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Keywords:

  • Haematopoietic stem cell transplantation;
  • invasive fungal infection

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Clin Microbiol Infect 2012; 18: 997–1003

Abstract

In recent years, we have successfully established a novel method of haploidentical haematopoietic stem cell transplantation (HSCT) without in vitro T-cell depletion. This study was aimed at analysing the incidence and risk factors of invasive fungal infection (IFI) with this transplantation method. The study comprised 291 patients who had undergone haploidentical HSCT from 1 January 2007 to 31 December 2008. IFI was diagnosed according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group 2002 criteria, and only proven or probable cases of IFI were regarded as true cases. A total of 39 patients were documented as having IFI, including four proven cases and 35 probable cases. The median time of diagnosis was 26 days (range: 6–405 days) after transplantation. The cumulative incidence rates of IFI at 40 days, 1 year, 2 years and 3 years after transplantation were 8.25%, 13.1%, 13.4% and 13.4%, respectively. Multivariate analysis identified platelet engraftment time (>17 days) (p 0.027; hazard ratio (HR) 2.432; 95% CI 1.105–5.355), a high risk of underlying disease (p 0.001; HR 2.916; 95% CI 1.515–5.611) and grade III–IV acute graft-versus-host disease (p 0.019; HR 2.407; 95% CI 1.154–5.022) as risk factors for IFI. The incidence rates of IFI in patients with no, one, two or three risk factors at 3 years after transplantation were 4.48%, 7.86%, 29.6% and 23.1%, respectively. In conclusion, IFI is an important complication following haploidentical HSCT without in vitro T-cell depletion.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Haploidentical haematopoietic stem cell transplantation (HSCT) is an effective option for patients with haematological malignancies without human leukocyte antigen (HLA)-matched siblings or unrelated donors. Long-lasting immunosuppression and severe graft-versus-host disease (GVHD), however, lead to high incidence rates of opportunistic infections. Invasive fungal infection (IFI) has been one of the major infectious complications after allogeneic HSCT, with a mortality rate of up to 80% [1]. The incidence of IFI varies in different transplantation models, and data for IFI from haploidentical HSCT cases are scarce.

Recently, we developed a new method for haploidentical allogeneic HSCT from family donors without in vitro T-cell depletion (TCD) [2–4]. Long-term outcomes were comparable to that of transplantation with HLA-matched siblings or unrelated persons as donors. Opportunistic infections, however, can occur in up to 39% of patients [4]. The incidence and risk factors related to IFI in the haploidentical HSCT model have not been studied. Our study analysed the incidence and risk factors related to IFI for this transplantation model.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Patients

Patients without HLA-matched siblings or unrelated donors were potential candidates for allogeneic HSCT from haploidentical family donors. From 1 January 2007 to 31 December 2008, 291 patients underwent haploidentical HSCT without in vitro TCD at the Peking University Institute of Haematology. All patients signed informed consent forms prior to treatment, and the treatment programme was approved by the Ethics Committee of Peking University People’s Hospital. The characteristics of all HSCT recipients are summarized in Table 1.

Table 1.   Characteristics of all haematopoietic stem cell transplant recipients (N = 291)
VariablesValue
  1. AL, acute leukaemia; CML, chronic myelogenous leukaemia; F, female; HLA, human leukocyte antigen; M, male; MDS, myelodysplastic syndrome; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; SAA, severe aplastic anaemia.

