Infections In Hematopoietic Stem Cell Transplantation Recipients Research Articles

Parasitic infections in hematopoietic stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) is a vital treatment for various hematological disorders. However, HSCT recipients face increased risks of infectious complications due to immunosuppression. Parasitic infections are a significant concern in this vulnerable population and can lead to substantial morbidity and mortality. This review examines parasitic infections in HSCT recipients, focusing on major infections affecting different organ systems, including intestinal parasites (Giardia spp., Entamoeba histolytica, and Cryptosporidium spp.), hematologic parasites (Plasmodium spp. and Babesia spp.), and tissue/visceral parasites (Toxoplasma gondii, Leishmania spp., and Trypanosoma cruzi). A systematic search of relevant literature was conducted and included studies up to August 2023. Databases included PubMed, Google Scholar, were queried using specific keywords related to parasitic infections in HSCT patients. The epidemiology, risk factors, clinical presentation, diagnostic methods, and treatment approaches for each infection were evaluated. Knowing the epidemiology, risk factors, and clinical presentationsare crucial for timely intervention and successful management. By emphasizing early detection, effective therapies, and the unique challenges posed by each of these infections, this review highlights the importance of tailored strategies for HSCT recipients. Future research can further refine management protocols to enhance care and outcomes for these patients.

Meta-Analysis of Diagnostic Performance of Next Generation Sequencing of Plasma Microbial Cell-Free DNA for Infections in Hematopoietic Stem Cell Transplant Patients

Introduction Hematopoietic stem cell transplant (HSCT) recipients experience periods of profound deficiency in both innate and adaptive immunity putting them at risk for a wide spectrum of infections, including organisms which are not normally pathogenic in immunocompetent hosts. Next generation sequencing (NGS) of plasma microbial cell-free DNA (mcfDNA) allows non-invasive untargeted diagnosis of human pathogens, making this modality appealing for this patient population (1). Here we perform a meta-analysis to evaluate the diagnostic value of NGS of plasma mcfDNA for infections in HSCT recipients. Methods We searched for relevant articles in BASE, PubMed, and ClinicalTrials.gov from inception to May 2022. Studies were eligible for inclusion if they assessed the diagnostic performance of NGS of plasma mcfDNA, included HSCT recipients with individual level data, and provided sufficient data to construct a two-by-two table, and were excluded if they were case reports or studies which only focused on the diagnosis of only one set of microorganisms. Two clinical adjudicators independently assigned the plasma mcfDNA test result as true positive, true negative, false positive, or false negative. The mcfDNA results were analyzed as a whole rather than by each individual organism if there was more than one organism reported. These data were then synthesized using random effect models and statistical analysis provided by the metadta module within the STATA statistical software package. Results A total of 6 studies were included for the analysis, which included a total of 71 patients. The pooled sensitivity was 0.925 (97.5% CI 0.50-0.99) and the pooled specificity was 0.74 (0.47-0.90). The positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 3.59 (1.42-9.09), 0.10 (0.01-1.10), and 35.6 (1.9-677.1). Discussion NGS of plasma mcfDNA was effective in diagnosing infections in HSCT recipients. The high pooled diagnostic odds ratio found in this study suggests that NGS of plasma mcfDNA may have a unique role in this specific patient population, especially when the pre-test probability is high. The diagnostic accuracy of the test varies depending on host factors, preceding antimicrobial treatment, infection site, and the organism being evaluated. With a non-targeted test, it is possible that organisms are detected that may not be clinically significant, which would affect the test specificity, especially in populations with disrupted mucosal barriers, and therefore test results need to be carefully interpreted. The negative likelihood ratio of 0.10 suggests that there may be a role for negative tests as well, although this will need to be further explored. Overall, NGS plasma mcfDNA is a promising test for the diagnosis of infections in HSCT recipients.

Epidemiology, Drug Resistance, and Risk Factors for Mortality Among Hematopoietic Stem Cell Transplantation Recipients with Hospital-Acquired Klebsiella pneumoniae Infections: A Single-Center Retrospective Study from China.

