Donor-derived tuberculosis (TB): isoniazid-resistant TB transmitted from a lung transplant donor with inadequately treated latent infection.

Donor-derived tuberculosis (TB) is an increasingly recognized complication of solid organ transplantation. We report a case of isoniazid-resistant pulmonary TB in a lung transplant recipient. The patient acquired the infection from the lung donor who was previously empirically treated with isoniazid for latent TB. The case highlights the caveat that, while adequate treatment of latent TB with isoniazid is presumed, meticulous screening of donors is required.

Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention.(AU)

Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative.

Donation-after-Determination-of-Cardiac-Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5-year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an "extra" 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 ± 4.0 min (range 18-89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO(2)/FiO(2) ratio 315 (range 50-507)]. Overall the incidence of grade 3 chronic rejections was 5%. One- and 5-year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain-dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs.

Myositis due to the microsporidian Anncaliia (Brachiola) algerae in a lung transplant recipient.

Microsporidia are obligate intracellular parasites, more closely related to fungi than protozoa on molecular phylogenetic analysis, and are known to be a rare cause of opportunistic infection in immune compromised patients including human immunodeficiency virus-positive patients and solid organ transplant recipients. We report the first case to our knowledge of microsporidial myositis in a lung transplant recipient. He was 49 years old and had received a lung transplant in 2000 for cystic fibrosis. He presented in 2009 with fevers, chronic diarrhea, myalgia, and pancytopenia, and developed progressive weakness and neurological symptoms before his death 35 days after hospital admission. Multiple investigations, including stool culture, rectal biopsy, colonoscopy, cerebrospinal fluid examination, bone marrow biopsy, lung biopsy, and bronchoalveolar lavage, failed to reveal a definite cause for the patient's deterioration. The diagnosis of microsporidial infection was made on post-mortem light microscopic examination of tissue sections of the tongue and deltoid muscle. Light microscopy diagnosed a microsporidial myositis, confirmed by transmission electron microscopy, which suggested that the organism was Brachiola species. The identity of the organism was confirmed by polymerase chain reaction as Brachiola algerae (recently renamed Anncaliia algerae). The case highlights the need to consider protozoal organisms in the differential diagnosis of myalgia and multisystemic infections in immune compromised patients.

Diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration compared with transbronchial and endobronchial biopsy for suspected sarcoidosis.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate and minimally invasive technique that has been shown to have excellent diagnostic yield in the investigation of mediastinal and hilar lymphadenopathy. There is, however, little evidence comparing this procedure to the traditional diagnostic approach of transbronchial lung (TBLB) and endobronchial (EB) biopsies combined with characteristic clinical and radiological features in sarcoidosis. AIM: To compare the diagnostic yield of EBUS-TBNA, TBLB and EB in patients with suspected sarcoidosis. METHODS: Data from 40 consecutive patients with suspected sarcoidosis who underwent combined EBUS-TBNA with TBLB and EB biopsies were recorded. RESULTS: A total of 37 patients was confirmed as sarcoidosis, and three had other diagnoses. There was no difference in diagnostic accuracy rates between EBUS-TBNA and TBLB for all stages of sarcoidosis (84% vs 78%, P= 0.77). Combined EBUS-TBNA and TBLB procedures yielded a diagnostic accuracy of 100%. There was a highly significant difference in diagnostic accuracy between EBUS-TBNA and EB in stage I (80% vs 27%) (P < 0.01) and stage II disease (86% vs 27%) (P < 0.01). Similarly, a highly significant difference in diagnostic accuracy was seen between TBLB and EB (P < 0.01). No adverse events occurred. CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspiration alone has a high diagnostic yield with a very low complication rate for patients with suspected sarcoidosis.

The impact of pandemic influenza A H1N1 2009 on Australian lung transplant recipients.