Age (years), median (range)25 (5–57)
Recipient sex, n (%)
 Male176 (60.5)
 Female115 (39.5)
Underlying diseases, n
 AL217
 CML44
 MM2
 MDS19
 SAA8
 NHL1
Risk, n (%)
 Standard risk234 (80.4)
 High risk57 (19.6)
Number of mismatched HLA loci, n (%)
 3178 (61.2)
 287 (29.9)
 126 (8.9)
Donor/recipient blood type, n
 Matched155
 Major mismatched50
 Minor mismatched67
 Bidirectional mismatched19
Donor/recipient sex
 F–M/F–F/M–M/M–F, n88/58/89/56
Previous IFI history, n (%)23 (7.9)
IFI prophylaxis, n (%)
 Fluconazole260 (89.3)
 Other31 (10.7)

Transplantation procedure

The transplantation procedure has been described in previous reports [2–4]. The modified busulphan/cyclophosphamide + antithymocyte globulin conditioning regimen was used to treat 288 patients. The regimen was as follows: cytosine arabinoside (4 g/m2/day, days –10 to –9), busulfan (0.8 mg/kg, every 6 h, 12 doses, days –8 to –6), cyclophosphamide (1.8 g/m2/day, days –5 to –4), simustine (Me-CCNU, 250 mg/m2, day –3), and thymoglobulin (rabbit antithymocyte globulin (Sangstat-Genzyme, Marcy L'Etoile, France), 2.5 mg/kg, days –5 to –2). The other three patients were treated with fludarabine (30 mg/m2, days –6 to –2) instead of cyclophosphamide. The patients received cyclosporin A, mycophenolate mofetil and short-term methotrexate for GVHD prophylaxis. Chimerism was determined with at least two of the following three methods: DNA-based HLA typing (for mismatched loci), PCR-based DNA fingerprinting of short tandem repeats, and chromosomal fluorescence in situ hybridization (for the Y chromosome). At 30, 60, 90, 180 and 365 days after transplantation, chimerism and peripheral blood lymphocytes (absolute lymphocyte numbers, CD4+ cells) were determined.

IFI prophylaxis

A total of 23 patients had a prior history of IFI: two patients were proven cases, six patients were probable cases, and 15 patients were possible cases. For prophylaxis during the transplantation period, three patients were treated with oral fluconazole, four were treated with amphotericin B, three were treated with voriconazole, two were treated with caspofungin, and 11 were treated with intravenous itraconazole. Of the 268 patients without a previous history of IFI, eight were treated with an itraconazole oral solution, three were treated with micafungin, and the remaining 257 were treated with oral fluconazole (200 mg/day). The prophylaxis lasted until 75 days after transplantation or until empirical/pre-emptive antifungal treatment was given.

Diagnosis of IFI

According to the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group criteria [5], IFI can be categorized as proven, probable or possible cases. In our study, only proven and probable cases were regarded as true cases. For proven cases, the diagnosis time was defined as the time at which histopathological evidence or the results of a sterile tissue culture were acquired. The diagnosis time for probable cases was the time at which positive results for culture/galactomannan (GM) were acquired. A GM index of ≥0.5 for two consecutive instances was regarded as positive. IFI was divided into early IFI (≤40 days) or late IFI (>40 days) according to the time of occurrence.

Definitions

Successful neutrophil engraftment was defined as ≥0.5 × 109/L for three consecutive days, and successful platelet engraftment was defined as ≥20 × 109/L for seven consecutive days without the need for transfusion. The patients were defined as high risk if they were in more than the third complete remission of acute leukaemia; were not in remission; had chronic myelogenous leukaemia beyond the first chronic phase. The other cases were defined as standard risk. The diagnosis and classification of GVHD was conducted according to the previous consensus [6,7]. IFI was regarded as the primary cause of death when the patient died of progressive organ failure, in which IFI was first found in the absence of other comorbidities, excluding GVHD.

