plaques usually spare the costrophrenic angles and lung apices; diffuse pleural thickening due to asbestos exposure rarely calci \201 es; diffuse pleural thickening is ill-de \201 ned and irregular from all angles, whereas plaques are well de \201 ned; plaques rarely ex tend over more than 4 rib interspaces unless multiple and con \202 uent. CT is more sensitive and speci \201 c for the detection of dif- fuse pleural thickening th an chest radiography. Symptoms include breathlessness and chest pain and lung function test s show a restrictive ventilatory defect with reduced total lung capacity. A high resolution CT thorax is usually required as part of the initial work up (especially if pain is one of the symp- toms) In cases of diffuse pleural thickening the pleura will be smooth, with no involvement of the mediastinal border. Whereas, in mesothelioma the pleural is likely to be irregularly thickened with mediastinal involvement (See Fig. 16.8.2a, a diffuse pleural th ickening and 16.8.2b, mesothelioma). If there is diagnostic uncertainty a biopsy is recomme nded. Fig. 16.8.1 CXR showing bilateral calci \201 ed pleural plaques. CHAPTER 16.8 Asbestos-related diseases (excluding mesothelioma) 415 Patients with symptomatic diffuse pleural thickening may be eligible for compensation. KEY POINT Patients with pleural thickening involving the costo- phrenic angles are more lik ely to be symptomatic. Asbestosis Asbestosis is a diffuse interstitial \201 brosis of the lung caused by asbesto s dust. It tends to be prominent in the lower lobes and subpleural areas. Radiographically, other than the presence of pleural plaques there a re no unique characteristics to differe ntiate it from usual interstitial \201 brosis. Asbestosis seldom develops less than 20 ye ars after expo- sure and requires heavy asbestos exposure. Fig. 16.8.2a Chest CT scan showing diffuse pleural thickening. Pathogenesis \200 Incomplete phagocytosis of asbestos \201 bres results in release of lysosomal enzymes, fi brogenic factors, cytokines and free radicals \200\223 all leading to \201 brosis. Asbes tos bodies are usually seen within areas of \201 brosis. Clinical features \200 Presentation is usually with gradual exertional shortness of breath and a dry cough. Examin ation reveals late inspiratory \201 ne crackles. Finger clubbing occurs in 40% of patient s and is an adverse prognostic feature. Cyanosis and cor pulmonale may occur in advanced di sease. Investigations HRCT is more sensitive than plain radiography and should be performed in all suspected cases. (See Fig. 16.8.4.) \200 HRCT features include: Parenchymal bands. \200 Basal ground glass opacities. \200 Subpl eural curvilinear lines. \200 Interlobular septal thickening. \200 Fibrosis. \200 Asb estos bodies may be found in sputum, BAL is more sensitive in detecting asbestos bodies. Hi stological con \201 rmation of asbestosis is unnecessary unless there are atypical feature s. In these cases trans- bronchial biopsies are inadequate and a thoracoscopic or open lung biopsy will be needed. Fig. 16.8.2b Lobulated irregular pleural thickening in mesothelioma. Not uncommonly patients with diffuse pleural thickening may have an area of folded lung. Th is is also known as Blesovsky syndrome or rounded atelectasis. It develops as contracting v isceral pleura pulls and twists adjacent lung. This results is a subpleural opacity which o ften has a comet tail of vessels and bronchi converging toward the lesion (see Fig. 16.8.3) . Management No drugs are of proven value. In advance cases palliative measures such as oxyge n, diuretics, opioids should be used as appropriate. Prognosis and complications \200 Asbestosis usually progress slowly after removal from exposure and only 40% will progress o ver the following decade. There is an increased risk of lung cancer in patients with asbest osis. Due to the sensitivity of CT scanning some early cases are now being picked up in asy mptomatic individuals. More research is required into the natural history of this subgroup. Fig. 16.8.3 Early folded lung in a patient with diffuse pleural thickening. A KHAN & N MASKELL 416 Further reading ATS statement: Diagnosis and initial management of nonmalignant diseases re lated to asbestos. Am J Respir Crit Care Med 2004; 170: 691. Fletcher DE & JR Edge. 1970. The early radiological changes in pul- monary and pleural asbestosis. Clin Radiol 21:355-365 McLoud TC, BO Woods, CB Carrington, et al. 1978. Diffuse pleural thickening in an asbestos- exposed population. Am J Roentgenol 579-585 Lynch DA, G Gamsu& DR Aberle. 