ObjectiveInfection is the most common complication and cause of death after hematopoietic stem cell transplantation (HSCT). Our study aims to investigate the clinical characteristics and risk factors for death of Klebsiella pneumoniae infections in HSCT recipients, so as to provide evidence for guiding antibiotic use and improving prognosis in the future.MethodsThe epidemiology, clinical manifestations and drug resistance rate with K. pneumoniae infections among HSCT recipients between January 1, 2012 and September 30, 2021 were retrospectively reviewed. Logistic regression model and Cox regression model were respectively used to determine the risk factors for carbapenem-resistant Klebsiella pneumoniae (CRKP) acquisition and death.ResultsFifty-nine HSCT recipients suffered from K. pneumoniae infections, with a mortality rate of 42.4%. The most common site was lung, followed by blood stream. The resistance rate of K. pneumoniae to various clinically common antibiotics was high, especially CRKP, which was only sensitive to amikacin and tigecycline. Independent risk factor for CPKP acquisition was a previous infection within 3 months before transplantation (OR=10.981, 95% CI 1.474–81.809, P=0.019). Independent risk factors for mortality included interval from diagnosis to transplantation > 180 days (HR=3.963, 95% CI 1.25–12.561, P=0.019), engraftment period > 20 days (HR=8.015, 95% CI 2.355–27.279, P=0.001), non-use of anti-CMV immunoglobulin/rituximab after transplantation (HR=10.720, 95% CI 2.390–48.089, P=0.002), and PCT > 5 μg/L (HR=5.906, 95% CI 1.623–21.500, P=0.007).ConclusionK. pneumoniae infection has become a serious threat for HSCT recipients, which reminds us to pay enough attention and actively seek new strategies.

Generation of Fungus-Specific T Lymphocytes for Use in HSCT Patients with Invasive Fungal Disease

Invasive fungal disease (IFD) is a major cause of morbidity and mortality in patients treated for haematological malignancies. The major determinants of outcome are the degree of the patient's immune incompetence, the fungal species and the presence of drug resistance in the infecting organism. As uncommon and drug resistant strains increase in frequency, effective alternative treatment strategies are needed to improve the dismal outcomes for IFD occurring after hematopoietic stem cell transplant (HSCT). Recent data provide strong evidence that a therapeutic benefit is seen using adoptive transfer of cryopreserved, partially human leukocyte antigen (HLA) matched 3rd party T-cells for post-transplant viral infections in HSCT recipients. We propose that a similar approach may be effective in IFDs.In the present study, we developed a method for rapid manufacture of large numbers of broadly reactive and highly specific antifungal T-cells starting with a stem cell product obtained from healthy donors as part of normal allogeneic transplant procedure. Water-soluble lysates of germinated conidia of Aspergillus and Candida species were used to stimulate 60.5 ± 21.7 x 106 mononuclear cells from the hematopoietic precursor cell (HPC) product. Reactive T-cells were selected using activation marker and magnetic bead isolation and expanded in culture with cytokines. After elution from the magnet, the enriched population measured 82.5±13.3 x103 cells of which 82.3±6.9% were CD4+ (n=6). All cultures were maintained for a total of 11 to 12 days, leading to 126.8±11.9x106 fungus-specific T cells, corresponding to approximately 1000 fold expansion within 12 days of culture initiation. At the end of culture greater than 97.3±0.9% of cells were CD3+, of which 91.7±1.2% were CD4+ cells and 3.6±0.7% were CD8+ cells.Responses against fungus were measured using cytokine flow cytometry after restimulation by specific fungal lysates. 59.4±0.9% of CD4+ cells were reactive against fungus-primed monocyte-derived dendritic cells (MoDCs). Production of the pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-17 and interferon (IFN)-γ following challenge showed that the expanded T-cell populations had broad reactivity against Aspergillus fumigatus / flavus / terreus, Candida albicans / krusei, Fusarium oxysporum / solani and Leptosporum (Scedosporium) prolificans (Figure 1).We previously demonstrated that antifungal reactivity is mediated through HLA-DR and can occur through a single matching HLA-DR molecule. We calculated that in our HSCT population, donors with the seven highest frequency HLA-DR molecules (DRB1 1:01, 3:01, 4:01, 7:01, 11:01, 13:01 or 15:01) could be used to generate a bank of cryopreserved fungus-specific T lymphocytes to treat IFDs in HSCT recipients. Using a bank of this size, approximately 85% of HSCT recipients would have a fungus-specific T cell product in the bank matching at least 1 HLA-DR molecule. Increasing the bank to add donors with four additional HLA-DR types (DRB1 4:04, 11:04, 13:02 and 15:02) would increase the percentage of recipients with a banked product matching at least 1 of HLA-DR molecules to almost 95%.In conclusion, we have identified a GMP compliant method to rapidly manufacture fungal T-cell products to high number with specificity against a range of clinically relevant fungal pathogens including yeasts and moulds. Using these cells, we intend to construct a bank of fungus-specific T cells from donors with common HLA-DRB1 types and to test their efficacy in HSCT recipients with IFD. If effective in restoring immunity, adoptive cell therapy using 3rd party broadly reactive antifungal T-cells could be useful in improving outcomes for HSCT patients with IFDs.Figure 1: Cytokine expression profile of reactive antifungal T cells expanded with Aspergillus and Candida lysates following rechallenge with lysates of specific fungal pathogens or a mix of all lysates. Results are means of 6 experiments (±s.e.m) and shown as percentage of CD4+ T cells. [Display omitted] DisclosuresGottlieb:Indee: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

