Abstract
Background
Bloodstream infections (BSIs) are major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to analyze the incidence, etiology, risk factors and outcomes of post-engraftment BSI in allo-HCT recipients.
Materials and Methods
The retrospective study included 261 patients with documented engraftment after first allo-HCT performed from January 2018 till September 2021.
Results
Of 261 patients 29 (11.1%) developed at least one post-engraftment BSIs episode with a median time to post-engraftment BSI of 49 days (range, 1 - 158 days from the engraftment). A total of 45 pathogens were isolated from blood – 64.4% (n = 29) were represented by Gram-negative bacteria, and 35.6% (n = 16) – by Gram-positive bacteria. Secondary graft failure (hazard ratio [HR]: 39.93; 95% confidence interval [CI]: 7.64-208.74; P <0.001), secondary poor graft function (HR: 18.07; 95% CI: 3.53 - 92.44; P <0.001), and acute gut graft-versus-host-disease (GvHD) grade II-IV (HR: 29.86; 95% CI: 10.53 - 84.68; P <0.001) were associated with the higher risk of Gram-negative post-engraftment BSIs. Overall 30-day survival after post-engraftment BSIs was 71.4%. By multivariate analysis post-engraftment BSIs (HR: 3.09; 95% CI: 1.29 – 7.38; P = 0.011), and acute gut GvHD grade II-IV (HR: 6.60; 95% CI: 2.78 - 15.68; P <0.001) were associated with the higher 180-day non-relapse mortality risk.
Conclusion
Gram-negative bacteria prevailed in the etiology of post-engraftment BSIs with secondary graft failure. secondary poor graft function. and acute gut GvHD being the main predisposing factors for their development. Post-engraftment BSIs were associated with the higher risk of non-relapse mortality after allo-HCT.
Keywords: Allogeneic hematopoietic cell transplantation, Post-engraftment, Bloodstream infections, Risk factors, Mortality
Graphical Abstract
Introduction
Bloodstream infections (BSIs) are major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT) [1,2,3]. Although the incidence of BSIs is higher during the pre-engraftment phase, they are still common after engraftment with reported incidence of post-engraftment BSIs in a range of 13.6 - 31.0% [4,5,6,7]. The major risk factors for their development are secondary neutropenia, steroid use, organ failure, and acute graft-versus-host-disease (GvHD) particularly with gut involvement [6,7,8,9]. However, in the largest to date intercontinental study on Gram-negative bacteriemia in allo-HCT recipients no association of acute GvHD with the higher risk of post-engraftment BSIs could be identified [10].
Although several studies have already tried to address the problem of post-engraftment BSIs, there is no trial from Europe to draw definitive conclusions about the overall rate and etiology of post-engraftment BSIs. That is of particular importance since a global shift in the etiology of BSIs after allo-HCT with increasing rate of Gram-negative bacteriemia and emergence of resistant strains has been observed during the last decade [11,12]. Moreover, the role of post-engraftment BSIs on survival outcomes is yet to be defined, since published studies have reported controversial results [4,5,6,10].
Taken all of the aforementioned to the account, this study aimed to analyze the incidence, etiology, risk factors and outcomes of post-engraftment BSIs in allo-HCT recipients.
Materials and methods
1. Study design
This is a retrospective study of 261 patients with documented engraftment after first allo-HCT performed at the National Research Center for Hematology in Moscow, Russia, from January 2018 till September 2021.
2. Ethics statement
All patients provided signed written informed consent for anonymous data collection before transplantation. BSIs registered between the day of engraftment and day +180 from engraftment were included. The Institutional Review Board approved the study (Nº163 25.01.2019).
3. Infection-related procedures
All patients during neutropenia were treated in wards equipped with high-efficiency particulate air filters. During the post-engraftment phase patients were assigned to the standard wards. Anti-bacterial prophylaxis with ciprofloxacin 500 mg BID starting from the first day of the conditioning regimen was administered only in patients non-colonized with extended-spectrum beta-lactamase (ESBL) producing Enterobacterales, fluoroquinolone non-susceptible Pseudomonas aeruginosa or carbapenem-resistant Gram-negative bacteria. Ciprofloxacin was discontinued after engraftment or after intravenous antibiotics administration in case of fever. Fluconazole 400 mg once daily was used for primary antifungal prophylaxis. Posaconazole was used for antifungal prophylaxis in patients receiving steroids due to GvHD in a dose ≥1 mg/kg/day. Valacyclovir 500 mg BID or acyclovir intravenously 5 mg/kg BID were administered for antiviral prophylaxis, and sulfamethoxazole/trimethoprim 480 mg QD for Pneumocystis jirovecii prophylaxis.
