ABSTRACT
Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is an effective treatment for multiple myeloma; however, the development of chronic graft‐versus‐host disease remains a significant challenge. Bronchiolitis obliterans syndrome (BOS) is one of the complications. Even with available medications for treatment, the prognosis of BOS remains poor. We present a 32‐year‐old female with multiple myeloma experienced BOS 6 months after allo‐HSCT. Even with medical treatment, her clinical condition and pulmonary function was deteriorating. Based on the indication of a BODE (Body‐mass index, Obstruction, Dyspnoea and Exercise) index of 7, she underwent bilateral lung transplantation 33 months after allo‐HSCT. Three months post‐operation, there was a significant improvement in pulmonary function. After approximately 5 years of follow‐up, her lung function remains stable, and she is able to work and live a normal life. Lung transplantation may be an effective therapeutic strategy for BOS developed after allo‐HSCT.
Keywords: allogeneic haematopoietic stem cell transplantation, bronchiolitis obliterans syndrome, lung transplantation, multiple myeloma
We present a case of a patient with multiple myeloma who experienced bronchiolitis obliterans syndrome following allogeneic haematopoietic stem cell transplantation and subsequently underwent lung transplantation.
1. Introduction
Bronchiolitis obliterans syndrome (BOS) following allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is one of the complications of chronic graft‐versus‐host disease (GVHD) affecting the lungs. The diagnosis of BOS is primarily pathological; however, it can also be diagnosed clinically, including chronic GVHD in other organs, typical pulmonary function and imaging [1].
Currently, the first‐line treatment for BOS recommends the use of systemic corticosteroids alone, or in combination with calcineurin inhibitors. Other treatment options may include inhaled corticosteroids (ICS) combined with long‐acting beta agonists (LABA), and non‐pharmacologic treatment like extracorporeal photopheresis (ECP) [2]. Despite these strategies, the prognosis for BOS remains poor. In this context, lung transplantation is another therapeutic option. We present a case of a patient with multiple myeloma who experienced BOS following allo‐HSCT and subsequently underwent lung transplantation.
2. Case Report
A 32‐year‐old female patient with the medical history of hypertension and α‐thalassemia underwent allo‐HSCT from her sibling on September 29, 2016 after achieving complete response with induction therapy with bortezomib, thalidomide, dexamethasone and autologous stem cell transplantation (auto‐HSCT) for IgG kappa multiple myeloma. She experienced dyspnoea and cough with whitish sputum 6 months later. The pulmonary function test (PFT) showed obstructive respiratory pattern (FEV1 [forced expiratory volume in 1 s]: 1.11 L, 43% of the predicted value [%FEV1], FVC [forced vital capacity]: 2.33 L, 79% of the predicted value [%FVC], FEV1/FVC ratio: 47.4%) with significant reversibility using short‐acting β‐agonist. She was treated as asthma initially and was prescribed LABA, long‐acting muscarinic antagonists, ICS, prednisolone and omalizumab.
Twenty‐three months after allo‐HSCT, she experienced type 2 respiratory failure and needed long‐term home bilevel positive airway pressure (BIPAP) used (pH: 7.294, PaCO2: 69 mmHg, HCO3: 32.7 mmol/L, PaO2: 161.4 mmHg, inspired fraction of oxygen: 35%). She accepted high‐resolution chest computer tomography (HRCT), which revealed bronchiectasis over bilateral lower lung fields with air trapping during expiratory phase (Figure 1). The PFT showed very severe obstructive coexisting with restrictive respiratory pattern (FEV1: 0.29 L, %FEV1: 11%, FVC: 0.76 L, %FVC: 26%, FEV1/FVC ratio: 38.2%). She was suspected to have BOS after allo‐HSCT. Due to BODE (Body‐mass index, Obstruction, Dyspnoea and Exercise) index greater than 5 and %FEV1 < 25%, she was referred to lung transplantation team for assessment for lung transplantation [3].