449 - Efficacy of Oral Ribavirin in Respiratory Syncytial Virus Infection in Hematopoietic Stem Cell Transplant Patients: A Single-Centre Experience

Background: Respiratory syncytial virus (RSV) is one of the most commonly encountered respiratory viruses among patients who have been diagnosed with a hematological malignancy or a hematopoietic stem cell transplantation (HSCT). In immunocompromised patients including HSCT recipients, RSV can progress to a more severe lower respiratory infection (LRI), often complicated by respiratory failure leading to increased morbidity and mortality. Little is known about the best management strategy in this immunocompromised group and strategies to manage RSV is challenging. Data on aerosolized ribavirin to treat RSV infections in HSCT recipients come from small, retrospective studies with heterogeneous treatment combinations but nevertheless, have shown to prevent poor outcomes. There is very little data on oral ribavirin treatment but the retrospective data so far has been promising. Aim: To evaluate the effectiveness of oral ribavirin in HSCT patients with RSV infection at our centre in London, Ontario. Methods: Eighteen HSCT patients with RSV were analyzed retrospectively. In 2012, there were 5 patients treated with supportive care alone. After 2012, there were 13 patients treated with oral ribavirin. RSV diagnosis was established by polymerase chain reaction assay via nasopharyngeal swabs. Oral ribavirin was initiated at 15 mg/kg/day in three divided doses for 7-10 days with possibility of extension in persistently symptomatic patients. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. Findings: An outbreak of RSV occurred in our oncology unit in early 2012 where 5 HSCT patients ((3 autologous HSCT and 2 allogeneic HSCT patients) contracted RSV infection as well. No definitive treatment options were available during this period and patients were managed with supportive care alone. 4/5 HSCT patients died of RSV infection leading into an 80% mortality rate. This experience led to the development of a protocol for the HSCT patients focusing on prevention of nosocomial transmission, early PCR testing and treatment with oral ribavirin for those confirmed with RSV infection and signs of pneumonia or LRI. Since 2012, 13 HSCT patients (4 autologous HSCT patients and 9 allogeneic HSCT patients) were diagnosed with RSV infection and promptly treated with oral ribavirin. The median treatment duration was 10 days (range: 7-12). All patients treated with oral ribavirin survived the infection. Oral ribavirin was well tolerated with minor adverse effects. Conclusion: We found that HSCT patients with lower respiratory RSV infections can be successfully managed by use of prevention strategies and oral ribavirin. Although, our experience reflects a small sample size, the protocol was associated with decreased mortality compared to patients who received supportive care alone. Our experience supports the use of oral ribavirin for the early treatment of HSCT patients with RSV associated LRI and may be an alternative to aerosolized RBV. But ongoing review of our experience with this protocol is necessary and large prospective studies are needed to determine the optimal therapy in this patient group. Disclosures No relevant conflicts of interest to declare.

Raoultella terrigena infections in hematopoietic stem cell transplant recipients: High rate of mortality in multidrug-resistant strains - A retrospective observational study

Background: Raoultella terrigena is a Gram-negative bacterium mainly reported as aquatic and soil organism. It is rarely involved in human infections. This study investigated the epidemiology of R. terrigena infections in the National Bone Marrow Transplant Center of Tunis (NBMTC) between January 2010 and March 2018, their associated antibiotics resistance patterns, and the molecular features of extended-spectrum β-lactamase (ESBL) producing strains. Materials and Methods: Our retrospective study concerned hematopoietic stem cell transplant (HSCT) adult recipients hospitalized at the NBMTC and infected with R. terrigena. The search of the ESBL and carbapenemases genes for multidrug-resistant strains was performed by PCR amplification. Results: Twelve strains of R. terrigena were responsible for infections in 10 hematopoietic stem cell transplant recipients (1.2% of total HSCT recipients). They were responsible for skin (n = 4) and urinary tract infections (n = 4). The first-line antibiotherapy was based on a monotherapy in one case and a dual therapy in eleven cases. Imipenem was the most prescribed antibiotic (n = 7/12). Mortality was attributable to R. terrigena infection in two over ten patients. Nine strains were producing ESBL. Five strains were resistant to ertapenem, two to imipenem, ten to ciprofloxacin, and five to amikacin. BlaCTX-M1, blaOXA-48, and blaKPC were found in seven, four, and one strains, respectively. Conclusion: Low prevalence of R. terrigena infections in HSCT recipients but high rates of attributable mortality and multidrug-resistant strains.

