Adult Stem Cell Transplant Recipients Research Articles

Serial frailty assessments following allogeneic stem cell transplant in older adults: A pilot study

IntroductionIncreasing numbers of older adults undergo allogeneic stem cell transplantation (SCT) as the only chance of meaningful survival for hematologic malignancies. However, toxicities in vulnerable patients may offset the benefits of SCT. Frailty and abnormal geriatric assessment (GA) prior to SCT have been associated with decreased overall survival in persons aged 60 and older. The purpose of this pilot study was to determine the prevalence of baseline GA deficits and frailty, the prevalence of frailty or death at three and six months after allogeneic SCT, and associations between baseline assessments and the presence of frailty or death post-SCT. MethodsWe enrolled 50 patients aged 60 years and older and completed a baseline GA including comorbidity, polypharmacy, nutrition, physical performance, functional status, social support, depression and anxiety, and cognition. Frailty was defined as three or more abnormalities of gait speed, grip strength, weight loss, physical activity, and exhaustion, and was assessed at baseline, three months, and six months after SCT. A composite outcome of frailty or death at three months and six months was analyzed. ResultsFrailty was present in 11/50 (22%) of patients at baseline. Ten patients did not complete three- month follow-up, and twelve patients did not complete six-month follow-up. Of those with follow-up data, 22 patients (55%) were frail or deceased three months after SCT, and 27 patients (71%) were frail or deceased six months after SCT. Frailty at baseline was not significantly associated with frailty or death at three or six months after SCT. However, the study's small enrollment limits conclusions on these associations. ConclusionGA deficits and frailty are prevalent in older adult SCT recipients at baseline and after transplant. Future studies should aim for larger enrollment in order to validate associations between these deficits and outcomes, especially survival, functional status, and quality of life following SCT.

2296. Development of a Sequencing-Based Assay for Detection of CMV Antiviral Resistance Mutations to Letermovir in UL56

BackgroundAntiviral resistance to human cytomegalovirus (CMV) is a growing concern for immunocompromised patients on prolonged antiviral regimens, and CMV remains the most clinically significant infection following allogeneic hematopoietic-cell transplantation. Letermovir targets subunit 2 of the viral terminase complex (UL56) and is approved for CMV prophylaxis in adult stem cell transplant recipients. Resistance to letermovir is conferred by point mutations in the UL56 gene, and with the potential clinical need for antiviral resistance testing, we have developed a UL56 sequencing assay covering 23 identified resistance mutations. Here we summarize the performance characteristics of the UL56 antiviral resistance assay.MethodsThis assay uses automated nucleic acid extraction followed by CMV UL56-specific polymerase chain reaction (PCR). PCR products are subjected to cycle sequencing and capillary electrophoresis, and the resulting sequences are analyzed for the The presence of known resistance mutations between codons 229 and 369 of the UL56 gene. The assay’s limit of detection (LOD), precision and accuracy were validated in accordance with accepted regulatory standards using multiple laboratory and clinical CMV strains.ResultsThe LOD was determined to be 99 IU/mL. Precision was demonstrated with multiple sample replicates over three days of testing, with 100% amino acid concordance within the region of interest (ROI). The assay also accurately identified 100% of amino acids within the ROI of 30 unique CMV-positive de-identified clinical samples. While some polymorphisms were detected, no mutations conferring resistance were identified in the clinical samples tested, which is in agreement with the literature indicating that naturally occurring polymorphisms in the UL56 gene have not been shown to confer resistance to letermovir.ConclusionThe CMV UL56 antiviral resistance assay was shown to be a rapid and sensitive means of detecting mutations conferring letermovir resistance. This expands current CMV antiviral resistance testing, which includes UL54 and UL97 sequencing, and provides physicians with the ability to monitor for the emergence of antiviral resistance mutations to all current FDA-approved anti-CMV drugs.Disclosures J. Grantham, Viracor Eurofins Clinical Diagnostics: Employee, Salary. J. Nutt, Viracor Eurofins Clinical Diagnostics: Employee, Salary. A. Tyler, Viracor Eurofins Clinical Diagnostics: Employee, Salary. E. Bixler, Viracor Eurofins Clinical Diagnostics: Employee, Salary. M. Altrich, Viracor Eurofins Clinical Diagnostics: Employee, Salary. S. Kleiboeker, Viracor Eurofins Clinical Diagnostics: Employee, Salary.