After a febrile episode 2 sets of blood were drawn from a peripheral vein and central venous catheter. Blood specimens were processed and incubated using BD BACTEC FX (Becton Dickinson, Franklin Lakes, NJ, USA). Pathogen identification was done by matrix-assisted desorption/ionization time-of-flight mass spectrometry using Microflex (Bruker Daltonics, Bremen, Germany). In case of common skin contaminants such as coagulase-negative staphylococci and Corynebacteria, BSIs was confirmed only after 2 consecutive blood cultures positive for the same strain. BSIs was considered polymicrobial if 2 or more pathogens were isolated within 72 hours. Antibiotic susceptibility was analyzed using BD PhoenixTM M50 (Becton Dickinson, USA). Results were interpreted in accordance with the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints [13].
4. Transplant related definitions
Engraftment was defined as the first of three consecutive days of an absolute neutrophil count more than 0.5 × 109/L. Secondary graft failure was defined as decline in hematopoietic function with mixed or full recipient hematopoiesis necessitating second allograft. Secondary poor graft function was defined as decline in hematopoietic function with full donor chimerism after having met the standard definition of engraftment and was mostly managed with blood products, growth factor support or CD34+ selected stem cell boost. Myeloablative conditioning was defined as per CIBMTR criteria [14]. GvHD prophylaxis was considered based on the donor and graft source as recently described [2]. GvHD was diagnosed and graded according to the well-established criteria [15]. Therapy of acute GvHD included methylprednisolone 1 mg/kg/day for grade II GvHD without gut involvement, and 2 mg/kg/day for grade III-IV GvHD or grade II GvHD with gut involvement. Second-line therapy was administered at the discretion of attending physician.
5. Statistical analysis
Categorical variables were analyzed using Pearson's Chi-square test or Fisher's exact test for small groups. Continuous variables were analyzed using the Mann-Whitney U-test or Kruskal-Wallis test. Cumulative incidence of BSIs was estimated by the Fine-Gray method with relapse, death, and second allo-HCT as competing events. Patients not experiencing any event were censored at day +180 after engraftment. Risk factors analysis was done in univariate and multivariate models. Factors significantly (P <0.05) associated with development of post-engraftment BSIs in univariate analysis were included in multivariate model using the stepwise backward Cox regression model. Patients were censored at the time of relapse, death, and second allo-HCT depending on the first occurring event. Patients not experiencing an event were censored at day +180 after engraftment. Overall survival by day +30 after all BSIs episodes was estimated using the Kaplan-Meier method, and the log-rank test was used to compare groups. P <0.05 was considered statistically significant. To estimate the impact of post-engraftment BSIs on transplant outcomes non-relapse mortality risk analysis by day +180 post-engraftment was performed in the entire cohort with univariate and multivariate models as previously described. Statistical analysis was performed using SPSS (version 23.0, IBM, Chichago, IL, USA) and R Statistical Software (version 3.3.0, R Foundation for Statistical Computing, Vienna, Austria).
Results
Detailed data on patient characteristics is given in Table 1. In brief, patients were equally distributed by gender, were most likely to receive an allo-HCT due to acute leukemias in complete remission using reduced-intensity conditioning regimen and peripheral blood stem cells as a graft source. During the follow-up period 24 (9.2%) of 261 patients included in the study experienced relapse of the underlying disease with a median time of 72.5 days (range, 10 - 120 days from the engraftment); 2 patients (0.8%) received second allograft due to secondary graft failure (day +56 and +129 from the engraftment, respectively); and 14 patients (5.4%) died at a median of 81.5 days (range, 19 - 137 days from the engraftment).
