Advances in lung transplantation: 60 years on

Lung transplantation is a well‐established treatment for advanced lung disease, improving survival and quality of life. Over the last 60 years all aspects of lung transplantation have evolved significantly and exponential growth in transplant volume. This has been particularly evident over the last decade with a substantial increase in lung transplant numbers as a result of innovations in donor utilization procurement, including the use donation after circulatory death and ex‐vivo lung perfusion organs. Donor lungs have proved to be surprisingly robust, and therefore the donor pool is actually larger than previously thought. Parallel to this, lung transplant outcomes have continued to improve with improved acute management as well as microbiological and immunological insights and innovations. The management of lung transplant recipients continues to be complex and heavily dependent on a tertiary care multidisciplinary paradigm. Whilst long term outcomes continue to be limited by chronic lung allograft dysfunction improvements in diagnostics, mechanistic understanding and evolutions in treatment paradigms have all contributed to a median survival that in some centres approaches 10 years. As ongoing studies build on developing novel approaches to diagnosis and treatment of transplant complications and improvements in donor utilization more individuals will have the opportunity to benefit from lung transplantation. As has always been the case, early referral for transplant consideration is important to achieve best results.


INTRODUCTION
Lung transplantation (LTx) was first performed by Hardy in 1963 with only short-term survival. 1However, it wasn't until Cooper evolved surgical technique and case selection in 1983 that long-term survival became a reality. 2 An exponential expansion of cases, clinical experience and research has followed.Forty years on, LTx has become a viable option for the treatment of many end-stage lung diseases. 3pproximately 4500 LTx are performed annually worldwide. 4Although activity remains limited by the pool of suitable donor lungs, there has been a major expansion into novel donor pools with new donor assessment tools, platforms and protocols.Strategies have also been developed to evaluate a wide range of candidates. 3With this, the lion's share of management of LTx candidates and recipients has now clearly moved from the hands of surgeons to those of physicians.
With enhanced long-term maintenance strategies in place, today's LTx recipients have an expected median survival of 10-years. 5Notwithstanding, chronic allograft rejection (known as Chronic Lung Allograft Dysfunction = CLAD), 6 increased cancer incidence and severity, as well as opportunistic infections remain problems still to be fully conquered. 7This review will highlight recent advances in LTx, note areas of current attention and draw attention to emerging technologies and strategies.

LUNG TRANSPLANT RECIPIENT SELECTION
Experience has shown that the pool of patients with advanced lung disease who can now be successfully transplanted is quite broad (Table 1).

Recipient referral and assessment
Early LTx referral, careful protocolised evaluation, optimisation of comorbidities with consideration of disease trajectory and expected local waitlist time, are key elements of a successful outcome. 3,9General LTx recipient considerations have been agreed upon in consensus documents. 9,10Specific issues that warrant further discussion however, include:

Recipient age limitations
There are no absolute age limitations, although it is obvious that increasing age generally brings with it increased risk of cardiac, renal and cerebrovascular complications, perioperative infectious morbidity and risk of acute confusional states.Typically, this has been clinically translated to limiting recipient selection to those less than 75 years of age.Notwithstanding, although not universally accepted, 11 there is evidence shows that careful case selection and assessment can result in very acceptable LTx results beyond age 70. 12

Frailty
The concept of frailty is recognized as an important factor that particularly impacts wait-list survival, perioperative morbidity and also potentially mortality. 13While a successful LTx can reverse the frailty phenotype in the short term, recent studies have linked frailty to long term morbidity in the form of fracture risk 14 and CLAD. 15Given the importance of characterizing frailty-related LTx outcomes, 16 a consensus Lung Transplant Frailty Scale has just been developed for future detailed frailty evaluation. 17

