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We report the case of a 4-year-old boy with β-thalassemia major, diagnosed at 1 year of age and managed with chronic transfusions. Due to the absence of a human leukocyte antigen (HLA)-matched donor and ongoing transfusion dependence, a T-cell replete haploidentical hematopoietic stem cell transplantation (HSCT) from his father was performed. Conditioning included busulfan, fludarabine, cyclophosphamide, and anti-thymocyte globulin. Rituximab was administered for post-transplant lymphoproliferative disorder (PTLD) prophylaxis, while graft versus host disease (GVHD) prophylaxis included cyclophosphamide, cyclosporine A, and mycophenolate mofetil. Engraftment achieved complete donor chimerism. Post-transplant complications included sinusoidal obstruction syndrome (defibrotide and therapeutic paracentesis), grade II acute cutaneous GVHD (steroid-responsive), Cytomegalovirus reactivations (cycles of valganciclovir), BK virus-associated hemorrhagic cystitis, and transient thrombotic microangiopathy. The most severe complication was pulmonary. Pre-transplant chest computed tomography (CT) was normal, except for an area of reduced ventilation in the middle lobe (ML). Spirometry was not feasible due to poor cooperation. One month post-HSCT, the patient developed acute respiratory distress requiring high-flow nasal cannula (HFNC) oxygen, intravenous corticosteroids, inhaled salbutamol, and respiratory physiotherapy. Microbiology was negative. Chest CT revealed bilateral consolidative striae involving the right upper lobe (RUL), ML, right lower lobe (RLL), lingula, and left lower lobe (LLL), with increased parenchymal thickness and absence of air bronchograms. After improvement, the patient was discharged. Despite partial response to inhaled corticosteroids (ICS) and salbutamol, exacerbations recurred. Two months post-HSCT, a follow-up chest CT with inspiratory and expiratory views showed resolution of the previous consolidations in the lingula and ML, with residual fibrotic striae and a new consolidation in the left upper lobe (LUL). Expiratory views revealed subsegmental air trapping involving approximately 60% of the upper lobes and segmental air trapping in the lower lobes, with mild bronchial and bronchiolar wall thickening—findings consistent with bronchiolitis obliterans (BO) (Figure 1). Bronchoscopy with bronchoalveolar lavage (BAL) and lung biopsy were not performed due to high procedural risk. ICS, salbutamol, montelukast, thrice-weekly azithromycin, ruxolitinib, and eight extracorporeal photopheresis sessions were initiated, but HFNC remained necessary. Six months post-HSCT, he contracted Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, requiring maximal HFNC support, intravenous corticosteroids, sotrovimab, and remdesivir. Imaging revealed bilateral ground-glass opacities but no active pneumonia. After stabilization, home HFNC cycling was introduced. At 11 months, chest CT demonstrated persistent bilateral ground-glass opacities, reticular thickening, fibrosis, and bronchiectasis in the ventral segment of the RUL, with expiratory views revealing mild air trapping—findings suggestive of chronic interstitial pneumonia, possibly busulfan-induced (Figure 2). One year post-HSCT, the patient's respiratory status worsened in the absence of infection or systemic inflammation, necessitating rehospitalization for continuous HFNC support and respiratory physiotherapy. High-dose ICS and intravenous methylprednisolone pulses (30 mg/kg/day for 3 consecutive days every 4 weeks) were administered. Overnight polygraphy revealed moderate obstructive sleep apnea syndrome (OSAS), with a peripheral capillary oxygen saturation (SpO₂) nadir of 94% and an elevated respiratory mechanical index (RMI 26%). The patient required nocturnal noninvasive ventilatory support, alternated with HFNC during daytime hours. Pulmonary hypertension was excluded. Spirometry remained unfeasible. Given the progression to end-stage lung disease and stable full donor chimerism, a multidisciplinary team recommended living donor lung transplantation (LDLT) from the father, chosen to leverage immunologic compatibility and minimize the need for post-transplant immunosuppression. Ten months post-LDLT, the patient exhibited clinical respiratory stability without ongoing immunosuppression, supporting the hypothesis of transplant tolerance mediated by full donor chimerism [1]. This case highlights the diagnostic and therapeutic challenges of post-HSCT pulmonary complications, particularly