Statistical analysis

The following variables were recorded and analysed: gender, age, type of underlying disease, underlying disease status, number of mismatched HLA loci (A/B/DRB1), neutrophil engraftment time, platelet engraftment time, previous history of IFI, antifungal prophylaxis, acute GVHD, chronic GVHD, reactivation of cytomegalovirus, and relapse of underlying disease. Statistical analyses were performed with SPSS 13.0 software. Grouped variables were compared by use of the chi-squared test, and continuous variables were compared by use of the non-parametric Mann–Whitney test. Risk factors were analysed with a Cox proportional hazard model. Acute GVHD and chronic GVHD were regarded as time-dependent variables. The Kaplan–Meier curve was used to present survival curves, and the cumulative incidence was analysed for competing risk with R software. A p-value of <0.05 for the two-sided test was considered to be statistically significant. The patients were followed until 30 March 2011, with a median follow-up time of 882 days (range: 9–1486 days).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Clinical results

There were 291 patients enrolled in this study. Full donor chimerism was achieved in all patients. The median time for successful neutrophil engraftment was 13 days (range: 9–29 days). Successful platelet engraftment occurred in 262 cases, and the median time for successful platelet engraftment was 17 days (range: 7–180 days). The cumulative incidence rates for acute GVHD of grades II–IV or III–IV at 100 days after transplantation were 47% and 14.7%, respectively. The 255 patients who survived for more than 100 days were evaluated for chronic GVHD, and the cumulative incidence rates of limited and extensive chronic GVHD at 3 years were 33.3% and 23.1%, respectively. The cumulative relapse rate at 3 years was 16.2%. The overall survival rate at 3 years was 64.6%, and the survival rate of the standard-risk group was significantly higher than that of the high-risk group (68.4% vs. 49.1%, respectively, p 0.002).

Peripheral blood lymphocytes were detected at fixed time-points (Fig. 1). Although the CD4+ cell count gradually recovered, the absolute CD4+ cell number was <400/μL at 1 year after transplantation.

image

Figure 1.  The reconstitution of peripheral blood lymphocytes after haploidentical haematopoietic stem cell transplantation. (a) Absolute lymphocyte counts. (b) CD4+ cell numbers.

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The incidence and clinical features of IFI

A total of 39 patients were documented as having IFI, including four proven cases and 35 probable cases (Table 2). The median time of IFI occurrence was 26 days (range: 6–405 days) after transplantation. The most common infection site was the lung, and 31 cases (79.5%) involved only the lungs. The other eight patients had disseminated infections. In one case, the infection occurred in the lumbar spine. Five cases involved the lungs and the central nervous system simultaneously or successively. In one case, the infection disseminated to the lungs, spleen, and the soft tissue of the foot. Most cases lacked direct microbiological evidence. Three proven cases were infected with Aspergillus plus Bacillus licheniformis, Mucor plus Rhizopus and Candida krusei, and Aspergillus fumigatus, respectively. The other proven case was diagnosed according to the septate hyphae in the lung biopsy specimen, but the specific strain could not be identified. Of the 35 probable cases, only three had direct evidence of Aspergillus, and the others were diagnosed according to the GM test. The cumulative incidence rates of IFI at 40 days, 1 year, 2 years and 3 years after transplantation were 8.25%, 13.1%, 13.4% and 13.4%, respectively.

Table 2.   Invasive fungal infection after haploidentical haematopoietic stem cell transplantation
IDPrior IFIProphylaxisTime of IFI (days)ImagingPathogenGMDiagnosisSite of infectionTreatmentOutcomeCause of death
  1. C, proven; CNS, central nervous system; D, disseminated; DAH, diffuse alveolar hemorrhage; GM, galactomannan; IFI, invasive fungal infection; L, lung; ND, not detected; NS, non-specific; P, probable.

