Healthcare Burden, Risk Factors, and Outcomes of Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infections after Stem Cell Transplantation

Accepted Manuscript Title: Healthcare Burden, Risk Factors, and Outcomes of Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections after Stem Cell Transplantation Author: Christopher E Dandoy, David Haslam, Adam Lane, Sonata Jodele, Kathy Demmel, Javier El-Bietar, Laura Flesch, Kasiani C. Myers, Abigail Pate, Seth Rotz, Paulina Daniels, Gregory Wallace, Adam Nelson, Heather Waters, Beverly Connelly, Stella M Davies PII: DOI: Reference:

S1083-8791(16)30133-1 http://dx.doi.org/doi: 10.1016/j.bbmt.2016.06.002 YBBMT 54302

To appear in:

Biology of Blood and Marrow Transplantation

Received date: Accepted date:

4-5-2016 3-6-2016

Please cite this article as: Christopher E Dandoy, David Haslam, Adam Lane, Sonata Jodele, Kathy Demmel, Javier El-Bietar, Laura Flesch, Kasiani C. Myers, Abigail Pate, Seth Rotz, Paulina Daniels, Gregory Wallace, Adam Nelson, Heather Waters, Beverly Connelly, Stella M Davies, Healthcare Burden, Risk Factors, and Outcomes of Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections after Stem Cell Transplantation, Biology of Blood and Marrow Transplantation (2016), http://dx.doi.org/doi: 10.1016/j.bbmt.2016.06.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title: Healthcare Burden, Risk Factors, and Outcomes of Mucosal Barrier InjuryLaboratory Confirmed Bloodstream Infections after Stem Cell Transplantation Short Title: MBI-LCBIs after HSCT Authors: Christopher E Dandoy, MD, MSc1; David Haslam, MD2; Adam Lane, PhD1; Sonata Jodele, MD1; Kathy Demmel, MHA, RN1; Javier El-Bietar, MD1; Laura Flesch, MSN, APRN, CFNP1; Kasiani C. Myers, MD1; Abigail Pate, BS1; Seth Rotz, MD1; Paulina Daniels, DO1; Gregory Wallace, DO1; Adam Nelson, MBBS1; Heather Waters, RN, BSN3; Beverly Connelly, MD2, 3; Stella M Davies, PhD, MBBS1 Affiliations: 1Division of Bone Marrow Transplantation and Immune Deficiency, 2Division of Infectious Diseases, 3Department of Infection Control, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Address Correspondence to: Christopher Dandoy, MD, MSc, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 11027, Cincinnati, OH 45229 USA, Phone 513-636-3459; Fax: 513-803-1969, E-mail: [email protected] Word Count: 2973 Abstract Word Count: 347 Disclosures: The authors have no financial relationships or other conflicts of interest relevant to this article to disclose. Key Words: bloodstream infection; mucosal barrier injury-laboratory confirmed bloodstream infection; central line associated bloodstream infection; CLABSI; MBI-LCBI; transplant associated thrombotic microangiopathy; hematopoietic stem cell transplantation

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Highlights: 

Mucosal barrier injury laboratory confirmed bloodstream infections lead to significant morbidity, mortality and healthcare resource utilization in hematopoietic stem cell transplant patients



Mucosal barrier injury laboratory confirmed bloodstream infections are associated with increased 1-year non-relapse mortality after stem cell transplantation



Patients undergoing allogeneic stem cell transplantation develop Mucosal barrier injury laboratory confirmed bloodstream infections at a much higher rate than those undergoing autologous stem cell transplantation

