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Clinical Meetings at RH Year 2001

2001 - Lung Transplantation in Hong Kong

Dr. J Lee, Dr. WW Yew, TB & Chest Unit, Grantham Hospital

History of Lung Transplantation in Hong Kong
The Lung Transplant Group, comprised respiratory physicians from various hospitals and thoracic surgeon in Grantham Hospital, was formed in early 1993. After thorough discussion and much preparative work, a lung transplant program was established in Grantham Hospital with the wait-listing of the first potential recipient in late 1993.

The first single lung transplantation was performed in July 1995. Up to May 2001, 2 single-lung, 4 double-lung and 1 heart-lung transplantations were performed. Twenty-one patients were waitlisted and their indications were shown in Figure 1. The mean waiting time for transplantation was 170 days and the overall attrition rate was 48%. The attrition rate was extremely high in patients with primary pulmonary hypertension (>75%). Compared with overseas statistics!, we have more patients with pulmonary vascular disease and lymphangiomyoleiomatosis (LAM) rather than COPD or pulmonary fibrosis as indications for lung transplantation. As cystic fibrosis is very rare in Chinese, the main septic lung condition indicated for lung transplantation is idiopathic diffuse bronchiectasis.



Immunosppression Protocol and Infection Prophylaxis
We adopted largely the protocol used in Papworth Hospital, UK. The induction therapy included intravenous azathioprine, peri operative methylprednisolone and anti-thymocyte globulin. Maintenance immunosuppression comprised cyclosporine, azathioprine and prednisolone. The latter might be taken off after one year.

All patients received prophylactic antibiotics during the first 1-2 weeks depending on the pre-transplant diagnosis, CMV prophylaxis for 4 weeks and life-long prophylaxis for pneumocystis carinii. In addition, all potentially pathogenic isolates from the tracheobronchial tree or other sites were treated pre-emptively with appropriate anti-microbials during the first 2-3 weeks.

Characteristics and Major Complications in the 7 Transplanted Patients
Patient
 
Sex/
Age
Diagnosis
 
Transplant
Procedures
Major Complications
1
2
3
1
F/27
LAM
SLT
Rejections
Nephrectomy
OBS
2
F/35
Esienmenger’s syndrome  
HLT
GVHD
Fungaemia
DIC
3
F/33
Bronchiectasis
BLT
Bronchostenosis & bronchomalacia
Delayed fungal sternotomy wound infection
Aspergillus bronchitis
4
F/35
LAM
SLT
Severe reperfusion response
Late rejection
 
5
F/35
LAM
BLT
CMV pneumonia
MDR-TB
 
6
F/35
Tuberose sclerosis
BLT
Bronchostenosis & bronchomalacia
 
 
7
M/52
Emphysema
BLT
Ulcerative Aspergillus bronchitis
 
 


Non-infective Complications
Reperfusion Response

Most recipients had rather uneventful early postoperative course. Severe reperfusion response occurred in a single lung recipient with LAM. This was further complicated by dynamic hyperinflation of the native lung. Independent ventilation was instituted and patient was successfully extubated at Day 3

Graft-versus-host Disease (GVHD)
This is an exceedingly rare complication after solid organ transplantation. It occurred in our 2nd patient, who received a minor-mismatched heart-lung bloc (group 0+ to B+) from a 52-year-old Caucasian with subarachnoid haemorrhage. She developed erythematous rash, alopecia, pancytopenia and markedly deranged liver function during the 3rd week after transplantation. GVHD was suggested by demonstration of chimerism of both donor and recipient HLA phenotypes in the peripheral blood and skin biopsies also showed compatible histological features of acute GVHD. Transfusion related GVHD was excluded, as there was no third party HLA-phenotypes in the peripheral blood.

Treatment with pulse steroid brought about improvement in liver function but not the pancytopenia. Mediastinal irradiated was experimentally explored with the hope to reduce the donor lymphocyte load2. There was initial improvement in blood counts but patient finally succumbed at Day 38 because of fungaemia (Candida lusitaniae) and gastrointestinal bleeding complicating disseminated intravascular coagulation(DIC). Postmortem examination confirmed the classical changes of GVHD. It was not certain whether the ethnic difference, the marked HLA disparity (with 6 unmatched loci) and the chronic ill health in our recipient that might have predisposed her to this rare complication.

Airways Complications
Airway complications were once the Achilles' heel in the early era of lung transplantation. Shennib reported lethal outcomes in 2-3% with late stricture occurring in 7-14% ofrecipients3. Admittedly, each center will have a learning curve and incidence tends to decrease with experience4. Airway ischaemia is the crucial predisposing factor. Two of the 7 recipients (ie 28%) had bronchostenosis and bronchomalacia requiring bilateral stenting (figure 2). The mean ischaemic time was marginally higher in the group with anastomotic complications (317 vs 259 min per anastomosis). However, other factors that might affect the retrograde perfusion from the pulmonary circulation, like early rejection, low cardiac output state including the use of cardiopulmonary bypass, and positive pressure ventilation, were also important. Apparently, all these factors were operating in patient 3. In addition, because of her bronchiectasis, the airways of her explanted lungs showed severe mucosal ulceration, micro-abscess formation, destruction of bronchial cartilage and micro-invasion by Aspergillus.