1989. Conventional and high resolution tomography in the diag nosis of asbestos-related diseases. Radiographic 9:523-551 Roggli VL, Oury TD, Sporn TA. Pathology of Asbestos-associated Diseases 2nd rev. edn. New York: Springer-Verlag 2004. Fig. 16.8.4 HRCT showing interstitial \201 brosis consistent with the diagnosis of asbest osis. 417 Chapter 17 Lung transplantation/ITU Chapter contents 17.1 Lung transplantation: considerations for referral and listing 418 17.2 Complications a fter lung transplantation 422 17.3 The care of lung transplant candidate or recipient 426 1 7.4 Acute respiratory distress syndrome 430 17.5 Severe acute respiratory syndrome 432 17.6 The ventilated patient 434 S PARKER & A FISHER 418 17.1 Lung transplantation: considerations for referral and listing Identifying potential lung transplant candidates Lung transplantation offers a realistic th erapeutic option to selected patients with end-stage respiratory disease who have failed to respond to maximal medical therapy. Poten- tial lung transplant recipients need to demonst rate under- standing of the risks and bene \201 ts of lung transplantation, appreciate the need for complicated mediation regimes and medication side-effects and be capable of and c ommit- ted to following speci \201 c guidance from healthcare profes- sionals within the t ransplant team. In the age of severe donor shortage it is essential that optimum use of thi s scarce resource occurs. This requires very careful assess- ment of potential candidates s o that only patients in whom the bene \201 t to risk ratio is favorable are taken on for l ung transplantation. Unstable psychiatric conditions: compliance with a com- plex medication regimen, regular at tendance at follow-up and early reporting of new symptoms are essential to pro- ducing good outcomes after lung transplantation. Patients who are unable to cope with these responsibi lities are at high risk of a poor outcome after transplantation. Relative contra-indications \200 Age >65 years for single and >60 for bilateral lung. \200 Poor rehabilitation potential. \200 Colonization with highly resistant micro-organi sms. \200 Obesity BMI >30. \200 Poor nutritional status BMI <18. \200 Severe symptoma tic osteoporosis. \200 Requirement for mechanical ventilation. \200 Critical or unstabl e clinical condition. \200 Other conditions causing signi \201 cant end-organ damage. Ad apted from International Guidelines for the selection of lung transplant candidates 2006 Up date. General guidance Indications and timing of referral Patients with end-stage lung disease who have failed to respond to maximal medical treatmen t can be considered for lung transplantation. Obviously many patients will have absolute or relative contra- indications and will not be suitable. Those in whom survival chance is es timated to be 50% at 2 \200\2233 years should be considered to have disease of suf \201 - cient severity for referral. Certain groups are at high risk of more rapidly progres- sive disease and are discussed below in disease speci \201 c guidance. Age Increasing age above 55 years is an independent risk factor for a poor early and late o utcome after lung trans- plantation. Potential recipients over 55 years therefore require p ar- ticular attention during assessment to exclude signi \201 cant co-morbidities which wi ll increase risk further. The international guidelines recommend an upper age limit of 65 y ears for lung transplant. This acts as a guide and patients beyond this age limit can be su ccessfully trans- planted if they have no other co-morbidities and biologi- cally are young er than their chronological age. Absolute contra-indications to lung transplantation \200 Smoking. \200 Substance abuse (alcohol or illicit drugs). \200 Severe dysfunction of other major organ. \200 Unresolv ed extra-pulmonary infection. \200 Chest wall or spinal deformity. \200 Poor compliance with therapies or follow-up. \200 Unstable psychiatric conditions. \200 Absence of rel iable social support system. \200 Malignancy within last 5 years. Adapted from Internatio nal Guidelines for the selection of lung transplant candidates 2006 Update. Smoking: curren t tobacco smoking is an absolute contra- indication to lung transplantation. Most centers w ill expect patients to demonstrate 3 \200\2236 months of complete absti- nence before they would consider a patient \200\231s suitability for lung transplantation. It is important th at patients are not simply still dependent on nictotine replacement prod- ucts having given up smoking, but are free of nicotine addiction. Malignancy: the risk of both lymphoprolife rative and solid organ malignancy after lung transplantation is increased signi \201 cantl y due to the effect of powerful immunosuppres- sive drugs. Therefore patients with a histor y of recent malignancy would be at high risk of recurrence. Locally treated skin malignancy and certain very low grade tumors can be considered after de \201 nitive surgical treat- ment. In all other cases a 5-year