Infectious Complications

Prediction of infectious complications by the combination of plasma procalcitonin level and localized infection before allogeneic hematopoietic cell transplantation

Abstract

We previously reported that the baseline C-reactive protein level did not predict infectious events after hematopoietic cell transplantation (HCT). Procalcitonin (PCT) has recently emerged as a powerful biomarker for the early diagnosis of bacterial infection. We evaluated the ability of the baseline PCT level to predict early infectious events after HCT in 79 recipients who received HCT between 2008 and 2012. The high-PCT group (0.07 ng/mL, n=27) frequently experienced documented infection (DI) (21.2% vs 44.4% at day 30, P=0.038) and bloodstream infection (BSI) (15.4% vs 37.0% at day 30, P=0.035). In a multivariate analysis, however, the baseline PCT level was not significantly associated with DI (HR 2.01, P=0.089) or BSI (HR 2.28, P=0.084). Localized infection, such as anal canal problems, before the start of conditioning was seen in 26 patients. When we stratified the patients according to the presence of elevated PCT and localized infection, the group with elevated PCT and localized infection (n=17) was significantly associated with increased DI (HR 3.40, P=0.0074) and BSI (HR 3.59 P=0.0078) after HCT. A larger prospective observation is warranted to confirm the impact of the baseline PCT level and clinical features on the outcome of HCT.

Introduction

Infectious complications still remain a major cause of non-relapse mortality (NRM) in allogeneic hematopoietic cell transplantation (HCT). We previously reported that the C-reactive protein (CRP) level before consolidation chemotherapy for acute myelogenous leukemia was useful for identifying patients who were at higher risk for febrile neutropenia and documented infection (DI), with cutoff values of 0.19 and 0.26 mg/dL, respectively.1 However, in allogeneic HCT patients, the baseline CRP level did not predict infectious events.2 On the other hand, a baseline CRP level 0.6 mg/dL was associated with higher NRM and inferior OS, probably due to the higher incidence of severe acute GVHD. CRP is generally a sensitive, but not a specific, marker of infectious disease, since it is increased in various non-infectious complications.3 Recently, procalcitonin (PCT) has been a focus of attention because PCT may be superior to CRP for discriminating between infection and other causes of inflammation in critically ill patients.4 PCT is a pro-hormone of calcitonin that is produced during systemic infection in response to circulating microbial toxins and host inflammatory mediators5 has been proven to be a biomarker with a good negative predictive value.6, 7, 8 In addition, the blood PCT level has been shown to correlate with the severity of infection, and reverts to its baseline level following successful therapy.9

To date, several reports have assessed the significance of PCT in infectious events after HCT.10, 11 However, it is not yet clear whether the baseline PCT level before HCT can predict infectious events. We hypothesized that the baseline PCT level before conditioning may be able to predict future infectious events more precisely than the baseline CRP level. In this study, we assessed the relationship between the plasma PCT level before conditioning and infectious events following allogeneic HCT, to evaluate its value for predicting early DI, early bloodstream infection (BSI) and NRM. Furthermore, we compared the predictive abilities of PCT and CRP levels.

Patients and methods

Patients

We reviewed the clinical charts of 104 consecutive patients who underwent their first allogeneic HCT between February 2008 and August 2012 in our institution and gave their consent for blood cryopreservation. Among these patients, 25 were excluded because they were receiving i.v. antibiotics for fever or DIs at the start of the conditioning regimen. Finally, 79 patients were included in this analysis. This cohort included 46 recipients in our previous study.2 This analysis was approved by the institutional review board of Saitama Medical Center, Jichi Medical University.

Transplant procedures

Myeloablative conditioning regimens included a combination of CHOP and either TBI or BU. Fludarabine-based reduced-intensity conditioning regimens, such as fludarabine combined with BU or melphalan, were used in elderly or clinically infirm patients. Patients with severe aplastic anemia received fludarabine, CHOP and anti-thymoglobulin, with or without low-dose TBI at 2 Gy. Alemtuzumab-containing regimens were used in HCT from a 2 or 3 Ag-mismatched donor.