Influenza A H1N1 2009 led to 189 deaths during the Australian pandemic. Community-acquired respiratory viruses not only can cause prolonged allograft dysfunction in lung transplant recipients but have also been linked to bronchiolitis obliterans syndrome (BOS). We report the impact of the 2009 H1N1 pandemic on Australian lung transplant recipients. An observational study of confirmed H1N1 cases was conducted across five Australian lung transplant programs during the pandemic. An electronic database collected patient demographics, clinical presentation, management and outcomes up to a year follow-up. Twenty-four H1N1 cases (mean age 43 ± 14 years, eight females) were identified, incidence of 3%. Illness severity varied from upper respiratory tract symptoms only in 29% to lung allograft dysfunction (≥10% decline FEV1) in 75% to death in 5 (21%) cases (pre-existing BOS grade 3, n = 4). Treatment with oseltamivir occurred in all but one case confirmed after death, reduced immunosuppression, n = 1, augmented corticosteroid therapy, n = 16, and mechanical/noninvasive ventilation, n = 4. There was BOS grade decline within a year in six cases (32%). In conclusion, Australian lung transplant recipients were variably affected by the H1N1 pandemic mirroring the broader community with significant morbidity and mortality. After initial recovery, a considerable proportion of survivors have demonstrated BOS progression.

Diversity of antiviral-resistant human cytomegalovirus in heart and lung transplant recipients.

Immunocompromised transplant recipients are at high risk for human cytomegalovirus (CMV)-related infection and disease. Antiviral prophylaxis and treatment have reduced CMV morbidity and mortality, but at times promote development of antiviral-resistant CMV strains that can significantly contribute to adverse clinical outcomes in transplant recipients. We have investigated CMV genotypes in transplant recipients (bone marrow, stem cell, kidney, heart, lung, and liver) receiving antiviral prophylaxis or preemptive therapy or treatment, to determine the viral characteristics and clinical impact of antiviral-resistant CMV in these different groups. Antiviral-resistant CMV strains were detected by polymerase chain reaction sequencing of the CMV protein kinase (UL97) and viral DNA polymerase (UL54) genes from clinical specimens. A trend toward more frequent detection of multidrug resistance and co-circulation of multiple resistant strains was seen in heart and lung transplant recipients compared with other transplantation types. A greater diversity and number of UL97 and UL54 mutations were observed in heart and lung transplant recipients; whereas antiviral-resistant CMV infections in other transplant recipients were predominantly the result of a single mutant genotype. Furthermore, 43% (6/14) of CMV-positive heart and lung transplant recipients were infected with CMV strains containing UL54 mutations conferring multidrug resistance compared with only 6% (1/18) of CMV-positive recipients of other transplanted organs or stem cells. Emergence of CMV strains containing previously unrecognized UL54 mutations (F412S and D485N) also occurred in 1 lung and 1 heart transplant recipient. The development of these mutations under antiviral selective pressure, and clinical outcome of infection suggests these mutations are likely to confer antiviral resistance. Emergence of CMV antiviral resistance remains a significant issue in immunocompromised patients treated with antiviral agents, and emphasizes the relevance of regular antiviral resistance testing when designing optimal patient-management strategies.

Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an 'orphan' area? A retrospective case-control study.

BACKGROUND: The aim of this study was to determine whether pre-existing diabetes mellitus increases the risk of rejection, infection and/or death in cystic fibrosis patients undergoing bilateral sequential single-lung transplantation. METHODS: A retrospective audit of 25 consecutive patients with cystic fibrosis who underwent bilateral sequential single-lung transplantation between 1 January 2003 and 31 December 2005 at a tertiary referral hospital was carried out. RESULTS: Although 32% patients had diabetes diagnosed before lung transplantation, 92% had random blood glucose levels > or =11.1 mmol/L requiring insulin during admission. Patients with pre-existing diabetes had increased infection-related (3.9 vs 1.2, P= 0.01) and putative rejection-related (1.4 vs 0.5, P= 0.04) hospital admissions post-transplantation compared with those without diabetes pre-transplant. During the period of observation, four of eight patients with a prior diagnosis of diabetes died compared with none of 17 patients without prior diabetes (P= 0.0055). CONCLUSION: Almost all cystic fibrosis patients develop hyperglycaemia after lung transplantation, but patients with prior diabetes have more complication-related admissions to hospital and a higher mortality rate.