Table 1. Patients characteristics.
| Feature | N, (%) | |
|---|---|---|
| Gender | ||
| Male | 125 (47.9) | |
| Female | 136 (52.1) | |
| Age, median (range) | 35 (17 - 65) | |
| Age adjusted HCT-CI | ||
| 0 | 137 (52.5) | |
| 1 | 102 (39.1) | |
| ≥2 | 22 (8.4) | |
| Diagnosis | ||
| Acute myeloid leukemia | 109 (41.8) | |
| Acute lymphoblastic leukemia | 79 (30.3) | |
| Myelodysplastic syndrome | 31 (11.9) | |
| Myelofibrosis | 12 (4.5) | |
| Non-Hodgkin lymphoma | 9 (3.5) | |
| Aplastic anemia | 7 (2.7) | |
| Chronic myeloid leukemia | 7 (2.7) | |
| Multiple myeloma | 3 (1.1) | |
| Others | 3 (1.1) | |
| Disease status | ||
| Remission | 235 (90.0) | |
| Active disease | 26 (10.0) | |
| Conditioning | ||
| Myeloablative | 72 (27.6) | |
| Reduced intensity | 189 (72.4) | |
| Graft source | ||
| Bone marrow | 62 (23.8) | |
| PBSC | 199 (76.2) | |
| Donor | ||
| Matched related | 81 (31.0) | |
| Matched unrelated | 61 (23.4) | |
| Mismatched unrelated | 30 (11.5) | |
| Haploidentical | 89 (34.1) | |
| GvHD Prophylaxis | ||
| ATG | 73 (28.0) | |
| PTCy | 88 (33.7) | |
| TCRab/CD19 - depletion | 47 (18.0) | |
| ATG + PTCy | 48 (14.6) | |
| None | 15 (5.7) | |
| Immunosuppressive therapy | ||
| CSA + MMF | 123 (47.1) | |
| CSA + MTX | 25 (9.6) | |
| TCRab/CD19 - depletion | 59 (22.6) | |
| CSA + MMF + MTX | 47 (18.0) | |
| None | ||
| Secondary graft failure | 9 (3.4) | |
| Secondary poor graft function | 10 (3.8) | |
| Acute GvHD grade II-IV | 59 (22.6) | |
| Acute GvHD grade II-IV with skin involvement | 38 (14.6) | |
| Acute GvHD grade II-IV with gut involvement | 35 (13.4) | |
| Acute GvHD grade II-IV with liver involvement | 14 (5.4) | |
| Chronic GvHD moderate or severe | 18 (6.9) | |
HCT-CI, hematopoietic cell transplantation-specific comorbidity index; PBSC, peripheral blood stem cell; ATG, antithymocyte globulin; PTCy, posttransplantation cyclophosphamide; CSA, cyclosporine A; MMF, mycophenolate mofetil; MTX, methotrexate; GvHD, graft-versus-host-disease.
Of 261 patients 29 developed at least one post-engraftment BSIs episode, that corresponded to the cumulative incidence of 11.1% (Fig. 1). Median time to post-engraftment BSIs was 49 days (range, 1 - 158 days from the engraftment). Among 29 patients with documented post-engraftment BSIs 23 patients (79.3%) had only 1 BSIs episode, and 6 patients (20.7%) – two episodes resulting in overall 35 post-engraftment BSIs episodes. Twenty six episodes (74.3%) were caused by single pathogen, whereas 9 (25.7%) were polymicrobial. A total of 45 pathogens were isolated from blood – 64.4% (n = 29) were represented by Gram-negative bacteria, and 35.6% (n = 16) were represented by gram-positive bacteria (Table 2). Among Gram-negative bacteria 72.4% were resistant to fluoroquinolones, 55.2% were resistant to third-generation cephalosporins, and 17.2% were carbapenem-resistant.
Figure 1. Cumulative incidence of post-engraftment bloodstream infections.
Table 2. Etiology of post-engraftment bloodstream infections.
| Pathogen | Total = 45 N, (%) |
|---|---|
| Klebsiella spp. | 9 (20.0) |
| K. pneumoniae | 8 (88.9) |
| K. pneumoniae ESBL-producing | 3 (37.5) |
| K. pneumoniae carbapenem-resistant | 3 (37.5) |
| K. oxytoca | 1 (11.1) |
| Escherichia coli | 8 (17.8) |
| E. coli ESBL-producing | 2 (25.0) |
| Enterococcus spp. | 7 (15.5) |
| E. faecium | 4 (57.2) |
| E. faecalis | 3 (42.8) |
| E. cloacae | 6 (13.3) |
| Coagulase negative staphylococci | 6 (13.3) |
| Pseudomonas aeruginosa | 4 (8.9) |
| P. aeruginosa carbapenem-resistant | 1 (25.0) |
| Acinetobacter ursignii | 1 (2.2) |
| Chryseobacterium gleum | 1 (2.2) |
| Staphylococcus aureus | 1 (2.2) |
| Viridans streptococci | 1 (2.2) |
| Bacillus cereus | 1 (2.2) |
ESBL, extended-spectrum beta-lactamase.