Vancomycin-resistant Enterococcal Bloodstream Infections in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancies: Impact of Daptomycin MICs of 3 to 4 mg/L

PurposeCase reports of treatment failure with standard-dose daptomycin (6 mg/kg) have recently surfaced in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) episodes with daptomycin MICs of 3 to 4 mg/L. The clinical implications of daptomycin MICs of 3 to 4 mg/L in VRE BSIs have not been elucidated. MethodsWe performed a single institutional retrospective analysis of adult stem cell transplant recipients and patients with hematologic malignancies diagnosed with VRE BSI from 2006 to 2014 and compared outcomes between those with daptomycin MICs of 3 to 4 mg/L those with 2 mg/L, as determined by Etest. FindingsForty-two daptomycin-treated VRE BSI episodes, all due to Enterococcus faecium were identified; 19 episodes with daptomycin MICs of 3 to 4 mg/L and 23 episodes with a daptomycin MIC of 2 mg/L. Patients in the higher daptomycin MIC group were more likely to be male, to be stem cell transplant recipients, and to have received high-dose daptomycin treatment (>6 mg/kg). In unadjusted analyses, microbiological failure in the daptomycin MICs 3 to 4 mg/L versus 2 mg/L groups (odds ratio = 1.79, 95% CI, 0.52–6.11; P = 0.35), the median duration of bacteremia (4 days in daptomycin MICs 3–4 mg/L vs 3 days in daptomycin MIC 2 mg/L; P = 0.18) and all-cause 30-day mortality (21% in daptomycin MICs 3–4 mg/L vs 35% in daptomycin MIC 2 mg/L group; P = 0.49) were not different. In adjusted analyses, the association between higher Pitt bacteremia scores and all-cause 30-day mortality was statistically significant (P = 0.0006), whereas the association between daptomycin MICs of 3 to 4 mg/L and all-cause 30-day mortality approached statistical significance (P = 0.06). ImplicationsDuration of bacteremia and microbiological failure rates did not differ by daptomycin MICs in VRE BSI episodes in our patients, composed of adult stem cell transplant recipients and patients with hematologic malignancies. There was a nonsignificant trend in multivariable analysis suggesting that all-cause 30-day mortality was lower in patients whose VRE bloodstream isolates were with daptomycin MICs of 3 to 4 mg/L.

Prospective assessment of white matter integrity in adult stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) is often used in the treatment of hematologic disorders. Although it can be curative, the pre-transplant conditioning regimen can be associated with neurotoxicity. In this prospective study, we examined white matter (WM) integrity with diffusion tensor imaging (DTI) and neuropsychological functioning before and one year after HSCT in twenty-two patients with hematologic disorders and ten healthy controls evaluated at similar intervals. Eighteen patients received conditioning treatment with high-dose (HD) chemotherapy, and four had full dose total body irradiation (fTBI) and HD chemotherapy prior to undergoing an allogeneic or autologous HSCT. The results showed a significant decrease in mean diffusivity (MD) and axial diffusivity (AD) in diffuse WM regions one year after HSCT (p-corrected <0.05) in the patient group compared to healthy controls. At baseline, patients treated with allogeneic HSCT had higher MD and AD in the left hemisphere WM than autologous HSCT patients (p-corrected <0.05). One year post-transplant, patients treated with allogeneic HSCT had lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the right hemisphere and left frontal WM compared to patients treated with autologous HSCT (p-corrected <0.05).There were modest but significant correlations between MD values and cognitive test scores, and these were greatest for timed tests and in projection tracts. Patients showed a trend toward a decline in working memory, and had lower cognitive test scores than healthy controls at the one-year assessment. The findings suggest a relatively diffuse pattern of alterations in WM integrity in adult survivors of HSCT.

Role of Primary Structure Variation in Structure and Function of Calcineurin

A. fumigatus is one of the leading causes of invasive fungal infections in solid organ transplant and adult stem cell transplant recipients. It is estimated that over 20% of Americans are infected with T. gondii. T. gondii is life threatening in immunocompromised patients. Here, we study the enzyme calcineurin that is critical for the virulence and pathogenicity of these organisms. CaN is activated when calcium‐loaded calmodulin (CaM) binds the regulatory domain (RD) of the A subunit. Upon binding to CaM, the RD of human calcineurin transitions from a disordered state to an ordered state, gaining alpha helical structure. Research done in our lab has determined that the C‐terminus of the RD forms a helix (distal helix) that is necessary for the normal function of human CaN. In A. fumigatus and T. gondii, the sequence for this helix is deleted. A. fumigatus and T. gondii CaN contain modular insertions and deletions in the RD. A Ser/Pro rich region (SPRR) found in the RD that is unique to A. fumigatus is critical for the function of CaN and survival. The phosphorylation of this SPRR has also been shown to be critical in the pathogenicity of the organism. Investigations into the protein sequence of CaN of T. gondii show a unique insertion in the same area as the SPRR in A. fumigatus, but the function of this insertion is unknown. Thus, we are probing into how structure affects function through evolutionary variations.