Abstract

Mucosal barrier injury laboratory confirmed bloodstream infections (MBI-LCBIs) lead to significant morbidity, mortality and healthcare resource utilization in hematopoietic stem cell transplant (HSCT) patients. Determination of the healthcare burden of MBILCBIs, and identification of patients at risk of MBI-LCBIs, will allow researchers the ability to identify strategies to reduce MBI-LCBI rates. The objective of our study was to describe the incidence, risk factors, timing and outcomes of MBI-LCBIs in hematopoietic stem cell transplant patients. We performed a retrospective analysis of 374 patients who underwent HSCT at a large free-standing academic children’s hospital to determine the incidence, risk factors, and outcomes of patients that developed a bloodstream infection including MBI-LCBI, central line associated bloodstream infection (CLABSI), or secondary bloodstream infection in the first year after HSCT. Outcome measures included non-relapse mortality (NRM); central venous catheter removal within 7 days of positive culture; shock; admission to the pediatric intensive care unit (PICU) within 48 hours of positive culture; and death within 10 days of positive culture. 170 bloodstream infections were diagnosed in 100 (27%) patients; 80 (47%) MBI-LCBIs, 68 (40%) CLABSIs, and 22 (13%) secondary infections. MBI-LCBIs were diagnosed at a significantly higher rate in allogeneic HSCT patients (18% vs 7%, p=0.007). Reduced intensity conditioning (OR 1.96, p=0.015) and transplant associated thrombotic microangiopathy (OR 2.94, p=0.0004) were associated with MBI-LCBI. Nearly 50% of all patients with a bloodstream infection developed septic shock, 10% died within 10 days of positive culture, and nearly 25% were transferred to the PICU. One-year NRM was significantly increased in patients

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with one (34%) and more than one (56%) bloodstream infection in the first year post HSCT compared with those who did not (14%) (p= <0.0001). There was increased oneyear NRM in patients with at least one MBI-LCBI (OR 1.94, p=0.018) and at least one secondary bloodstream infection (OR 2.87, p=0.0023), but not CLABSIs (OR 1.17, p=0.68). Our data demonstrate that MBI-LCBIs lead to substantial use of healthcare resources, and are associated with significant morbidity and mortality. Reduction in frequency of MBI-LCBI should be a major public health and scientific priority. Background Patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for bloodstream infections (BSI), and associated morbidity and mortality1. BSIs in the healthcare setting are classified as being either a primary BSI, related to a central venous catheter (CVC) or other hospital acquired source, or secondary BSI (e.g. associated with abscess or pneumonia)2. Central line-associated bloodstream infections (CLABSIs) are among the most serious complications in HSCT recipients and lead to prolonged hospitalization, intensive care admissions, prolonged antibiotic treatment and increased mortality1,3,4. CVC maintenance care has been shown to be effective in reducing CLABSIs in a broad range of healthcare delivery settings5-7. Recently, it has become evident that some BSI that occur in patients with CVCs do not arise from the catheter, but instead are derived from other sources, such as translocation of bacteria through non-intact mucosa2,8. The Centers for Disease Control and Prevention developed a modification of the CLABSI definition, termed “mucosal barrier injury laboratory-confirmed bloodstream infection” (MBI-LCBI) on the basis of literature review and expert opinion. In 2013, this definition was integrated into National Healthcare Safety Network (NHSN) methods for primary BSI surveillance to aid in identifying a subset of BSI reported as CLABSIs that are likely related to mucosal barrier injury and not the presence of a central line2. Currently, primary BSIs in patients with a CVC, are now defined as either a laboratory-confirmed bloodstream infections (LCBI, hereafter referred to as CLABSI) or MBI-LCBI9. Additionally, the 2016 NHSN guidelines

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require additional validation steps to categorize a BSI as a secondary infection, thus decreasing the amount of subjectivity in primary and secondary BSI determination9. Unlike CLABSIs, MBI-LCBIs are not expected to be prevented by improved CVC maintenance care. As this is a recent classification of BSI, there are few data describing the incidence, timing and consequences of MBI-LCBIs after HSCT, and no data regarding healthcare resource utilization due to MBI-LCIs after HSCT. Moreover, there are currently no potential strategies to prevent bacteremia secondary to mucosal barrier injury after HSCT. The aim of this study was to describe the incidence, risk factors, timing and outcomes of MBI-LCBIs, CLABSI, and secondary BSIs in HSCT recipients. Determination of the healthcare burden of MBI-LCBI, and identification of patients at risk of MBI-LCBIs is essential to allow researchers the ability to identify strategies to reduce MBI-LCBI rates in HSCT patients.

