Faculty Bibliography

BACKGROUND:Respiratory virus infection (RVI) in pediatric solid organ transplant (SOT) recipients poses a significant risk; however, the epidemiology and effects of an RVI after pediatric SOT in the era of current molecular diagnostic assays are unclear. METHODS:A retrospective observational cohort of pediatric SOT recipients (January 2010 to June 2013) was assembled from 9 US pediatric transplant centers. Charts were reviewed for RVI events associated with hospitalization within 1 year after the transplant. An RVI diagnosis required respiratory symptoms and detection of a virus (ie, human rhinovirus/enterovirus, human metapneumovirus, influenza virus, parainfluenza virus, coronavirus, and/or respiratory syncytial virus). The incidence of RVI was calculated, and the association of baseline SOT factors with subsequent pulmonary complications and death was assessed. RESULTS:Of 1096 pediatric SOT recipients (448 liver, 289 kidney, 251 heart, 66 lung, 42 intestine/multivisceral), 159 (14.5%) developed RVI associated with hospitalization within 12 months after their transplant. RVI occurred at the highest rates in intestine/abdominal multivisceral (38%), thoracic (heart/lung) (18.6%), and liver (15.6%) transplant recipients and a lower rate in kidney (5.5%) transplant recipients. RVI was associated with younger median age at transplant (1.72 vs 7.89 years; P < .001) and among liver or kidney transplant recipients with the receipt of a deceased-donor graft compared to a living donor (P = .01). The all-cause and attributable case-fatality rates within 3 months of RVI onset were 4% and 0%, respectively. Multivariable logistic regression models revealed that age was independently associated with increased risk for a pulmonary complication (odds ratio, 1.24 [95% confidence interval, 1.02-1.51]) and that receipt of an intestine/multivisceral transplant was associated with increased risk of all-cause death (odds ratio, 24.54 [95% confidence interval, 1.69-327.96]). CONCLUSIONS:In this study, hospital-associated RVI was common in the first year after pediatric SOT and associated with younger age at transplant. All-cause death after RVI was rare, and no definitive attributable death occurred.

BACKGROUND:Multidrug-resistant (MDR) and extensively drug-resistant (XDR) gram-negative bacteria may be transmitted from organ donors to solid organ transplant recipients and are associated with poor outcomes post-transplant. METHODS:We reported the prevalence of MDR/XDR gram-negative respiratory colonization among 702 deceased organ donors in the New York City area from 2011-2014 and performed chart reviews for a subset of recipients to determine if donor respiratory culture results were predictive of subsequent recipient infection or used to guide post-transplant antimicrobial therapy. RESULTS:50 donors (7% of the cohort) had MDR or XDR gram-negative bacteria isolated from endotracheal aspirate or bronchoalveolar lavage culture. Organs from these 50 donors were transplanted into 120 recipients; chart review was performed for 89 of these recipients (38 kidney, 32 liver, 11 heart, 6 kidney/pancreas, 1 liver/kidney, 1 lung). None of the 89 recipients of organs from donors with MDR/XDR gram-negative respiratory colonization were reported to have a donor-derived infection post-transplant, and chart review for the 88 non-lung recipients indicated that peri-transplant antibiotics were not adjusted specifically for donor respiratory culture results. CONCLUSION/CONCLUSIONS:These results suggest that donor respiratory culture results are not predictive of post-transplant infection in non-lung recipients and are unlikely to impact post- transplant management. This article is protected by copyright. All rights reserved.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HHV-6A, HHV-6B, HHV-7, and HHV-8 in the pre- and post-transplant period. The majority of HHV-6 (A and B) and HHV-7 infections in transplant recipients are asymptomatic; symptomatic disease is reported infrequently across organs. Routine screening for HHV-6 and 7 DNAemia is not recommended in asymptomatic patients, nor is prophylaxis or preemptive therapy. Detection of viral nucleic acid by quantitative PCR in blood or CSF is the preferred method for diagnosis of HHV-6 and HHV-7 infection. The possibility of chromosomally integrated HHV-6 DNA should be considered in individuals with persistently high viral loads. Antiviral therapy should be initiated for HHV-6 encephalitis and should be considered for other manifestations of disease. HHV-8 causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease and is also associated with hemophagocytic syndrome and bone marrow failure. HHV-8 screening and monitoring may be indicated to prevent disease. Treatment of HHV-8 related disease centers on reduction of immunosuppression and conversion to sirolimus, while chemotherapy may be needed for unresponsive disease. The role of antiviral therapy for HHV-8 infection has not yet been defined.

Background/UNASSIGNED:Respiratory virus infections (RVIs) pose a threat to children undergoing hematopoietic stem cell transplantation (HSCT). In this era of sensitive molecular diagnostics, the incidence and outcome of HSCT recipients who are hospitalized with RVI (H-RVI) are not well described. Methods/UNASSIGNED:A retrospective observational cohort of pediatric HSCT recipients (between January 2010 and June 2013) was assembled from 9 US pediatric transplant centers. Their medical charts were reviewed for H-RVI events within 1 year after their transplant. An H-RVI diagnosis required respiratory signs or symptoms plus viral detection (human rhinovirus/enterovirus, human metapneumovirus, influenza, parainfluenza, coronaviruses, and/or respiratory syncytial virus). The incidence of H-RVI was calculated, and the association of baseline HSCT factors with subsequent pulmonary complications and death was assessed. Results/UNASSIGNED:Among 1560 HSCT recipients, 259 (16.6%) acquired at least 1 H-RVI within 1 year after their transplant. The median age of the patients with an H-RVI was lower than that of patients without an H-RVI (4.8 vs 7.1 years; P < .001). Among the patients with a first H-RVI, 48% required some respiratory support, and 14% suffered significant pulmonary sequelae. The all-cause and attributable case-fatality rates within 3 months of H-RVI onset were 11% and 5.4%, respectively. Multivariate logistic regression revealed that H-RVI onset within 60 days of HSCT, steroid use in the 7 days before H-RVI onset, and the need for respiratory support at H-RVI onset were associated with subsequent morbidity or death. Conclusion/UNASSIGNED:Results of this multicenter cohort study suggest that H-RVIs are relatively common in pediatric HSCT recipients and contribute to significant morbidity and death. These data should help inform interventional studies specific to each viral pathogen.