disease free period after de \201 nitive treatment is re quired. Weight and nutritional status The physical stress associated with the transplant proce- dur e causes most patients to lose 10% of their body weight in the post-operative period. This may be more if complica- tions arise and there is a prolonged ITU stay. If the patient is a lready underweight this is likely to be lost as muscle mass which will affect the ability t o wean from ventilation and to rehabilitate. It is essential that patients therefore enter transplantation with suf \201 cient nutritional reserve to cope with this stress. Patients with cystic \201 brosis (CF) are particularly at risk where pancreatic insuf \201 cienc y, CF-related diabetes and advanced suppurative lung disease can cause a very poor nutritio nal status. Patients with advanced COPD can also suffer from severe nutritional compromise due to the catabolic state and muscle dysfunction associated with the disease. Careful atte ntion to nutritional status is essential in these groups and in CF is achieved by aggressiv e enteral feeding (via NG tube or PEG), good glycaemic control and control of sepsis. Most centers would expect a minimum BMI of 18 in patients with CF or advanced Emphysema before l isting for lung transplantation. As important as being underweight are the risks associated with patients who are overweight or obese. As with all surgical interventions, obesity is associated with a higher complication rate. CHAPTER 17.1 Lung transplantation: considerations for referral and listing 419 After lung transplantation, poor mobility, poor wound healing and dif \201 cult weaning fr om ventilation can be expe- rienced in those signi \201 cantly overweight. This is seen as a correctable contra-indication to transplantation. transplantation. However as with many relative contra- indications it needs to be assessed in its own right and also by examining its contribution to the individuals total risk. Sign i \201 cant \202 ow limiting or symptomatic coronary disease would increase risk of post -operative complications signi \201 - cantly and most centers would not accept such patien ts for lung transplant. Patients with less severe disease may be suitable for pre- transpla nt coronary stenting or for consideration of bypass grafting at the time of transplant in t hese cases patients should be in otherwise excellent condition and have no other relative c ontraindications. Mild left ventricular dysfunction can be treated with ACE inhibition and response followed by echocardiography. KEY FACT BMI of 30 acts as an upper limit to consideration for list- ing for lung transplan tation in most transplant centers. Disease severity Clearly, to be considered for lung transplantation patients will have adva nced end-stage lung disease. However, potential transplant recipients also need to be \201 t enough to survive the physical stress of transplant surgery and to manage the rehabi litiation necessary as part of their recovery. There is thus a widow of opportunity for tra ns- plantation after which the severity of a patient \200\231s condition may make the chanc es of surviving the surgery and achiev- ing recovery afterwards diminish rapidly (Fig. 17.1 .1). In these cases, palliative care would be a more appropriate approach to management. Un fortunately, deterioration in a patient \200\231s condition beyond the window of opportunit y may happen to those on the active lung transplant waiting list. This can necessitate remo ving them from the transplant waiting list and focusing on palliative approaches. This shou ld be remembered when considering patients for initial refer- ral. Many patients referred a re already beyond the transplant window and the false hope that transplant referral can giv e may be detrimental to their remaining survival time. Psychosocial aspects Social support network Undergoing lung transplantation places not only signi \201 cant physical stress on an individual but also places many psy- chological and social strains on an individual. The complex nature of the follow-up arrangements, the tra veling to and from the transplant center and the complexity of the medication regimen means that transplant recipients need to be able to cope with these stresses as effetively as th ey can with physical stresses. \200 Support from carers at the time of and in the post-tr ans- plant period is essentially to optimize the chances of a good outcome. Most transplant centers will insist that potential recipi- ents have an identi \201 ed pri mary carer or team of carers who will provide support in the post-transplant period. \200 This individual(s) should also be involved in the pre- transplant assessment so they are f ully informed as to what to expect in the post-transplant period. Ideal time of referral y