GVHD prophylaxis consisted of the continuous infusion of CsA or tacrolimus combined with short-term MTX (10–15 mg/m2 on day 1, 7–10 mg/m2 on days 3 and 6, and an optional dose on day 11). Acute GVHD was graded as described previously.12 Prophylaxis against bacterial, fungal and Pneumocystis jiroveci infection consisted of fluoroquinolones, fluconazole or itraconazole, and sulfamethoxazole/trimethoprim or inhalation of pentamidine, respectively. As prophylaxis against HSV infection, acyclovir was administered from day 7 to day 35, followed by long-term low-dose administration for varicella zoster reactivation.13 Preemptive therapy against CMV with ganciclovir was administered by monitoring CMV antigenemia by the C10/11 method weekly after engraftment.

Measurement of PCT and CRP

The PCT levels in plasma that had been cryopreserved before the start of the conditioning regimen were retrospectively measured using an electrochemiluminescence immunoassay method (ELECSYS* BRAHMS* PCT, Roche Diagnostics GmbH, Mannheim, Germany). The minimum detection level was 0.02 ng/mL and thus a PCT level below 0.02 ng/mL was assumed to be 0 ng/mL in the following statistical analyses.

The CRP level was routinely measured just before the start of the conditioning regimen and at least twice weekly thereafter, exclusively using a kit based on the latex agglutination reaction (Nanopia CRP, Sekisui Medical, Tokyo, Japan; minimum detection level 0.01 mg/dL).

Definition of transplant-related complications

DI included microbiologically documented infections, including bloodstream infection, and presumed infections based on clinical and/or radiological findings.1 BSI was defined by at least one positive blood culture, except that coagulase-negative Staphylococci required at least two positive blood cultures. NRM was defined as death without relapse after HCT. Acute leukemia in first or second remission, chronic myelogenous leukemia in first or second chronic phase, and myelodysplastic syndrome or myeloproliferative neoplasm without leukemic transformation were defined as standard-risk diseases, and others were defined as high-risk diseases based on previous Japanese studies.14, 15

Statistical analysis

We assessed the potential of the PCT and CRP levels for predicting early DI and BSI within 30 days after HCT and NRM within 100 days after HCT by using the area under the receiver-operating characteristic curve. The cutoff value was also determined by the receiver-operating characteristic curve analysis. The abilities of PCT and CRP levels to predict DI, BSI and NRM within 100 days were compared using the respective area under the curve (AUC) values. The cumulative incidences of DI, BSI and NRM with a 95% confidence interval (95% CI) were estimated for each group and compared by Gray’s test, while treating death without these events as a competing risk. In the multivariate analysis, the hazard ratio (HR) of PCT was obtained by Fine and Gray’s proportional-hazard model, while adjusting for factors with at least borderline significance (P<0.15) in univariate analyses. P-values less than 0.05 were considered to be significant. All statistical analyses were performed with EZR on R commander (version 1.6-3) (Saitama Medical Center, Jichi Medical University, accessed 10 January 2013, at http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html), which is a graphical user interface for R (Version 2.13, The R Foundation for Statistical Computing, Vienna, Austria).16

Results

Patients

There were 79 patients with a median age of 45 years, including 45 males and 34 females (Table 1). The underlying disease was acute leukemia in 44, myelodysplastic syndrome in 9, aplastic anemia in 8, adult T-cell leukemia in 7 and lymphoma in 7. Eleven patients (14%) had high-risk disease. The median PCT and CRP levels before the start of the conditioning regimen were 0.04 ng/mL (range 0.00–0.73) and 0.18 mg/dL (range 0.01–8.09), respectively. No significant correlation was observed between the levels of PCT and CRP (r2=0.014, P=0.29). Patients with myelodysplastic syndrome, high-risk disease and a HLA-mismatched donor tended to have a higher baseline PCT level (Table 1). The group with a higher baseline CRP level included more females, patients aged 45, myelodysplastic syndrome and unrelated donors.

Table 1 Patient characteristics

Transplant outcome

Among the 79 allogeneic HCT recipients, febrile neutropenia developed in 78, DI in 38 (23 within 30 days), and BSI in 26 (18 within 30 days). Other DI included central venous catheter-related infection in 10, pneumonia in 8, cystitis in 3, oral infection in 1, and cholecystitis in 1.The most frequently isolated organism was Staphylococcus epidermidis. There were 11 deaths without relapse, including 7 deaths within 100 days after HCT (early NRM). The cause of early NRM included pneumonia in 3, GVHD in 1, pulmonary proteinosis in 1, engraftment syndrome in 1 and acute renal failure in 1.