Malnutrition and obesity
Extremes of BMI are associated with increased mortality after LTx. 9, 10 In a recent US study, compared to a BMI of 24 kg/m 2 , a LTx recipient with a BMI <16 kg/m 2 had a 38% increase in mortality-related particularly to acute respiratory failure, CLAD and infection.Data in cystic fibrosis (CF) populations is similar, with recipients with BMI <17 having a greater risk of death, though this was ameliorated by BMI recovery in the first year post transplant. 18y contrast, a LTx recipient with a BMI >36 kg/m 2 had a 44% increased risk of death from acute respiratory failure, CLAD and primary graft dysfunction (PGD). 19There are local cultural and management differences around cut-offs around malnutrition and obesity definitions, however the concept that optimizing weight enhances the safety and utility of LTx is usually agreed upon. 20Hopefully, the recent introduction of novel weight loss drugs, such as semaglutide, will provide a much-needed tool to tackle the common obesity challenge. 21

Psychosocial assessment
Identifying psychosocial issues that might impact LTx outcomes is an important LTx assessment task.In consideration of this the Stanford Integrative Psychosocial Assessment for Transplant (SIPAT) tool has been used to measure suitability for LTx. 22While patients with higher SIPAT score were more likely to be declined for LTx, the SIPAT score did not predict post-LTx outcomes.A subgroup of patients with high SIPAT scores successfully underwent LTx suggesting that unfavourable psychosocial variables are potentially modifiable.

Referral indications
Specific underlying disease parameters that are referral indications for LTx have not changed significantly in recent years. 9,10LTx referral should be considered where the baseline physiology, even if stable, is low enough to portend a poor prognosis (e.g., in chronic obstructive pulmonary disease [COPD] an FEV 1 of approximately 20% predicted) or where the individual is rapidly deteriorating and LTx will be time critical (e.g., in interstitial lung disease [ILD] when gas transfer [TLCO] is approximately 30% predicted but dropping every visit).Whilst referral criteria have not changed, what has changed is that these two diseases of older patients make up approximately 80% of all LTx now undertaken. 4he broad management of ILD pre-LTx has been enhanced with the introduction of antifibrotic drugs.After some initial concerns that these drugs might impact post-LTx healing, it has been confirmed this is not the case and indeed may yet prove to have a useful role in the management of CLAD. 23,24A B L E 1 Contraindications to LTx.

Untreatable second organ dysfunction
For example, heart, liver, kidney unless multi organ transplant is appropriate.

Age
Assessment of age and physiological reserve required for all recipients.
Malnutrition or morbid obesity

Substance abuse
For example, alcohol, tobacco, marijuana or other illicit substances.Consider evidence of risk reduction behaviours and abstinence using serial blood/urine testing.

Non-adherence
Consider task setting testing.
Poor social supports Absence of an adequate or reliable social support system.

Poor rehabilitation potential/frailty
Note: Adapted from Reference 8.
CF and pulmonary arterial hypertension (PAH) have historically contributed many young adults to LTx numbers, but with effective gene and vasodilator therapy, such referrals are now much less common. 4ndications for LTx in children differ to that in adults, with the commonest indications still being CF and PAH.Lung fibrosis in children is usually related to inherited surfactant deficiency. 25,26Most children receive bilateral LTx, with heart-lung transplants potentially considered for the smaller child (typically <20 kg) with PAH in whom the enlarged heart restricts space within the chest cavity.

Waitlist management
Having assessed that an individual indeed is a suitable LTx waiting-list candidate, then immediate consideration of the local likely waitlist time is critical.Local allocation policies, as well as recipient blood group, height, sensitisation (i.e., the prior production of anti-HLA antibodies following pregnancy, transfusion or previous transplants), acuity and disease trajectory will inform a realistic and appropriate entry onto a wait-list. 9Reflecting their small size and a relative paucity of paediatric organ donors, it is recognized that children, in general, are exposed to higher waitlist mortality than adults and priority should be considered. 26

ECMO as a bridge to transplant
Extra-corporeal membrane oxygenation (ECMO) can be used to support a subset of selected critically ill candidates to be 'bridged' successfully to LTx. [27][28][29] In most circumstances this has provided better outcomes than the prior approach of mechanical ventilation alone.It is commonly cited that an ECMO bridge to LTx can be achieved with similar outcomes to non-ECMO LTx. 27However, this often relies on only transplanting the most optimal candidates and a favourable donor allocation system with organ availability within days to several weeks.US Registry analyses suggest the picture is not always perfect. 29ECMO LTx candidates were 23.8 times more likely to be die or be too sick to advance to LTx, with an increased post-LTx excess mortality of between 45% and 67%. 29

