Diana F. Florescu

Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit.

Introduction:Cytomegalovirus is the most common viral opportunistic infection in immunocompromised patients. However, recent studies have demonstrated active cytomegalovirus infection in nonimmunosuppressed intensive care unit patients. Objective:To define the frequency and mortality rate associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Methods:A systematic review up to October 2008 was performed. Pooled results were analyzed by fixed- and random-effects models. Cochran Q and I2 were performed for heterogeneity. Results:Thirteen studies (n = 1258) were selected. The overall rate of active cytomegalovirus infection was 17% (95% confidence interval [CI], 11% to 24%; p < .0001; I2 = 86%). When the patients were screened for ≥5 intensive care unit days, the overall rate of infection increased to 21% (95% CI, 15% to 29%; p < .001). The infection rate for studies that used cytomegalovirus DNA/antigen for diagnosis was 20% (95% CI, 13% to 31%; p < .0001) and for studies that used culture was 12% (95% CI, 6% to 22%; p < .0001). The cytomegalovirus rate for patients with unknown serology was 7% (95% CI, 3% to 14%; p < .0001), whereas the rate for patients with positive serology was 31% (95% CI, 22% to 42%; p < .0001). The rate of infection was higher in patients with severe sepsis: 32% (95% CI, 22% to 45%; p < .0001). And in patients with high disease severity: 32% (95% CI, 23% to 42%; p < .0001). The overall mortality rate associated with active cytomegalovirus infection was 1.93 times (95% CI, 1.29 to 2.88; p = .001) as high as that without cytomegalovirus infection. Conclusions:Active cytomegalovirus infection occurs frequently in nonimmunosuppressed patients in intensive care, especially in those with positive cytomegalovirus serology, intensive care unit stay ≥5 days, severe sepsis, and high disease severity, in whom the rate of cytomegalovirus infection is up to 36%. Mortality rate is significantly doubled with cytomegalovirus, but a cause-effect relationship cannot be established yet. A large prospective cohort study on the patient population identified by our findings is needed to define who is at the highest risk for developing active cytomegalovirus infection and to determine its effects on mortality.

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

What Is the Efficacy and Safety of Colistin for the Treatment of Ventilator-Associated Pneumonia? A Systematic Review and Meta-Regression

BACKGROUND Experience with intravenous and aerosolized forms of colistin for the treatment of ventilator-associated pneumonia (VAP) in patients without cystic fibrosis is limited. We aimed to assess the safety and efficacy of colistin for the treatment of VAP. METHODS We searched MEDLINE and Cochrane Database of Systematic Reviews for studies comparing colistin vs other antibiotics for treatment of VAP in patients without cystic fibrosis. QUOROM guidelines were followed, the I(2) method was used for heterogeneity, and a random-effects model for odds ratio (OR) estimates. RESULTS Six controlled studies met the inclusion criteria. Clinical response did not differ significantly between colistin and control groups (OR, 1.14; 95% confidence interval [CI], .74-1.77; P = .56; I(2) = 0%). The efficacy of colistin was independent of study design (prospective OR, 0.89 [95% CI, .48-1.66; P = .71; I(2) = 0%]; retrospective OR, 1.45 [95% CI, .79-2.68; P = .23; I(2) = 0%]); randomized trials OR, 0.86 [95% CI, .43-1.74; P = .68; I(2) = 0%]). There was no indication of a significant change in clinical response after controlling for concomitant antibiotic treatment (intercept, 0.121; slope, 0.0315; P = .95). Treatment with colistin vs controls did not affect hospital mortality (OR, 0.92; 95% CI, .50-1.67; P = .78; I(2) = 34.59%) or nephrotoxicity (OR, 1.14; 95% CI, .59-2.20; P = .69; I(2) = 0%). Fourteen single-arm studies have been analyzed, and the results were in concordance with the findings of the controlled studies. CONCLUSIONS Our results suggest that colistin may be as safe and as efficacious as standard antibiotics for the treatment of VAP.

What is the impact of hypogammaglobulinemia on the rate of infections and survival in solid organ transplantation? A meta-analysis.

Hypogammaglobulinemia has been described after solid organ transplantation and has been associated with increased risk of infections. The aim of the study was to evaluate the rate of severe hypogammaglobulinemia and its relationship with the risk of infections during the first year posttransplantation. Eighteen studies (1756 patients) that evaluated hypogammaglobulinemia and posttransplant infections were included. The data were pooled using the DerSimonian and Laird random‐effects model. Q statistic method was used to assess statistical heterogeneity. Within the first year posttransplantation, the rate of hypogammaglobulinemia (IgG < 700 mg/dL) was 45% (95% CI: 0.34–0.55; Q = 330.1, p < 0.0001), the rate of mild hypogammaglobulinemia (IgG = 400–700 mg/dL) was 39% (95% CI: 0.22–0.56; Q = 210.09, p < 0.0001) and the rate of severe hypogammaglobulinemia (IgG < 400 mg/dL) was 15% (95% CI: 0.08–0.22; Q = 50.15, p < 0.0001). The rate of hypogammaglobulinemia by allograft type: heart 49% (21%–78%; Q = 131.16, p < 0.0001); kidney 40% (30%–49%; Q = 24.55, p = 0.0002); liver 16% (0.001%–35%; Q = 14.31, p = 0.0002) and lung 63% (53%–74%; Q = 6.85, p = 0.08). The odds of respiratory infection (OR = 4.83; 95% CI: 1.66–14.05; p = 0.004; I2 = 0%), CMV (OR = 2.40; 95% CI: 1.16–4.96; p = 0.02; I2 = 26.66%), Aspergillus (OR = 8.19; 95% CI: 2.38–28.21; p = 0.0009; I2 = 17.02%) and other fungal infections (OR = 3.69; 95% CI: 1.11–12.33; p = 0.03; I2 = 0%) for patients with IgG <400 mg/dL were higher than the odds for patients with IgG >400 mg/dL. The odds for 1‐year all‐cause mortality for severe hypogammaglobulinemia group was 21.91 times higher than those for IgG >400 mg/dL group (95% CI: 2.49–192.55; p = 0.005; I2 = 0%). Severe hypogammaglobulinemia during the first year posttransplantation significantly increased the risk of CMV, fungal and respiratory infections, and was associated with higher 1‐year all‐cause mortality.

Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses.

CMX001 (hexadecyloxypropyl-cidofovir, Brincidofovir) is a broad spectrum, lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate. The lipid conjugation results in oral bioavailability, higher intracellular concentrations of active drug, lower plasma concentrations of cidofovir and increased antiviral potency against dsDNA viruses.

Effects of prolonged use of azithromycin in patients with cystic fibrosis: A meta-analysis

Azithromycin has been studied as potential therapeutic anti-inflammatory agent for cystic fibrosis (CF) patients. Azithromycin (AZM) has been used as an immunomodulating agent, based on few small studies. Considering the cost and potential side effects of long-term azithromycin therapy, it is important to identify the group of patients that would benefit the most. Weighted mean difference was used for pulmonary function tests, and risk ratios for all other variables. The random-effects model was applied for all reports. Combining four studies (N=368), azithromycin showed increase in FEV(1) (3.53%, 95% CI 0.00, 7.07, p=0.05; I(2)=38%) and FVC (4.24%, 95% CI 2.02, 6.45, p=0.0002; I(2)=0%). When trials were analyzed by baseline Pseudomonas sputum colonization, the heterogeneity decreased (I(2)=0%), FEV(1) significantly increased to 4.66% (95% CI 1.18, 8.15, p=0.009), and FVC increased to 4.64% (95% CI 2.11, 7.17, p=0.0003). The GI side effects were 72% higher with azithromycin use (RR 1.72, 95% CI 1.33, 2.21, p=0.00003), the main side effects being nausea (RR 2.04, 95% CI 1.19, 3.45, p=0.009), and diarrhea (RR 2.12, 95% CI 1.10, 4.08, p=0.02). Azithromycin improves lung function of CF patients, especially in the subgroup colonized with Pseudomonas. However, nausea and diarrhea are significantly more frequent with azythromycin.

Two cases of Norwalk virus enteritis following small bowel transplantation treated with oral human serum immunoglobulin

Abstract:  Protracted diarrhea is a challenging problem after small bowel transplantation. We report two patients who developed Norwalk virus enteritis after small bowel transplantation. Both received oral HSIG with resolution of diarrhea within 48 h.

Is there a role for oral human immunoglobulin in the treatment for norovirus enteritis in immunocompromised patients

Florescu DF, Hermsen ED, Kwon JY, Gumeel D, Grant WJ, Mercer DF, Kalil AC. Is there a role for oral human immunoglobulin in the treatment for norovirus enteritis in immunocompromised patients? Pediatr Transplantation 2011: 15: 718–721.

Adenovirus infections in pediatric small bowel transplant recipients.

Background. Adenovirus is commonly isolated from pediatric small bowel transplant recipients, but its clinical consequences remain poorly understood. Methods. The medical records of pediatric small bowel transplant recipients transplanted between January 2003 and December 2007 were reviewed. Thymoglobulin and basiliximab induction and tacrolimus-based immunosuppression were the standard of care. Logistic regression analysis was performed to determine risk factors for infection, descriptive analysis to determine adenovirus incidence, and Kaplan-Meier curve analysis to determine the timing of events after transplantation. Results. Ninety-eight patients were included; 38 were positive for adenovirus (incidence 23.5%), 23 for viral shedding, 23 for infections. Nine infections developed in the first month after transplantation and 8 during the following 5 months. The small bowel was involved in 19 cases. Younger age at transplantation was a risk factor for adenovirus infection (odds ratio=0.81, 95% confidence interval, 0.663–0.994, P=0.04). Treatment of rejection did not increase the risk of adenovirus infection. Cytomegalovirus D+/R− sero-status was a protective factor (odds ratio=0.26, 95% confidence interval, 0.06–1.089, P=0.04). Conclusions. Adenovirus infections affected 24% of recipients and developed mostly during the first 6 months after transplantation. Small bowel is the most frequently involved site. Younger age at transplantation is a risk factor for adenovirus infection; whereas cytomegalovirus D+/R− sero-status seems to be protective.

Adenovirus: Current Epidemiology and Emerging Approaches to Prevention and Treatment

Infections caused by adenoviruses are associated with significant morbidity and mortality in both hematopoietic stem cell and solid organ transplant recipients. The risk seems to be highest in allogeneic hematopoietic stem cell transplant recipients as well as heart, lung and small-bowel transplant recipients. Management of these infections may be difficult and includes reduction of immunosuppression whenever possible combined sometimes with antiviral therapy (mainly cidofovir). The currently available antiviral therapy is limited by the need for intravenous administration, potentially significant renal and hematologic toxicities. New emerging therapies such as brincidofovir and transfusion of adenovirus-specific T-lymphocytes may increase the available armamentarium for these potentially life-threatening infections.