Materials and Methods We retrospectively reviewed the records of 374 consecutive patients who underwent HSCT at Cincinnati Children’s Hospital Medical Center (CCHMC) from May 2011 to January 2015. Patient data were collected through the first year post-HSCT. The study was approved by the Institutional Review Board at CCHMC. Patient Demographics Seventy-five percent (282 of 374) of patients were allogeneic HSCT recipients, and 25% (92 of 374) were autologous. The median patient age was 5.9 years (IQR 2.913.7), 206 (55%) were male. The majority of patients underwent transplant for an underlying malignancy (n=170; 45%) or immune deficiency (n=113; 30%). A myeloablative conditioning regimen was used in 256 patients (68%) and a reduced intensity regimen was used in 118 (32%). All autologous HSCT recipients underwent

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transplant for a solid tumor malignancy and received a myeloablative preparative regimen. The median time to neutrophil engraftment was 12 days (IQR 10-15). We retrospectively applied the most recent (2016) NHSN criteria in the classification CLABSIs, MBI-LCBIs, and secondary BSIs to all infections occurring in HSCT recipients through the first year post-transplant (both inpatient and outpatient)9. Bloodstream Infection (BSI) Definitions BSIs were classified as a CLABSI if they were either a common commensal organism, isolated from a blood culture on 2 occasions or a recognized pathogen isolated from one blood culture, AND did not meet criteria for an MBI-LCBI or secondary BSI. BSIs were classified as an MBI-LCBI if both the organism and patient criteria described below were met. Eligible organisms include those commonly found in the gastrointestinal tract such as Enterococcus species and Enterobacteriaceae species9. In addition, the BSI had to occur in a patient with one of the following: o

An allogeneic HSCT recipient with grade 3–4 graft versus host disease (GVHD) diagnosed within the same hospitalization.

o

An allogeneic HSCT recipient with ≥1 L of diarrhea (20 mL/kg for those <18 years of age) in a 24-hour period of time within 7 days of the positive blood culture.

o

Neutropenia, defined as an absolute neutrophil count (ANC) or total white blood cell count less than 500 cells/mm3 within 3 days before or after the positive blood culture.

Secondary BSIs (i.e. related to an infection at another site, such that the primary site of infection may have seeded the bloodstream secondarily) were determined according to NHSN criteria9.

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Patients did not receive routine prophylactic antibacterial agents. Empiric antibiotics, including piperacillin/tazobactam, meropenem, or cefepime, were used empirically during febrile episodes or when shock was present. All patients received prophylactic antifungal therapy. Patients with positive blood cultures were treated for a minimum of 10–14 days. Covariates Patient clinical data were collected from the electronic medical record, including demographics, disease and therapy characteristics, transplant complications, and outcomes. Evaluation of the following variables: gender, age at transplant, diagnosis, donor relationship, HLA match, stem cell graft source, conditioning regimen, neutrophil engraftment defined as an ANC >500/mm3 daily for 3 days. Currently accepted clinical criteria were used for diagnosis of acute GVHD10, chronic GVHD, transplant associated thrombotic microangiopathy11,12, and engraftment syndrome in allogeneic stem cell recipients 13. One-year non-relapse mortality (NRM) was defined as death without progression or relapse of disease during the first year post-HSCT. Infection Specific Outcomes Outcome variables were obtained related to each infection including CVC removal within 7 days of the positive culture; shock, defined as requirement of at least 40 ml/kg of fluid resuscitation and/or inotropic medication within 24 hours of the positive culture; admission to the pediatric intensive care unit (PICU) within 48 hours of the positive culture; length of stay in the PICU after admission; and death within 10 days of positive culture. Statistical Analysis Descriptive statistics were presorted as medians, interquartile ranges (IQR), and frequencies. Univariate patient demographic and transplant-related factors were compared between groups using Fisher exact for categorical variables and the Wilcoxon