LUNG DONOR EVALUATION AND MANAGEMENT
There are three main pathways to lung donation 1 : Donation after brain death (DBD) 2 ; donation after circulatory death (DCD) and 3 live-donor (usually from a relative).The DBD pathway represented the historical norm until the last decade.The DCD pathway has emerged as a significant feasible source of quality donor lungs, accounting for up to 30% of all LTx in some European and Australian LTx centres. 30,31Despite this, DCD donation is not extensively utilized in the United States where DCD transplants continue to make up less than 5% of total LTx numbers. 32ive-donor LTx is practically, ethically and psychologically complex in placing the donor(s) (typically two parents each donating a lung lobe to a child) at risk of serious morbidity and mortality, 33 and is only performed currently in Japan. 34

Donation after circulatory death
Although logistically challenging, DCD LTx has significant further potential to expand with donors from other endof-life situations, for example, cardiac arrest presented suddenly to the Emergency Department (Category I), observed in a hospital ward or Intensive Care Unit (Category II) where appropriate lung donation protocols have been developed 35,36 (Table 2).In contrast to other transplantable solid organs, the lungs tolerate warm ischemia and can be still viable for transplantation where other organs cannot. 38or the standard DCD III lung donor, predicting the likelihood of cardiac asystole within the typically assigned 90-min waiting time can be challenging, however a recent tool can assist with this. 39Considering the potential DCD III donor pool further, it is evident that quality donor lungs can also be retrieved even many hours for cardiac arrest-so called 'time-extended' DCD III.In one study, it was noted that approximately 50% of all planned DCD lung donors that failed to reach asystole in 90 min will reach this by 6 h after withdrawal of life support. 40CD V donation has been increasing in extent with emerging activity in a number of countries. 41,42LTx Intermediate term results are excellent. 41,42Donation protocols need to sensitively dovetail with the local legal and cultural environment. 43urvival after DCD LTx is excellent and equal to that of DBD. 44As such, DCD donation and transplant presents an opportunity to significantly increase donor and transplant numbers both through its more widespread acceptance in jurisdictions such as the United States, and through expansion of the DCD categories which lead to donation.

Donor evaluation
Careful evaluation of all organ donors is essential to both optimize LTx opportunities and lung quality.A thorough history is acquired from the donor's relatives or close friends, assessing for a history of smoking, high risk behaviours, malignancy and lung disease.Donor chest CT scanning aids in this assessment.

Key criteria for donor acceptability
Ideally, key criteria for donor lung acceptability include; PaO 2 /FiO 2 ratio >300, normal chest imaging and an absence of significant secretions or aspiration 45 (Table 3).In reality, lungs that are believed to be inherently acceptable (both structurally and functionally) but are acutely impaired (socalled extended criteria donor lungs), will often become suitable over time if managed appropriately. 49,50][52] Donor age beyond 65 years has historically been associated with an increased risk of mortality and CLAD. 45,53wever, two recent series present very clear data showing LTx outcomes from over 70 year old donors match those seen from donors less than 70 years. 54,55Expansion into the large untapped donor lung pool above age 70 years has potentially very significant implications for increasing LTx numbers.

Ex vivo lung perfusion
Ex vivo lung perfusion (EVLP) of donor lungs describes the use of a mechanical perfusion and ventilation device for the evaluation and potential therapeutic manipulation of explanted donor lungs prior to recipient implantation.It primarily enables reassessment and potentially reconditioning of donor organs not found immediately suitable.Typically, such lungs undergo 3-6 h of EVLP 'assessment', with 60%-90% subsequently found suitable for LTx. 56,57A clinical centralized specialized EVLP service has been set up in the US to assess donor lungs deemed initially to be of questionable quality. 58ith standard acellular perfusion It is unclear how much true reconditioning of donor lungs actually occurs.
There is now evidence that some reported EVLP inclusion criteria may have overestimated the true extent of the baseline donor lung dysfunction 40,48 and that LTx outcomes may have been the same where LTx was undertaken without EVLP. 59,60This has particularly been demonstrated around the use of EVLP to assess standard quality, controlled DCD lungs for LTx. 48,61In contrast, EVLP continues to have a role in enabling evaluation and management of the wider untapped pool of uncontrolled DCD donor lungs where traditional lung donor assessment techniques aren't possible. 62Recognizing EVLP is an expensive, resource intense strategy for lung assessment alone, a case can be made for tighter EVLP selection criteria, further cost effectiveness evaluation and randomized trials. 63owever, beyond just an assessment tool, EVLP has other potential LTx roles 64 : • As a strategy to safely prolong donor organ ischaemia for logistic reasons, including to routinely convert LTx surgery into a daytime operating timeslot, 65 allow long distance movement of organs 66 or enable complex multiorgan transplantation. 37 As a platform to facilitate therapies to repair damaged donor lungs.In experimental models and emerging clinical applications EVLP has provided a vehicle to treat donor lungs with high-dose antibiotic, UV light to treat hepatitis C, fibrinolytics, viral vector-induced interleukin 10, surfactant and mechanical cytokine and inflammatory cell traps.a See Table 2.