4058594NoFluconazole10Dense lesion+PLCaspofunginDeathIFI
4061011NoFluconazole159Cavity+PLMicafunginDeathDAH
4061385NoFluconazole163NS+PLVoriconazoleAlive
4061520NoFluconazole155NS+PLItraconazoleAlive
4055517NoFluconazole102CNS lesion+PL + CNSVoriconazoleDeathIFI
4063238NoFluconazole28NS+PLMicafunginAlive
4058305NoFluconazole222NS+PLItraconazoleDeathRelapse
4059365NoFluconazole14Cavity Aspergillus +PL + CNSItraconazoleDeathIFI
4062852NoFluconazole53NS+PLItraconazoleAlive
4065860NoFluconazole214 Aspergillus NDCLumbarAmphotericin BAlive
4046090NoFluconazole27NS+PLItraconazoleDeathIFI
4066238YesFluconazole31NS+PLItraconazoleAlive
4066318NoItraconazole24NS+PLItraconazoleDeathOther
4061465NoFluconazole11NS+PLItraconazoleAlive
4068175NoFluconazole29Cavity+PLItraconazoleDeathIFI
4070559NoFluconazole26Cavity+PL + CNSVoriconazoleDeathIFI
4071631NoFluconazole21Cavity+PLItraconazoleDeathIFI
4071827NoFluconazole18Air crescent+PLItraconazoleDeathIFI
4072144YesAmphotericin B6Cavity Aspergillus fumigatus +CLVoriconazoleDeathIFI
292590NoFluconazole8Nodule+PLVoriconazoleDeathRelapse
4077848NoFluconazole13NS Aspergillus +PL + CNSItraconazoleDeathIFI
4072652NoFluconazole22DisseminatedMixed+CDAmphotericin BDeathOther
4078950YesCaspofungin20NS+PLCaspofunginDeathRelapse
4077751NoFluconazole26NS+PLItraconazoleDeathIFI
4066683NoFluconazole21Air crescent+PLAmphotericin BDeathRelapse
4081004NoFluconazole230NS+PLCaspofunginDeathIFI
4077669NoFluconazole324NS+PLItraconazoleDeathRelapse
4082237YesVoriconazole337NS+PLItraconazoleDeathRelapse
4082592NoFluconazole316NS+PLItraconazoleDeathRelapse
4083345NoFluconazole405NS Aspergillus +PL + CNSAmphotericin BDeathIFI
4085026NoFluconazole14NS+PLItraconazoleDeathOther
4083419NoFluconazole12NS+PLItraconazoleDeathIFI
4086708NoFluconazole23Cavity+PLItraconazoleDeathIFI
4078419NoFluconazole9Cavity+PLItraconazoleAlive
4088390NoFluconazole7Cavity+PLItraconazoleDeathIFI
4090075NoFluconazole10NS+PLItraconazoleAlive
4091170NoFluconazole14Cavity+PLItraconazoleDeathOther
4091855NoFluconazole16Air crescent Aspergillus +CLItraconazoleAlive

Risk factors for IFI

Table 3 shows the results of the univariate and multivariate analyses. The univariate analysis demonstrated that a high risk of underlying disease (p 0.004), neutrophil engraftment time of >13 days (p 0.054), platelet engraftment time of >17 days (p 0.009) and grade III–IV acute GVHD (p 0.052) were risk factors for IFI. Age, gender, cytomegalovirus reactivation, the number of mismatched HLA loci, a prior history of IFI, antifungal prophylaxis (fluconazole vs. non-fluconazole), relapse and peripheral blood lymphocyte/CD4+ cell numbers at fixed time points (days 30, 60, 90, 180, and 365) were not statistically significant. Factors with p <0.10 in the univariate analysis were used for the multivariate analysis with the Cox proportional hazards model. The variables acute GVHD and chronic GVHD were also included in the analysis. The results showed that platelet engraftment time (p 0.027; hazard ratio (HR) 2.432; 95% CI 1.105–5.355), a high risk of underlying disease status (p 0.001; HR 2.916; 95% CI 1.515–5.611) and grade III–IV acute GVHD (p 0.019; HR 2.407; 95% CI 1.154–5.022) were risk factors for IFI. The 1-year cumulative incidence rates of IFI in patients with no, one, two or three risk factors were 4.48%, 7.86%, 29.6% and 23.1%, respectively. Patients with two or three risk factors had a significantly higher incidence of IFI than those with no or one risk factor (p <0.001) (Fig. 2b).