Matched unrelated donor transplantation (P = 0.050), secondary graft failure (P <0.001), secondary poor graft function (P <0.001), and acute gut GvHD grade II-IV (P <0.001) were significantly associated with the development of any post-engraftment BSIs (Table 3). In multivariate model secondary graft failure (HR: 79.45; 95% CI: 23.86 - 264.53; P <0.001), secondary poor graft function (HR: 25.67; 95% CI: 7.48 - 88.04; P <0.001), and acute gut GvHD grade II-IV (HR: 34.09; 95% CI: 13.78 - 84.36; P <0.001) retained their independent value (Table 4). Monomicrobial Gram-negative post-engraftment BSIs were registered in 20 patients (7.7%). Matched unrelated donor transplantation (P = 0.038), secondary graft failure (P = 0.003), secondary poor graft function (P = 0.007), acute gut GvHD grade II-IV (P <0.001), and acute liver GvHD grade II-IV (P = 0.047) were significantly associated with their development in the univariate analysis (Table 3). By multivariate analysis, again, only secondary graft failure (HR: 39.93; 95% CI: 7.64 - 208.74; P <0.001), secondary poor graft function (HR: 18.07; 95% CI: 3.53 - 92.44; P <0.001), and acute gut GvHD grade II-IV (HR: 29.86; 95% CI: 10.53 - 84.68; P <0.001) remained significant (Table 4). Monomicrobial Gram-positive BSIs during the post-engraftment phase was detected in 6 patients (2.3%). No risk factors associated with their development could be identified (Table 3).
Table 3. Univariate analysis of factors predisposing to any, Gram-negative (Gram-), and Gram-positive (Gram+) post-engraftment BSI.
| Factor | Any BSI n, (%) | P | Gram- BSI n, (%) | P | Gram+ BSI n, (%) | P | |
|---|---|---|---|---|---|---|---|
| Age | 0.066 | 0.598 | 0.593 | ||||
| ≥40 years | 13 (8.2) | 9 (8.7) | 3 (1.9) | ||||
| <40 years | 16 (15.5) | 11 (7.0) | 3 (2.9) | ||||
| Gender | 0.220 | 0.220 | 0.352 | ||||
| Male | 12 (8.8) | 11 (8.8) | 4 (3.2) | ||||
| Female | 17 (13.6) | 9 (6.6) | 2 (1.5) | ||||
| Age adjusted HCT-CI | 0.165 | 0.434 | 0.579 | ||||
| <2 | 5 (19.2) | 3 (11.5) | 1 (3.8) | ||||
| ≥2 | 24 (10.2) | 17 (7.2) | 5 (2.1) | ||||
| Phase of disease | 0.227 | 0.738 | 0.432 | ||||
| Active | 4 (19.0) | 2 (9.5) | 1 (4.8) | ||||
| Remission | 25 (10.4) | 18 (7.5) | 5 (2.1) | ||||
| Conditioning | 0.659 | 0.440 | 0.545 | ||||
| Myeloablative | 9 (12.5) | 7 (9.7) | 1 (1.4) | ||||
| Reduced intensity | 20 (10.6) | 13 (6.9) | 5 (2.6) | ||||
| Time from diagnosis to allo-HCT | 0.405 | 0.788 | 0.079 | ||||
| ≥10 months | 13 (9.6) | 11 (8.1) | 1 (0.7) | ||||
| <10 months | 16 (12.8) | 9 (7.2) | 5 (4.0) | ||||
| Donor | 0.050 | 0.038 | 0.194 | ||||
| Matched related | 4 (4.9) | 2 (2.5) | 0 (0) | ||||
| Matched unrelated | 12 (19.7) | 9 (14.8) | 2 (3.3) | ||||
| Mismatched unrelated | 3 (10.0) | 1 (3.3) | 2 (6.7) | ||||
| Haploidentical | 10 (11.2) | 8 (9.0) | 2 (2.2) | ||||
| Graft Source | 0.072 | 0.338 | 0.167 | ||||