Donor lung preservation
Donor lung preservation by antegrade and retrograde cold flush-perfusion with an extracellular type solution with high oncotic pressure (Perfadex™ [XVIVO AB, Göteborg, Sweden]) followed by static cold storage in the icebox at 0-4 C remains the current standard practice performed worldwide. 69However, a recent non-randomized trial shows that transplantation of lungs after prolonged preservation (10-14 h) in an incubator at 10 C results in low rates of PGD, and early outcomes are similar to those of lungs transplanted using conventional ice-cooler methods, with significantly shorter preservation times. 70Combined with previous 24h storage experimental work, 71 a realistic prolonged window of 12-18 h of cold static preservation at a 10 C temperature has the potential to improve LTx logistics and performance.
Normothermic regional perfusion Normothermic regional perfusion (NRP) has been growing as a novel procurement strategy for the recovery of DCD organs, initially abdominal organs, but more recently in the context of increasing the recovery rate of viable hearts for transplantation.Abdominal NRP (A-NRP) involves the use of ECMO, with potential risks to the lungs based on the difference in abdominal and lung temperature or to inadequate perfusion pressure in the pump due to bleeding into the chest after the heart-lung block is removed or after vena caval clamping. 72Although a higher PGD rate has been note 1 and 5-year survivals in single centre study were comparable. 72Thoraco-abdominal NRP (TA-NRP) involves the rapid restoration of circulation after death by cannulating the aorta and right atrium and employing high perfusion rate cardiopulmonary bypass to facilitate heart recovery. 73n this situation ventilation and antegrade pulmonary arterial perfusion are delayed until cardiac reanimation.A US retrospective analysis showed no major LTx outcome issues-although lung utilization rates were very low in both the in-situ TA-NRP perfused donors (14.9%) and the directly procured donors (13.8%). 73

LUNG DONOR AND RECIPIENT MATCHING AND COMPATIBILITY
Lung donor allocation to a particular recipient is a process wholly determined by the jurisdictional structures around each individual transplant unit.In general, donor-recipient matching decisions are based on a combination of ABO blood group and size compatibility, an acceptable virtual or solid-phase crossmatch, clinical urgency, logistics, potential recipient long-term outcome and recipient waitlist time. 3,9dvances in technology and techniques have provided useful clinical variations of the above.