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rank sum test for continuous variables. The incidences of BSI (any type) and MBI-LCBI for the first infection event were determined using the cumulative incidence function with death as a competing risk and were censored at the earlier of 1-year or second transplant, and were compared using Grey’s test. A multivariate competing risk regression using backward selection was performed to assess risk factors for MBI-LCBI and CLABSI infection separately. Gray’s competing risk method was used to compute the 1-year NRM cumulative incidence curve in patients that developed at least two BSIs, and one BSI versus those that did not develop a BSI in the first year post transplant. NRM was calculated with relapse as competing risk and were censored at 1-year or the time of second transplant. A multivariate competing risk regression model was used to compare overall NRM by type of infection, with acute GVHD and TA-TMA included in the model. All statistical tests conducted were two-sided and p-values less than 0.05 were considered significant. Cumulative incidence was calculated in R14,15.

RESULTS Bloodstream Infections One hundred and seventy BSIs were diagnosed in 100 (27%) patients. The median time to first BSI was 49 days post-transplant (IQR 7-103 days), and 46% of the 100 patients had at least 1 BSI prior to neutrophil engraftment. Eighty (47%) infections were classified as MBI-LCBIs, 68 (40%) as CLABSIs, and 22 (13%) secondary infections. Allogeneic stem cell recipients developed BSIs at a significantly higher rate than autologous recipients. Thirty-one percent (88 of 282) of allogeneic and 13% (12 of 92) of autologous HSCT recipients developed at least one BSI after transplant (p=0.0007) (Figure 1a). In addition, MBI-LCBIs were diagnosed at a significantly higher rate in allogeneic stem cell recipients (18% vs 7%, p=0.007) (Figure 1b). The median time to

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first MBI-LCBI was 61 days post-HSCT (IQR 6-102 days) and 38% of MBI-LCBI occurred prior to engraftment. In light of the lower number of infections in the autologous HSCT population, we focused our analysis of risk factors on the allogeneic HSCT recipients and autologous recipients are not considered further in this paper. Risk Factors for MBI-LCBI in Allogeneic HSCT Recipients Eighteen percent (52 of 282) of allogeneic stem cell recipients developed at least one MBI-LCBI, 15% (43 of 282) developed at least one CLABSI, and 6% (16 of 282) developed at least one secondary infection. Table 1 details the pre-transplant and posttransplant variables associated with each type of infection. In univariate analysis, reduced intensity conditioning was associated with development of a MBI-LCBI, and patients transplanted for an immune deficiency were more likely to develop CLABSIs, while CLABSIs were less frequent in those with marrow failure syndromes. Graft source, age and gender did not alter risk of any category of BSI. In univariate analysis MBI-LCBIs and secondary infections were significantly associated with grade 2-4 acute GVHD in allogeneic recipients (p=0.012 and 0.023 respectively), while CLABSIs were not (p=0.07). In contrast, MBI-LCBIs (p=0.0003), CLABSIs (p=0.0004), and secondary BSIs (p=0.017) were all associated with transplant associated thrombotic microangiopathy (TA-TMA). Chronic GVHD and engraftment syndrome were not associated with increased risk of a BSI. In multivariate analysis (Table 2) use of reduced intensity conditioning (OR 1.96, p=0.015) was associated with increased risk of at least one MBI-LCBI. The only preHSCT variable associated with increased risk of CLABSI in multivariate analysis was transplant for immune deficiency (OR 4.42, p=0.0061). TA-TMA was associated with both MBI-LCBI and CLABSI (OR 2.94, p=0.0004 and OR 2.97, p=0.0019 respectively). There were too few secondary infections to support multivariate analysis of that endpoint.