The prevention and management of cytomegalovirus (CMV) remain challenging in children who have undergone solid organ transplantation, despite the availability of effective antiviral medications and sensitive diagnostic assays. The primary objective of this invited commentary is to provide an updated and multidisciplinary approach to persistently challenging CMV cases that commonly occur in pediatric transplantation candidates and recipients, including cases for which published data are frequently lacking.

BACKGROUND: Multiple host defense mechanisms protect the female genital tract from pathogens, but the impact of sexual intercourse on defense is unknown. METHODS: As part of a hypothesis-generating study, 17 women provided cervicovaginal lavage (CVL) specimens at baseline (all had abstained from sexual intercourse, masturbation, and vaginal product use for 72 hours prior to screening), 2-6 hours and 10-14 hours after vaginal intercourse with a male condom, and 2-6 hours and 10-14 hours after vaginal intercourse without a male condom (5 visits total, including the baseline visit). Vaginal pH, concentrations of immune molecules, and antimicrobial activity at postcoital visits were compared to baseline values. RESULTS: Vaginal pH and the transforming growth factor beta1 level increased, but human beta-defensin 2 (HBD-2), HBD-3, and interleukin 8 levels decreased after unprotected sex. Median Escherichia coli inhibitory activity in CVL specimens decreased significantly from baseline at the visit 2-6 hours after unprotected sex (63% [range, -34% to 99%] vs 5% [range, -51% to 100%]; P = .02) and remained low at the visit 10-14 hours after unprotected sex (6% [range, -19% to 92%]; P = .02). Pooled human seminal plasma enhanced E. coli growth in vitro in a dose-dependent manner and, when added to CVL samples with high anti-E. coli activity, reversed the inhibition. CONCLUSIONS: Unprotected vaginal sex results in a reduction in endogenous anti-E. coli activity, which may reflect, in part, enhancement of bacterial growth by seminal plasma. This finding may contribute to the risk of E. coli vaginal colonization following sexual intercourse.

Greater inhibitory activity against Escherichia coli and levels of human beta defensin (HBD)-2 in genital tract secretions predicted HIV acquisition in women in the HPTN 035 trial. We investigated whether higher levels of E. coli inhibitory activity and antimicrobial peptides in cervicovaginal lavage (CVL) samples predicted HIV acquisition in women in the CAPRISA 002 Acute Infection Study. E. coli inhibitory activity and antimicrobial peptides were quantified in CVL from a subset of CAPRISA 002 participants who did not seroconvert (n=39) and from seroconverting women prior to infection (n=17) and during acute infection (n=11). Women who acquired HIV had significantly greater preinfection CVL E. coli inhibitory activity (p=0.01) and HBD-1 levels (p=0.02) compared to women who remained uninfected. Preinfection E. coli inhibitory activity remained significantly associated with seroconversion following adjustment for the presence of bacterial vaginosis (OR 1.45; 95% CI 1.07, 1.97). Partial least squares discriminant analysis confirmed that preinfection CVL E. coli inhibitory activity, together with higher CVL concentrations of HBD-1 and secretory leukocyte protease inhibitor, distinguished seroconverters from nonseroconverters with 67% calibration accuracy. CVL concentrations of human neutrophil peptides (HNP) 1-3 increased significantly with acute infection (p=0.001) and correlated with plasma viral set point (r=0.66, p=0.03). E. coli inhibitory activity in genital tract secretions could provide a biomarker of HIV risk. The correlation between HNP 1-3 and viral set point merits further investigation of the relationship between mucosal inflammation during early HIV infection and disease progression.

INTRODUCTION: Innate activity against Escherichia coli in female genital secretions may represent contributions from vaginal bacteria and host soluble immune mediators. We analyzed the relationship between E. coli inhibitory activity, soluble immune mediators, and vaginal bacteria in participants in MTN-004, a placebo-controlled trial of VivaGel((R)) , a candidate product for topical HIV pre-exposure prophylaxis. METHODS: Escherichia coli inhibitory activity was quantified by colony reduction assay. Endocervical concentrations of interleukin (IL)-1beta, IL-6, IL-12p40, macrophage inflammatory protein (MIP)-1alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), lactoferrin, and secretory leukocyte protease inhibitor (SLPI) were quantified to generate a cumulative mediator score. Vaginal bacteria were characterized by quantitative cultures. RESULTS: In the two placebo arms, higher soluble immune mediator score was associated with greater E. coli inhibitory activity (beta = 17.49, 95% CI [12.77, 22.21] and beta = 13.28, 95% CI [4.76, 21.80]). However, in the VivaGel arm, higher concentrations of E. coli (beta = -3.80, 95% CI [-6.36, -1.25]) and group B Streptococcus (beta = -3.91, 95% CI [-6.21, -1.60]) were associated with reduced E. coli inhibitory activity. CONCLUSIONS: Both host mediators and vaginal bacteria impact E. coli inhibition in genital secretions. The relative contributions of host mediators and bacteria varied between women who used VivaGel vs placebos.