ABO matching
Identical ABO matches are predominantly used.However, with careful planning, serial measurement and minimisation of anti-ABO antibody titres (using combinations of plasmapheresis, anti-B cell antibodies and intravenous gammaglobulin), successful LTx is possible. 74,75ze matching Size matching of donor to recipient is usually based on donor and recipient height, plus estimates of lung volumes from chest x-rays.Whilst the optimal fit remains unknown, a close match is preferred and leads to superior outcomes. 76,77Downsizing large lungs through removing lobes, stapling off peripheral areas or simply just performing a single transplant of one larger lung can also be successfully undertaken to enable a lifesaving transplant in centres with experience. 74,78munological assessment Immunologic assessment of potential donor-recipient matching combinations has increasingly been linked to LTx outcomes.Potential LTx recipients are universally human leucocyte antigen (HLA) allele typed and screened for the presence of HLA antibodies.Antibodies are not made to self-antigens, but rather to another individual's HLA.
Sensitizing events such as blood transfusions (particularly platelets), prior pregnancies or organ transplantation often results in the formation of HLA antibodies.If an individual already has antibodies pre-LTx, and/or spontaneously forms antibodies post-LTx to their lung donor (donor-specific antibodies = DSA), serious adverse events, such as CLAD and death are more common. 79,80he immunologic LTx focus for the last decade has been avoid matching a recipient to a specific donor where significant DSAs to that donor's HLA are already present.A pre-LTx virtual cross match has proved robust at alerting clinicians to particularly adverse combinations. 81,82here there is uncertainty a solid-phase Hallifaster crossmatch assessment can add further prognostic information. 80Great skill and collaboration with Tissue Typing Services is needed to navigate difficult sensitized cases in critically ill potential recipients. 80,83Aggressive desensitization and DSA reduction strategies are used by an increasing number of centres and include use of plasmapheresis, intravenous immunoglobulins and antithymocyte globulin, [83][84][85][86] enabling them to successfully negate the adverse effects of high-level DSA.The future will see further exploration of therapeutic strategies to reduce specific DSA load while simultaneously using epitope assessment tools to assess the overall extent of immunologic risk of specific matches and mismatches. 87

OUTCOMES OF LUNG TRANSPLANTATION
Median survival following LTx has continued to improve with median survival now reported as greater than 5 years by ISHLT, 4 with some centres reporting median survival as greater than 10 years. 5Survival is in general limited by CLAD with 50% of recipients report to have CLAD by 5-years. 88The last decade has seen an evolution of diagnostic tools focussed on monitoring of allograft function and newer drugs and technologies focused on the treatment of CLAD.

Lung function
Spirometry has formed the backbone of allograft monitoring since standardized definitions of chronic rejection and in particular bronchiolitis obliterans syndrome (BOS) were first developed in 1993 by Cooper et al. 89 As our understanding of the patterns and pathophysiology of lung allograft function has evolved, so has the classification of CLAD. 6,90CLAD is defined as a substantial and persistent decline (≥20%) of measured FEV 1 value from the individual recipient's reference (baseline) value.This baseline is calculated as the mean of the best two post-operative FEV 1 measurements taken at least 3 weeks apart.CLAD can present as a predominantly obstructive ventilatory pattern, a restrictive ventilatory pattern or a mixed obstructive and restrictive patten. 90OS, the physiological manifestation of obliterative bronchiolitis (OB) remains the most common form of CLAD.It is defined by a fall in FEV 1 of at least 20% compared to baseline with evidence of airflow limitation and without pulmonary opacities on radiology. 90Approximately 30% of LTx recipients with CLAD develop a restrictive defect which when associated with pulmonary opacities is defined as restrictive allograft syndrome (RAS).Physiologically, this is defined as a persistent decline in FEV 1 ± FVC of at least 20% compared to baseline and a decrease in total lung capacity to ≤90% of baseline as defined as the average of two measurements obtained at the same time to or very near to the best two post-operative FEV 1 measurements and the presence of persistent opacities on chest imaging. 6ecent consensus definitions 6,90 have attempted to unify classifications of CLAD but there are limitations in the current methods of allograft monitoring due to the reliance on a spirometric baseline that can only be identified retrospectively in the setting of lung function decline and a CLAD diagnosis.Alternative methods of allograft monitoring continue to be explored.Two recent studies have shown that spirometric attainment prior to the development of CLAD is also predictive of outcomes.Liu et al. demonstrated that baseline spirometry that did not normalize (i.e., FEV 1 and FVC ≥80%) and which was termed baseline lung allograft dysfunction (BLAD), was associated with impaired survival. 91This was additionally supported by single centre study showing that failure to normalize spirometry by 1-year following transplant (FEV1 and FVC ≥80% and FEV/FVC >0.7) was associated with both mortality and an increased risk of CLAD. 92That peak lung function attainment is predictive of long-term outcomes seems an obvious finding.The recognition that failure to normalize lung function in the post-transplant period may yet prove to be a novel marker of allograft function and could potentially be targeted for intervention prior to the development of CLAD.
Forced oscillation technique (FOT) is a non-invasive method to characterize the mechanical properties of the respiratory system.Interest in the use of FOT after lung transplantation continues to grow though to date mixed findings have been reported.Despite this, studies have suggested that FOT parameters can distinguish between forms of allograft dysfunction both of CLAD 93 and baseline allograft dysfunction. 94Further research is required to establish the role of FOT in lung transplant monitoring.

