Busulfan-Induced Lung Injury in Pediatric Oncology Patients—Review of the Literature with an Illustrative Case

Abstract

Background: Impaired lung function has been detected in up to 65% of all childhood cancer survivors. It is often caused by exposure to radiation therapy and various chemotherapeutics. The first cytotoxic drug ever identified as a causative agent of lung injury was busulfan, reported in the early 1960s. Signs and symptoms of busulfan lung are nonspecific and it is therefore difficult to differentiate the condition from pulmonary impairment caused by other pulmotoxic agents, infections, pulmonary metastases, graft-versus-host disease, or other noninfectious post-transplant complications involving the lungs. Methods: A case example is provided to illustrate the difficulties in management of busulfan-induced lung injury in children. A retrospective review of cases of busulfan-induced lung injury indexed in PubMed until March 2019 was performed. Inclusion criteria for articles was available in full text in English. Results: Impaired lung function caused by busulfan may become an increasing problem for young survivors. Conclusion: Newly developed dyspnea or subclinical damage detected on pulmonary function tests, indicating primarily restrictive disease, should always arouse suspicion of busulfan-induced lung injury in a child conditioned with busulfan, especially after excluding other leading culprits of pulmonary damage affecting oncology patients.

Modulation of COX-2 and NADPH oxidase-4 by alpha-lipoic acid ameliorates busulfan-induced pulmonary injury in rats

“…Yet, the exact mechanism of busulfan-induced lung injury still unknown. According to Matijasic et al [5] the purpose was that increased alveolar wall permeability results in fibrin leakage, motivating alveolar lining cells to enlarge and undergo bizarre changes. In addition, it was hypothesized that these changes in type II alveolar cells cause aberrant surfactant secretion, all leading to increased surface tension and suction pressure, again promoting pulmonary edema.21 Moreover, patients with busulfan lung frequently displays both lymphocytosis and neutrophilia results from a delayed hypersensitivity reaction in which numerous chemokines and proinflammatory cytokines mediate a sustained CD8 cytotoxic T cell response, resulting in tissue damage.…”

Hematopoietic Stem Cells Transplant (HSCT)-Related Chronic Pulmonary Diseases: An Overview

“…Busulfan may produce lung injury in both the acute and long term. Almost 4% of patients develop acute interstitial pneumonitis within the first 100 days from transplantation, but alveolar hemorrhage, pleural effusions, bronchospasm, and veno-occlusive disease related to Busulfan may occur [ 13 ]. On the other hand, some patients develop chronic pulmonary interstitial fibrosis with bronchiolitis obliterans, which usually becomes clinically evident after a median of 3.5 years from exposure.…”

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease

“…Indeed, of the various classes of chemotherapy agents, alkylating agents, such as busulfan, pose the highest risk to fertility and are associated with premature ovarian insufficiency [29]. Further, alkylators are also associated with therapy-related malignancies, specifically acute leukemia and myelodysplasia [30], as well as delayed lung toxicity; BU, in particular, is known for its potential pulmonary effects [31].…”