| Bone marrow | 3 (4.8) | 3 (4.8) | 0 (0) | ||||
| Peripheral blood stem cells | 26 (13.1) | 17 (8.5) | 6 (3.6) | ||||
| GvHD Prophylaxis | 0.378 | 0.121 | 0.888 | ||||
| ATG | 11 (15.1) | 10 (13.7) | 1 (1.4) | ||||
| PTCy | 7 (8.0) | 3 (3.4) | 3 (3.4) | ||||
| TCRab/CD19 - depletion | 6 (12.8) | 4 (8.5) | 1 (2.1) | ||||
| ATG + PTCy | 5 (13.2) | 3 (7.9) | 1 (2.6) | ||||
| None | 0 (0) | 0 (0) | 0 (0) | ||||
| Secondary graft failurea | <0.001 | 0.003 | 0.073 | ||||
| Yes | 6 (66.7) | 3 (33.3) | 1 (11.1) | ||||
| No | 23 (9.1) | 17 (6.7) | 5 (2.0) | ||||
| Secondary poor graft functiona | <0.001 | 0.007 | 0.098 | ||||
| Yes | 5 (50.0) | 3 (30.0) | 1 (10.0) | ||||
| No | 24 (9.6) | 17 (6.8) | 5 (2.0) | ||||
| Acute skin GvHD grade II-IVa | 0.664 | 0.547 | 0.882 | ||||
| Yes | 5 (13.2) | 2 (5.3) | 1 (2.6) | ||||
| No | 24 (10.8) | 18 (8.1) | 5 (2.2) | ||||
| Acute liver GvHD grade II-IVa | 0.207 | 0.047 | 0.555 | ||||
| Yes | 3 (21.4) | 3 (21.4) | 0 (0) | ||||
| No | 26 (10.5) | 17 (6.9) | 6 (2.4) | ||||
| Acute gut GvHD grade II-IVa | <0.001 | <0.001 | 0.147 | ||||
| Yes | 15 (42.9) | 11 (31.4) | 2 (5.7) | ||||
| No | 14 (6.2) | 9 (4.0) | 4 (1.8) | ||||
| Chronic GvHD moderate or severea | 1.000 | 0.569 | 0.500 | ||||
| Yes | 2 (11.1) | 2 (11.1) | 0 (0) | ||||
| No | 27 (11.1) | 18 (7.4) | 6 (2.5) | ||||
aCalculated as time-dependent covariate.
BSI, bloodstream infection; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; GvHD, graft-versus-host-disease; ATG, antithymocyte globulin; PTCy, posttransplantation cyclophosphamide; TCRab, T-cell receptor alpha/beta.
Table 4. Multivariate analysis of factors predisposing to any or Gram-negative post-engraftment BSI.
| Factor | HR (95% CI) | P | |
|---|---|---|---|
| Any post-engraftment BSI | |||
| Secondary graft failurea | <0.001 | ||
| Yes | 79.45 (23.86 - 264.53) | ||
| No | 1.00 | ||
| Secondary poor graft functiona | <0.001 | ||
| Yes | 25.67 (7.48 - 88.04) | ||
| No | 1.00 | ||
| Acute gut GvHD grade II-IVa | <0.001 | ||
| Yes | 34.09 (13.78 - 84.36) | ||
| No | 1.00 | ||
| Donor | 0.418 | ||
| Matched related | 1.00 | ||
| Matched unrelated | 2.77 (0.82 - 9.30) | ||
| Mismatched unrelated | 1.81 (0.36 - 9.09) | ||
| Haploidentical | 2.10 (0.58 - 7.60) | ||
| Gram-negative post-engraftment BSI | |||
| Secondary graft failurea | <0.001 | ||
| Yes | 39.93 (7.64 - 208.74) | ||
| No | 1.00 | ||
| Secondary poor graft functiona | <0.001 | ||
| Yes | 18.07 (3.53 - 92.44) | ||
| No | 1.00 | ||
| Acute gut GvHD grade II-IVa | <0.001 | ||
| Yes | 29.86 (10.53 - 84.68) | ||
| No | 1.00 | ||
| Acute liver GvHD grade II-IVa | 0.149 | ||
| Yes | 2.90 (0.68 - 12.27) | ||
| No | 1.00 | ||
| Donor | 0.241 | ||
| Matched related | 1.00 | ||
| Matched unrelated | 4.29 (0.84 - 21.83) | ||
| Mismatched unrelated | 1.17 (0.10 - 14.31) | ||
| Haploidentical | 3.45 (0.65 - 18.17) | ||
aCalculated as time-dependent covariate.