Ethical and equity issues in lung transplantation and lung volume reduction surgery.

New medical and scientific disciplines are often developed in haste with rampant enthusiasm and scant regard for the balance between action and thoughtful deliberation. Driven by the desire to prolong life and provide a better quality of life for desperately sick individuals, the twin modalities of lung transplantation and lung volume reduction therapy have only just reached their majority. Both are invested with the capacity to help and to harm so it is right to consider carefully their ethical and equitable distribution. Much has been learned in the last 20 years to assist in these deliberations. First, how can we ensure equity of access to transplant services and equality of outcomes? How do we balance resource allocation of a precious and scarce resource with individual recipient needs? Does the concept of distributive justice prevail in our daily work in this field? How do we honour the donor and their family? How do we as practitioners avoid ethical dilemmas related to personal bias and justifiable reward for services rendered? Finally, how do we learn to incorporate ethical forethought and planning guided by experts in the area into everyday behaviour?

Lung transplantation for chronic obstructive pulmonary disease at St Vincent's Hospital.

BACKGROUND: Lung transplantation (LTx) offers selected patients with end-stage chronic obstructive pulmonary disease (COPD) an improved quality of life and possibly enhanced survival. AIM: To determine local outcomes of LTx for COPD we analysed 173 consecutive heart-LTx (n = 8), single LTx (SLTx; n = 99) and bilateral LTx (BLTx; n = 66) carried out at a single institution during 1989-2003 for smoking-related emphysema (E) (n = 112) and emphysema related to alpha-1 antitrypsin deficiency (AATD) (n = 61). METHODS: There were 98 men and 75 women with a mean age of 50 +/- 6 years (standard deviation) (range 32-63 years). Median waiting time was 113 days (interquartile range (IQR) 50-230 days), and median inpatient stay was 13 days (IQR 9-21 days). RESULTS: Perioperative survival (30 days) was 95% with deaths from sepsis (n = 5), cerebrovascular accident (n = 3) and multiorgan failure (n = 1). Mean follow-up period was 1693 +/- 1302 days (2-4,805 days). The 1-, 5- and 10-year survivals (%) were similar for patients with E and AATD (P = 0.480 log rank) at 86 +/- 5, 57 +/- 7 and 31 +/- 11, respectively, but 1- and 5-year survivals for E were higher after BLTx than after SLTx (97 +/- 2 and 81 +/- 8 vs 85 +/- 4 and 47 +/- 6) (P = 0.015). Pretransplant body mass index, forced expiratory volume in 1 second, forced vital capacity, PaCO(2), PaO(2), six-minute walk distance, home oxygen use, age, sex, cytomegalovirus donor-recipient mismatch, cardiopulmonary bypass use, year of transplant and ischaemic time did not influence survival after LTx. Increasing donor age was a survival risk factor for patients with E but not for those with AATD (hazard ratio 1.043; 95%confidence interval 1.014-1.025). CONCLUSION: Survival after LTx for COPD is similar to survival for other forms of solid organ transplantation, in part reflecting risk factor management.

Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial.

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV1 >15%[deltaFEV1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of deltaFEV1 >15%, deltaFEV1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.