A prospective evaluation of changes in brain structure and cognitive functions in adult stem cell transplant recipients

Hematopoietic stem cell transplantation (HSCT) is an efficacious treatment for many hematologic malignancies. However, the conditioning regimen of high-dose (HD) chemotherapy with or without total body irradiation (TBI) can be associated with neurotoxicity. In this prospective study, we used quantitative neuroimaging techniques to examine regional gray matter and ventricular volumes, and standardized neuropsychological tests to assess cognitive function before and 1 year after HSCT in 28 patients with hematologic malignancies and in ten healthy controls evaluated at similar intervals. Nineteen patients received conditioning treatment with HD chemotherapy alone and nine had both TBI and HD chemotherapy. There was a significant reduction in gray matter volume in the middle frontal gyrus bilaterally and in the left caudate nucleus in the patient group (all patients combined) but not among healthy controls over the 1-year follow-up period. There was a significant increase in left lateral ventricle volume and in total ventricle volume in the patient group, relative to healthy controls. Similar brain structural changes were seen for patients treated with HD chemotherapy alone. The neuropsychological results showed that 21% of patients could be classified as impaired at baseline. The Reliable Change Index suggested no significantly different rates of cognitive decline between patients and healthy controls. The findings suggest that HSCT patients may be at an increased risk for developing regional brain volume loss, and that subgroups may experience cognitive dysfunction prior to and 1 year following the transplant.

Infection and Coinfection of Human Rhinovirus C in Stem Cell Transplant Recipients

In 54 adult stem cell transplant recipients, the presence and persistence of human rhinoviruses (including the novel lineage C) were evaluated by molecular detection and phylogenetic analysis, independently from respiratory symptoms. In the same group of patients, the presence of other coinfecting respiratory pathogens, including the novel enterovirus 109, was also evaluated.

Epidemiological, molecular and clinical features of Enterovirus 109 infection in children and in adult stem cell transplant recipients

BackgroundA novel human enterovirus (HEV) type within the species HEV-C, named EV109, was discovered from cases of respiratory illness in Nicaragua in September 2010. The aim of this study, was to retrospectively examine the presence and the role of EV109 in respiratory samples from two patients populations; infants below the age of 2 years, hospitalized for acute respiratory diseases (ARDs) and adult hematopoietic stem cell transplantation recipients.ResultsA total of 1149 nasopharingeal aspirates were collected and tested for the presence of EV109 by reverse transcription-PCR (RT-PCR). In positive samples, the presence of the most common respiratory viruses was also assayed and clinical symptoms were evaluated. Samples from 2 of the 974 infants tested positive for EV109 RNA (0.2%) and belonged to patients with lower ARDs; co-infection with other viral pathogens under study was observed in both cases. In transplant recipients, one out of the 175 samples analyzed, from a patients with upper respiratory simptoms tested positive for HEV 109 in the absence of co-infecting viruses. Sequence analysis of amplified EV109 genomic regions, showed only a few nucleotide differences when compared with the Nicaraguan strains.ConclusionsOverall these results indicate that HEV109 variants have circulated and differentiated in different lineages worldwide. Although more cases and larger studies are needed, HEV109 infection may be associated to ARDs both in infants and in hematopoietic stem cell transplantation recipients. If these preliminary observations will be confirmed, improved molecular methods with a wider panel of potential pathogens will be useful for monitoring these categories of patients.

High lethality of human adenovirus disease in adult allogeneic stem cell transplant recipients with high adenoviral blood load

Background Human adenoviruses (HAdV) can cause disseminated disease as a severe complication after haematopoietic stem cell transplantation (SCT) and may originate from the reactivation of latent infections. However, data about the clinical relevance of HAdV DNAaemia and disease in adults are scarce. Objectives To retrospectively analyse the outcome of adult allogeneic SCT recipients with high HAdV loads in peripheral blood. Study design Our diagnostic database was screened for allogeneic SCT recipients with peak HAdV DNAaemia above 1.0 × 10 4 copies/ml (tested by quantitative real-time PCR) and medical records were reviewed retrospectively. Results From 1674 adult allogeneic SCT recipients 539 (32.2%) received HAdV DNAaemia testing. In twenty-seven of these HAdV blood loads above 1.0 × 10 4 (range: 1.6 × 10 4–1.8 × 10 9) copies/ml were observed. Seven of these 27 succumbed to HAdV disease and their median peak HAdV DNAaemia was significantly higher than in patients without HAdV-associated death (1.0 × 10 8 vs. 3 × 10 5 copies/ml, p < 0.001). T-cell depletion was a risk factor for fatal HAdV disease. HAdV of species C predominated (66.7%) and were of high virulence (6 of 7 fatal cases). HAdV of species B were observed more frequently ( n = 6) in our study than reported for paediatrics, indicating a different pattern of HAdV reactivation in adults. Conclusions The presence of several HAdV-associated deaths in adult SCT recipients with high-level HAdV DNAaemia confirmed the clinical relevance of HAdV DNAaemia testing in adults. Quantitative HAdV DNAaemia testing is a promising tool to predict the outcome of HAdV disease.

