (ALC) as a predictor of relapse following treatment for CMV disease. Methods: We performed a retrospective cohort study of heart, liver, and kidney transplant recipients treated for an episode of CMV disease. Our primary outcome was time to relapse of CMV within 6 months. Data on potential predictors of relapse including ALC were collected at the time of CMV treatment completion. Univariate and multivariate hazard ratios (HRs) were calculated with a Cox model. Multiple imputation was used to complete the data. Results: Relapse occurred in 33 of 170 participants (19.4%). Mean ALC in relapse-free patients was 1.08 ± 0.69 vs 0.73 ± 0.42 × 103 cells/µL in those who relapsed, corresponding to an unadjusted hazard ratio of 1.11 (95% confidence interval, 1.03-1.21; P = .009, n = 133) for every decrease of 100 cells/µL. After adjusting for potential confounders, the association between ALC and relapse remained significant (HR, 1.11 [1.03-1.20]; P = .009). Conclusions: Low ALC at the time of CMV treatment completion was a strong independent predictor for recurrent CMV disease. This finding is biologically plausible given the known importance of T-cell immunity in maintaining CMV latency. Future studies should consider this inexpensive, readily available marker of host immunity.

A repeat offender: Recurrent extraintestinal Clostridium difficile infection following fecal microbiota transplantation.

Extraintestinal infection with Clostridium difficile has been reported but remains uncommon. Treatment of this unusual complication is complex given the limitations of current therapeutic options. Here we report a novel case of recurrent extraintestinal C. difficile infection that occurred following fecal microbiota transplantation. Using whole genome sequencing, we confirmed recrudescence rather than reinfection was responsible. The patient ultimately responded to prolonged, targeted antimicrobial therapy informed by susceptibility testing.

Role of Secondary Prophylaxis With Valganciclovir in the Prevention of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) is a major contributor to morbidity and mortality in solid organ transplant recipients (SOTRs). Ganciclovir and valganciclovir are highly effective antiviral drugs with a well-established role in primary prophylaxis and treatment of CMV disease. Our objective in this study was to examine the effect of secondary prophylaxis (SP) on the risk of relapse in SOTRs following an episode of CMV disease. METHODS: We performed a retrospective cohort study of SOTRs from 1995 to 2015 and used propensity score-based inverse probability of treatment weighting methodology to control for confounding by indication. A weighted Cox model was created to determine the effect of SP on time to relapse within 1 year of treatment completion. RESULTS: Fifty-two heart, 34 liver, 79 kidney, and 5 liver-kidney transplant recipients who completed treatment for an episode of CMV infection/disease were included. A total of 120 (70.6%) received SP (median duration, 61 days; range, 5-365) and 39 (23%) relapsed. SP was protective against relapse from 0 to 6 weeks following treatment completion (hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.05-0.69). However, after 6 weeks, risk of relapse did not significantly differ between the 2 groups (HR, 1.18; 95% CI, 0.46-2.99). CONCLUSIONS: Our findings demonstrate that use of SP following treatment of CMV disease did not confer long-term protection against relapse, although it did delay relapse while patients were receiving antivirals. This suggests that SP has limited clinical utility in the overall prevention of recurrent CMV disease.

Fosfomycin for Treatment of Prostatitis: New Tricks for Old Dogs.

Treatment options for prostatitis caused by multidrug-resistant gram-negative bacilli are limited. We report two cases cured with oral fosfomycin and provide a pharmacokinetic analysis of fosfomycin predose concentrations during treatment.

Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis.

OBJECTIVES: As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. METHODS: Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. RESULTS: Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. CONCLUSIONS: Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L.

COVID-19 infection is mild and has minimal impact on lung function in well vaccinated and widely treated lung transplant recipients.

BACKGROUND: COVID-19 has become a common infection affecting lung transplant recipients (LTR), who are at high risk for poor outcomes. Outcomes early in the pandemic were poor, but since the rollout of vaccination and novel COVID-19 treatments, outcomes of LTR have not been well described. Our aim was to evaluate the effect of COVID-19 on the clinical course and lung function trajectory in an Australian cohort of LTR. METHODS: Data were retrospectively collected from LTR with confirmed COVID-19 managed at Alfred Health, between August 2020 and December 2022. Baseline demographics, COVID-19 disease details (including severity) and spirometry pre- and postinfection have been analyzed. RESULTS: A total of 279 LTR were included. The cohort was comorbid, but well vaccinated, with 275/279 (98.6%) having ≥2 COVID-19 vaccines at symptom onset. Severe disease occurred in only 17 cases (6%) and overall mortality was very low (4%). Prompt treatment with antivirals, particularly remdesevir (OR 0.18, 95% CI 0.04-0.81, p = 0.02) and vaccination (OR 0.24, CI 0.08-0.81, p = 0.01), was protective. There was not a clinically significant drop in lung function post-COVID-19 with the median absolute decline in forced expiratory volume (FEV1) being 40 ml (IQR 5-120 ml, p < 0.001), with a decline of >10% occurring in only 42 patients (17%). After multivariate adjustment, only rejection before COVID-19 was significantly associated with FEV1 decline afterward (OR 3.74, 1.12-11.86, p = 0.03). CONCLUSIONS: In our highly COVID-19 vaccinated, promptly treated LTR, the majority of COVID-19 infections were mild and did not result in a clinically significant decline in lung function.

