Microbial Issues

Pre-transplant risk factors for cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia after hematopoietic cell transplantation

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  • A Corrigendum to this article was published on 09 October 2013

Abstract

Cryptogenic organizing pneumonia (COP), previously known as bronchiolitis obliterans organizing pneumonia (BOOP), is a significant complication after allogeneic hematopoietic SCT (HCT). However, the pathogenesis of this complication has not yet been elucidated. Therefore, we identified the pre-transplant risk factors for the development of COP/BOOP using the Japan transplant registry database between 2005 and 2009. Among 9550 eligible recipients, 193 experienced COP/BOOP (2%). HLA disparity (odds ratio (OR) 1.51, P=0.05), female-to-male HCT (OR 1.53, P=0.023), and PBSC transplant (OR 1.84, P=0.0076) were significantly associated with an increased risk of COP/BOOP. On the other hand, BU-based myeloablative conditioning (OR 0.52, P=0.033), or fludarabine-based reduced-intensity conditioning (OR 0.50, P=0.0011) in comparison with a TBI-based regimen and in vivo T-cell depletion (OR 0.46, P=0.055) were associated with a lower risk. Of the 193 patients with COP/BOOP, 77 died, including non-relapse death in 46 (59%). Pulmonary failure and fatal infection accounted for 41% (n=19) and 26% (n=12) of the non-relapse death. Allogeneic immunity and conditioning toxicity could be associated with COP/BOOP. Prospective studies are required to elucidate the true risk factors for COP/BOOP and to develop a prophylactic approach.

Introduction

Cryptogenic organizing pneumonia (COP), previously known as bronchiolitis obliterans organizing pneumonia (BOOP),1 is a rare but significant pulmonary complication following allogeneic hematopoietic SCT (HCT).2, 3, 4 COP/BOOP is characterized by fever with nonproductive coughing and the presence of granulation tissue within the alveolar ducts and alveoli, leading to an intraluminal organizing pneumonia.2, 3, 5, 6, 7 The incidence of COP/BOOP after HCT has been reported to range from 1 to 10%, and it appears at a median of 100 days or later after HCT.2, 3 Although COP/BOOP has been reported to respond to steroid treatment,8, 9, 10, 11, 12 recurrence is often observed and prolonged steroid treatment is frequently required.2, 3, 5, 9 COP/BOOP occasionally progresses to thoracic air-leak syndrome and can be refractory to treatment.13 Therefore, it is important to elucidate the risks for the development of COP/BOOP. To date, several groups have identified GVHD as a risk factor for COP/BOOP. However, the other factors reported previously remain a matter of debate. One of the reasons for the controversy is the small number of patients with COP/BOOP. Almost all of the previous studies were limited to case reports or series that did not include more than 10 cases of COP/BOOP, and/or did not analyze COP/BOOP independently but rather as a part of late-onset non-infectious pulmonary complications.6, 7, 10, 11, 12, 14, 15, 16, 17 To the best of our knowledge, only one report, from Seattle, has included more than 20 cases (49 cases with COP/BOOP).8 Thus, we performed a large retrospective study that included about 200 patients with COP/BOOP.

Patients and methods

Patient selection

This study included all-aged recipients who received the first allogeneic HCT between January 2005 and December 2009, and achieved successful engraftment. Their data were reported to the Japan transplant outcome registry database and confirmed by the Transplant Registry Unified Management Program in 2010.18 For eligible recipients, information on age, sex, the presence of COP/BOOP and survival status at the end of follow-up were required (7.5% was deleted). This retrospective analysis was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board at Saitama Medical Center, Jichi Medical University.

Definitions of categories

COP/BOOP after HCT was reported according to the diagnostic criteria for idiopathic COP/BOOP, based on clinical restrictive dysfunctions/radiological assessment/histological examinations.2, 3, 5 As PBSC transplantation (PBSCT) from unrelated donors was not available in Japan during the evaluation period, HCT was categorized into four groups as follows: related BMT, related PBSCT, unrelated BMT and unrelated cord blood transplantation (CBT). The diagnosis and severity of GVHD were reported based on the clinical grading scores.19, 20 Serological HLA mismatch was defined when at least HLA-1 Ag mismatch was detected at serological levels of HLA-A and -B, or DR. Conditioning regimens were classified into myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) based on the report by Giralt et al.21 Briefly, we classified the conditionings including TBI >8 Gy, melphalan 140 mg/m2 or oral BU 9 mg/kg (i.v. BU 7.2 mg/kg) into MAC. Other regimens were classified into RIC. Then, the conditioning regimens were divided into five groups: CY+TBI-based MAC, BU+CY-based MAC, other MAC, fludarabine (Flu)-based RIC and other RIC. In vivo T-cell depletion was defined as anti-thymocyte globulin and alemtuzumab as a part of conditioning.