Vaccines for prophylaxis of viral infections in patients with hematological malignancies

Viral infections cause significant morbidity and mortality in patients with hematological malignancies. It remains uncertain whether viral vaccinations in these patients are supported by good evidence. We aimed to determine the effectiveness and safety of viral vaccines in patients with hematological malignancies. We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL (June 2010), reference lists of relevant papers, abstracts from scientific meetings and contacted vaccine manufacturers. Randomized controlled trials (RCTs) evaluating viral vaccines in patients with hematological malignancies were included. Relative risk (RR) was used for binary data and mean difference (MD) for continuous data. Primary outcome was incidence of infection. Secondary outcomes were mortality, incidence of complications and severe viral infection, hospitalization, immune response and adverse effects. Fixed-effect model was used in meta-analyses. Eight RCTs were included, with 305 patients in the intervention groups and 288 in the control groups. They evaluated heat-inactivated varicella zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials) and inactivated poliovirus vaccine (IPV) (one trial). Seven trials had high and one trial had moderate risk of bias.VZV vaccine might reduce herpes zoster compared to no vaccine (RR 0.54, 95% CI 0.3 to 1.0, P=0.05), but not statistically significant. Vaccination also demonstrated efficacy in immune response but frequently caused local adverse effects. One trial reported severity score of zoster, which favored vaccination (MD 2.6, 95% CI 0.94 to 4.26, P=0.002).Two RCTs compared inactivated influenza vaccine with no vaccine and reported lower risk of lower respiratory infections (RR 0.39, 95% CI 0.19 to 0.78, P=0.008) and hospitalization (RR 0.17, 95% CI 0.09 to 0.31, P<0.00001) in vaccine recipients. However, vaccine recipients more frequently experienced irritability and local adverse effects. There was no significant difference in seroconversion between one and two doses of influenza vaccine (one trial), or between recombinant and standard influenza vaccine (one trial), or influenza vaccine given with or without re-induction chemotherapy (one trial).The IPV trial comparing vaccination starting at 6 versus 18 months after stem cell transplant (SCT) found no significant difference in seroconversion. Inactivated VZV vaccine might reduce zoster severity in adult SCT recipients. Inactivated influenza vaccine might reduce respiratory infections and hospitalization in adults with multiple myeloma or children with leukemia or lymphoma. However, the quality of evidence is low. Local adverse effects occur frequently. Further high-quality RCTs are needed.

Large pericardial effusion as a complication in adults undergoing SCT

Large pericardial effusion (LPE) leading to cardiac tamponade is a rare complication described in patients undergoing SCT. This complication is considered to be a manifestation of chronic GVHD; however its pathophysiology is poorly understood. Currently, there are no published data systematically describing the incidence, clinical characteristics and outcomes of LPEs in adult stem cell transplant recipients. We retrospectively evaluated 858 adult patients (512 autologous, 148 related and 198 unrelated donor) who underwent hematopoietic stem cell and BM transplants at our institution from 2005 to 2008 for the development of post transplant LPE. Seven patients (0.8%) were found to have LPEs and all these patients had undergone unrelated allografts. The median day of diagnosis post transplant was 229 (range 42-525). None of these patients had active manifestations of GVHD other than serositis at the time of LPE detection. Pericardial window (PW) was successfully placed in all patients who developed cardiac tamponade and most patients with LPE were effectively treated by increasing immunosuppression. We conclude that LPE is a rare late complication after allogeneic transplant in adults and in our study developed only after unrelated transplant. PW can be safely performed in these patients and LPEs can be successfully treated with intensification of systemic immunosupression.

