Predictive implications of albumin and C-reactive protein for progression to pneumonia and poor prognosis in Stenotrophomonas maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation

S. maltophilia bacteremia was defined as at least one positive blood culture of S. maltophilia with clinical signs of infection. Initial source of infection consisted of central line-associated blood stream infection (CLABSI), pneumonia, cellulitis, and sources unknown. CLABSI was diagnosed when S. maltophilia was detected from the CVC tip with a positive blood culture, or according to the widely accepted definition of differential time to positivity [14]. Pneumonia and cellulitis were defined as active clinical signs and symptoms with newly detected imaging findings consistent with the site of infection, with or without isolation of the organism from concomitant specimens [11, 15]. The BacT/Alert 3D (bioMérieux, France) automated blood culture system was used. Identification and antimicrobial susceptibility testing of isolates also were conducted using the MicroScan Walkaway plus System (Beckman Coulter, Inc., USA) based on Manual M100-S23 of the Clinical and Laboratory Standards Institute. Polymicrobial, continuous, and breakthrough bacteremia were defined as follows: bacteremia due to multiple organisms including S. maltophilia; bacteremia due to S. maltophilia that was detected persistently in the same patient; bacteremia in patients receiving appropriate therapy for the microorganism that was grown from the blood [11, 16]. Effective antimicrobial therapy was defined as the use of one or more agent active against S. maltophilia in an adequate dose [17]. Severe sepsis and septic shock were defined by the SSCG2012 criteria [18]. S. maltophilia-related mortality was judged by a review of the medial chart. Patients who succumbed to S. maltophilia bacteremia or complications of the bacteremia, not primary hematological disease itself, were judged as S. maltophilia-related deaths. In the analysis of S. maltophilia-related mortality, patients who died, but were not judged as S. maltophilia-related deaths, were censored on the date of death. Neutropenia was defined as an absolute neutrophil count (ANC) less than 0.5 × 10⁹/L. Profound and prolonged neutropenia were defined as an ANC less than 0.1 × 10⁹/L and less than 0.5 × 10⁹/L for more than 14 days, respectively. Neutrophil engraftment was defined by an ANC of at least 0.5 × 10⁹/L for 3 consecutive days. Adverse events, such as diarrhea and mucositis, were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Conditioning intensity was classified as myeloablative or reduced-intensity conditioning according to Center and International Blood and Marrow Transplant Research classification [19]. Our policies of antimicrobial prophylaxis in allo-HSCT were as follows: levofloxacin for bacterial infections; fluconazole, itraconazole, or voriconazole for fungal infections; trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine inhalation for Pneumocystis jirovecii pneumonia; and acyclovir for viral infections. Cefepime, tazobactam-piperacillin, or meropenem was administered for empirical treatment of febrile neutropenia according to the IDSA guidelines [20].

We compared allo-HSCT recipients with patients not receiving allo-HSCT to investigate the incidence, clinical characteristics, and mortality. Patients not receiving allo-HSCT were consisted of those with non-malignant hematological disorders, and those who received chemotherapies or auto-HSCT. Fisher’s exact test for categorical variables and the Mann-Whitney U-test for continuous variables were used. Prognostic factors associated with 90-day mortality among allo-HSCT recipients only were analyzed by log-rank test according to age, sex, C-reactive protein (CRP), albumin, creatinine, neutropenia, onset of bacteremia, existence of acute GVHD, primary disease risk, presence of polymicrobial bacteremia, severe sepsis or septic shock, initial source of infection, removal of CVC, source of transplantation, related or unrelated source, HLA mismatching, conditioning intensity, sex mismatching, antibody of cytomegalovirus in recipients, ABO mismatching, and study period. The serum values of CRP, albumin, and creatinine were assessed at the onset of bacteremia. The cut-off values of albumin and CRP were determined using Receiver Operating Characteristics curve analysis (Additional file 1: Figure S1). Significant variables in the univariate analysis were included in the multivariate Cox proportional-hazards regression model with stepwise method, and both hazard-ratios and 95% confidence intervals (95% CI) were calculated. Two-tailed p-values of less than 0.05 were considered significant. All statistical analyses were conducted using EZR software [21].

There were 5679 admissions and 720 allo-HSCTs with 191,090 patient-days during the study period. A total of 65 patients with S. maltophilia bacteremia were identified, with the incidence of 1.14 cases per 100 admissions and 3.40 cases per 10,000 patient-days. The incidence of S. maltophilia bacteremia was significantly higher in allo-HSCT recipients compared to patients not receiving allo-HSCT (6.53 vs. 0.36 per 100 admissions, respectively; p < 0.01, and 6.19 vs. 1.56 per 10,000 patient-days, respectively; p < 0.01). Notably, the overall incidence of S. maltophilia bacteremia increased during the latter 5-year period compared to the former 5-year period (1.79 vs. 0.63 per 100 admissions, respectively; p < 0.01; Fig. 1). Among the 720 allo-HSCT cases during the study period, there were no significant differences in the incidence of S. maltophilia bacteremia between each stem cell source, 7.3% (34/468) in bone marrow, 4.4% (7/158) in peripheral blood, and 6.3% (6/94) in cord blood (p = 0.42).