Efficacy of Oral Ribavirin in Respiratory Syncytial Virus Infection in Hematopoietic Stem Cell Transplant Patients: A Single-Centre Experience

Background: Respiratory syncytial virus (RSV) is one of the most commonly encountered respiratory viruses among patients who have been diagnosed with a hematological malignancy or a hematopoietic stem cell transplantation (HSCT). In immunocompromised patients including HSCT recipients, RSV can progress to a more severe lower respiratory infection (LRI), often complicated by respiratory failure leading to increased morbidity and mortality. Little is known about the best management strategy in this immunocompromised group and strategies to manage RSV is challenging. Data on aerosolized ribavirin to treat RSV infections in HSCT recipients come from small, retrospective studies with heterogeneous treatment combinations but nevertheless, have shown to prevent poor outcomes. There is very little data on oral ribavirin treatment but the retrospective data so far has been promising. Aim: To evaluate the effectiveness of oral ribavirin in HSCT patients with RSV infection at our centre in London, Ontario. Methods: Eighteen HSCT patients with RSV were analyzed retrospectively. In 2012, there were 5 patients treated with supportive care alone. After 2012, there were 13 patients treated with oral ribavirin. RSV diagnosis was established by polymerase chain reaction assay via nasopharyngeal swabs. Oral ribavirin was initiated at 15 mg/kg/day in three divided doses for 7-10 days with possibility of extension in persistently symptomatic patients. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. Findings: An outbreak of RSV occurred in our oncology unit in early 2012 where 5 HSCT patients ((3 autologous HSCT and 2 allogeneic HSCT patients) contracted RSV infection as well. No definitive treatment options were available during this period and patients were managed with supportive care alone. 4/5 HSCT patients died of RSV infection leading into an 80% mortality rate. This experience led to the development of a protocol for the HSCT patients focusing on prevention of nosocomial transmission, early PCR testing and treatment with oral ribavirin for those confirmed with RSV infection and signs of pneumonia or LRI. Since 2012, 13 HSCT patients (4 autologous HSCT patients and 9 allogeneic HSCT patients) were diagnosed with RSV infection and promptly treated with oral ribavirin. The median treatment duration was 10 days (range: 7-12). All patients treated with oral ribavirin survived the infection. Oral ribavirin was well tolerated with minor adverse effects. Conclusion: We found that HSCT patients with lower respiratory RSV infections can be successfully managed by use of prevention strategies and oral ribavirin. Although, our experience reflects a small sample size, the protocol was associated with decreased mortality compared to patients who received supportive care alone. Our experience supports the use of oral ribavirin for the early treatment of HSCT patients with RSV associated LRI and may be an alternative to aerosolized RBV. But ongoing review of our experience with this protocol is necessary and large prospective studies are needed to determine the optimal therapy in this patient group. Disclosures No relevant conflicts of interest to declare.

Antigenic competition in the generation of multi-virus-specific cell lines for immunotherapy of human cytomegalovirus, polyomavirus BK, Epstein-Barr virus and adenovirus infection in haematopoietic stem cell transplant recipients

Adoptive transfer of multivirus-specific T cell lines (MVST) is an advanced tool for immunotherapy of virus infections after hematopoietic stem cell transplantation (HSCT). Their preparation includes activation of donor virus-specific T cells by the mixture of oligopeptides derived from immunodominant antigens of several most harmful viruses, i.e. human cytomegalovirus (HCMV), polyomavirus BK (BKV), Epstein-Barr virus (EBV) and adenovirus (ADV). The aim of our study was to find out whether antigenic competition may have an impact on the expansion of virus-specific T cells. MVST from several heathy blood donors were generated using a pulse of overlapping oligopeptides (PepMixes™, derived from the IE1 and pp65 CMV antigens, VP1 and LTAG BKV antigens, BZLF1 and EBNA1 proteins of EBV and hexon protein from ADV) and short time culture in the presence of IL-7 and IL-4. The amount of virus-specific T cells in MVST was measured by ELISPOT and flow cytometry after re-stimulation with individual antigens. To evaluate antigenic competition, MVST were expanded either with a complete set of antigens or with the mixture lacking some of them. MVST expanded with the antigen mixture including CMV antigens contained a lower proportion of the T cells of other antigen specificities. A similar inhibitory effect was not apparent for EBV-derived peptides. The competitive effect of CMV antigens was most pronounced in MVST from CMV-seropositive donors and was mediated by both IE1 and pp65-derived peptides. Antigenic competition did not influence the phenotype of either CMV- or BKV-specific T cells. Both T cell populations had an effector memory phenotype (CD45RO+, CD27-, CCR7-). However, CMV-specific T cells preferentially consist of CD8+ while in BKV-specific T cells, the CD4+ phenotype predominated. Modification of the MVST manufacture protocol to prevent antigenic competition may increase the efficacy of MVST in therapy of BKV infections in HSCT recipients.