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Healthcare Resource Utilization Table 3 describes outcomes of patients after developing a BSI after HSCT. Forty-six percent of patients with an MBI-LCBI, 50% of those with a CLABSI, and 45% of those with a secondary infection developed septic shock at the time of the infection (p=0.88), and almost a quarter of children with MBI-LCBI or CLABSI were transferred to the PICU in association with their infection. Similar numbers of patients with each category of infections underwent line removal as a consequence of their infection (p=0.75). The median number of PICU days was similar between patients developing an MBI-LCBI (6 days) and CLABSI (5 days); however, patients developing a secondary infection spent a median of 32 days in the intensive care unit. Non-Relapse Mortality One-year NRM was significantly increased in patients with one (34%) and more than one (56%) BSI in the first year post HSCT compared with those who did not (14%) (p= <0.0001) (Figure 2). Multivariate analysis revealed increased risk of one-year NRM in patients with at least one MBI-LCBI (OR 1.94, p=0.018) and at least one secondary bloodstream infections (OR 2.87, p=0.0023), but not CLABSIs (OR 1.17, p=0.68) (Table 4). When acute GVHD is included in the multivariate analysis, risk of NRM remained significantly increased in those with secondary bloodstream infections (OR 2.35, p=0.02), and increased in those with MBI-LCBI (OR 1.73, p=0.055) (Table 4). Finally, NRM was similar in autologous stem cell recipients that did and did not develop at least one BSI and/or MBI-LCBI.

Discussion In this study, we evaluated all bloodstream infection events in 374 consecutive children and young adults undergoing HSCT at a single center, and retrospectively applied the 2016 NHSN criteria. This is the first study to describe the incidence and risk

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factors, as well as outcomes of patients to develop MBI-LCBIs after HSCT. The MBILCBI definition was first developed in 2013 to define BSIs amongst immunecompromised patients that may not be related to central lines2. Our data show that nearly 50% of bloodstream infections in our HSCT population met the MBI-LCBI definition, and constitute a significant burden to this high-risk patient population. We were particularly interested to determine whether the definition was effective in identifying groups of transplant recipients with different outcomes, and in need of different strategies to reduce infections and healthcare resource utilization. Our data show clear differences in risk factors, morbidity and mortality in transplant recipients with CLABSI, MBI-LCI and secondary infections, suggesting that the definitions are clinically meaningful and identify categories of patients in whom different strategies are needed to prevent infection. An important goal of our study was to examine risk factors for MBI-LCBI and identify high-risk patients for future intervention studies. Surprisingly, univariate and multivariate analyses show that risk of MBI-LCBI is almost doubled in allogeneic recipients treated with a reduced intensity preparative regimen. In contrast, the intensity of the preparative regimen did not modify risk of CLABSI or secondary infections. Reduced intensity preparative regimes are generally thought to reduce tissue damage and mucositis16,17, and might be expected to reduce risk of MBI-LCBI. In our clinical practice, reduced intensity preparative regimens are typically used for immune deficiency and bone marrow failure patients, and myeloablative regimens are used for children with malignancy. It is possible that differences in risk by diagnosis are confounding the association with reduced intensity conditioning. In support of this, univariate analysis in children with immune deficiency, who often have severe enteropathy prior to transplant, were at increased risk of CLABSI, and there was a nonsignificant increase in number of MBI-LCBI. However, inclusion of diagnosis in the