A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation

AbstractAbstract 2313Immunologic reconstitution following stem cell transplantation (SCT) arises from thymic-independent peripheral expansion of memory T-cells transplanted with the stem cell graft, and thymic-dependent maturation of stem cell derived lymphoid progenitor cells. As a consequence of thymic involution, adult stem cell transplant recipients rely largely upon the thymic-independent pathway. This process is facilitated by a plentiful supply of mature T-cells contained within peripheral blood or bone marrow grafts. Umbilical cord blood (UCB) grafts contain predominantly naive T-cells thereby limiting the potential for thymic-independent immune recovery. Recent reports have documented slow immune recovery in adult UCB recipients, however it has yet to be described in the context of a comparable population of adult allogeneic matched sibling or unrelated donor SCT. Methods:Between 2007 and 2009, we characterized cellular immune reconstitution in a consecutive cohort of adult patients undergoing myeloablative SCT using either matched sibling (MSD), matched unrelated donor (MUD) peripheral blood stem cell (PBSC) or dual UCB donor grafts. Dual UCB transplant recipients were conditioned with TBI 1350cGy and fludarabine 160mg/m2 (Flu). PBSC recipients were conditioned with either TBI 1350cGy or IV busulfan 12.8mg/kg (Bu) and cyclophosphamide 120mg/kg, or Bu/Flu. PBSC grafts were allele-level matched at HLA-A, B, C and DRB1. UCB grafts were mismatched at no more than 2 class I or class II loci. Both cohorts received GvHD prophylaxis with Tacrolimus for at least 6 months. UCB recipients received mycophenolate mofetil 2g/day for at least 60 days instead of standard dose methotrexate GvHD prophylaxis for PBSC recipients. Quantification of the following lymphoid subsets were performed by flow cytometry on fresh peripheral blood prior to, and then at approximately 45, 100, 180, and 360 days following transplantation: NK and NKT cells, B-cells, plasmacytoid dendritic cells, CD3+, CD4+, CD8+, regulatory and na•ve T-cells. T-cell receptor excision circles (sjTREC) were quantified by real time PCR on DNA collected from an isolated fraction of CD3+ T-cells. Cumulative corticosteroid usage prior to day 100 (as determined by area under the curve) was determined as a method for comparing acute GvHD severity. The Kruskal-Wallis test with adjustments for multiple comparisons was used compare immune recovery values at 45, 100, 180 and 360 days post transplantation. The PearsonÕs Chi-square test was used to compare the CMV reactivation rate of UCB to MSD/MUD. Results:Forty-two recipients of allogeneic SCT (MSD-13, MUD-14, UCB-15) with successful donor engraftment and who survived a minimum of 6 months were evaluated. The MSD, MUD and UCB recipients had a median age of 41, 42 and 31 years, respectively (p = 0.13). There was no significant difference in corticosteroid administration before day 100 or chronic GvHD in the three cohorts (p=0.74). There were no differences in the kinetics of immune recovery between MSD and MUD recipients. At 45 days following transplantation, UCB recipients had significantly lower levels of CD4+ (figure), CD8+ and NKT-cells. By day 100, UCB recipients had similar numbers of CD4+ T-cells, but remained lower in the other major T-cell subsets. By day 180 however, all T-cell subsets except NKT cells (p=0.033) were similar to the MSD/MUD recipients. NK cell recovery was faster in the UCB recipients (figure). There was also no difference in B-cell recovery among the 3 cohorts. TREC levels were not significantly different in recipients of all graft types, but were uniformly low (figure). The slow recovery of T-cells in the UCB cohort corresponds with a higher Kaplan-Meier estimate of CMV reactivation compared to the MSD/MUD cohort (90% vs. 36%; p = 0.0078). Conclusion:Compared to HLA-identical MSD and MUD adult SCT recipients, quantitative lymphoid recovery in UCB transplant recipients is slower in the first two months, but these differences are erased by 4–6 months following transplantation. NK reconstitution is more rapid in UCB recipients. Reduction of early opportunistic infections affecting UCB transplant recipients may arise from effective techniques to boost early T-cell recovery. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

“Large Pericardial Effusions as a Manifestation of Graft Versus Host Disease: a Single Institution Retrospective Study”.