Table 3.   Risk factors for developing invasive fungal infection (IFI) after haematopoietic stem cell transplantation
VariablesIFIp-valueHazard ratio (95% CI)
YesNoUnivariateMultivariate
  1. ANC, absolute neutrophil count; CMV, cytomegalovirus; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; PLT, platelet.

Sex (male/female)22/17154/980.601
Age0.393
Disease status (standard risk/high risk)24/15210/420.0040.0012.916 (1.515–5.611)
Prior IFI history (yes/no)4/3519/2330.527
Prophylaxis with non-fluconazole4/3527/2250.931
Number of mismatched HLA locui0.477
ANC engraftment >13 days22/1799/1530.054
PLT engraftment >17 days29/10130/1220.0090.0272.432 (1.105–5.355)
Grade III–IV acute GVHD10/2933/2190.0520.0192.407 (1.154–5.022)
Extensive chronic GVHD (n = 257)11/2151/1740.293
CMV reactivation23/16147/1050.940
Relapse8/3139/2130.482
CD4+ cells at day 30 (n = 186)0.533
CD4+ cells at day 60 (n = 162)0.915
CD4+ cells at day 90 (n = 176)0.311
CD4+ cells at day 180 (n = 110)0.788
CD4+ cells at day 365 (n = 79)0.606
Lymphocytes at day 30 (n = 283)0.264
Lymphocytes at day 60 (n = 267)0.300
Lymphocytes at day 90 (n = 250)0.540
Lymphocytes at day 180 (n = 203)0.163
Lymphocytes at day 365 (n = 141)0.441
image

Figure 2.  (a) Cumulative incidence of invasive fungal infection (IFI) after haploidentical haematopoietic stem cell transplantation without in vitro T-cell depletion. (b) Cumulative incidence of IFI in patients with 0–1 or 2–3 of the following factors: at high risk for underlying disease, grade III–IV acute graft-versus-host disease, and platelet engraftment time of >17 days.

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We further divided IFI into early IFI (≤40 days) and late IFI (>40 days) according to the time of occurrence. An analysis of the risk factors for each group showed that a high risk of underlying disease status (p 0.001; HR 4.157; 95% CI 1.844–9.370) was a risk factor for early IFI. Platelet engraftment time (p 0.044; HR 3.975; 95% CI 1.038–15.230) and extensive chronic GVHD (p 0.003; HR 5.051; 95% CI 1.756–14.531) were risk factors for late IFI.

Treatment and outcome of IFI

The initial antifungal drugs used for treatment in the 39 cases of IFI were as follows: caspofungin for three cases, micafungin for two cases, voriconazole for five cases, intravenous itraconazole for 25 cases, and amphotericin B for four cases. Only ten patients survived, and the survival rate was 25.6% (Fig. 3a). Fot the 29 cases of mortality, the median time from diagnosis to death was 233 days (range: 0–1131 days). The causes of mortality were as follows: 16 patients died of IFI, seven of disease recurrence, and six from other causes. The occurrence of IFI significantly decreased overall survival. The 3-year survival rates for those with and without IFI were 24.4% and 71.2%, respectively (p <0.001) (Fig. 3b).

image

Figure 3.  (a) Probability of survival after diagnosis of invasive fungal infection (IFI) in 39 recipients of haematopoietic stem cell transplants from haploidentical donors. (b) The impact of IFI on overall survival. Patients without IFI had significantly better overall survival than patients with IFI (p <0.001).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Previous studies have suggested that patients undergoing haploidentical HSCT with in vitro TCD have a higher incidence of IFI than those undergoing matched sibling HSCT [8], possibly because of the increased incidence of GVHD or prolonged immunosuppression caused by in vitro TCD. However, no exact data related to the incidence of IFI after haploidentical HSCT with in vitro TCD were available. The Perugia group [9,10] and the Tubingen group [11] have reported fungal-related mortality rates of 4.95% and 6%, respectively. The above data, however, provided only the incidence of lethal fungal infection, without reporting the incidence of IFI.