Potential of the PCT level for predicting the clinical outcome

To evaluate the potential of the baseline PCT level for predicting transplant-related complications, we performed receiver-operating characteristic curve analyses and evaluated the AUC. The predictive value for febrile neutropenia was not analyzed, since it was observed in 78 of the 79 recipients. The AUC was 0.60 (95% CI: 0.45–0.75) for DI within 30 days after HCT. The sensitivity and specificity were 52 and 73% respectively, with a cutoff value of 0.07 ng/mL. AUC was 0.61 (95% CI: 0.44–0.77) for BSI within 30 days after HCT. The sensitivity and specificity were 56% and 72%, respectively, with a cutoff value of 0.07 ng/mL. With this cutoff value of 0.07 ng/mL, the cumulative incidence of DI at 30 days was 21.2% (95% CI: 11.2–33.2%) in the low-PCT group (n=52) and 44.4% (95% CI: 25.1–62.2%) in the high-PCT group (n=27) (P=0.038, Figure 1a). In the multivariate analysis, the PCT level was not a significant factor (HR 2.01 (95% CI: 0.90–4.72), P=0.089, Table 2), after adjusting for disease status and donor types. Cumulative incidence of BSI at 30 days was 15.4% (95% CI: 7.1–26.5%) in the low-PCT group (n=52) and 37.0% (95% CI: 19.2–55.0%) in the high-PCT group (n=27) (P=0.035, Figure 1b). In the multivariate analysis, the PCT level was not a significant factor (HR 2.28 (95% CI: 0.90–5.81), P=0.084, Table 3), after adjusting for HLA matching, donor types and cell sources. Next, we assessed the impact of PCT on NRM. The AUC for early NRM within 100 days after HCT was 0.73 (95% CI: 0.56–0.90). The sensitivity and specificity were 86% and 53%, respectively, with a cutoff value of 0.04 ng/mL (Figure 2a). With this cutoff level, the cumulative incidence of NRM at 100 days was 2.6% (95% CI: 0.2–11.7%) in the low-PCT group (n=39) and 15.0% (95% CI: 6.0–27.8%) in the high-PCT group (n=40) (P=0.11, Figure 2b). In the multivariate analysis, the PCT level was not an independent significant factor (HR 2.92 (95% CI: 0.58–14.77), P=0.19, Supplementary Table), after adjusting for age, disease and HLA matching. PCT levels did not significantly affect other complications in a univariate analysis with a cutoff value of 0.04 ng/mL: acute GVHD grade II–IV (38.5% (95% CI: 23.3–53.5%), 45.1% (95% CI: 29.1–59.9%), P=0.59), acute GVHD grade III–IV (12.8% (95% CI: 4.6–25.4%) vs 17.5% (95% CI 7.6–30.8%), P=0.58) and OS (77.7% (95% CI: 58.0–89.0%) vs 69.4% (95% CI: 51.0–82.0%), P=0.55).

Figure 1
figure1

Cumulative incidences of DI (a) and BSI (b) grouped according to the baseline PCT level.

Table 2 Univariate and multivariate analyses for DI
Table 3 Univariate and multivariate analyses for BSI
Figure 2
figure2

Receiver-operating characteristic curve for PCT and CRP levels for NRM (a). Cumulative incidences of NRM grouped according to the baseline PCT level (b) and baseline CRP level (c).

Potential of the CRP level for predicting the clinical outcome

Similarly, we evaluated the value of the baseline CRP level for predicting early infectious events. The AUCs were 0.63 (95% CI: 0.50–0.76) for DI and 0.58 (95% CI: 0.42–0.73) for BSI within 30 days after HCT. The sensitivity and specificity were 57% and 68% for DI, and 50 and 64% for BSI, respectively, with a cutoff value of 0.25 mg/dL. With this cutoff level, the cumulative incidences of DI and BSI at 30 days after HCT were 20.8% (95% CI: 10.7–33.3%) and 18.8% (95% CI: 9.2–31.0%) in the low-CRP group (n=48) and 41.9% (95% CI: 24.3–58.6%) and 29.0% (95% CI: 14.3–45.6%) in the high-CRP group (n=31), (P=0.062 and P=0.34), respectively. In the multivariate analysis for DI, the CRP level was not an independent significant variable (Table 4).