Abstract 4659 IntroductionLarge pericardial effusion (LPE) as a manifestation of polyserositis is a known complication of GVHD. Due to its rarity, the incidence and natural history of LPEs are lacking in adult stem cell transplant recipients and current evidence is based on published case reports. MethodsWe retrospectively evaluated the incidence post-transplant LPE development for all adult patients who underwent transplants at our institution from 2005 to 2008. ResultsDuring this period, 858 transplants were performed, 512 autologous and 346 allogeneic (148 related and 198 unrelated). No LPEs were documented in post-autologous transplant patients. One patient developed polyserositis with LPE after allogeneic transplant on imatinib therapy and was excluded from this analysis. Seven patients (2%) who received unrelated transplant developed LPEs a median 229 days (range 42-525 days) post-transplant (Table 1). Only two patients developed large LPEs less than 100 days post-transplant, however in both cases LPEs developed after the second transplant. Six patients (86%) developed biopsy proven GVHD prior to the detection of LPEs; among them 5 (83%) had skin and GI tract involvement and 1 (17%) had GVHD of the liver. Six patients (86%) had concomitant pleural effusions (PEs). No patients had active manifestations of GVHD besides polyserositis at the time of LPE detection. Six patients (86%) required pericardial window (PW) placement with a pericardial biopsy; none had evidence of a malignant or infectious process involving the pericardium. Four patients were alive a median of 172 days (range 20-274 days) post LPE detection and all 4 had PW placed. Out of 4 survived patients, 3 had steroids initiated or increased with a clinical improvement of polyserositis on subsequent follow up in 2 patients and 1 patient had persistent pleural effusions. One patient had a systemic relapse shortly after LPE detection. Three patients died, among them 2 had PW placed and died less than 100 days after LPE detection; the first patient died at day 93 from MRSA pneumonia and the second one died at day 7 from polymicrobial sepsis and multiorgan failure. Both these patients had undergone a second transplant when the LPE occurred. The third patient, who did not receive a PW, died of progressive bronchiolitis obliterans, 542 days after LPE detection, her polyserositis symptoms resolved while on cyclosporine therapy. ConclusionLPE is a rare complication after allogeneic transplant in adults and in our study developed only after unrelated transplant. PW can be safely performed in these patients and polyserositis can be successfully treated with systemic steroids, although patients might continue having polyserositis despite aggressive immunosupression. AbbreviationsMUD= matched unrelated donor, S=skin, L=liver, GI=gastrointestinal tract, Bu= busulfan, Flu= fludarabine, TBI= total body irradiation, CVB= cyclophosphamide, etoposide and BCNUTable 1#AgeDiag-nosisDonorHLA matchCyto-reductionGVHDPost-transplant day LPE detectedConco-mitant PEPeri-cardial windowPericardial biopsyImmunosuppression at the LPE detection136ALLMUD10/10VP16-TBIS,GI (not active)217YesYesInflammationTacrolimus241AMLMUD10/10Bu-FluS (not active)51NoYesInflammationTacrolimus358AMLMUD10/10Bu-FluS,GI,L (not active)290YesYesInflammationTacrolimus+methylprednisolone464MDSMUD10/10Bu-Flu-TBINot present42YesYesNormalTacrolimus541AMLMUD10/10Bu-FluS,GI (not active)525YesYesInflammationTacrolimus+rituximab+methylprednisolone647NHLMUD9/10Bu-Flu-TBIGI (not active)230YesYesInflammationTacrolimus747NHLMUD8/10CVBS,GI (not active)250YesNoNot performedCyclosporine Disclosures:Abidi:Merck Pharmaceuticals: Research Funding. Lum:Transtarget Corporation: Founder.

Caspofungin as Primary Antifungal Prophylaxis in Stem Cell Transplant Recipients

To assess the effectiveness and tolerability of caspofungin as primary prophylaxis against invasive fungal infections in stem cell transplant recipients who are poor candidates for triazole or lipid amphotericin B prophylaxis due to renal or hepatic dysfunction, and to determine whether any patient characteristics are independently associated with an increased risk of breakthrough invasive fungal infection during caspofungin prophylaxis. Retrospective medical record review. Tertiary care comprehensive cancer center. One hundred twenty-three adult stem cell transplant recipients who received caspofungin 35-50 mg/day for up to 100 days after transplantation as primary antifungal prophylaxis between January 1, 2002, and June 30, 2005. Data were collected on host and transplant characteristics such as transplant type, neutropenia, graft-versus-host disease (GVHD), and corticosteroid use, as well as evidence of breakthrough invasive fungal infections. Of the 123 patients, 117 (95.1%) were allogeneic recipients, and the median time to engraftment was 12 days (range 6-26 days). Fifty (40.7%) of the patients developed GVHD of grade 2 or greater and received corticosteroids for more than 21 days. Median duration of caspofungin prophylaxis was 73 days (range 10-100 days). Nine patients (7.3%) developed breakthrough invasive fungal infections (two cases of mixed Aspergillus species and one each of Aspergillus terreus, Rhizopus, Exserohilum, an unspecified mold, Cryptococcus, Candida glabrata, and Candida tropicalis). Median time to invasive fungal infection development was 65 days (range 12-88 days). Only one case occurred during the neutropenic period before engraftment. Multivariate analysis showed that Pseudomonas coinfection (p=0.04) and infliximab therapy (p=0.02) were associated with breakthrough invasive fungal infections in patients receiving caspofungin. By day 100, there were five (4.1%) deaths, two of which were directly attributable to invasive fungal infections. No caspofungin-related adverse events were reported. Caspofungin seems to be an effective and well-tolerated option for primary antifungal prophylaxis in the highly immunosuppressed stem cell transplant patient population.