In vitro studies of lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is associated with abnormal airway smooth muscle that leads to the characteristic pathology of lung nodule formation and destruction of lung tissue. The current authors have previously identified abnormal behaviour of airway smooth muscle cells from patients with asthma. In this study, cells and tissue sections derived from patients with LAM (n=7), asthma (n=8), and nonasthmatic controls (n=9) were compared. The presence of the antigen human melanosome (HM)B-45 was investigated, along with the proliferation and release of extracellular matrix proteins, release of endogenous prostaglandin E2 (PGE2), vascular endothelial growth factor and connective tissue growth factor, and the expression of integrins. Positive HMB-45 staining was found in all LAM patients and no controls. Proliferation of LAM cells was not different from control cells nor was its inhibition by beta-agonists, corticosteroids, rapamycin or PGE2. However, endogenous PGE2 levels were markedly decreased in LAM cells, and this was associated with decreased expression of the inducible form of cyclooxygenase (COX-2). The increased levels of connective tissue growth factor seen in asthma cells were not observed in LAM. Elastin mRNA in response to transforming growth factor-beta stimulation was markedly lower in LAM cells than either asthma or control cells. In conclusion, lymphangioleiomyomatosis cells exhibit abnormal properties in vitro that may contribute to pathophysiology and symptomatology in patients with lymphangioleiomyomatosis.

Indications, patient selection and timing of referral for lung transplantation.

Lung transplantation (LTx) is now generally accepted as a useful modality of care for patients with severe life-threatening respiratory diseases that are refractory to other medical or surgical therapies. With the huge development of LTx over the last 15 yrs, the disparity between the number of potential recipients and the number of donor organs available has become a major constraint, with many patients dying on the waiting lists. Therefore, it is of primary importance to control and optimise the use of this limited organ resource by weighting the risks and benefits of transplantation in individual patients, and to identify those patients who have a better chance of having a favourable outcome with transplantation. This article discusses the selection process of potential candidates and the currently accepted absolute and relative contraindications, and proposes general and disease-specific recommendations for optimising the timing of referral. Early referral for consideration of lung transplantation is highly desirable as it enhances the patient's chance of surviving to transplant and allows the transplant team to actively manage identified comorbidities during the waiting period.

Prophylactic nasopharyngeal tube insertion prevents acute hypoxaemia due to upper-airway obstruction during flexible bronchoscopy.

Insertion of a nasopharyngeal tube (NT) is a highly effective approach to the management of acute hypoxaemia during flexible bronchoscopy (FB) in lung -transplant recipients. We noted that lung transplant recipients undergoing FB who had been treated previously with NT insertion had further episodes of oxygen desaturation (<90%), despite supplemental oxygen therapy. Prophylactic NT insertion prevented acute hypoxaemia in the majority of lung transplant recipients, with previously documented FB-related oxygen desaturation secondary to UAO. Additional jaw support may be needed in some patients with severe upper-airway obstruction.

Achilles tendon disease in lung transplant recipients: association with ciprofloxacin.

Achilles tendonitis or rupture are uncommon complications following the use of fluoroquinolones, with a reported incidence in the general population of 0.4%. The aims of the current study were to determine the incidence of Achilles tendon disease (ATD) in lung transplant recipients (LTR) and to identify risk factors. Questionnaires were sent to 150 LTR of whom 101 responded (67%). Twenty-two LTR (21.8%) experienced ATD (tendonitis 16, rupture six). The mean age of LTR who developed ATD was 52.9+/-6.1 yrs (range: 19-63.5 yrs). Only the use of ciprofloxacin was significantly associated with ATD (p<0.05). Age, sex, underlying disease necessitating transplantation, serum creatinine and cyclosporine levels were not associated with ATD. The association between ciprofloxacin and ATD was not dose related. Of the 72 LTR who had received ciprofloxacin, 20 (28%) developed ATD (tendonitis 15, rupture five). In patients receiving ciprofloxacin, there was no association between the mean cumulative dose of prednisolone and ATD. Tendon rupture occurred with a lower ciprofloxacin dosage than tendonitis and the mean recovery duration was significantly longer. To conclude, lung transplant recipients receiving ciprofloxacin are at significant risk of developing Achilles tendon disease. The association between ciprofloxacin and Achilles tendon disease appears to be idiosyncratic rather than dose-related.