Statistical analysis

Logistic regression analysis was performed using pre-transplant factors. On multivariate analysis, OR were obtained after adjusting with variables having P<0.1 on univariate analysis. Although HLA was NS on univariate analysis, it was included into multivariate analysis because it is supposed to be the strong predictor for GVHD, which is also known to be associated with COP/BOOP.8 In this analysis, the association between COP/BOOP and GVHD was assessed separately, as GVHD was supposed to be a post transplant factor, and the onset date of COP/BOOP was not available in the registry database. The associations with severity and target organs of GVHD were independently assessed. All patients were analyzed for the association with acute GVHD (aGVHD), but only the patients who survived more than 100 days were included for the association with chronic GVHD (cGVHD). Regarding the target organs of cGVHD, we performed multivariate analysis using the organ variables having P<0.1 on univariate analysis. The cumulative probabilities of relapse and non-relapse mortality (NRM) from allogeneic HCT were estimated by Gray’s method, considering each other as a competing risk. The day of HCT was considered as the relapse day for the patients who received HCT on disease and had never achieved disease remission. OS from allogeneic HCT was estimated by the Kaplan–Meier method and compared by log-rank test. These probabilities were estimated from time of transplantation with 95% confidence intervals (95% CIs). Statistical significance was defined as P<0.05. All analyses were performed using Stata version 12.0 (StataCorp, College Station, TX, USA) and EZR on R commander (R version 2.13.0.) (Satima Medical Center, Jichi Medical University, Saitama, Japan).22

Results

Patient characteristics

The cohort information was obtained from 9550 allogeneic HCT recipients, including 1423 (15%) pediatric recipients. Their median age was 42 years (range 0–82). They received HLA-mismatched allogeneic HCT in 3030 (32%) and female-to-male allogeneic HCT in 2207 (24%) patients. The donor source was related BMT in 1935 (20%), related PBSCT in 1909 (20%), unrelated BMT in 3912 (41%) and CBT in 1751 (18%) patients. The conditioning intensity was MAC in 5755 (61%) and RIC in 3728 (39%) patients. CYA and taclorimus-based GVHD prophylaxis was administrated in 4172 (44%) and 5201 (55%) patients, respectively. Of them, 3644 recipients (38%) experienced grade 2–4 aGVHD.

Among the 9550 eligible recipients, 193 experienced COP/BOOP (2%). Table 1 shows the patient distribution and impact of the patient and transplant characteristics.

Table 1 Patient and transplant characteristics and their impact on COP/BOOP

Pre-transplant risk factors for the development of COP/BOOP

Patient- or donor-based risk factors

In the univariate analysis, male recipients, adult recipients and patients with advanced disease tended to experience COP/BOOP more frequently. CMV status was not associated with COP/BOOP. On the multivariate analysis, no patient-based factors were identified (Table 1). On the other hand, several adverse donor-based factors were identified as follows: HLA disparity (OR 1.51 (1.00–2.27), P=0.05), female-to-male HCT (OR 1.53 (95% CI: 1.06–2.20), P=0.023) and related PBSCT (OR 1.84 (95% CI: 1.18–2.87), P=0.0076, Table 1). Unrelated BMT and CBT were not associated with the development of COP/BOOP.

Procedure-oriented risk factors

Both univariate and multivariate analysis revealed that the risk of the development of COP/BOOP was lower not only in recipients with Flu-based RIC (OR 0.50 (95% CI: 0.33–0.76), P=0.0011) but also in those with BU-based MAC (OR 0.52 (95% CI: 0.29–0.95), P=0.033, Table 1) in comparison to those who received CY+ TBI-based MAC. Furthermore, in vivo T-cell depletion also tended to reduce the risk of the development of COP/BOOP (OR 0.46 (95% CI: 0.21–1.02), P=0.055, Table 1), although the difference was of borderline significance. GVHD prophylaxis was not associated with the development of COP/BOOP.

Association with GVHD

The association with severity and target organs of GVHD was analyzed separately, as GVHD was supposed to be a post transplant factor.

The presence of COP/BOOP was significantly associated with grade 2–4 aGVHD (OR 1.65 (95% CI: 1.24–2.20), P=0.00055) and skin involvement (OR 1.65 (95% CI: 1.22–2.24), P=0.0012, Table 2).

Table 2 Associations between COP/BOOP and acute GVHD

Next, we analyzed the association between COP/BOOP and cGVHD, focusing on 8282 recipients who survived more than 100 days after allogeneic HCT. COP/BOOP was significantly associated with the presence of extensive cGVHD (OR 3.97 (95% CI: 2.87–5.50), P<0.001, Table 3). Regarding the target organs of cGVHD, multivariate analysis revealed that the presence of COP/BOOP was significantly associated with skin (OR 1.51 (95% CI: 1.05–2.18), P=0.027) and liver cGVHD (OR 1.65 (95% CI: 1.11–2.45), P=0.014) (Table 3).

Table 3 Associations between COP/BOOP and acute GVHD among recipients who survived for more than 100 days after transplantation

Survivals of patients with COP/BOOP

The median observational duration of survivors with COP/BOOP was 783 days (range 96–2011). Of the 193 patients, 49 experienced relapse and 77 died during the observational period. Of the 77 deaths, the proportion of non-relapse death was 59% (n=46). Pulmonary failure and fatal infection accounted for 41% (n=19) and 26% (n=12) of the non-relapse death. The relapse date was available in 184 patients with COP/BOOP (95%). The 3-year NRM and OS in the COP/BOOP group were 29.0% (95% CI: 20.2–38.3; Figure 1a) and 60.5% (95% CI: 49.9–69.5%; Figure 1b), respectively. The NRM of patients with COP/BOOP seemed to be increased overtime. Namely, OS did not seem to stay in plateau.

Figure 1
figure1

(a) Cumulative incidence of NRM and (b) OS in the patients with COP/BOOP.

Next, we compared OS and NRM between the patients with and without COP/BOOP. Because COP/BOOP is a post transplant event, the control group without COP/BOOP might potentially include the patients who died before the COP/BOOP usually developed.8 Therefore, OS and NRM were compared between the groups among the patients who survived for at least 30, 100, 180 and 365 days after allogeneic HCT. Of the 193 patients with COP/BOOP, 193 (100%), 182 (94%), 167 (87%) and 137 (71%) recipients were included in the corresponding OS analysis. Among the 30-day survivors, no significant difference in OS was observed (the 3-year OS: 51.4% (95% CI: 42.3–59.7%) in the COP/BOOP group vs 54.1% (95% CI: 52.9–55.3%) in the control group, P=0.20, Figure 2a). However, their OS curves were crossed around 2 years after allogeneic HCT. When the longer term survivors were focused on, the OS curve of the COP/BOOP group fell below that of the control group. Finally, the 3-year OS in the COP/BOOP group became significantly lower than that of control group among the 365-day survivors (63.9% (95% CI: 53.0–72.8%) vs 79.2% (95% CI: 77.9–80.5%), P=0.0018, Figures 2a–d).

Figure 2
figure2

Comparison of OS between the patients with and without COP/BOOP, among at least (a) 30-, (b) 100-, (c) 180- and (d) 365-day survivors.

Similarly, among the 30-day survivors, no significant difference in NRM was observed (27.5% (95% CI:19.8–35.7%) in the COP/BOOP group vs 19.8% (95% CI: 18.9–20.7%) in the control group, P=0.35, Figure 3a). As the longer term survivors were focused on, the 3-year NRM in the control group tended to decrease (19.8% (95% CI: 18.9–20.7%), 15.0 %(95% CI: 14.1–15.9%), 12.1% (95% CI: 11.3–13.0%) and 7.7% (95% CI: 6.9–8.6%) among the 30-, 100-, 180 and 365-day survivors, respectively). On the other hand, the 3-year NRM in the COP/BOOP group remained high (27.5% (95% CI:19.8–35.7%) and 22.0% (95% CI: 13.9–31.2%) among the 30- and 365-day survivors, Figures 3a–d). The 3-year NRM got significantly higher in the COP/BOOP group even focusing on the 100-day survivors, and the significance became progressively greater in 180- and 365-day survivors.

Figure 3
figure3

Comparison of NRM between the patients with and without COP/BOOP, among at least (a) 30-, (b) 100-, (c) 180- and (d) 365-day survivors.

Discussion

Pre-transplant risk factors for the development of COP/BOOP were retrospectively identified using Japan Transplant registry data that included about 200 patients with COP/BOOP. HLA disparity, female-to-male HCT and related PBSCT were associated with an increased risk of COP/BOOP. On the other hand, the risk was significantly lower in patients who received BU+CY-based MAC and Flu-based RIC in comparison with CY+TBI-based MAC, and in those patients who received in vivo T-cell depletion with a borderline significance.

This study addressed several critical issues. First, this study suggested that allogeneic immunity could be associated with the development of COP/BOOP. No patient-based factors, but several donor-based factors, were associated with the development of COP/BOOP: HLA disparity, female-to-male HCT and related PBSCT. These findings suggested that allogeneic reactive immunity may contribute to the development of COP/BOOP, as GVHD is thought to be associated with COP/BOOP,8 and all of those three factors are known to be associated with GVHD.23, 24 Actually, in vivo T-cell depletion, which is thought to reduce allogeneic immunity and the risk of GVHD, also reduced the risk for the development of COP/BOOP in our cohort, although it was of borderline significance. Therefore, the risk of the development of COP/BOOP might mirror the risk for GVHD. However, unrelated BMT and CBT were not associated with the development of COP/BOOP, even though these factors are well known to affect the development and severity of GVHD.

Second, this study suggested that radiation toxicity could be associated with the development of COP/BOOP. The risk for the development of COP/BOOP was lower in recipients with Flu-based RIC in comparison to those who received CY+TBI-based MAC, which suggest that a high intensity of conditioning was associated with the development of COP/BOOP. However, BU-based MAC was also associated with low incidence. Thus, lung toxicity due to high-dose radiation might be another mechanism for the development of COP/BOOP. This is the first study to show the significant relationship between conditioning and the development of COP/BOOP, although the possibility of adverse impacts of radiation has been reported.8, 9 The association with CY+TBI-based MAC is a critically important difference between COP/BOOP and bronchiolitis obliterans syndrome, as BU-based conditioning, rather than TBI-based conditioning, has been reported to be associated with bronchiolitis obliterans syndrome.25, 26

Third, GVHD was associated with COP/BOOP as seen in previous reports.8 Especially, COP/BOOP was significantly associated with the presence of skin involvement of both aGVHD and cGVHD, although the association with GVHD was analyzed separately. The close association between skin and lung complications as observed in connective tissue diseases might shed light on a novel therapeutic approach such as tyrosine-kinase inhibitors, which has been investigated for both skin and lung involvement of systemic sclerosis.27

Taking these above findings into consideration, one of the triggers of COP/BOOP might be lung-injury caused by conditioning, especially high-dose TBI. Then, allogeneic reactions and subsequent abnormal immune reconstitution associated with GVHD would induce chronic abnormal wound repair with granulation formations, finally leading COP/BOOP. Lung-shielding TBI and sufficient immunosuppression would be beneficial as in TBI-induced pneumonia.28

COP/BOOP has been reported to respond to steroid treatment.8, 9, 10, 11, 12 However, it frequently recurs and repeatedly deteriorates.2, 3, 5, 9 Taking the fact into consideration, COP/BOOP might affect survivals in a later phase of allogeneic HCT rather than that in an early phase. In fact, the NRM curves of the COP/BOOP group seemed to increase linearly, and the 3-year NRM remained high even focusing on the longer survivors, whereas the 3-year NRM in the control group tended to decrease as the longer survivors were focused on. However, it should be noted that the true impact of COP/BOOP on NRM and OS remains unclear, as COP/BOOP was not treated as a time-dependent event in this analysis.

This analysis may have several limitations because of the study design and its retrospective nature. First, the severity and treatment details of COP/BOOP were not available from the registry data. Second, we could not assess the time-dependent impact of COP/BOOP on relapse and survival rates because the dates on which COP/BOOP developed were also not available. Third, the presence of COP/BOOP was based on the reports by attending physicians, not diagnosed on a central review. The information on histological examination was not also available. Truly, only prospective cohort studies using shared diagnostic criteria can reveal the true risk factors for the incidence and outcome of COP/BOOP. However, the strength of this study is the largest number of recipients with COP/BOOP, which could clearly reveal the pre-transplant risk factors.

In summary, this study suggested that allogeneic immunity and conditioning toxicity are associated with the development of COP/BOOP, and confirmed the strong association between COP/BOOP and GVHD. Prospective studies are required to elucidate the true risk factors for COP/BOOP and to develop a prophylactic approach against it.

Change history

  • 09 October 2013

    This article has been corrected since Advance Online Publication and a Corrigendum is also printed in this issue

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Acknowledgements

We greatly appreciate the work of all of the physicians and data managers at the centers that contributed valuable data on transplantation to the Japan Society for Hematopoietic Cell Transplantation (JSHCT), the Japanese Society of Pediatric Hematology and Oncology (JSPHO) the Japan Marrow Donor Program (JMDP) and the Japan Cord Blood Bank Network (JCBBN). We also thank all of the members of the Transplant Registry Unified Management committees at JSHCT, JSPHO, JMDP and JCBBN for their dedication.

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Correspondence to H Nakasone.

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The authors declare no conflicts of interest.

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Author contributions

HN designed the study, analyzed data and wrote the manuscript. MO, NS and NF advised on methods, analyzed the data and wrote the manuscript. KK, TE, and KM collected the data. HS, HY, YM, and KK collected the data and were responsible for managing the data from JSHCT, JSPHO, JMDP and JCBBN, respectively. RS analyzed and managed the unified registry database, and wrote the manuscript. TF analyzed the data, wrote the manuscript and was responsible for the study and the Complications-Working Group of JSHCT.

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Keywords

  • cryptogenic organizing pneumonia
  • bronchiolitis obliterans organizing pneumonia
  • risk factors
  • female-to-male transplantation
  • TBI
  • GVHD

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