Nevertheless, such complications can now be satisfactorily dealt with using stenting +/-balloon dilatation and occasionally laser photo-resection. These were demonstrated in one of our patients. The functional outcomes are often acceptably good after intervention ( Figure 3).



Acute Rejection
Acute rejection was relatively uncommon in our recipients. Only 6 rejection episodes were documented among our 7 recipients so far, amounting to ~0.45 rejection /patient /year. Chest X-ray abnormalities were uncommon except in the first month. The response to pulse steroid was good and this was confirmed by follow-up transbronchial biopsies 4 weeks later. As exemplified in one of our recipients, the monitoring of small airway function such as FEF25-75% in addition to FEV 1 increased the sensitivity of detection of graft dysfunction. There are still controversies over regular surveillance bronchoscopic biopsies. versus biopsies as indicated. Although abnormal findings might be found in 25% of the surveillance biopsies, one study did not show that there was any significant improvement in the overall outcomes. Besides, the chance of abnormal findings diminished after 2 years. Currently, like most British centers, we only perform bronchoscopic biopsies as indicated.

Obliterative Bronchiolitis Syndrome (OBS)
Obliterative bronchiolitis syndrome remains the main limitation of long-term survival after lung transplantation 1. Incidence increases with time of transplantation (~40-50% by the 4th year). Our first recipient succumbed to OBS 56 months after transplantation. She had 2 episodes of acute rejections (Grade A3, B2) at month 3 and 17. Her tolerance to immunosuppression was poor as a result of leucopenia with azathioprine and compromised renal function, related to right nephrectomy at month 22 for recurrent bleeding from renal angiolipoma. She showed signs of OBS stage I at month 26 and had a precipitous fall in FEV1 at month 39 despite pulse steroids and lympholytic therapy.

In general, the risk factors for OBS include: frequent and severe acute rejection, late acute rejection, lymphocytic bronchiolitis, increasing number of HLA mismatches, CMV pneumonitis, prolonged ischaemic time (>8 hrs) and donor age >501. Many investigators currently believe that OBS is the final common pathway of insults to the airway rather that chronic rejection alone. Treatment modalities advocated include pulse steroid, lympholytic therapy, methotrexate, cyclophosphamide, tacrolimus, mycophenolate mofetil and aerosolized cyclosporine. However, the response is generally disappointing.

Infective Complications
CMV pneumonia

CMV is the most common infective complication after lung transplantation. Two recipients had documented CMV pneumonia. Both were suspected to have ganciclovir-resistant CMV disease as the clinical symptoms and peripheral blood antigenaemia persisted despite many days of ganciclovir therapy. Both finally responded to foscamet. Ganciclovir resistance is increasingly reported and most often, this is associated with mutation at UL97 viral genome. Less frequently, a mutation in the viral DNA polymerase occurs and this may cause cross-resistance with cidofovir or foscamet, making treatment extremely difficult. With development of reliable early rapid diagnostic tools such as CMV antigenaemia (pp65) and quantitative PCR, increasing numbers of transplant centers have advocated pre-emptive treatment instead of universal prophylaxis. This addresses the problem of surging ganciclovir-resistant CMV, as well as the costs and complications of prolonged prophylaxis. However, universal CMV prophylaxis should still be continued for all seronegative recipients who receive a seropositive donor organ. Although mortalities from CMV disease have improved with anti-viral treatment, the long-term morbidities remain and these include increased risk of chronic rejection, co-infection with other pathogens and a reduced overall survival.

Fungal Injections
Isolation of fungi (colonization) is common after lung transplantation. Invasive fungal disease is relatively rare but account for significant overall mortality (~6%). Majority of cases were caused by Aspergillus (~60%) but increasingly, other opportunistic fungi were reported. Two of our recipients had major invasive fungal infections.

Patient 7 had invasive endobronchial aspergillosis detected during surveillance bronchoscopy at Day 11. He had minimal respiratory symptoms and the Chest X-ray was relatively normal. The only suggestion of problem was an unexplained leukocytosis. At bronchoscopy, extensive necrotic exudates and mucosal ulcerations were noticed around the anastomoses, extending distally to the sub segmental bronchi (figure 4a) Biopsies confirmed invasive aspergillosis with fruiting heads suggestive of A. niger (figure 4b). He was successfully treated with oral itraconazole and nebulized amphotericin B. The clinical findings in our patient were compatible with that of aspergillus ulcerative tracheobronchitis, a specific form of invasive aspergillosis among lung transplant recipients, reported by Kramers.