Histopathology: Molecular diagnostics
Lung allograft rejection has traditionally been diagnosed by the histopathological examination of transbronchial biopsies (TBB) interpreted using the International Society for Heart and Lung Transplantation (ISHLT) guidelines. 95The limitations of this technique include the risk of the procedure, requirement for sufficient tissue and the heterogenicity of changes seen within the lung allograft. 96The key lesions representing T-cell mediated rejection are: perivascular mononuclear cell infiltrates or acute cellular rejection (A grade) 97 and lymphocytic bronchiolitis (B grade). 98With C grade representing obliterative bronchiolitis. 99hilst histopathological identification of T-cell mediated rejection is well established, the diagnosis of antibody mediated rejection (AMR) is more challenging as the histological features are non-specific 100 and the clinical diagnosis of AMR include factors unrelated to histological assessment. 101More recently molecular diagnostics have emerged as an alternative to histological assessment. 102 microarray based diagnostic system (molecular microscope diagnostic system [MMDx]) has been developed in heart and kidney transplants to detect T-cell mediated rejection and AMR.103,104 Learnings from other solid organ transplant groups have led to the INTERLUNG study, a prospective multicentre trial applying machine learning algorithms to lung tissue transcriptomic data.102 The focus of this was to define a molecular signature for lung ACR based on the genes associated with histological rejection in kidney transplantation.The Halloran group showed some elements of the ACR molecular signature were strongly associated with ACR but no AMR signature was identified.102 Whilst this technique is not currently in clinical use it shows promise in improving CLAD diagnostics.
Biomarkers: Cell free DNA Circulating cell-free DNA (cfDNA) is a marker of tissue injury.Consisting of short fragments of DNA released by necrotic or apoptotic cells, cfDNA is normally rapidly degraded and cleared from the blood.If however, its production outstrips clearance capacity, accumulation can occur. 105After transplantation, circulating cfDNA represents both the donor and recipient genomes.Levels of donor derived cfDNA (dd-cfDNA) increase in cases of damage to the allograft.With dd-cfDNA reported as a fraction of total cfDNA.dd-cfDNA levels vary over time in LTx recipients without rejection or infection.dd-cfDNA levels are elevated in the early post-transplant period representing organ injury due to ischemia-reperfusion.7][108][109] Unfortunately whilst the sensitivity of using dd-cfDNA to detect lung allograft injury is promising, it lacks specificity and cannot reliable distinguish between ACR, AMR and infection limiting its clinical utility at present. 110,111

TREATMENT OF CLAD
The management of CLAD is imperfect.Current practice tends toward the augmentation of immunosuppression with high dose methylprednisolone and/or antithymocyte globulin. 112,113These practices have limited outcomes in many LTx recipients and as such newer modalities are being investigated.

Extracorporeal photopheresis
Extracorporeal photopheresis (ECP) is a cell based immunomodulatory therapy.It involves leukopheresis to isolate leukocytes followed by ex-vivo treatment with psoralen and ultraviolet light.Whilst it has not been systemically investigated to date, ECP is increasingly used as a management of CLAD in units with access to the technology.Whilst the underlying mechanisms are not fully understood, its impact on in the lung allograft is likely due to induction of apoptosis of leucocytes which triggers a series of downstream immunomodulatory effects including increase in regulatory T cells, deactivation of natural killer cells and general release of anti-inflammatory cytokines to induce some sort of immune tolerance. 114 number of retrospective and one prospective trial have reported the efficacy of ECP in the treatment of BOS.Showing a reduction in the rate of decline of FEV 1 and stabilization of lung function after initiation of ECP. 115,116hough ECP has been shown to reduce the rate of decline in those with RAS, 115 most studies suggest that those with RAS are less likely to respond. 117There are currently a number of prospective trials in the United States and United Kingdom underway assessing the impact of ECP on the clinical course of CLAD.