BSI, bloodstream infections; HR, hazard ratio; CI, confidence interval; GvHD, graft-versus-host-disease.
Overall 30-day survival after all post-engraftment BSIs episodes was 71.4%. No significant difference was identified between Gram-negative, Gram-positive, and polymicrobial post-engraftment BSIs (80.0% vs. 75.0% vs. 42.9%, respectively; P = 0.140). Moreover, no survival differences were detected after post-engraftment BSIs due to carbapenem-resistant Gram-negative bacteria, ESBL-producing Enterobacterales or carbapenem-sensitive non-ESBL-producing bacteria (60.0% vs. 60.0% vs. 76.0%, respectively; P = 0.548). Overall 180-day survival post-engraftment was 87.8% with the corresponding non-relapse mortality rate of 11.1% (n = 29). The most important factors associated with the higher risk of non-relapse mortality by multivariate analysis (Table 5) were acute gut GvHD grade II-IV (HR: 6.60; 95% CI: 2.78 - 15.68; P <0.001), and post-engraftment BSIs (HR: 3.09; 95% CI: 1.29 – 7.38; P = 0.011).
Table 5. Univariate and multivariate analysis of day +180 non-relapse mortality predisposing factors.
| Factor | Univariate analysis, n (%) | P | Multivariate analysis, HR (95% CI) | P | |
|---|---|---|---|---|---|
| Age | 0.854 | - | - | ||
| ≥40 years | 11 (9.7) | ||||
| <40 years | 18 (10.4) | ||||
| Gender | 0.431 | - | - | ||
| Male | 16 (11.6) | ||||
| Female | 13 (8.8) | ||||
| Phase of disease | 0.181 | - | - | ||
| Active | 24 (9.3) | ||||
| Remission | 5 (17.2) | ||||
| Age adjusted HCT-CI | 0.353 | - | - | ||
| <2 | 4 (15.4) | ||||
| ≥2 | 25 (9.6) | ||||
| Conditioning | 0.896 | - | - | ||
| Myeloablative | 8 (10.5) | ||||
| Reduced intensity | 21 (10.0) | ||||
| Donor | 0.016 | 0.257 | |||
| Matched related | 3 (3.6) | 1.00 | |||
| Matched unrelated | 13 (18.8) | 2.95 (0.80 - 10.88) | |||
| Mismatched unrelated | 5 (15.2) | 3.67 (0.86 - 15.74) | |||
| Haploidentical | 9 (8.6) | 1.88 (0.50 - 7.02) | |||
| Graft Source | 0.109 | - | - | ||
| Bone marrow | 3 (4.8) | ||||
| Peripheral blood stem cells | 26 (11.7) | ||||
| GvHD Prophylaxis | 0.087 | - | - | ||
| ATG | 12 (15.8) | ||||
| PTCy | 5 (5.0) | ||||
| TCRab/CD19 - depletion | 2 (3.8) | ||||
| ATG + PTCy | 6 (14.3) | ||||
| None | 0 | ||||
| Secondary graft failurea | 0.034 | 0.082 | |||
| Yes | 3 (30.0) | 1.00 | |||
| No | 26 (9.4) | 3.22 (0.86 - 11.99) | |||
| Secondary poor graft functiona | 0.293 | - | - | ||
| Yes | 2 (20.0) | ||||
| No | 27 (9.8) | ||||
| Acute skin GvHD grade II-IVa | 0.112 | - | - | ||
| Yes | 7 (17.1) | ||||
| No | 22 (9.0) | ||||
| Acute liver GvHD grade II-IVa | 0.240 | - | - | ||
| Yes | 3 (18.8) | ||||
| No | 26 (9.6) | ||||
| Acute gut GvHD grade II-IVa | <0.001 | <0.001 | |||
| Yes | 15 (6.0) | 1.00 | |||
| No | 14 (36.8) | 6.60 (2.78 - 15.68) | |||
| Chronic GvHD moderate or severea | 0.206 | ||||
| Yes | 1 (2.9) | ||||
| No | 28 (11.4) | ||||
| Post-engraftment BSIa | <0.001 | 0.011 | |||
| Yes | 12 (41.4) | 3.09 (1.29 - 7.38) | |||
| No | 17 (6.6) | 1.00 | |||
| Post-engraftment BSI caused by | 0.519 | - | - | ||
| Carbapenem-sensitive and non-ESBL-producing bacteria | 12 (15.6) | ||||
| ESBL-producing Enterobacteriaceae | 3 (20.0) | ||||
| Carbapenem-resistant Gram-negative bacteria | 2 (33.3) | ||||
aCalculated as time-dependent covariate.