t i r e v e s Late referral e s a e s i D Social worker input is therefore an invaluable part of the assessment team. Death Time in years Psychological status The journey to successful lung transplantation involves many hurdles, each of which can cause signi \201 cant stress to an individual and their family. The unce rtainty in the assessment process, the waiting for a potential donor organ and the high ris k of post-operative complications can place tremendous pressure on the individual and their carer(s). \200 Potential recipients must therefore show that they are Transplant window Fig. 17.1.1 Schematic representation of the transplant window and the timing of ideal refer ral for transplant assessment and when referral may be too late to successfully achieve tra nsplantation. Extra-pulmonary disease Renal disease \200 Calcineurin-inhibitors (ciclosporine and tacro limus) form the cornerstone of immunosuppression regimens after lung transplantation. psychologically robust enough to get through this. A history of uncontrolled psychiatric illness, poor cop- ing skills and extreme levels of a nxiety may signi \201 cantly impair the chance of achieving a good outcome from transplant ation. Although these factors may be considered soft com- pared to other physical contraindication s their impor- tance should not be underestimated. Both these agents have nephrotoxic potential. \200 Most patients experience a deteriorati on in renal function after transplant and in some cases this can progress to renal failure requiring renal replacement therapy. Disease-speci \201 c guidance COPD and emphysema: worldwide this is the most com- mon reas on for referral and is the commonest indication for lung transplants performed. The value o f the BODE score as guide to predicting prognosis in COPD has been adopted by the Internati onal Society of Heart and Lung Transplantation (ISHLT) in their disease speci \201 c guida nce. However evidence that the BODE score is useful in guiding the decision to refer or lis t the younger COPD patient under consideration for lung transplant is lacking. To minimize this possibility, patients being considered for lung transplantation should hav e well preserved renal func- tion as demonstrated by an isotope glomerular \201 ltration rate >60 ml/min. Acute renal failure in the early post- transplant failure can prolong inte nsive care unit stay and have an adverse effect on outcome. Cardiac disease The presence of known coronary disease or left ventri- cular dysfunction is a relative contra-indication for lung S PARKER & A FISHER 420 The international guidance suggests COPD patients with a BODE score of >5 should be conside red for referral. Those deemed unsuitable for lung volume reduction surgery may be consider ed for active listing when some or all of the following criteria are met: \200 BODE >7. \200 Repeated hospitalisations with acute hypercapnic res- KEY FACT The ISHLT guidelines suggest a 10% or more fall in vital capacity or a 15% or more fall in diffusing capacity over 6 months indicate a need to list for transplant. This is p robably more important than any absolute cut off for diffusing capacity or lung volumes. piratory failure. Pulmonary \201 brosis Idiopathic pulmonary \201 brosis is a common indication for refer ral for lung transplant assessment. Unfortunately many patients with this condition will li e outside the upper age limit for transplantation and will not be suitable for referral. \200 Patients within the appropriate age group who have usu- al interstitial pneumonia (UI P) or \201 brotic non-speci \201 c interstitial pneumonia ( \201 brotic NSIP) should be consid- ered for referral early as they can progress very rapidly. \200 Clinicians shoul d not be falsely reassured by a diagnosis of NSIP as the mortality risk is as high as UIP i n the \201 rst 2 years after diagnosis. Pulmonary hypertension and cor pulmonale despite oxygen therapy. FEV1 less than 20% predicted. \200 Diffusing capacity less than 20% predicted. The rate o f progression of lung disease in COPD patients can be very slow and as a result lung transp lantation may not offer a survival advantage to patients with this condi- tion. In these ca ses lung transplantation can be performed predominantly for improvements in quality of life . CF and bronchiectasis: patients with CF, of all the indica- tions for lung transplantatio n, have a lot to gain in terms of an early survival advantage and the best long-term surviv al figures. However the multi-system nature of CF and chronic pulmonary sepsis with resista nt organisms mean this group of patients require very careful assessment prior to acceptanc e for lung transplantation. CF patients should be considered for referral when they have ad vanced lung disease as demonstrated by \200 An