Antifibrotics
The pathological similarities between RAS and other fibrotic lung diseases has led to the increasing interest in the use of antifibrotic therapies in this setting.Pirfenidone and nintedanib are two antifibrotic drugs shown to reduce functional decline and disease progression in IPF. 118,119Given their impact on fibroblast proliferation there is growing interest in whether these drugs could impact the development of OB associated with BOS and the parenchymal and interstitial fibrosis associated with RAS.Current evidence is limited to case series, but evidence suggest a reduction in the rate of decline of lung function in those with RAS with the use of pirfenidone. 120There are several studies currently being undertaken, and whilst it appears that pirfenidone does not impact the clinical course of BOS 121 studies exploring its impact on RAS are awaited.

MANAGEMENT OF INFECTION
The consequences of the use of immunosuppression to prevent CLAD is an increased risk of both infection and malignancy.There has been an evolution in the treatment of infective complications of LTx with the increasing availability of newer drugs and delivery methods to minimize complications and better target infection.

Novel antifungals
Invasive fungal disease is a risk for all immunosuppressed individuals but especially for lung transplant recipients.Aspergillus infection accounts for 60% of all fungal disease in this cohort. 122Voriconazole is the recommended first line treatment for invasive aspergillosis, but its use is complicated by drug interactions and toxicities.As a strong inhibitor of CYP3A4 it increases the levels of calcineurin inhibitors (tacrolimus/cyclosporin) requiring dose reduction and increasing the risk of developing renal impairment.Additionally, a number of other adverse effects including hepatotoxicity, visual disturbance and increased risk of skin cancers are commonly seen. 123,124s such investigation of novel delivery methods and newer agents is underway.

Inhaled voriconazole
As the bronchial anastomotic sites are susceptible to ischaemic injury, systemic antifungals may be less effective and locally delivered antifungals may prove to be superior.Whilst inhaled amphotericin B has been used as prophylactic agent in combination with systemic antifungals, more recent studies have explored the use of nebulised voriconazole in an attempt to increase pulmonary exposure but reduce systemic side effects.Though evidence supporting the use of inhaled antifungals is limited to case series and case reports, there are two publications involving three lung transplant recipients that have reported on the treatment of invasive pulmonary aspergillosis with nebulised voriconazole that demonstrated clinical and radiological improvement. 125,126Whilst not in routine use, this is a treatment that warrants further investigation.

Isavuconazole
Isavuconazole is a new extended spectrum triazole with activity against invasive aspergillosis and mucormycosis.It has fewer drug-related adverse events and interactions and has shown non-inferiority to voriconazole in the treatment of those with invasive aspergillosis. 127,128Recent data shows it achieves adequate bronchopulmonary penetration 129 and a number of case series report its successful use in lung transplantation. 130,131orofim Olorofim is a first-in class orotomide antifungal.It selectively inhibits fungal dihydroorortate dehydrogenase, a key enzyme in fungal pyrimidine biosynthesis.With action against aspergillus, moulds and dimorphic fungi its use has been reported in a number of case reports and case series in lung transplant recipients. 132Given its tolerability and lower incidence of side effects, it may be better suited to prophylaxis than some of the currently available drugs though higher level evidence is required.

Management of cytomegalovirus
Cytomegalovirus (CMV) is a major contributor to morbidity and mortality after lung transplant.Associated with both clinical disease and the development of CLAD 133,134 significant effort is undertaken to prevent CMV infection.Effective antivirals for CMV prevention are essential in the management of LTx recipients.Most commonly valganciclovir and ganciclovir are prescribed.The use of these agents, however, is commonly complicated by intolerance including myelosuppression and the development of antiviral resistance. 135,1366][137] Attempts to optimize treatment protocols for solid organ transplant recipients has led to the exploration of novel agents, vaccines and immunologic monitoring tools.