An overview of letermovir: a cytomegalovirus prophylactic option

ABSTRACTIntroduction: Human cytomegalovirus (HCMV) or human herpesvirus 5 (HHV-5) is a β-herpesvirus that causes widespread infection in nearly all members of the human population worldwide. Its persistence in humans after primary infection in a latent phase as well as a partial non–protective immune response is the basis for repeated re-activation/re-infection episodes occurring both in immunocompetent and immunocompromised subjects. In the latter patient populations, which include hematopoietic stem cell transplant (HSCT) recipients, HCMV reactivation episodes may be particularly severe, leading to both systemic and end-organ diseases. Since the 90s, at least four antiviral drugs targeting the DNA polymerase complex have been developed for the prevention and treatment of HCMV infections in transplant recipients, used as first-line (ganciclovir and valganciclovir) and second-line therapy (foscarnet and cidofovir). However, due to their toxicity and drug-resistance induction, new drugs with different targets were needed.Areas covered: In 2017, a new drug named letermovir (LTV), which targets the HCMV DNA terminase complex, was licensed for prophylaxis of HCMV infections in HSCT recipients. This is the focus of this review.Expert opinion: LTV safety and efficacy are promising. However, long-term adverse events and the emergence of drug-resistant HCMV strains must be investigated in extended clinical trials prior to drawing final conclusions.

In Vitro Expansion of Anti-viral T Cells from Cord Blood by Accelerated Co-cultured Dendritic Cells

Hematopoietic stem cell transplantation (HSCT) using unrelated cord blood (CB) donors is a suitable approach when an HLA-matched donor is not available. However, one important drawback is the risk of life-threatening viral infections prior to immune reconstitution, particularly from adenoviruses (AdVs). Although adoptive therapy with ex vivo expanded virus-reactive donor T cells has proven effective to treat these infections in HSCT recipients, the manufacturing process is complex and requires large numbers of cells, which is incompatible with CB donor units. Here, we have adapted our previous accelerated co-cultured dendritic cell (acDC) method, which allows to efficiently and rapidly expand peripheral blood T cells reactive to a given antigen, for use on limited CB material. Selected cytokine cocktails induced DC differentiation and maturation from unfractionated CB mononuclear cell cultures and simultaneously stimulated and expanded, within 10 days, functional CD8+ T cells specific for the model antigen MelanA or AdV immunodominant peptides. In addition, the use of G-Rex cultures yielded numbers of AdV-reactive CD8+ T cells compatible with adoptive cell therapy applications. Our acDC strategy, which uses reagents compatible with good manufacturing practices, may be promptly translated into the clinic for treating intercurrent infections in CB HSCT recipients.

Extended spectrum beta-lactamase-producing Enterobacteriaceae infections in hematopoietic stem cell transplant recipients: Epidemiology and molecular characterization

BackgroundExtended spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) create a therapeutic challenge and have high potential for dissemination. The purpose of our study was to investigate the epidemiology of these infections in hematopoietic stem cell transplant (HSCT) recipients and to determine the genes encoding ESBL. Material/methodsThis retrospective study comprised adult patients hospitalized at the National Bone Marrow Transplant Center (NBMTC) and infected with ESBL-E post-HSCT between January 2006 and December 2016. The search for the ESBL and carbapenemase genes was performed by polymerase chain reaction (PCR) amplification. Molecular typing was performed by pulsed field gel electrophoresis (PFGE) after digestion with XbaI. ResultsForty ESBL-E were responsible for infections in 34 HSCT recipients (3.3% of total HSCT recipients). Prior hospital stay, prior antibiotic therapy and prior colonization with ESBL-E were reported in 62.5%, 70% and 50% of the infectious episodes, respectively. The initial antibiotic treatment was appropriate in 67.7% of cases. Imipenem was the most prescribed antibiotic (64.5%). The mortality rate due to ESBL-E infection was 8.8%.The ESBL-E, isolated mainly from blood cultures (40%), belonged mostly to K. pneumoniae (n=19) and E. coli (n=17). Associated antibiotic resistance rates were 17.5% for ertapenem, 85% for ciprofloxacin and 30% for amikacin. The predominant gene encoding ESBL was blaCTX-M (55%). Among the seven carbapenem-resistant strains, four had the blaOXA-48 gene and two the blaKPC gene. There was no clonal relationship between the strains. ConclusionThere was low prevalence of ESBL-E infections in HSCT recipients in our center, with no epidemic distribution but non-negligible mortality rate.