Table 4 Impact of PCT and CRP before conditioning on the clinical outcome

On the other hand, the AUC for NRM was 0.77 (95% CI: 0.51–1.00). The sensitivity and specificity were 71% and 89%, respectively, with a cutoff value of 0.7 mg/dL (Figure 2a). With this cutoff level, the cumulative incidence of NRM at 100 days was 3.0% (95% CI: 0.6–9.4%) in the low-CRP group and 38.5% (95% CI: 13.0–63.9%) in the high-CRP group (P=0.0041, Figure 2c). In the multivariate analysis, the CRP level remained significant (HR 5.86 (95% CI: 1.53–22.36), P=0.0096, Table 4). These findings were consistent with our previous study.2

When we compared the AUCs of the PCT and CRP levels, there was no significant difference in the ability to predict the clinical outcome (DI: P=0.67, BSI: P=0.71, NRM: P=0.66, Figure 2a).

Effect of localized infections at the time of measurement

Twenty-six (33%) of the patients had localized infectious problems at the time of measurement, including slight redness and swelling due to the central venous catheter-related infection in 9, anal canal problems in 3, minor oral problems in 11, cystitis in 1, cutaneous infection in 1, and upper respiratory tract infection in 2. The PCT level in these patients with localized infectious problems was 0.075 ng/mL (range 0.06–0.73). While 17 of these 26 patients (65%) showed elevated PCT levels (PCT0.07 ng/mL), only 10 (19%) of the 53 remaining patients without localized infections showed elevated PCT levels (P<0.0001).

Next, we re-evaluated the risk of DI using the combination of elevated PCT and localized infection. The cumulative incidence of DI within 30 days was 20.9% (95% CI: 10.2–34.2%) in patients with low-PCT levels and without localized infection (n=43), 10.0% (95% CI: 0.5–37.4% ) in patients with elevated PCT levels and without localized infection (n=10), 22.2% (95% CI: 2.8–53.0%) in patients with low-PCT levels and localized infection (n=9) and 64.7% (95% CI: 36.0–83.1%) in patients with elevated PCT levels and localized infection (n=17) (P=0.0047, Figure 3a). The cumulative incidence of BSI within 30 days was 16.3% (95% CI: 7.1–28.8%) in patients with low-PCT and without localized infection (n=43), 10.0% (95% CI: 0.5–37.4%) in patients with elevated PCT and without localized infection (n=10), 11.1% (95% CI: 0.5–40.6%) in patients with low-PCT and localized infection (n=9) and 52.9% (95% CI: 26.4–73.8%) in patients with elevated PCT and infection (n=17) (P=0.014, Figure 3b). In a multivariate analysis, the combination of elevated PCT and localized infection was significantly associated with an increased risk for both DI (HR 3.40, (95%CI: 1.39–8.32), P=0.0074, Table 5) and BSI (HR 3.59, (95%CI: 1.40–9.22), P=0.0078, Table 5).

Figure 3
figure3

Cumulative incidences of DI (a) and BSI (b) grouped according to the presence of localized infection at the time of measurement and elevated PCT levels.

Table 5 Impact of PCT and CRP combined with clinical features

Next, we re-evaluated the risk of DI and BSI using the combination of elevated CRP and localized infection. The cumulative incidences of DI and BSI within 30 days were 16.2 (95% CI: 6.5–29.8%) and 13.5% (95% CI: 4.9–26.6%)in patients with low-CRP levels and without localized infection (n=37), 25.0 (95% CI: 7.3–48.0%) and 18.8% (95% CI: 4.3–41.0%) in patients with elevated CRP levels and without localized infection (n=16), 36.4 (95% CI: 10.1–64.0%) and 36.4%(95% CI: 10.1–64.0%) in patients with low-CRP levels and localized infection (n=11), and 60.0 (95% CI: 30.0–80.5%) and 40.0%(95% CI: 15.6–63.6%) in patients with elevated CRP levels and localized infection (n=15) (P=0.022, P=0.14, Table 5). In a multivariate analysis, the combination of elevated CRP and localized infection was significantly associated with an increased risk for DI (HR 3.74 (95% CI: 1.40–9.99), P=0.0085, Table 5), while a similar significant association was not seen for BSI (HR 2.30 (95% CI: 0.83–6.41), P=0.11, Table 5).