FIGURE 1.
HRCT scan before and 5 months after lung transplantation. Both imaging sets were acquired using a 1‐mm slice thickness scanning protocol. (A) The CT scans show mosaic attenuation, emphysematous change and bronchiectasis before lung transplantation. (B) CT scans taken at 5 months after lung transplantation showing the improvement of aforementioned findings. A consolidation at RML is caused by recent respiratory infection. HRCT, high resolution chest computed tomography; RML, right middle lobe.
At age 35 years, 33 months after allo‐HSCT, according to the indication of BODE index of 7, %FEV1 < 15% to 20% predicted and one severe exacerbation with acute hypercapnic respiratory failure, she underwent bilateral cadaveric lung transplantation at Linkou Chang Gung Memorial Hospital [3]. The macroscopic findings of the native removed lungs revealed emphysematous change. Microscopical specimen was obtained from the left upper lobe. It revealed constrictive bronchiolitis which was characterised by subepithelial fibrosis, leading to luminal narrowing, and were consistent with BO which is a complication of bone marrow transplantation (Figure 2). In the postoperative period, total mechanical ventilation time was 3 days, length of intensive care unit stay was 10 days, and the length of hospitalisation stay was 40.6 days.
FIGURE 2.
Pathological specimen obtained from a resection of the left upper lobe of the native lung. (A) The bronchioles showed a mild to severe degree of subepithelial fibrosis, leading to luminal narrowing. Some of the bronchioles showed complete obliteration of the lumen (black arrow). The peribronchiolar alveolar tissue is unremarkable. (haematoxylin and eosin stain, 100×). (B) The elastic stain revealed the elastica of the bronchiole (yellow arrow) (100×, elastic stain).
The PFT records from the 5‐year follow‐up period after lung transplantation are summarised in Figure 3. Five months after lung transplantation, she visited the emergency department due to productive cough for 1 month. The chest computed tomography (CT) showed a small consolidation in the peripheral right middle lobe (Figure 1). She was discharged with the oral antibiotics and the symptoms improved following treatment. Six months after lung transplantation, the PFT showed normal (Figure 3). The histopathologic report showed negative of rejection in the specimen obtained from the transbronchial lung biopsy. Four years after lung transplantation, an inspiratory lung volume 2448 mL and an expiratory lung volume of 1100 mL were measured by the CT scan. Since November 2019, she has not visited the emergency department for respiratory symptoms. The patient is able to maintain employment and a normal lifestyle for 5 years following lung transplantation.
FIGURE 3.
Pulmonary function measured by spirometry and the distance of 6‐min walk test before and 1, 3, 4, 12, 36 and 60 months after lung transplantation. FVC, forced vital capacity; %FVC, FVC of the predicted value; FEV1, forced expiratory volume in 1 s; %FEV1, FEV1 of the predicted value.
3. Discussion
We present a case of young female who achieved successful complete remission following allo‐HSCT. Six months later, she began to exhibit symptoms of BOS. Despite pharmacological management, her obstructive respiratory disease continued to deteriorate. After lung transplantation, her PFT showed significant improvement within 3 months, and it remained within the normal range for 5 years thereafter.
Despite advancements in pharmacotherapy that have improved the prognosis for patients with multiple myeloma, it remains a challenging disease to cure. Allo‐HSCT can offer patients with multiple myeloma the potential for long‐term survival, or even cure. However, this approach also exposes patients to immunosuppression and GVHD. Therefore, allo‐HSCT is not a standard treatment and must be carefully considered for select patients, such as younger individuals without comorbidities.
Approximately 5.5% of patient who undergo allo‐HSCT develop BOS; however, this prevalence can increase to 14% in patients with chronic GVHD [4]. Several factors may contribute to the risk of developing BOS after allo‐HSCT, including development of acute GVHD, busulfan‐based regimen use in allo‐HSCT, mismatched donor, lower pre‐transplantation FEV1, female sex of donor, recipient age younger than 20 years, and respiratory viral infections occurring within the first 100 days post‐transplant [5].