Immune monitoring
Assays that monitor CMV-specific immune response have been developed in an attempt to individualize risk prediction and guide prophylaxis duration. 138The QuantiFERON-CMV (QF-CMV) is a commercially available enzyme-linked immunosorbent assay (ELISA) that detects CMV-specific CD8+ T-cell activity by measuring interferon-γ release following stimulation with CMV-specific peptides and can be performed in most clinical laboratories.9][140] However, a recent study in LTx recipients demonstrated that whilst there was less CMV in those who received QF-directed prophylaxis, QF-CMV results provided minimal additional predictive value beyond CMV serostatus. 141This difference in utility in the LTx population compared to other solid organ groups may reflect the greater immunosuppression required for LTx and greater risk of CMV infection seen in LTx recipients.

Letermovir
Letermovir is an antiviral drug with a unique mechanism of action as an inhibitor of the CMV DNA terminase complex.This site is involved late in the viral replication process and is separate from targets of other antiviral agents therefore letermovir does not have issues of cross resistance seen with other agents. 142It additionally is not associated with myelotoxicity, does not need dose adjustment for kidney impairment and has high bioavailability and can be administered both orally and intravenously.
A recent randomized control trial in renal transplant recipients has explored the use of letermovir as CMV prophylaxis.The study by Limaye et al. showed that letermovir was non-inferior to valganciclovir in adult high-risk CMV renal transplant recipients who received an organ from a CMV-seropositive donor, with reduced incidence of bone marrow suppression and other adverse drug effects. 143aullo et al. have reported on the largest cohort of thoracic organ transplant recipients (including 37 LTx recipients) who received letermovir as CMV prophylaxis.In this cohort, letermovir was instituted predominantly in the setting of myelosuppression as an alternative to valganciclovir.With letermovir prophylaxis, a significant increase in white blood cell count was seen which allowed the reintroduction of antimetabolite immunosuppression in several LTx recipients.CMV infection was rare, with only and a single episode of breakthrough CMV infection reported. 144With its improved side effect profile and tolerability, letermovir has potential in improving CMV prophylaxis.

UNDERLYING DISEASE THERAPIES
Evolution in the management of a number of respiratory diseases prior to transplant has had implications on both timing of transplant and post-transplant care.This is most apparent in CF where the availability of highly effective CFTR modulators is likely to continue to improve CF survival and delay if not obviate the need for transplant in many individuals with CF.Whilst not extensively studied in post-transplant care, CFTR modulators have the potential to improve extrapulmonary complications of CF including nutritional status, glycaemic control and sinopulmonary disease. 145Given their cost and potential for drug interactions their use is likely to be only appropriate in select candidates.

FERTILITY AFTER LUNG TRANSPLANT
With increasing life expectancy, there is an increasing interest in parenthood following lung transplant.Historically, pregnancy in LTx recipients has been discouraged but an increasing number of female recipients have been reported to have had successful pregnancies. 8,146,147Whilst the relative infrequency of pregnancy following LTx makes it difficult to establish definitive recommendations a recent ISHLT consensus statement on reproductive health after thoracic transplantation has been published. 148Individual risk assessment, preconception counselling and close monitoring are all necessary to increase the likelihood of a good pregnancy outcome for LTx recipients.In general, LTx recipients should only consider pregnancy if they are 1-2 years following transplant with stable lung function and no end-organ issues.Immunosuppression regimens including tacrolimus, azathioprine and prednisolone are recommended, with mycophenolate contraindicated due to its association with first trimester miscarriage.Whilst there is no conclusive evidence that pregnancy increases the risk of CLAD, it is a sensitizing event and may contribute to the development of DSAs.It is also important to recognize the limited life span of LTx which may impact long-term care of any child.

CONCLUSION
Lung transplantation is a well-established treatment for individuals with advanced lung disease resulting in both improved survival and quality of life.The last decade has seen a significant increase in transplant numbers as donor and procurement strategies continue to improve with DCD donors and EVLP providing increased donor numbers.Whilst longer term outcomes continue to be limited by CLAD, the evolution in diagnostics and treatment strategies currently occurring hold promise for new diagnostic tools and therapeutic targets.Concurrent developments in infection prevention and treatment also promises to improve tolerability of treatments and long-term outcomes.As active clinical and translational research programs continue to provide insights into transplant immunology, diagnostic and treatment strategies lung transplantation will continue to evolve as a successful treatment for those with severe lung disease.
Categories of DCD lung donors.