Cytomegalovirus Immunity Assays Predict Viremia but not Replication Within the Lung Allograft.

Cytomegalovirus (CMV) infection causes significant morbidity and mortality in lung transplant recipients. Current guidelines use pretransplant donor and recipient CMV serostatus to predict the risk of subsequent CMV replication and length of antiviral prophylaxis. Immunological monitoring may better inform the risk of CMV infection in patients, thereby allowing for improved tailoring of antiviral prophylaxis. In this study, we compared 2 commercially available assays, the QuantiFERON-CMV (QFN-CMV) and T-Track-CMV (enzyme-linked immunosorbent spot assay), to predict the risk of CMV disease in lung transplant recipients. Methods: We performed CMV immunity assays on 32 lung transplant recipients at risk of CMV disease as defined by serostatus (CMV-seropositive recipients, n = 26; or CMV-seronegative lung transplant recipient receiving a CMV-seropositive donor organ, n = 6). QFN-CMV and T-Track were performed on peripheral blood mononuclear cells, and episodes of CMV replication in both serum and bronchoalveolar lavage were found to be correlated to the CMV immune assays. The predictive ability of the assays was determined using Kaplan-Meier curves. Results: There was a degree of concordance between tests, with 44% of recipients positive for both tests and 28% negative for both tests; however, test results were discordant in 28% of cases. A negative result in either the QFN-CMV (P < 0.01) or T-Track (P < 0.05) assays was obtained in a significantly higher number of recipients who experienced CMV replication in the blood. Using these assays together gave higher predictability of CMV replication, with only 1 recipient experiencing CMV replication in the blood who obtained a positive test result for both assays. Neither assay was able to predict recipients who experienced CMV replication in the lung allograft. Conclusions: Our study demonstrates that CMV immunity assays can predict viremia; however, the lack of association with allograft infection suggests that CMV-specific T-cell immunity in the circulation is not associated with the control of CMV replication within the transplanted lung allograft.

Real-world experience of Quantiferon-CMV directed prophylaxis in lung transplant recipients.

BACKGROUND: The Quantiferon-Cytomegalovirus (QF-CMV) assay was introduced to predict CMV infection and inform prophylaxis duration in our lung transplant recipients (LTR) from 2012. The aims of this retrospective cohort study were to review our QF-CMV experience, understand factors associated with positive results and further explore its predictive utility. METHODS: LTR with QF-CMV testing performed at 5 months post-transplant were included. Patients receiving QF-directed prophylaxis (5 or 11 months) were compared to those receiving our prior standard of care (5 months). Outcomes were CMV infection >1,000 IU/mL in blood and/or bronchoalveolar lavage fluid. Factors associated with positive QF-CMV results were identified. Patients were compared based on serostatus, QF-CMV results and prophylaxis duration. RESULTS: Our cohort included 263 LTR (59 D+/R-, 204 R+). QF-directed prophylaxis was used in 195 of 263 (74%) and was associated with reduced CMV infection (84/195, 43% vs 41/68, 60%, p < .001). Patients receiving extended prophylaxis experienced less CMV if negative and/or indeterminate (43% vs 70%, p < .01) or positive (10% vs 51%, p < .01). Only 5 of 59 (8%) D+/R- patients were QF-CMV positive compared to 155 of 204 (76%) R+ patients (adjusted OR 0.03, 0.01-0.07, p < .001). After controlling for prophylaxis duration, only D+/R- serostatus remained independently associated with CMV infection (adjusted HR 4.90, 95% CI 2.68-9.00, p < .0001). CONCLUSIONS: QF-CMV results were strongly correlated with serostatus, with D+/R- patients unlikely to test positive while receiving prophylaxis. Extended prophylaxis was associated with delayed onset, reduced frequency and severity of CMV infection across all subgroups. After accounting for serostatus, the incremental predictive value of QF-CMV in this cohort was limited.