Lung transplantation for diffuse panbronchiolitis: 5 cases from a single centre

Abstract

Diffuse panbronchiolitis is a rare complex genetic disease predominantly affecting East Asians, and is characterized by chronic inflammation of the respiratory bronchioles and sinobronchial infection. Although long-term macrolide therapy has been shown to significantly improve the survival in patients with diffuse panbronchiolitis, some patients continue to deteriorate, eventually requiring lung transplantation. However, lung transplantation for diffuse panbronchiolitis has rarely been reported and the outcome in these patients remains unknown. We describe our experience of lung transplantation for diffuse panbronchiolitis. A total of 5 patients received long-term macrolide therapy and had airway colonization by Pseudomonas aeruginosa preoperatively. Three patients had undergone sinus surgery for chronic rhinosinusitis before the transplantation. Bilateral cadaveric lung transplantation was performed in 4 patients, and living-donor lung transplantation in 1. After the lung transplantation, 1 patient developed an A3 acute rejection episode; however, none of the recipients developed severe pneumonia or any fatal infections. One recipient developed chronic lung allograft dysfunction 3 years after the transplantation; however, none developed recurrence of diffuse panbronchiolitis. All of the 5 patients were still surviving after a median follow-up period of 4.9 years (3.7–12.3 years). Lung transplantation is a viable option for the treatment of progressive diffuse panbronchiolitis resistant to long-term macrolide therapy.

INTRODUCTION

Diffuse panbronchiolitis (DPB) is a rare complex genetic disease predominantly affecting East Asians [1, 2]. In addition to the limited number of DPB cases reported from outside East Asia, about a half of the limited number of DPB cases reported from Western countries are Asian immigrants [2]. While DPB is frequently compared with cystic fibrosis, a common genetic disease encountered in Caucasians, neither pancreatic insufficiency nor any obvious abnormalities of the sweat electrolytes are seen in DPB, and the two are considered to be entirely different diseases [2]. Clinically, DPB is characterized by chronic inflammation of the respiratory bronchioles and sinobronchial infection [1, 2]. Moreover, DPB is a progressive suppurative and obstructive airway disease, resulting in bronchiectasis, respiratory failure and death, if left untreated [2]. Long-term therapy with macrolide antibiotics has been shown to significantly improve the survival of DPB patients [1]; however, some DPB patients deteriorate despite macrolide therapy, eventually requiring lung transplantation (LTx). To date, LTx for progressive DPB patients has rarely been reported, except for a case of early recurrence of DPB after LTx [3] and our successful case [4], and the outcomes of LTx for progressive DPB are unknown. In this study, we describe our experience of LTx for DPB.

CLINICAL SUMMARY

Between October 1998 and March 2014, we performed 124 LTx, including 51 cadaveric LTx and 73 living-donor lobar LTx in patients with various end-stage lung diseases. Among these, 5 patients were cases of DPB. The patients' characteristics are reported in Table 1 [4]. After the clinical diagnosis of DPB (Fig. 1), all 5 patients received long-term macrolide therapy for 5–20 years. Pseudomonas aeruginosa was preoperatively isolated in the sputum of all 5 patients. According to the results of otolaryngological evaluation, 3 of the 5 patients had undergone sinus surgery for severe rhinosinusitis before the LTx, while the remaining 2 patients had received only nasal care. Non-invasive positive pressure ventilation had been adopted in 2 of the 5 patients before the LTx. One patient had had a brain abscess that had been treated before he was registered on the LTx waiting list, whereas another patient had secondary pulmonary hypertension associated with progressive DPB. The median waiting time for the LTx was 709 (371–1029 days).

Table 1:

Patient characteristics

Characteristics	Patient
	1	2	3	4	5
Age/sex	37/F	27/M	36/F	40/F	40/F
Macrolide therapy (years)	5	7	9	6	20
Pseudomonal colonization	Yes	Yes	Yes	Yes	Yes
Pretransplant sinus surgery	Yes	Yes	Yes	No	No
Pretransplant ventilator	NIPPV	None	None	NIPPV	None
Comorbidity	None	Brain abscess	None	None	Secondary PH
Waiting time (days)	None	1029	874	544	371
Lung transplant donor	Living	Brain-dead	Brain-dead	Brain-dead	Brain-dead
Total number of HLA-A, HLA-B and HLA-DR mismatches	1	6	2	5	4
Lung transplant procedure	Bilateral	Bilateral	Bilateral	Bilateral	Bilateral
Graft ischaemic time (min)	160	578	463	519	787
PGD grade	0	0	0	1	3
Acute rejection episode (frequency)	2	0	0	0	0
Post-transplant complication	Pneumothorax	None	None	None	Rectal cancer
CLAD	No	No	No	Yes	No
Recurrence of DPB	No	No	No	No	No
Follow-up period (years)	12.3	5.1	4.9	4.3	3.7