A randomized comparison of empiric or pre-emptive antibiotic therapy after hematopoietic stem cell transplantation

We performed a randomized comparison of pre-emptive and empiric antibiotic therapy for adult patients undergoing allogeneic or autologous stem cell transplantation. One hundred and fifty-three patients were randomized to receive cefepime either pre-emptively on the day that neutropenia (ANC<1.0 x 10(9) cells/l) developed irrespective of the presence of fever, or at onset of fever and neutropenia (empiric). Although there was no difference between the two arms in the proportion of patients developing fever or in the median number of days of fever, the time to onset of fever was a mean of 1 day longer in each patient on the pre-emptive arm (log rank P<0.001). The number of patients with bloodstream infections was significantly reduced in those receiving pre-emptive therapy (16/75) compared to the empiric arm (31/76) (P<0.01) but this did not translate into an appreciable clinical benefit as measured by days of hospitalization, time to engraftment, use of additional antimicrobial agents or mortality at 30 days. This study does not support the use of pre-emptive intravenous antibiotic therapy in adult stem cell transplant recipients.

Treatment of Adenovirus Disease in Stem Cell Transplant Recipients with Cidofovir

Invasive adenovirus (AdV) disease is fatal in >50% of allogeneic hematopoietic stem cell transplant (SCT) recipients. Treatment with cidofovir may improve outcomes based on in vitro susceptibility data and case reports. Six consecutive cases of invasive AdV disease treated with cidofovir were reviewed among 84 allogeneic adult SCT recipients (incidence, 7.1%). Cidofovir was administered intravenously at 5 mg/kg per dose (1-7 doses). All patients received intravenous immune globulin. Blood AdV DNA levels (viral loads, VLs) were monitored with a real-time quantitative polymerase chain reaction assay. Published reports of cidofovir treatment of AdV disease in SCT recipients were critically reviewed. The primary manifestations of AdV disease were hepatitis (n = 3), colitis (n = 2), and nephritis (n = 1). All patients had detectable AdV VLs, with peak values from 5 × 10 5 to 2 × 10 8 copies/mL. All patients received CD34 + selected grafts (n = 3) and/or had graft-versus-host disease (n = 4) and had CD4 counts <100 cells/mm 3. Only 1 of 5 patients (20%) who received ≥2 doses of cidofovir died with active AdV disease. Four patients exhibited improvement within days of treatment with cidofovir as documented by clinical criteria and declines in AdV VLs (without a change in immunosuppression). In contrast, 1 patient treated late after onset of AdV disease died after 1 dose of cidofovir. In our review of 70 published cases treated with ≥2 doses of cidofovir, 13 (19%) died from AdV disease. In conclusion, early treatment of AdV disease with cidofovir inhibits viral replication in vivo and reduces mortality in allogeneic SCT recipients compared with historical data.

Parainfluenza Virus Type 3 Post Stem Cell Transplant: High Prevalence but Low Mortality.

Parainfluenza virus type 3 (PIV 3) is a well recognised cause of respiratory illness after stem cell transplant (SCT) with an estimated incidence of 2–7%.(Wendt et al. N Engl J Med 1992; 326: 921–926, Nichols et al. Blood 2001; 98: 573–578). Persistently high mortality rates have been documented in this population. The largest series to date reported 75% mortality from PIV 3 lower respiratory tract infection.(Nichols et al). Treatment options are limited. There are anecdotal reports of successful use of ribavirin treatment but no randomised controlled trials have been undertaken.We undertook a retrospective review of 23 cases of PIV 3 occurring in adult SCT recipients over a 12 month period. A total of 145 patients had received a SCT in the same time period and 20 developed PIV3 infection (13.8%). The frequency of infection was 36.1% (13 of 36) in matched unrelated donor SCT recipients, 23.8% (5 of 21) in sibling allogenic SCT recipients and only 2.3% (2of 88) in autologous transplant recipients. Fourteen patients had received Campath 1-H as part of their conditioning regimen. The remaining three PIV 3 cases had a transplant date prior to the 12 month period. The median time from transplant to PIV 3 diagnosis was 54 days (range −7 to 2037 days). Only 6 cases were inpatients at diagnosis. Seventeen cases were outpatient or community acquired despite standard infection control procedures. Cases were identified by nasopharyngeal aspirate taken at the first sign of coryzal symptoms. Immunofluorescence (IF) identified PIV 3 in 13 patients and the virus was cultured in the remaining 10 cases. Eleven patients developed only upper respiratory tract symptoms and all survived. Lower respiratory tract symptoms and signs developed in 12 patients, of which 8 had a new infiltrate on chest X-ray. Four patients required invasive ventilation and one required non-invasive ventilation. Overall mortality at 30 days from PIV3 diagnosis was 4% (1 of 23). Three patients died in total but PIV 3 was not believed to be the primary cause of death in any of these patients. Autopsy confirmed post transplant lymphoproliferative disorder in one patient. The second case had septicaemia from a multiresistant coliform. Bronchoscopy in the remaining patient revealed invasive aspergillosis but IF and culture were negative for PIV 3. Early ribavirin treatment was administered in 8 patients. The primary indication for ribavirin treatment was lower respiratory tract infection. Six cases received aerosolised treatment, one intravenous and one patient received both aerosolised and IV therapy. Only one patient who received ribavirin treatment died. These results suggest a higher prevalence of PIV 3 but lower mortality than previously documented particularly in allogenic transplant recipients. We propose that the high prevalence reflects our unit policy of active surveillance for respiratory viruses and the difficulty in preventing transmission of PIV 3 especially in the outpatient setting. Ribavirin treatment may improve outcome in patients with lower respiratory tract infection but is not required in all patients with PIV 3 infection.