Patient 3 had delayed sternotomy wound infection due to Paecilomyces varioti, an ubiquitous opportunistic fungus. She had loosened sternal wire discovered at month 10 and osteomyelitis involving the lower sternum and adjacent cartilage at month 11. She received surgical debridement plus liposomal amphotericin B, followed by itraconazole therapy. Recurrence of sternal infection occurred 4 months later and a second surgical debridement was needed. She had a total of one year of itraconazole therapy and remained well afterwards, indicating that adequate surgical treatment was crucial in treating localized invasive fungal disease of the soft tissues.

Mycobacterium Tuberculosis
Mycobacterium tuberculosis is not a common infective complication after lung transplantation. The reported incidence ranged 1- 6.5% in the literature but the estimated annual incidence was 20-80 times higher than the general population6. Development of disease can be due to exogenous infection, reactivation of host infection, and transmission from the donor organ 6,7. The latter may be most problematic. Patient 5, a case of LAM, received a double lung bloc from a 51-years old hypertensive man. He had no prior history of tuberculosis and had clear CXR at time of organ donation. The recipient developed subfever (37-37.50C) and malaise with elevated ESR from month 5 onwards. Chest X-ray and then CT thorax revealed a shadow in left upper lobe abutting onto the aortic arch. Percutaneous trans-thoracic needle biopsy confirmed tuberculosis (granulomatous inflammation with stainable AFB). She was given isoniazid(H), ethambutol(M), pyrazinamide(Z) and rifabutin(Rb). Rifabutin was introduced after documented unmanageable drug interaction between rifampicin(R) and cyclosporine, resulting in marked reduction of serum level of the latter. After 2 months of HMZRb, her clinical symptoms improved but CXR remained relatively static. Culture and sensitivity revealed in-vitro resistance to Streptomycin & HRMZ. Regimen was changed to levofloxacin, prothionamide, PAS, and cycloserine. She experienced multiple drug intolerance such as severe GI upsets, deranged liver function, and neutropenia requiring temporary modification of regimen and withdrawal of co-trmoxazole and azathioprine. Finally all 4 drugs were reintroduced and after 1 year of treatment, the chest X-ray showed significant improvement.

Pharmacokinetic drug interactions between anti-tuberculous drugs and immunosuppressive drugs, as well as side-effects related to polypharmacy can pose a formidable task in treating these difficult cases of tuberculosis, especially in the presence of multiple drug resistance. Our patient, most likely, acquired the infection from the donor lung in view of the early onset, the finding of ill-defined epithelioid granuloma on surveillance transbronchial biopsies at first month, a negative Mantoux test before transplantation, and absence of tuberculous lesion in the ex-planted lungs. She did not have any documented contact history any case of MDR- TB. Our patient exemplifies the additional risk of using older donors, who may have resided in area with high endemicity for tuberculosis or MDR- TB.

Survivals and Quality of Life
The calculated 1, 2, 3 & 4-year survivals of the 7 transplant recipients were 85, 80, 75 & 66% respectively, which is comparable with the international figures I. The FEV1 of the 6 lung transplant recipients (excluding the heart-lung recipient) were given in figure 5. Most are currently doing well and will be expected to survive for another few years unless major complications occur. For the 5 long term survivors, they all enjoy an active life style and 3 have returned to work while one has become a voluntary worker.



Conclusion
Managing lung transplant recipients is challenging as most recipients have one or more major complications. However, with collaborative and dedicated efforts from various specialties, these complications are often manageable. Most recipients enjoy active life style after transplantation and survivals in our recipients are comparable to international standards. Obliterative bronchiolitis syndrome and shortage of donor organs remain the most difficult problems.

References
  1. Hosenpud JD, Bennett LE, et al. The registry of the international society for heart and lung transplantation: seventeenth official report-2000. J Heart Lung Transplant 2000; 19:909-931.
  2. Chau E, Lee J, et al. Mediastinal irradiation for graft-versus-host disease in a heart-lung transplant recipient. J Heart Lung Transplant 1997; 16: 974-9.
  3. Shennib H, Massard O. Airway complications in lung transplantation. Ann Thorac Surg 1994; 57:506-11.
  4. Date H, Trulock EP, et al. Improved airway healing after lung transplantation. An analysis of348 bronchial anastomoses. J Thorac Cardiovasc Surg 1995; 110: 1424-32.
  5. Kramer MR, Denning DW, et al. Ulcerative tracheobronchitis after lung transplantation. Am Rev Respir dis 1991; 144: 552-556.
  6. Dromer C, Nashef SA, et al. Tuberculosis in transplanted lungs. J Heart Lung Transplant 1993; 12: 924-7
  7. Ridgeway AL, Warner OS, et al. Transmission of Mycobacterium tuberculosis to recipients of single lung transplants from the same donor. Am J Respir Crit Care Med 1996; 153: 1160-8.
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