Diagnostic usefulness of dynamic changes of CMV-specific T-cell responses in predicting CMV infections in HCT recipients

BackgroundCMV-specific cell mediated immune responses before and after hematopoietic stem cell transplantation (HCT) can categorize patients as at high or low risk of CMV development. ObjectivesWe evaluated the usefulness of the CMV-specific T-cell ELISPOT assay for predicting the development of CMV infections after HCT in recipients with donor-positive and recipient-positive CMV serology (D+/R+ ). Study designCMV pp65 and IE1-specific ELISPOT assays were performed before HCT (D0), and at 30 (D30) and 90 (D90) days after HCT. ResultsOf the 84 HCT recipients with D+/R+, 42 (50%) developed≥1 episode of CMV infection. Thirty-nine (64%) of 61 patients with Δ(D30-D0) pp65<42 developed CMV infections compared with 3 (14%) of 21 patients with Δ(D30-D0) pp65≥42 (P<0.001). Twenty-three (74%) of 31 patients with Δ(D30-D0) IE1<−4 developed CMV infections compared with 19 (37%) of 51 patients with Δ(D30-D0) IE1≥−4 (P=0.001). pp65 Δ(D30-D0) ≥42 had 93% sensitivity for ruling out subsequent CMV infection, and pp65 Δ(D30-D0)<42 followed by Δ(D30-D0) IE1<−4 had 100% specificity for ruling in the subsequent CMV infection. In addition, 10 (53%) of 19 patients with Δ(D90-D30) pp65<23 had relapsing CMV infections, compared with 3 (15%) of 20 patients with Δ(D90-D30) pp65≥23 (P=0.02). The sensitivity and specificity of Δ(D90-D30) pp65 were 77% (95% CI 50–92) and 65% (95% CI, 46–81). ConclusionDynamic change in the CMV-specific ELISPOT assay before versus after HCT appears to predict the subsequent development of CMV infection and relapsing CMV infection.

Invasive fungal infections in pediatric hematopoietic stem cell transplant patients

Background: Pediatric hematopoietic stem cell transplant (HSCT) recipients are at high risk of invasive fungal infections (IFIs). Methods: To characterize IFIs and changes in fungal organisms over time in pediatric HSCT patients, we performed a retrospective cohort study of all HSCTs performed in pediatric patients at UCLA between 1991 and 2006. Results: In all, 318 patients underwent 324 HSCT transplants over the 15-year period and 69 unique fungal infections were identified in 47 transplant patients. The overall incidence of fungal infections in HSCT recipients was 14.5%, with predominant organisms including Candida species (51%) and Aspergillus species (26%), with Candida albicans accounting for 18.8% of all fungal species. The distribution of organisms over time demonstrated a strong trend towards an increase in rare molds in more recent years. The respiratory tract was the main site of infection (52.6%), with urine and blood also noted as significant sites. Of all deaths in the patients with IFIs, fungal-related mortality accounted for 67.6% of deaths. Conclusions: HSCT patients have a much higher risk of fungal infections with rarer organisms becoming more prevalent, a finding likely linked to evolving antifungal practices over time. This emphasizes the need for the development and implementation of improved diagnostic, prophylactic, and therapeutic strategies to improve patient survival.

Infections Caused by Stenotrophomonas maltophilia in Recipients of Hematopoietic Stem Cell Transplantation.

Stenotrophomonas maltophilia (S. maltophilia) is a globally emerging Gram-negative bacillus that is widely spread in environment and hospital equipment. Recently, the incidence of infections caused by this organism has increased, particularly in patients with hematological malignancy and in recipients of hematopoietic stem cell transplantation (HSCT) having neutropenia, mucositis, diarrhea, central venous catheters or graft versus host disease and receiving intensive cytotoxic chemotherapy, immunosuppressive therapy, or broad-spectrum antibiotics. The spectrum of infections in HSCT recipients includes pneumonia, urinary tract and surgical site infection, peritonitis, bacteremia, septic shock, and infection of indwelling medical devices. The organism exhibits intrinsic resistance to many classes of antibiotics including carbapenems, aminoglycosides, most of the third-generation cephalosporins, and other β-lactams. Despite the increasingly reported drug resistance, trimethoprim-sulfamethoxazole is still the drug of choice. However, the organism is still susceptible to ticarcillin-clavulanic acid, tigecycline, fluoroquinolones, polymyxin-B, and rifampicin. Genetic factors play a significant role not only in evolution of drug resistance but also in virulence of the organism. The outcome of patients having S. maltophilia infections can be improved by: using various combinations of novel therapeutic agents and aerosolized aminoglycosides or colistin, prompt administration of in vitro active antibiotics, removal of possible sources of infection such as infected indwelling intravascular catheters, and application of strict infection control measures.

Comparison of the diagnostic value of procalcitonin and C‐reactive protein after hematopoietic stem cell transplantation: a systematic review and meta‐analysis

To conduct a systematic review and meta-analysis of the performance of the procalcitonin (PCT) diagnostic test for identifying infectious complications after hematopoietic stem cell transplantation (HSCT). We searched EMBASE, MEDLINE, the Cochrane database, and reference lists of relevant articles, with no language restrictions, through December 2011. We selected original articles that reported diagnostic performance of PCT alone or compared with other biomarkers for identifying serious infections in HSCT recipients. We quantitatively evaluated test accuracy parameters with the use of forest plots, hierarchical summary receiver operating characteristic curves, and bivariate random effect models. We found 6 qualifying studies (studying 1344 episodes of suspected infection with confirmed infectious episodes) from 3 countries. These 6 studies examined both PCT and C-reactive protein (CRP) test performance. Bivariate pooled sensitivity, specificity, positive likelihood ratios, and negative likelihood ratios were 0.66 (95% confidence interval [CI] 0.60-0.72), 0.72 (95% CI 0.65-0.79), 2.39 (95% CI 1.84- 3.09), and 0.47 (95% CI 0.39-0.57) for PCT, and 0.80 (95% CI 0.54-0.93), 0.73 (95% CI 0.56-0.86), 3.00 (95% CI 1.86-4.84), and 0.27 (95% CI 0.11-0.65) for CRP. In terms of area under the curve (AUC), CRP was superior to PCT in detecting infectious complications, with an AUC of 0.82 for CRP versus an AUC of 0.69 for PCT. The pooled accuracy estimates of 6 different studies indicated only a moderate rule-out diagnostic value of both PCT and CRP in discriminating infection from other inflammatory complications following allogeneic HSCT.

Molecular Diagnosis and Management of Viral Infections in Hematopoietic Stem Cell Transplant Recipients

Viral infections after allogeneic hematopoietic stem cell transplantation (HSCT) are important complications associated with high morbidity and mortality. In this setting, reactivations of persisting latent viral pathogens from donor and/or recipient cells play a central role whereas the sterile environment of transplant units renders new infections less likely. The viruses currently regarded as most relevant in the HSCT setting include particularly the herpes virus family--specifically cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6)--as well as human adenoviruses (AdVs) and the polyoma virus BK (BKV). Timely detection and monitoring of virus copy numbers are prerequisites for successful preemptive treatment approaches. Pre- and post-transplant surveillance by sensitive and quantitative molecular methods has therefore become an essential part of the diagnostic routine. In this review, we discuss diagnostic aspects and the clinical management of the most important viral infections in HSCT recipients, with a focus on pediatric patients.

Comparison of In Vitro Susceptibility Characteristics of Candida Species from Cases of Invasive Candidiasis in Solid Organ and Stem Cell Transplant Recipients: Transplant-Associated Infections Surveillance Network (TRANSNET), 2001 to 2006

Invasive fungal infections (IFI) are a major cause of morbidity and mortality among both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Candida is the most common cause of IFI in SOT recipients and the second most common cause of IFI in HSCT recipients. We determined susceptibilities to fluconazole, voriconazole, itraconazole, posaconazole, amphotericin B, and caspofungin for 383 invasive Candida sp. isolates from SOT and HSCT recipients enrolled in the Transplant-Associated Infection Surveillance Network and correlated these results to clinical data. Fluconazole resistance in C. albicans, C. tropicalis, and C. parapsilosis isolates was low (1%), but the high percentage of C. glabrata and C. krusei isolates within this group of patients increased the overall percentage of fluconazole resistance to 16%. Voriconazole resistance was 3% overall but was 8% among C. glabrata isolates. On multivariable analysis, among HSCT recipients fluconazole nonsusceptibility was independently associated with C. glabrata, non-Hodgkin's lymphoma, cytomegalovirus (CMV) antigenemia, diabetes active at the time of the IFI, and any prior amphotericin B use; among SOT recipients, fluconazole nonsusceptibility was independently associated with any fluconazole use in the 3 months prior to the IFI, C. glabrata, ganciclovir use in the 3 months prior to the IFI, diabetes acquired since the transplant, and gender.

Impaired pulmonary immunity post-bone marrow transplant.

Infectious complications are a serious cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT), and the lung is a particular target organ post-transplant. Our laboratory has used a murine bone marrow transplant model to study alterations in immunity that occur as a result of transplantation. Our studies focus on immune responses that occur following immune cell reconstitution in the absence of immunosuppressive drug therapy or graft-versus-host disease. We have found that impaired clearance of both bacterial and viral pulmonary infections is related to specific alterations in immune cell function and cytokine production. Our data offer insight into mechanisms that contribute to opportunistic infections in HSCT recipients.

Invasive mould infections in the setting of hematopoietic cell transplantation: current trends and new challenges

Invasive mould infections remain major causes of infection-related mortality following hematopoietic stem cell transplantation (HSCT). In this review, we summarize the recent advances in the diagnosis, prevention, and management of invasive mould infections in HSCT recipients. The evolving epidemiologic characteristics of post-HSCT invasive mould infections, specifically the rising incidence of Aspergillus and non-Aspergillus mould infections in the postengraftment period, necessitate the development of preventive strategies. The efficacy of prophylactic broad-spectrum triazoles against invasive mould infections in HSCT recipients has now been demonstrated in two large prospective studies. However, concerns over drug absorption, interactions, and costs may shift attention from universal prophylaxis to risk stratification and preemptive strategies. In this regard, recent studies have highlighted the potential of genetic polymorphism analysis to identify HSCT recipients at risk for invasive aspergillosis, and efforts are underway to improve the predictive values of antigen and nucleic acid detection assays. Emerging data on risk factors for invasive aspergillosis relapse after HSCT, antifungal drug monitoring, and the use of galactomannan testing to monitor treatment response may help inform therapeutic decisions for HSCT recipients. Evidence-driven management of invasive mould infections in HSCT recipients is becoming increasingly individualized, integrating host factors and pharmacologic and epidemiologic considerations. However, the optimal approach to invasive mould infection prevention in HSCT recipients remains to be resolved by prospective clinical studies.

Streptococcus pneumoniae Infections in 47 Hematopoietic Stem Cell Transplantation Recipients

Streptococcus pneumoniae infections can cause serious systemic disease in patients following hematopoietic stem cell transplantation (HSCT), and the response to pneumococcal vaccine is inadequate in most HSCT recipients. We evaluated the clinical spectrum of pneumococcal disease and vaccine-breakthrough infections in HSCT recipients at our cancer center in a retrospective analysis of all consecutive episodes of S. pneumoniae infection from 1989 through 2005. During the study period, 7888 patients underwent HSCT at our center; we identified 47 HSCT recipients with 54 S. pneumoniae infections. The overall incidence of S. pneumoniae infection was 7 per 1000 HSCTs. The incidence was higher in recipients of allogeneic grafts than in recipients of autologous grafts (9 vs. 5 per 1000 HSCTs, respectively; p <or= 0.012). Thirty-two of the 47 patients (68%) had leukemia or lymphoma; 24 patients (51%) had a malignancy that was in complete remission. Seventeen patients (36%) had graft-versus-host disease, which was chronic in 16. The 54 episodes of S. pneumoniae infection occurred 433 +/- 669 days after HSCT; 5 patients (11%) had multiple episodes. Four episodes of S. pneumoniae infection occurred within 100 days following transplantation (45 +/- 49 d); 2 of these were during the pre-engraftment period and 3 were nosocomial infections. All 50 late post-transplant episodes (93%), which occurred 473 +/- 671 days following transplantation, were community-acquired infections (p < 0.00016). Thirty-three episodes (61%) presented as bacteremic pneumonia, 10 (19%) as pneumonia, and 8 (15%) as uncomplicated S. pneumoniae bacteremia alone. Logistic regression analysis showed that patients receiving systemic corticosteroids had increased risk for bacteremic pneumonia (odds ratio [OR], 11.7; 95% confidence intervals [CI], 1.371-99.280; p <or= 0.025). Patients with lymphoma (OR, 6.101; 95% CI, 1.106-33.640; p <or= 0.04) were more likely to develop pneumonia alone. In 27 episodes (93%) among 29 in which S. pneumoniae susceptibility testing was performed, the patients received concordant antimicrobials. Among the 6 patients (13%) who died of S. pneumoniae infection, 4 had S. pneumoniae bacteremic pneumonia and only 1 had chronic GVHD. Admission to a critical care unit at the onset of infection (OR, 15.5; 95% CI, 2.116-113.541; p <or= 0.007) and each unit increase in APACHE II score increase the probability of death (OR, 1.9; 95% CI, 1.181-3.054; p <or= 0.008). All 5 (11%) patients who developed vaccine-breakthrough S. pneumoniae infection (546 +/- 732 d following vaccination) had pneumonia, and in 4 patients concurrent bacteremia also occurred. A serious S. pneumoniae infection in HSCT recipients occurred more commonly in patients with lymphoma and patients receiving high-dose systemic corticosteroid therapy. It is noteworthy that there were no cases of extrapulmonary organ infection in HSCT recipients who presented with S. pneumoniae infection at our institution.