Most previous reports primarily describe cases of BOS following allo‐HSCT in patients with leukaemia, with little mention of those in multiple myeloma. A case report describes a 25‐year‐old female who developed BOS diagnosed clinically 1 year following allo‐HSCT [6]. With the medication, ECP and pulmonary infection control, her pulmonary function was stable for 3 years. Another case involves a 67‐year‐old male with multiple myeloma, who was clinically diagnosed with BOS following HSCT; however, different from our case, he underwent auto‐HSCT [7].
While there are currently medications and ECP available to treat BOS, the prognosis remains poor. Lung transplantation may represent another viable treatment option. Previous report demonstrated seven patients who developed BOS following allo‐HSCT; five of them had leukaemia and two had lymphoma. The median overall survival following lung transplantation was 24 months [8]. Another retrospective study reported 9 patients with leukaemia and aplastic anaemia who developed BOS after undergoing allo‐HSCT and subsequently received lung transplantation. With a median follow‐up of 17 months, seven of them were still alive, including one who was placed on the waiting list for re‐transplantation due to recurrent BOS 45.3 months post‐lung transplantation [9]. Previous report Liang et al. described six patients with leukaemia who developed BOS after allo‐HSCT showed an average survival of 53 ± 23 months post‐lung transplantation in those with leukaemia who developed BOS after allo‐HSCT. Their average %FEV1 improved from 16.7% ± 5.9% to 57.9% ± 15.3% 3 months post‐operatively [10]. Patients who develop BOS following allo‐HSCT have shown favourable outcomes with lung transplantation, achieving good survival rates and improvements in lung function. The 1, 3 and 5 years survival rates following lung transplantation after allo‐HSCT related BOS are 85%, 72% and 67%, respectively, which are comparable to the outcomes of other end‐stage lung diseases without any specific HSCT factors impact on outcome [11]. The main complications following lung transplantation for BOS after HSCT are infection and recurrent BOS, with approximately 27% of patients developing BOS again [11, 12]. However, the cases included in previous studies lack patients with the multiple myeloma who underwent allo‐HSCT.
International indications for lung transplantation in patients with obstructive lung disease include the following criteria: (1) BODE index ≥ 7, (2) FEV1 < 15%–20% predicted, (3) three or more severe exacerbations during the preceding year, (4) one severe exacerbation with acute hypercapnic respiratory failure, and (5) moderate to severe pulmonary hypertension. Patients who meet any of these criteria are eligible to be placed on the transplant list [3]. Currently, there are no specific lung transplantation indications established for patients with multiple myeloma who develop BOS following HSCT.
In conclusion, cases of BOS following allo‐HSCT in multiple myeloma are exceedingly rare, and there is currently limited evidence indicating whether these patients are at a higher risk for developing BOS. Moreover, the prognosis for such patients after lung transplantation remains unclear. Our presented case demonstrates patient with this condition can achieve significant improvement in lung function and quality of life following lung transplantation, with these benefits sustained over and extended period. In managing these patients, in addition to pharmacological treatments, lung transplantation may represent another effective therapeutic option.
Author Contributions
Shih‐Wei Huang wrote the manuscript and figure legends. Ko‐Wei Chang, Pin‐Li Chou and Chih‐Wei Wang gathered patient's medical and health records. Wei‐Hsun Chen, Chien‐Hung Chiu, Yun‐Hen Liu and Tung‐Liang Lin were involved in the care of the patient. Hsiao‐Wen Kao and Shaw‐Woei Leu contributed to the conceptualization and design. Kuo‐Chin Kao and Han‐Chung Hu reviewed and edited the final manuscript. All authors have approved the submitted version of the manuscript and agreed to be accountable for any part of the work.
Ethics Statement
The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.
Conflicts of Interest
The authors declare no conflicts of interest.
Associate Editor: Arata Azuma
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.