In this study, the non-TCD method was adopted. To our knowledge, this study presents the exact incidence of IFI after haploidentical HSCT without in vitro TCD for the first time. The IFI-related mortality was 5.5% (16/291), which is similar to that of TCD transplantation. The 1-year cumulative incidence of IFI was 13.1%, which is similar to that of transplantation from alternative donors. Some early studies reported that the 1-year cumulative incidence of IFI after allogeneic HSCT from matched sibling donors could be up to 14–15% [12,13]; however, recent data have shown that the incidence of IFI after transplantation from matched siblings is significantly lower than that after transplantation from alternative donors [14]. It seems that the incidence determined with this novel protocol was higher than that of HSCT with HLA-matched siblings. However, a direct comparison requires a prospective head-to-head study. Our unpublished data suggest that immune reconstitution after non-TCD haploidentical transplantation is significantly lower than that after HLA-matched transplantation in the first 90 days (52nd American Society of Hematology Annual Meeting, 2010, Abstract 2312). Most fungal infections occurred within this period, suggesting that poorer immune reconstitution may be responsible for the high incidence. However, a proper comparison is lacking, and this is an issue that needs to be addressed in future investigations.

We found that grade III–IV acute GVHD and extensive chronic GVHD were important risk factors for IFI after haploidentical HSCT without in vitro TCD, which is consistent with the findings of the HLA-matched transplant studies mentioned above. In addition, our results show that the risk of IFI in patients with delayed platelet engraftment (>17 days) was 2.43 times higher than in those without delayed platelet engraftment. The prognostic impact of delayed platelet recovery on survival and infection has been studied previously [15,16]. Persistent thrombocytopenia after allogeneic matched sibling peripheral blood stem cell transplantation was found to be an independent predictor of opportunistic infection and overall survival [17,18]. Our study showed that delayed platelet recovery increased the risk of IFI. We hypothesize that the impact of platelet recovery on IFI may be attributable to the advanced disease status or the number of infused CD34+ cells. These two factors were shown to be the main ones affecting platelet recovery after haploidentical HSCT without in vitro TCD in our previous study [19]. However, the exact role of delayed platelet recovery in IFI occurrence requires further investigation.

Although CD4+ Th1 cells have been shown to be protective against fungal infection in many studies [20,21], there have been no studies focusing on total CD4 cell numbers. In this study, the low lymphocyte/CD4+ counts were unable to predict IFI at any of the time-points. It seems that the total CD4+ cell number is not proportional to specific antifungal immunity.

Some authors have considered patients with prior IFI to be at high risk for IFI after transplantation, especially those with a proven or probable IFI history [22]. In our study, a history of IFI was not identified as a risk factor. The low proportion (8/23) of proven or probable cases of prior IFI may explain the difference between our study and the literature. Active prophylaxis with broad-spectrum antifungal agents may also be the cause of this difference.

There are several issues in our study that cannot be neglected. First, because G test detection has only recently begun in our institute, only a minority of patients had G test results during this period. Therefore, this study was based on the early EORTC criteria. Because great differences exist between the EORTC 2002 and EORTC 2008 criteria [23], the results may also be different. This may be an important limitation of this study. Second, the number of proven cases was limited in this study, and possible IFI cases were considered to be non-fungal infections, which may have led to an underestimation of the actual incidence.

In conclusion, IFI was an important complication after haploidentical HSCT without in vitro TCD. The prophylaxis strategy should be optimized to reduce the IFI incidence, especially for those at high risk. The therapeutic strategy should also be improved to decrease IFI-related mortality.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

This work was supported in part by grants from the National Outstanding Young Scientist’s Foundation of China (No. 30725038), Special Research Fund of the Health Programme of Ministry of Health of China (No. 200802027), National Natural Science Foundation of China (No. 30725038), and Beijing Medical Award Foundation (No. ZJGRYSBDRM-002). We thank American Journal Experts (http://www.journalexperts.com) for their assistance in editing this manuscript.

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  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
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