HR, hazard ratio; CI, confidence interval; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; GvHD, graft-versus-host-disease; ATG, antithymocyte globulin, PTCy, posttransplantation cyclophosphamide; TCRab, T-cell receptor alpha/beta; ESBL, extended-spectrum beta-lactamase.
Discussion
In this single-center study we analyzed the incidence, etiology, risk factors and outcomes of post-engraftment BSIs in 261 allo-HCT recipients. The main findings of this research are that (1) Gram-negative bacteria prevailed in the etiology of BSIs during the post-engraftment phase; (2) secondary graft failure, secondary poor graft function, and acute gut GvHD were the main predisposing factors for their development; (3) post-engraftment BSIs were associated with the higher risk of non-relapse mortality after allo-HCT.
The incidence of post-engraftment BSIs in this study was 11.1%, which was lower as compared to published reports [4,5,6,7]. Despite low incidence, the main proportion of isolates obtained from blood was represented by Gram-negative bacteria (64.4%). In contrast, the rate of Gram-negative bacteria isolated from blood during the post-engraftment phase was previously reported in a range of 11.4-37.6% [4,6,7]. The revealed proportion of Gram-negative bacteria was even higher compared to the pre-engraftment phase investigated in the same cohort of patients and recently published by our group (52.2%) [2]. This might be associated with the higher rate of gut colonization with Gram-negative bacteria and bacterial translocation from gut mucosal surface coming to the forefront as the main source of post-engraftment BSIs, which was confirmed by the predominance of Enterobacterales and Enterococcus spp. as the leading causative agents of BSIs.
The main risk factors associated with the higher risk of post-engraftment BSIs were secondary graft failure, secondary poor graft function, and acute gut GvHD. Although the role of secondary neutropenia has already been demonstrated in one single-center study from the USA, the unique feature of our report was associated with the implementation of modern definitions for post-engraftment neutropenia, and demonstration of distinctive role of both secondary graft failure, and secondary poor graft function in the development of post-engraftment BSIs, and particularly Gram-negative post-engraftment BSIs [6]. The same applied for acute gut GvHD, since to date no report was able to demonstrate its specific association with Gram-negative BSIs. More concretely, the largest to date intercontinental study on Gram-negative BSIs in stem cell transplant recipients revealed no role of gut GvHD in the development of post-engraftment BSIs [10].
Another important aspect of this analysis was related to the negative impact of post-engraftment BSIs on survival after allo-HCT. Overall 30-day survival after post-engraftment BSIs was only 71.4% compared to 94.4% after BSIs documented during the pre-engraftment phase in the same cohort of patients in our previous analysis [2]. This could be attributed to posttransplant complications such as secondary graft failure, and acute gut GvHD, which are life-threatening themselves, and predispose to post-engraftment BSIs development, thus raising the risk exponentially. The independent negative role of post-engraftment BSIs on survival was also confirmed by the higher risk of 180-day non-relapse mortality in patients developing post-engraftment BSIs, which was in line with the CIBMTR analysis demonstrating a higher risk of one year non-relapse mortality in allo-HCT recipients with documented post-engraftment BSIs [5].
In conclusion, we believe that current study adds important evidence to the understanding of the problem of BSIs after allo-HCT. This is the first report to demonstrate the predominance of Gram-negative bacteria in the etiology of post-engraftment BSIs, and to highlight the specific role of secondary graft failure, secondary poor graft function, and acute gut GvHD in the development of Gram-negative post-engraftment BSIs. Moreover, this is the first single center study to confirm the negative impact of post-engraftment BSIs on non-relapse mortality after allo-HCT.
Footnotes
Funding: None.
Conflict of Interest: No conflict of interest.
- Conceptualization: MA, GK, EP.
- Data curation: MA, LA, AF.
- Formal analysis: MA, MD, AF.
- Investigation: MA, GK.
- Methodology: MA, GK, EP.
- Project administration: MA, GK, LK, AF, EP.
- Resources: GK, LK, AF, EP.
- Supervision: GK, EP.
- Writing - original draft: MA.
- Writing - review & editing: MA, GK, LK, AF, MD, EP.
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