FEV1 of <30% predicted. \200 A rapid los s of lung function (young female patients who appear to be at higher risk of rapidly progre ssive lung disease). Rate of progression of disease is an important indicator for need to list a patient for transplant. Pulmonary arterial hypertension The last 10 years has seen a dramatic increase in therapeu- tic options for patients with pulmonary arterial hyperten- sion (PAH). As a result the pro gnosis for patients with PAH is better. Whether these therapies mean fewer PAH pa- tients w ill ever be referred for lung transplant or will simply delay referrals by several years is too early to ascertain. Patients who are WHO class III or IV who have progressive disease despite maximal medical therapies, including intra- venous prostanoids, should be referred for assessment. When the following indicators are reached, patients should be considered fo r listing as these are markers of a poor prognosis. \200 Six-minute walk distance falls w ell below 350m. \200 Cardiac output <2 litres/min/m2 or \200 Right atrial pressure >15m mHg. An increasing frequency of exacerbations requiring admis- sion or home intravenous antibiotics. Recurrent or refractory pneumothoraces or haemoptysis. Assessment in potential CF recipient s needs careful atten- tion to the resistance patterns of organisms infecting their lungs, their nutritional status and the presence of liver dis- ease. All of which can adversely af fect outcomes after transplant. Fig. 17.1.2 Plain CXRs from a young male patient with CF before and after bilateral lung tr ansplantation. CHAPTER 17.1 Lung transplantation: considerations for referral and listing CHAPTER 7.0 Home oxygen therapy 421 Further reading Orens J, Estenne M, Arcasoy S, et al. International guidelines for the sele ction of lung transplant candidates: 2006 update \200\223 a con- sensus report from the pu lmonary scienti \201 c council of the inter- national society of heart and lung transplant ation. J Heart Lung Transplant 2006; 25:745 \200\223755. Others indications There are a number of other rarer indications for lung transplant referr al such as sarcoidosis, Langerhans cell his- tiocytosis (LCH) and lymphangioleimyomytosis ( LAM). It is more dif \201 cult to provide disease speci \201 c guidance for these conditi ons due to their rarity. Disucssion with the transplant center on a case-by-case basis is b est to guide referral criteria in such cases. S PARKER & A FISHER 422 17.2 Complications after lung transplantation The clinical course after lung transplantation varies mark- edly between individuals. This is due to development of common complications that range in severity from mild to potential ly fatal and may impact on the recipient \200\231s quality of life. The common post-lung tr ansplant complications can be categorized by their timing after transplant. Early complicat ions arise as a result of the surgical inter- vention and can affect the transplanted lungs themselves or other organ systems. Subsequent complications arise due to a loss of balance between alloimmune activity against the transplanted lungs and the level of immunosup- pre ssion used. Long-term complications arise due to the chronic toxic effects of immunosuppres sion and are due to chronic allograft dysfunction. Management of patients after lung transp lantation can be complex but meticulous atten- tion allows early detection and minimizes th e effect of such complications. 3% patients in experienced centers but occur after several weeks and may require stenting t o relieve the air \202 ow obstruction. Primary graft dysfunction Primary graft dysfunction is a clinical diagnosis de \201 ned as signi \201 cant impairment of oxygenation together with diffuse radiological in \201 ltr ates in the lung allograft within the \201 rst 72 hours after transplantation. It is anal ogous to acute lung injury and ARDS and requires exclusion of other causes such as hyperacu te rejection, venous anastomotic obstruc- tion, cardiogenic oedema and pneumonia. \200\231 Primary graft dysfunction, previously called \200\230reperfusion oedema \200\231 or ischae mia-reperfusion-induced lung injury accounts for increased perioperative mortality, impaire d lung function and worse longer-term survival. Management of primary graft dysfunction is supportive with oxygen and ventilation strategies including permissive hypercapnia and pron e positioning. Avoidance of \202 uid overload is important and approaches such as inhaled nitric oxide or prostaglandin infusions may be helpful to improve oxygenation. In severe c ases extra-corporeal membrane oxygenation (ECMO) and surfactant therapy have been successfu lly used. Survival after lung transplant International registry shows survival figures of 50% at 5 ye ars and 25% at 10 years. This compares