in distinguishing between BO and drug-induced lung injury. Our patient likely developed multifactorial lung damage involving both BO and busulfan-related toxicity. BO syndrome (BOS), a manifestation of chronic lung GVHD, affects approximately 4.5%−8.3% of pediatric HSCT recipients, typically within 3 months post-transplant, and is characterized by progressive small airway obstruction. Due to its frequently insidious and asymptomatic onset, early detection through pulmonary function testing (PFT) is crucial. However, in pediatric populations, especially pre-school children, spirometry is often unfeasible due to limited cooperation and may fail to detect early peripheral airway involvement. Recognizing these challenges, the American Thoracic Society (ATS) conditionally recommends surgical lung biopsy in children with suspected BOS when there is persistent diagnostic uncertainty, and the potential benefit of biopsy outweighs the procedural risks. Such uncertainty is defined by discordant clinical, radiological (specifically, chest CT scan with inspiratory/expiratory views), and functional findings; absence of noninvasive alternatives; or suspicion of an alternative or coexisting condition [2]. In our patient, obstructive symptoms, persistent oxygen dependence, and expiratory air trapping on chest CT supported the diagnosis of BO, while bronchoscopy and lung biopsy were not performed due to high procedural risk in a critically ill child. At the same time, busulfan-induced lung injury remains a plausible contributing factor. As an alkylating agent, busulfan is associated with pulmonary toxicity, usually appearing within 30 days to 1 year post-transplant. Proposed mechanisms include CD8+ T-cell activation, alveolar epithelial apoptosis, and interstitial inflammation leading to pneumonitis and fibrosis. Histological findings may include intra-alveolar fibrinous edema and hyperplastic type II pneumocytes, possibly driven by surfactant dysregulation and increased alveolar wall permeability. Clinical presentation is nonspecific, with symptoms such as dyspnea, dry cough, fatigue, and weight loss. Imaging may show bilateral ground-glass opacities or reticulations, while BAL may reveal nonspecific inflammatory changes (i.e., lymphocytosis, neutrophilia, and hyperplastic pneumocytes). Treatment is mainly supportive, with corticosteroids used in rapidly progressive cases, although supporting evidence is primarily observational [3]. Given the failure of maximal medical therapy, LDLT from the original HSCT donor offered a novel strategy. This approach may confer immunological benefits in patients with full donor chimerism, potentially enhancing graft tolerance and reducing the need for long-term immunosuppression [1, 4, 5]. Our patient's stable outcome supports this hypothesis and highlights the potential for individualized transplant strategies in severe pediatric HSCT complications. In conclusion, this case illustrates the possibility of overlapping etiologies in post-HSCT lung disease. A combination of BO and busulfan-induced toxicity likely contributed to respiratory failure. Such multifactorial pathogenesis emphasizes the importance of multidisciplinary evaluation and individualized management in pediatric HSCT recipients with complex pulmonary presentations. Conceptualization: Grazia Fenu. Methodology: Simone Foti Randazzese. Software: Enrico Lombardi. Validation: Grazia Fenu, Veronica Tintori, and Enrico Lombardi. Formal analysis: Simone Foti Randazzese. Investigation: Claudia Calogero, Chiara Caparrelli, Paolo Del Greco, and Daniela Cuzzubbo. Resources: Enrica Rossi. Data curation: Matteo Masolini, Stefano Frenos, and Eleonora Gambineri. Writing the original draft preparation: Grazia Fenu and Simone Foti Randazzese. Writing, review, and editing: Veronica Tintori and Enrico Lombardi. Visualization: Grazia Fenu, Simone Foti Randazzese, Claudia Calogero, Chiara Caparrelli Paolo Del Greco, Matteo Masolini, Enrica Rossi, Daniela Cuzzubbo, Stefano Frenos, Eleonora Gambineri, Veronica Tintori, and Enrico Lombardi. Supervision: Grazia Fenu and Enrico Lombardi. All authors have read and agreed to the published version of the manuscript. The authors have nothing to report. The authors have nothing to report. Written informed consent was obtained from the patient's parents for publication. Ethical review and approval were waived in accordance with the institutional policy of the Clinical Ethics Committee, Meyer University Hospital, IRCCS Florence. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.