Discussion

We retrospectively analyzed the impact of baseline PCT and CRP levels on the clinical outcome after allogeneic HCT. The cumulative incidence of DI was increased in patients with a baseline PCT level higher than the cutoff value determined by the receiver-operating characteristic curve analysis. However, a multivariate analysis showed that neither the baseline PCT level nor the baseline CRP level was an independent significant predictor of infectious events. However, the combination of the PCT level and localized infection could identify patients who were at higher risk for DI and BSI.

We did not find any statistically meaningful results when we focused only on the ability of PCT to predict infectious events. This might be due to the insufficient sample size, but the AUC of 0.60 for DI suggested that the baseline PCT level, like the baseline CRP level, was not a strong biomarker for predicting infectious events after HCT. A possible explanation is the effect of prophylactic antibiotics. Hausfater et al.17 reported that a false-negative PCT test result was frequently observed in patients aged <42 years, those with a WBC count of <4000 or >12 000 cells/mm3 and those who were receiving antibiotic therapy before measurement of the PCT level. In fact, our cohort included 9 patients with both localized infection and a low baseline PCT level. Since all of the patients were receiving oral antibiotics for prophylaxis at the measurement of PCT, these antibiotics may have impaired the sensitivity of PCT.

Another possible explanation is the low cutoff value in this study, less than 0.1 ng/mL, which is much lower than the previously reported cutoff level of PCT for discriminating between bacterial and non-bacterial infection (0.5–1.3 ng/mL).18, 19, 20 Recent highly-sensitive technology has made it possible to detect very low levels of PCT. This cutoff is close to the upper limit of the normal range (0.5 ng/mL) and may increase the incidence of false-positive results.17, 21 In this study, the PCT level could be used to identify patients who were at higher risk for infectious events among those with localized infections. The combination of PCT as a biomarker and localized infection as a clinical manifestation may be useful for reducing false-positive results. In addition, this combination may enable us to evaluate the significance of localized infection as a predictor of systemic infection. In fact, the incidence of DI in patients with localized infection and high PCT levels was 64.7%, whereas it was only 22.2% in patients with localized infection with low PCT levels.

CRP and PCT are two commonly used biomarkers. Unlike CRP, PCT is thought to not rise in response to non-infectious inflammation. However, at present, the test for CRP is less expensive and more widely used in Japan. Although the tests for CRP and PCT have similar diagnostic properties, they might have different values at different points in the course of illness, since theoretically PCT levels increase earlier than those of CRP. However, this possible benefit of PCT may not be of value in the current study, since we tried to predict infectious events after HCT based on the PCT levels before HCT.

This study had several limitations because of the retrospective study design and small sample size. The statistical power for detecting the impact of PCT might be inadequate due to the small sample size. Furthermore, heterogeneous transplantation procedures may have biased the result. The impact of biomarkers may differ according to the transplantation procedure. For example, in cord blood transplantation, the baseline PCT or CRP values before HCT may have a greater impact, since the neutropenic period after HCT is generally longer after cord blood transplantation.

In conclusion, we did not find a significant association between baseline PCT levels and infectious events following allogeneic HCT. However, patients who have localized infection with a concurrent elevated PCT level might have an increased risk for DI and BSI after HCT. Further studies are required to establish risk assessment and management strategies based on the baseline biomarkers in allogeneic HCT.

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Correspondence to Y Kanda.

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The authors declare no conflict of interest.

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Author contributions

MS designed the study, collected and analyzed the data, and wrote the manuscript. H Nakasone designed the study, analyzed the data and wrote the manuscript. KT-S, KS, R Yamazaki, YT, YA, H Nakano, TU, HW, R Yamasaki, YI, KK, MA, TM, S Kimura, MK, AT, JK, S Kako and JN collected the data. YK designed the study, analyzed the data, wrote the manuscript and was responsible for the study.

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Sato, M., Nakasone, H., Terasako-Saito, K. et al. Prediction of infectious complications by the combination of plasma procalcitonin level and localized infection before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 49, 553–560 (2014). https://doi.org/10.1038/bmt.2013.217

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Keywords

  • transplant-related complications
  • infectious events
  • procalcitonin
  • allogeneic hematopoietic cell transplantation

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