poorly with other solid organ transplants such as li ver, heart and kidney. Improvements in lung transplant mortality in the \201 rst 3 months after transplantation have occurred over recent years largely due to improvements in surgi cal technique and postoperative critical care. Morbidity and mortality after lung transplan t can be con- sidered in terms of time periods. Mortality within 30 days is mainly due to: \200 Surgical complications (bleeding, anastomotic failure). \200 Primary graft dysfunc tion (early acute lung injury or Infection Infections, bacterial, viral and fungal can contribute sub- stantially to both mo rbidity and mortality after lung trans- plant, the incidence is much higher than is seen af ter other solid organ transplants. The majority of infections occur within the thorax. The time after transplant is important when considering the possible cause. ARDS). Ventilator acquired lung injury or infection. \200 Sepsis. The leading cause of death at one year is infection as a consequence of common or opportunistic infections and immunosupp ression. Infection is the leading cause of death after the \201 rst year re \202 ecting increased susceptibility with impaired host defenses, exposure of the allograft to the exte rnal environment and the development of chronic allograft dysfunction characterized by the development of the bronchiolitis obliterans syndrome (BOS). Bacterial infections: Usually presents as bronchopneumonia, commonest in the \201 rst few months after transplant. Responsible organisms include: Pseudomonas aeruginosa and other p seudomonas species, Staphylococcus aureus, coagulase-negative staphy- lococci, Enterococcus and Haemophilus in \202 uenzae. Infection with organisms such as Listeria, Nocardia and \200\230atypical \200\231 pneumonias are rare. Patients with cystic \201 brosis generally fare well with a rate of bacterial pulmonary infections comparable to those encountered in other patient populations. However, patients infected with the Burkholderia cenocepacia st rain of the Burkholderia cepacia complex are at high risk of severe postoperative infection s and septic death. Subclinical colonization with bacteria such as pseudomonas aeruginosa i s seen in the later period after transplantation even in clinically stable allograft recipi ents. Clinically signi \201 cant bacterial infection is a frequent complication of BOS wit h Gram-negative pathogens such as pseudomonas most frequently implicated. Mycobacterial inf ection with M. tuberculosis or non-tuber- culous mycobacteria is fortunately not frequent b ut is dif \201 cult to treat and effects long term outcomes. M. tuber- culosis should be t reated with the usual antituberculous drugs but blood levels of immunosuppressant drugs may be decreased due to cytochrome p450 activation. Non- tuberculous mycobacteria should only be treated if there is evidence of active disease. Infection with M. abscessus is a particu lar cause for concern. KEY FACT BOS is the leading cause of death in the long term and affects up to 70% of surviv ors by 5 years and accounts for 40 \200\22350% deaths at 3 \200\2235 years after lung trans plant. Surgical complications Virtually all patients undergoing the procedure have reduced physica l conditioning due to their signi \201 cant underlying lung disease and are therefore at h igher risk of post-operative complications. Complications relating to the transplant surger y include hemorrhage, venous thrombosis, pulmonary arterial or venous stenosis, bronchial a nastamotic dehiscence and intrathoracic sepsis. Vagus nerve injury may predispose to gastro paresis and gastroesophageal re \202 ux disease. Phrenic nerve injury can occur and may be compromising if the diaphragmatic paralysis affects the side of single lung trans- plant. Anastomotic stenosis, due to ischaemia, affects only CHAPTER 17.2 Complications after lung transplantation 423 Viral infections Community respiratory viruses: infection with respiratory viruses (rhinovi rus, respiratory syncytial virus, parain \202 u- enza 1,2, and 3, in \202 uenza A and B) is common affecting up to 20% of recipients with signi \201 cant associated morbidity. A p ossible link with the subsequent development of BOS has been suggested. Cytomegalovirus (CM V) disease most frequently presents in the \201 rst 4 months after transplantation. Altho ugh the introduction of effective antiviral therapy, prophylaxis and viral surveillance has markedly reduced the frequency and severity of CMV infection, it remains a signi \201 can t problem. CMV predisposes to secondary bacterial and fungal infection and may be an indepe ndent risk factor for the development of BOS. Infection may be primary with seron- egative recipients acquiring infection from a seropositive allograft, or secondary due to