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multivariate model did not favor this hypothesis. The reduced intensity preparative regimen most frequently used at our center includes the alkylating agent melphalan, while the myeloablative regimens generally include busulfan, cyclophosphamide and radiation. It is possible that there is a differential effect of melphalan on bowel permeability that facilitates MBI-LCBI. Alternatively, the gut microbiome might differ in the two populations, modifying risk of translocation with over-representation of pathogenic bacteria, and studies are underway to address this question. Univariate and multivariate analyses also showed a strong association between GVHD and MBI-LCBI. This finding is not surprising, as occurrence of GVHD is one criterion for definition of MBI-LCBI9. Perhaps less intuitively, the occurrence of transplant-associated thrombotic microangiopathy (TA-TMA) was also strongly associated with MBI-LCBI. Recent work from our own center has shown that a degree of TA-TMA is frequent after HSCT, occurring in about one third of patients if monitored carefully12,18. Moreover, it is evident that TA-TMA leads to systemic vascular injury and widespread tissue injury, including the intestine19,20. It is therefore not surprising that translocation of bacteria occurs in these patients, and transplant recipients with symptoms or signs of TA-TMA are a high-risk group who would benefit from strategies to reduce frequency of MBI-LCBI. Our data demonstrate that BSI in HSCT recipients lead to increased use of healthcare resources, including treatment for septic shock, transfer to the PICU and need for central line removal and replacement. Interestingly, we saw a similar frequency of septic shock in children with MBI-LCBI, CLABSI and secondary infections, although PICU utilization was markedly higher in those with secondary infections. In multivariate analysis, both MBI-LCBI and secondary infections were associated with a significant increase in risk of NRM, while CLABSIs were not, increasing the imperative to reduce the frequency of MBI-LCBI and secondary infections. It might be argued that MBI-LCBI

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are simply a “marker” for sicker patients and do not directly cause mortality, but clinical experience and our data showing frequent transfer to the PICU support a more direct role in mortality. One of the original incentives for defining MBI-LCBI was to separate infections that could be reduced by attention to line care from those that could not. A recent study demonstrated no change in MBI-LCBI rates with CLABSI prevention standard compliance, while the interventions did impact CLABSI rates, further supporting the value of the definition21. Unfortunately, this has led to the belief in some quarters that MBI-LCBI cannot be prevented. We believe that it will be possible to reduce frequency of MBI-LCBI, but that novel and innovative strategies will be needed to achieve this goal. Our data show for the first time an association of BSIs with TA-TMA, and our group has recently described genetic markers that allow prediction of patients at high risk of TATMA prior to transplantation22. The frequency of TA-TMA (and perhaps MBI-LCBI) in high risk patients could be reduced by use of alternative transplant regimes (e.g. reduced use of sirolimus and calcineurin inhibitors) or careful screening for TA-TMA and early institution of complement blockade23. In alternative strategies, we are currently studying dietary approaches to improve gut permeability and reduce MBI-LCBI, including vitamins A and D, use of non-digestible oligosaccharides to maintain bowel microbiome diversity, and human behavior strategies to improve compliance with mouth care, another potential site of translocation24,25. Our current study has some limitations. Our data are a retrospective review of BSIs in a single pediatric institution. Our practice has a particular focus on care of immune deficiencies and bone marrow failure syndromes, and these data may not be applicable to all HSCT populations. In particular, our data may underestimate the morbidity and mortality seen in adult transplant programs because older patients may tolerate chemotherapy and subsequent sepsis more poorly. Despite these limitations,

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our data clearly show a heavy burden on healthcare utilization from BSIs, and in particular MBI-LCBI, that merits further attention to potential strategies to reduce these infections. In summary, our data show that about half the BSIs at our pediatric HSCT center meet the definition of MBI-LCBI, and that this definition is successful in identifying a different category of patient from those with CLABSI or secondary infections. Today more than 50,000 HSCT are carried out annually worldwide, and these numbers increase each year. MBI-LCBIs lead to significant morbidity and mortality and healthcare resource utilization. Reduction in frequency of MBI-LCBI should be a major public health and scientific priority.

Acknowledgement We would like to thank Joshua Schaffzin, MD, for manuscript edits; Carol Frese, RN, and Deborah Hacker, RN for their assistance in data acquisition. The authors have no financial relationships or other conflicts of interest relevant to this article to disclose.

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Figure 1 Title: Cumulative incidence of bloodstream infections in autologous and allogeneic stem cell recipients (n=374) Figure 1 Legend: Cumulative incidence of the first a) any bloodstream infection and b) MBI-LCBI in allogeneic and autologous stem cell transplant recipients. Abbreviations: Allo=allogeneic; Auto=autologous; BSI= bloodstream infection; HSCT=hematopoietic stem cell transplant; MBI=mucosal barrier injury laboratory confirmed bloodstream infection

Figure 2 Title: Non-relapse mortality in allogeneic stem cell recipients who develop a bloodstream infection after stem cell transplant (n=282) Figure 2 Legend: Non-relapse mortality in allogeneic stem cell transplant recipients who do not develop a bloodstream infection; one bloodstream infection; and two or more bloodstream infections in the first year after stem cell transplant. Abbreviations: BSI= bloodstream infection; HSCT=hematopoietic stem cell transplant

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Table 1: Univariate analysis of allogeneic stem cell recipients who develop and do not develop at least (a) one mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI); (b) central line associated bloodstream infection (CLABSI); and (c) secondary infection in the first year post transplant (n=282). Infection classification is not mutual exclusive. MBI-LCBI

CLABSI

Secondary Infections

Pre-Transplant Variables

(a) At least one MBI-LCBI (n=52)

No MBI-LCBI (n=230)

P value

(b) At least one CLABSI (n=43)

No CLABSI (n=239)

P Value

Median age in years (IQR)

9.6 (2.9 – 16.3)

0.132

5.3 (2.4 – 13.2) 29 (67%)

26 (50%) 11 (21%) 7 (13%) 5 (10%) 3 (6%)

87 (38%) 67 (29%) 52 (23%) 12 (5%) 12 (5%)

0.560 0.118

6.4 (2.3 – 12.9) 150 (63%)

0.795

36 (69%)

6.1 (2.2 – 12.4) 143 (62%)

27 (63%) 9 (21%) 4 (9%) 2 (5%) 1 (2%)

86 (36%) 69 (29%) 55 (23%) 15 (6%) 14 (6%)

29 (56%) 23 (44%)

89 (39%) 141 (61%)

24 (56%) 19 (44%)

94 (39%) 145 (61%)

39 (75%) 13 (25%) 34 (65%)

162 (70%) 68 (30%) 166 (72%)

32 (74%) 11 (26%) 31 (72%)

169 (71%) 70 (29%) 169 (71%)

41 (79%) 6 (12%) 5 (9%)

180 (78%) 32 (14%) 18 (8%)

34 (79%) 6 (14%) 3 (7%)

187 (78%) 32 (13%) 20 (9%)

18 (42%) 30 (70%) 5 (12%) 5 (12%)

65 (27%) 95 (40%) 13 (5%) 30 (13%)

Male (n=179) Diagnosis - Immunodeficiency (n=113) - Malignancy (n=78) - Marrow Failure (n=59) - Benign Hematology (n=17) - Genetic (n=15) Preparative Regimen - Reduced Intensity (n=118) - Myeloablative (n=164) Donor - Unrelated donor (n=201) - Related donor (n=81) Full match (n=200) Graft - Bone Marrow (n=221) - PBSC (n=38) - Cord (n=23) Post Transplant Variables Grade 2-4 acute GVHD (n=83) TA-TMA (n=125) Chronic GVHD (n=18) Engraftment Syndrome (n=35)

23 (44%) 35 (67%) 4 (8%) 7 (13%)

60 (26%) 90 (39%) 14 (6%) 28 (12%)

0.029 0.612 0.398 0.693

0.012 0.0003 0.759 0.817

0.609 0.001

0.064 0.716 1.000 1.000

0.068 0.0004 0.166 1.000

(c) At least one secondary infection (n=16) 7.0 (2.7 – 18.7)

No secondary infections (n=266) 6.2 (2.2 – 12.9)

P value

11 (69%)

168 (63%)

6 (38%) 4 (25%) 4 (25%) 1 (6%) 1 (6%)

107 (40%) 74 (28%) 55 (21%) 16 (6%) 14 (5%)

0.792 1.000

7 (44%) 9 (56%)

111 (42%) 155 (58%)

13 (81%) 3 (19%) 11 (69%)

188 (71%) 78 (29%) 189 (71%)

12 (75%) 2 (3%) 2 (3%)

209 (79%) 36 (14%) 21 (7%)

9 (56%) 12 (75%) 3 (19%) 4 (25%)

74 (28%) 113 (42%) 15 (6%) 31 (12%)

0.517

1.000 0.570 0.784 0.756

0.023 0.017 0.072 0.122

Abbreviations: CLABSI=central line associated bloodstream infection; GVHD=graft versus host disease; IQR=interquartile range; MBI-LCBI=mucosal barrier injury laboratory confirmed bloodstream infection; PBSC=peripheral blood stem cells; TA-TMA=transplant associated thrombotic microangiopathy

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Table 2: Multivariate analysis comparing allogeneic stem cell recipients (n=282) who develop at least one MBI-LCBI and CLABSI in the first year post transplant versus those who do not. Allogeneic recipients that developed at least one MBI-LCBI

Allogeneic recipients that developed at least one CLABSI

Multivariate

Multivariate

Variable

OR

P value

OR

P value

1

--

1

--

-Immunodeficiency

1.93

0.15

4.42

0.0061

-Malignancy

1.24

0.68

2.14

0.21

-Benign Hematology

2.59

0.14

1.74

0.54

-Genetic

2.62

0.19

1.61

0.67

1.96 1.07 0.68 1.67 2.94

0.015 0.86 0.23 0.07 0.0004

1.27

0.51

0.88

0.73

0.98

0.96

1.20

0.57

2.97

0.0019

Diagnosis

+

-Marrow Failure

RIC Unrelated donor Full Match Grade 2-4 acute GVHD +

TA-TMA

Diagnosis variables were considered for exclusion or inclusion together. Bold indicates variables were included in final model. Abbreviations: CLABSI=central line associated bloodstream infection; GVHD=graft versus host disease; MBI-LCBI=mucosal barrier injury laboratory confirmed bloodstream infection; RIC=reduced intensity conditioning; TA-TMA=transplant associated thrombotic microangiopathy Table 3: Outcomes and Resource Utilization of Patients who developed a bloodstream infection after stem cell transplant (n=170)

Septic Shock within 24 hours of Infection Central line Removed Within 7 Days Death Within 10 Days Transfer to PICU within 48 hours Patients in PICU at time of infection* Median days in the PICU days in patients transferred from floor (IQR)

MBI-LCBI (n=80) 37 (46%)

CLABSI (n=68)

p value

34 (50%)

Secondary Infections (n=22) 10 (45%)

31 (39%)

30 (44%)

10 (45%)

0.75

7 (9%) 17 of 73 (23%)

7 (10%) 14 of 59 (24%)

3 (14%) 2 of 13 (15%)

0.79 0.80

7

9

9

--

6 (3-10)

5 (3-15)

32 (18-46)

--

0.88

*Patients already in PICU not included in days calculation Abbreviations: CLABSI=central line associated bloodstream infection; GVHD=graft versus host disease; IQR=interquartile range; MBI-LCBI=mucosal barrier injury

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laboratory confirmed bloodstream infection; PICU=pediatric intensive care unit; TATMA=transplant associated thrombotic microangiopathy Table 4: Univariate and Multivariate non-relapsed mortality in allogeneic stem cell transplant recipients by infection category, TA-TMA, and acute GVHD (n=282). Univariate

Multivariate without acute GVHD OR p-value 1.94 0.018

Multivariate with acute GVHD OR p-value 1.73 0.055

MBI-LCBI (n=52)

OR 3.04

p-value 0.0005

CLABSI (n=43)

2.57

0.0014

1.17

0.68

1.08

0.83

Secondary(n=16)

5.06

<0.0001

2.87

0.0023

2.35

0.02

2-4 acute GVHD (n=83) TA-TMA (n=130)

3.43 6.07

<0.0001 <0.0001

-4.72

-0.0003

2.25 4.23

0.0036 0.0009

Bold indicates it was included in the final model Abbreviations: CLABSI=central line associated bloodstream infection; GVHD=graft versus host disease; MBI-LCBI=mucosal barrier injury laboratory confirmed bloodstream infection; TA-TMA=transplant associated thrombotic microangiopathy

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