Frequent Detection of Respiratory Viruses in Adult Recipients of Stem Cell Transplants with the Use of Real-Time Polymerase Chain Reaction, Compared with Viral Culture

Background. Respiratory virus infections have been recognized as important causes of severe pneumonia in patients who have undergone stem cell transplantation (SCT). Reported incidences of respiratory virus infection in adult SCT recipients vary in the literature from 3.5% to 36% when determined by viral culture. However, a more sensitive method to assess the presence of respiratory viruses in the lower airways may be important for delineation of the true incidence of respiratory virus—associated pneumonia and may be essential for guidance on implementation of antiviral therapy and prevention or limitation of nosocomial spread of infection with respiratory viruses. Methods. To determine the incidence and severity of respiratory tract illness (RTI) and to assess the diagnostic value of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) versus viral culture, 72 SCT recipients were monitored during a 6-month period. Results. A respiratory virus was detected in 21% of episodes of RTI by viral culture and in 63% of RTI episodes by real-time RT-PCR (P < .0001). In lower respiratory tract illness, real-time RT-PCR was much more sensitive than viral culture for detection of respiratory virus (73% vs. 9%; P = .008). The mortality rate for patients with respiratory virus—associated lower respiratory tract illness (25%) was similar to rates reported elsewhere. Respiratory viruses (predominantly rhinovirus) were detected by real-time RT-PCR in 9% of samples obtained from symptom-free SCT recipients at predetermined times by real-time RT-PCR and by viral culture in 1% (P < .0001), indicating that asymptomatic shedding of respiratory viruses also occurs. Conclusion. We conclude that, although asymptomatic shedding of respiratory virus occurs, respiratory viruses are frequent causes of RTI in SCT recipients.

Alveolar macrophage activity and the pulmonary complications of haematopoietic stem cell transplantation

BACKGROUNDThe success of haematopoietic (bone marrow or peripheral blood) stem cell transplantation (SCT) is compromised by pulmonary complications. We hypothesised that a proinflammatory alveolar microenvironment, reflected in alveolar macrophage (AM)...

Non-Tunneled Central Venous Catheters in Adult Stem Cell Transplantation Recipients: An Effective Option

Stem cell transplantation (SCT) recipients require central venous catheter (CVC) insertion for the administration of chemotherapy, antibiotics and total parenteral nutrition. Traditionally, tunneled CVC have been considered as the golden standard although they require surgery for both insertion and removal. We prospectively evaluated the use of a non-tunneled CVC in 182 consecutive patients who had undergone allogenic or autologous SCT. The median duration of CVC was 4 weeks (range 1-24) with a significant difference between allogenic (8 weeks, range 2-24) and autologous SCT (4 weeks, range 1-24) (p<0.0001). The life expectancy of the CVC was significantly influenced by spontaneous removal, which occurred in 26 patients (13.8%). There was a significant increase of this complication in allogenic SCT (p=0.039). The overall incidence of sepsis was 24.5%, although catheter-related sepsis was microbiologically documented by positive culture of the tip only in 17 cases (9%). Non-tunneled CVC in adult SCT recipients allowed (a) bedside insertion and removal, (b) guidewire replacement for diagnostic or therapeutic purposes (dialysis or pheresis procedures) thus reducing the need for repeated venipunctures. (The Journal of Vascular Access 2001; 2: 168-174).