CLAD: chronic lung allograft dysfunction; DPB: diffuse panbronchiolitis; HLA: human leucocyte antigen; NIPPV: non-invasive positive pressure ventilation; PGD: primary graft dysfunction; PH: pulmonary hypertension.

Figure 1:

Representative chest X-ray (A) and computed tomographic (CT) image (B) in Patient 1 and representative histology of the lung (C) in Patient 2. (A) Chest X-ray shows bilateral, diffuse, small nodular shadows with pulmonary hyperinflation. (B) Chest CT image shows nodular shadows distributed in a centrilobular fashion, extending to small, branching linear areas of attenuation (‘tree-in-bud’ pattern). (C) Histological findings show chronic inflammation localized mainly in the respiratory bronchioles with characteristic interstitial accumulation of foamy histiocytes and lymphocyte infiltration, suggestive of diffuse panbronchiolitis (haematoxylin and eosin staining ×40).

Four patients underwent bilateral cadaveric LTx, whereas the remaining 1 patient underwent bilateral living-donor lobar LTx. Cardiopulmonary bypass was used in all the 5 patients during the LTx. The median ischaemic time of the second graft was 463 (160–787 min). One patient with grade 3 primary graft dysfunction required postoperative extracorporeal membrane oxygenation. In all the 5 recipients, the post-transplant immunosuppression therapy consisted of tacrolimus, mycophenolate mofetil and corticosteroid. One recipient developed steroid-resistant acute A3 rejection diagnosed by open lung biopsy, which necessitated OKT3 administration.

In the postoperative period, the only recipient of living-donor lobar LTx developed pneumothorax, which necessitated a repair operation. Another recipient was diagnosed as having rectal cancer 14 months after the LTx, which necessitated colorectal resection. None of the recipients developed severe pneumonia or fatal infectious diseases. Pseudomonas aeruginosa, which was detected in the sputum of all the recipients before the LTx, disappeared transiently from the sputum within 1 year after the LTx. Four of the 5 patients, including 2 patients who had not undergone sinus surgery, developed pseudomonal airway recolonization in the long term after LTx. Histological examination revealed chronic inflammation localized mainly in the respiratory bronchioles with characteristic interstitial accumulation of foamy histiocytes and lymphocyte infiltration, suggestive of DPB (Fig. 1). In the follow-up period, we applied the same basic approach to the management of LTx recipients, because outcomes after LTx were similar between living-donor lobar LTx and cadaveric LTx at our institution. No patient required periodic intravenous immunoglobulin for hypogammaglobulinaemia after LTx. One recipient developed obstructive chronic lung allograft dysfunction (CLAD), 3 years after the LTx. No recipient developed recurrence of the DPB. All of the 5 recipients were still surviving after a median follow-up period of 4.9 (3.7–12.3 years).

DISCUSSION

Because LTx is not yet commonly practised in East Asia, which is the region most individuals with DPB reside in, the outcomes of LTx for DPB have never been reported. To the best of our knowledge, this is the first report of long-term outcomes of LTx for DPB. In this study, no cases of recurrence of DPB were encountered in the long term after LTx. Recurrence of DPB 10 weeks after LTx was reported two decades ago, which was the first report of recurrence of the native lung disease after LTx [3]. Subsequently, recurrence developing 4 months after LTx was reported in 2 cases of diffuse bronchiectasis [5], which had been preoperatively diagnosed as DPB. In these cases, sinus surgery or nasal care for chronic rhinosinusitis seemed not to have been performed before the LTx [5]. In this study, control of rhinosinusitis with sinus surgery or continuous nasal care might be important in preventing recurrence of DPB and fatal infection after LTx. However, 1 patient receiving only nasal care developed CLAD after the LTx. Pretransplant sinus surgery might be required to prevent the development of CLAD in DPB patients, similar to patients with cystic fibrosis.

Funding

This work was supported by grant-in-aid for Scientific Research grant no. 15K10256 from the Japan Society for the Promotion of Science.

Conflict of interest: none declared.