Of all patients with S. maltophilia bacteremia, 47 (72.3%) had received allo-HSCT. Compared with patients not receiving allo-HSCT, allo-HSCT recipients were younger (median; 49 vs. 59 years old; p = 0.02), and more likely to have diarrhea (55.3% vs. 16.7%; p < 0.01), mucositis (42.6% vs. 5.6%; p < 0.01), CVC (95.7% vs. 61.1%; p < 0.01), total parenteral nutrition (44.7% vs. 5.6%; p < 0.01), and insulin therapy within 7 days (27.7% vs. 0%; p = 0.01) (Table 1). Although the overall 90-day mortality rate in allo-HSCT recipients was nominally higher (42.6% [20/47] in allo-HSCT vs. 27.8% [5/18] in non-allo-HSCT), the difference was not significant (p = 0.28; Fig. 2a). Similarly, the S. maltophilia-related 90-day mortality rate was nominally higher in allo-HSCT recipients compared to non-allo-HSCT recipients, but this difference was not statistically significant (34.0% [16/47] vs. 22.2% [4/18], respectively; p = 0.35; Fig. 2b).

Among allo-HSCT recipients, 8 out of 47 (17%) patients developed breakthrough S. maltophilia bacteremia. One of these 8 patients had received levofloxacin, and the other 7 of 8 were receiving TMP-SMX at the onset of S. maltophilia bacteremia. The probabilities of development of all-graded and graded II to IV acute GVHD at the onset of S. maltophilia bacteremia among 47 allo-HSCT recipients were 31.9% and 23.4%, respectively. Most of the patients with all-graded acute GVHD (14/15) had skin manifestations, and only 4 out of 15 patients had gut manifestations. Days from transplantation to onset of S. maltophilia bacteremia was 18 days (range, −6 to 1434), and 17 of the 47 (34.1%) allo-HSCT recipients developed S. maltophilia bacteremia after achievement of neutrophil engraftment.

Among 47 allo-HSCT recipients, univariate analysis showed that high levels of serum CRP (≥10.0 mg/dl), low levels of serum albumin (<3.0 g/dl), increased serum creatinine levels (≥1.0 mg/dl), high disease risk, severe sepsis or septic shock, initial source of infection, time to appropriate therapy, non-removal of CVC, and reduced-intensity conditioning regimens were significant risk factors for overall 90-day mortality. Independent risk factors associated with overall 90-day mortality were high levels of serum CRP (adjusted hazard ratio [aHR], 3.28; 95% CI, 1.00–10.72; p = 0.05) and low levels of serum albumin (aHR, 10.86; 95% CI, 3.27–36.12; p < 0.01) (Table 2). Figure 3 shows overall 90-day mortality stratified by levels of serum albumin and CRP at the onset of bacteremia. Overall 90-day mortalities in patients with or without low levels of albumin were 87.5% and 20.7%, respectively (p < 0.01), and those in patients with or without high levels of CRP were 71.4% and 30.3%, respectively (p < 0.01). The distribution of the values of albumin and CRP, and the correlation of the values of albumin or CRP and survival days are shown in Additional file 2: Figure S2 and Additional file 3: Figure S3, respectively.

Details for patients with low levels of albumin and high levels of CRP are shown in Table 3. Among 9 recipients with both high CRP and low albumin levels, 4 recipients had neutrophil counts equal to or exceeding 500/μl at the onset of bacteremia, and 8 recipients had severe sepsis or septic shock. Although 5 recipients had pneumonia at the onset of bacteremia, the remaining 4 recipients developed pneumonia, even under effective treatments, in a median of 3 days (range, 1 to 8 days). All 9 patients eventually died in a median of 2 days (range, 2 to 32 days), and all of these deaths were attributable to S. maltophilia bacteremia. One individual (Patient No. 9) survived 32 days from the onset of bacteremia after receiving a combination therapy of tigecycline (TGC) and TMP-SMX. The probabilities of developing pneumonia in patients with or without high CRP and low albumin levels were 100% (9/9) and 10.5% (4/38), respectively (p < 0.01).

Allo-HSCT recipients with S. maltophilia bacteremia received various combination therapies or monotherapies, which consisted of ciprofloxacin, levofloxacin, TMP-SMX, minocycline, TGC, or the combination thereof. The overall 90-day mortality rate for the antimicrobial regimens did not differ significantly (39.4% with TMP-SMX or minocycline, 66.7% with ciprofloxacin or levofloxacin, and 37.5% without any effective antibiotic; p = 0.42).

The rate of receiving effective antimicrobials within 3 days from the onset of bacteremia was 42.6%. Landmark analysis showed that there was no significant difference in overall 90-day mortality between patients with or without receiving effective antimicrobials within 3 days from the onset (42.9% vs. 26.3%, respectively; p = 0.16), even among recipients with high CRP or low albumin levels (37.5% vs. 37.5%, respectively; p = 0.74).