reactivat ion of endogenous virus acquired previously by the recipient. Manifestations of CMV infecti on range from asymptomatic through to a mononucleosis like viraemia to severe inva- sive di sease, most commonly affecting the lungs and some- times disseminated to the central nervou s system, gastrointestinal tract and retina. CMV pneumonitis, the commonest form of invasiv e dis- ease may be dif \201 cult to diagnose. The use of lung biopsy or bronchoalveolar la vage to demonstrate speci \201 c viral cytopathic changes has a low sensitivity. A signi \201 cantly rising viral titre on PCR may be diagnostic. Treatment is with an appropriate a nti-viral such as oral val- ganciclovir with foscarnet being an alternative in cases of gan ciclovir resistance. Some centers also add anti-CMV immunoglobulin to the treatment of seve re and relapsing disease. Relapse \200\223rates following treatment are high, up to 60% for primary and 20% for secondary infection. Routine antiviral prophylaxis to prevent CMV has been shown to reduce the incidence and severity of CMV infection. Epstein \200\223Barr Viru s (EBV) is common within the general population with more than 90% of adults over the age o f 35 seropositive for the virus. Reactivation of the virus occurs in a signi \201 cant num ber of patients post transplant and EBV is the major risk factor for the development of pos t-transplant lymphoproliferative disease (PTLD). renal function begins in the \201 rst 6 months post transplant and 4 \200\22310% progress to end-stage renal failure requiring renal replacement therapy. The renal toxicity of the calcineurin inhibitor immunosup- pressants is the most important cause of renal dysfunction after lung transplant. These drugs cause a dose dependent acute renal injury due to intens e afferent arteriolar vaso- constriction that may be reversible. However chronic use produc es irreversible injury associated with structural remodeling of the glomeruli. Complication s of CKD include hypertension, anemia and cardiovascular disease, patients with CKD post lu ng trans- plant have a 4 \200\2235-fold increase in mortality. Strategies aimed at minimizi ng renal failure include introducing an alterna- tive immunosuppressive agent such as rapam ycin to allow a reduction in calcineurin inhibitor dose, aggressive control of blood pressu re and therapy for hyperlipidaemia. Patients with end-stage renal failure should ideally be listed for a renal transplant as it carries a signi \201 cantly lower risk of death than long term dialysis. Osteoporosis Osteoporosis de \201 ned as a bone mineral density more than 2.5 standard dev iations below the age related mean confers an increased risk of fracture. An increased rate of non-traumatic fractures has been reported in lung transplant recipients, studies indica te over 70% of transplant recipients having osteoporosis with BMI and cumulative steroid do se being the main predictors. Osteoporosis related fractures are painful, debilitating and may impair lung function as a result of thoracic restriction secondary to vertebral compres sion fractures. For this reason many centers consider patients with signi \201 cant osteop orosis to be unsuitable for lung transplantation. Treatment of osteoporosis in post-transpl ant patients includes calcium and vitamin D supplementation and oral bisphosphonates. Neoplastic complications Immunosuppression impairs T-lymphocyte mediated tumor surveillance , predisposing patients to malignancy. Tumors tend to be more aggressive than is seen in th e general population. The commonest tumor is PTLD. Other tumors include Kaposi \200\231s sa rcoma and cancers involving the skin, lung, pros- tate, colon, head and neck and kidneys. P TLD is a non Hodgkin \200\231s lymphoma predominantly of B cell type whose proliferation is driven by EBV. The risk of PTLD is highest in EBV seronegative recipients who receive an E BV positive graft. Most PTLD occurs in the \201 rst year after transplant and involves th e allograft with pulmonary nodules and possible mediastinal lymphadenopathy. Disease presen ting later tends to be more disseminated and carries a worse prog- nosis with an overall mo rtality of 40 \200\22350%. Diagnosis of PTLD is best achieved by tissue biopsy. Pa- tients are staged by CT scanning. The main treatment is a signi \201 cant reduction in immunosupp ression to restore some host immunity to EBV. If this fails, other options in- clude surgic al resection of localized disease and chemo- therapy/radiotherapy in refractory cases. Chem otherapy is poorly tolerated, infectious complications are frequently seen as a result of t he additional immunosuppression. Fungal infection Routine trimethoprim-sulfamethoxazole prophylaxis has reduced Pneumocystis carinii infection rates from 70% to virtually zero. