Noninfectious Generalized Bronchiolitis in the Setting of Allogeneic Stem Cell Transplantation

Rationale and Objectives

To describe a little-known therapy-related small-airway phenomenon presumably caused by mucosal irritation in patients undergoing allogeneic stem cell transplantation (allo-SCT).

Materials and Methods

Retrospective database search at our institution identified 739 hematologic patients who underwent chemotherapy + allo-SCT between September 2004 and March 2014. After infectious pulmonary complications were excluded, 75 patients (female = 24; male = 51; median age = 47 years) with signs of generalized bronchiolitis (GB) on chest high-resolution computed tomography were identified. Computed tomography (CT) was performed proximate to chemotherapy onset; 92% had follow-up CT (mean, 1.9 weeks). The presence of centrilobular nodules, bronchial wall thickening (BWT), tree-in-bud (distributed diffuse vs. focal), ground-glass opacity, airspace opacification, luminal impactions, and air trapping was correlated with occurrence and duration of oral mucositis and therapy characteristics. Intensity of tree-in-bud and centrilobular nodules was graded absent (grade = 0), moderate (grade = 1), or marked (grade = 2).

Results

Overall incidence of GB among allo-SCT patients was 10.14%. GB was diagnosed at the time point of transplantation with a mean duration of CT findings of 4 weeks (±2.7). Tree-in-bud (17% [grade 2] and 83% [grade 1]) and BWT were present in 100% of the patients. Centrilobular nodules diffusely distributed were found in 45.5% of patients (20% [grade 2], 24% [grade 1], and 56% [none]). Air trapping and mosaic pattern were found in 13% and 16% of the patients, respectively. Resolution of GB was spontaneous. GB and its severity correlated with the temporal course and grade of oral mucositis; frequency and degree were not significantly influenced by the chemotherapy regimen. The incidence of GB in high-resolution computed tomography was statistically and significantly higher in patients with oral mucositis ( P < 0.035).

Conclusions

GB is frequent during chemotherapy for allo-SCT and is characterized by an even distribution of tree-in-bud, BWT, centrilobular nodules, mild clinical symptoms, and spontaneous resolution.

Introduction

llogeneic stem cell transplantation (allo-SCT) is a potential curative therapy for many hematologic diseases. Recently, reduced intensity conditioning (RIC) regimens have been developed to allow allo-SCT even in elderly patients. Unfortunately, these therapies are frequently accompanied by both infectious and noninfectious complications affecting primarily the lungs. Severe pulmonary complications occur in 40–60% of patients undergoing allo-SCT, causing increased transplant-related deaths . Classically, these pulmonary complications are categorized early or late (before versus after day 100 post transplant) depending on time elapsed after SCT. Bacterial, viral, and fungal infections are among the most common “very early” posttransplant pulmonary complications occurring within 2 weeks after therapy onset because of maximal immunodeficiency (neutropenic phase). Pulmonary edema, diffuse alveolar hemorrhage, transfusion-related acute lung injury, veno-occlusive disease, and mucositis are also frequent and have been extensively analyzed in particular in the setting of allo-SCT , but some (e.g. engraftment syndrome) are joining hematopoietic regeneration and are also frequent in the setting of autologous SCT . Treatment strategy depends primarily on differentiation between infectious and noninfectious pulmonary complications based on clinical, laboratory, and imaging markers that help for more accurate classification of these disorders. In the setting of respiratory symptoms and imaging findings compatible with small-airway diseases on chest high-resolution computed tomography (HRCT), lower respiratory tract infection, mostly caused by respiratory viruses and less frequently by bacteria, must be suspected. However, knowledge of potential mimics is essential for accurate patient management. At this point, mucosal barrier injury (mucositis) represents a common complication and a potential differential diagnosis affecting patients receiving cytotoxic preparative chemotherapy regimens prior to allo-SCT . Whereas clinical manifestations of oral and gastrointestinal mucositis are well known, involvement of bronchial and bronchiolar mucosa is generally running on a mild clinical or even subclinical level and has been therefore paid less attention.

Based on a single-center long-year experience in dealing with imaging in patients undergoing allo-SCT, we decided to retrospectively analyze all patients developing pulmonary complications during neutropenia with the focus on generalized bronchiolitis (GB). Our purpose was to characterize it from a radiological–clinical point of view, differentiate it from other mimics, and describe its spontaneous course.

Materials and Methods

Patient Characteristics

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TABLE 1

Underlying Diseases of All Patients Undergoing Stem Cell Transplantation and Incidence of Generalized Bronchiolitis

Overall GB Incidence_n_ %n % %Total 739 100 75 100 10.14 AML 355 48.04 41 54.66 11.54 ALL 91 12.31 13 17.33 14.28 NHL 84 11.37 5 6.66 5.95 MDS 51 6.90 12 16.00 23.52 Multiple myeloma 36 4.87 — — — CML 28 3.79 1 1.33 3.57 MPS 23 3.11 — — — OMF 17 2.30 — — — CLL 16 2.17 1 1.33 6.25 Pure red cell aplasia 15 2.03 — — — Aplastic anemia 10 1.35 2 2.69 20.00 Hodgkin’s lymphoma 7 0.95 — — — Secondary MDS 5 0.68 — — — Systemic sclerosis 1 0.14 — — —

ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; GB, generalized bronchiolitis; MDS, myelodysplastic syndrome; MPS, myeloproliferative syndrome; NHL, non-Hodgkin lymphoma; OMF, osteomyelofibrosis.

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High-resolution CT Technique

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Imaging Analysis

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Standard of Reference

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Statistics

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Results

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TABLE 2

Major CT Imaging Findings

Tree-in-bud sign (%) 100 Grade 1 83 Grade 2 17 Bronchial wall thickening (%) 97 Nodules (%) 45.5 Grade 0 56.0 Grade 1 24.0 Grade 2 20.0 Mosaic pattern (%) 16.0 Air trapping (%) 13.3 Mucoid impaction (%) 5 Bronchiectasia (%) 0

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The Course of Pulmonary Findings at Chest HRCT at Follow-up

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Correlation of Chest HRCT Imaging Findings and Their Incidence with the Chemotherapy Regimen, TBI, and Graft Characteristics

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TABLE 3

Elements of Conditioning Regimen

TBI ( n ) 35 Chemotherapy ( n ) Cyclophosphamide 29 Fludarabine 30 Busulfan 20 Melphalan 8 FLAMSA 7 Alternative idarubicin 2

FLAMSA, fludarabine, cytarabine, and amsacrine; TBI, total body irradiation.

Some patients received chemotherapy regimens consisting of a combination of more agents.

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Comparing Patients’ Characteristics in the Group Developing GB Versus the Group with Allo-SCT without GB

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Discussion

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References

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Noninfectious Generalized Bronchiolitis in the Setting of Allogeneic Stem Cell Transplantation

Rationale and Objectives

Materials and Methods

Results

Conclusions

Introduction

Materials and Methods

Patient Characteristics

High-resolution CT Technique

Imaging Analysis

Standard of Reference

Statistics

Results

The Course of Pulmonary Findings at Chest HRCT at Follow-up

Correlation of Chest HRCT Imaging Findings and Their Incidence with the Chemotherapy Regimen, TBI, and Graft Characteristics

Comparing Patients’ Characteristics in the Group Developing GB Versus the Group with Allo-SCT without GB

Discussion

References

Further Reading

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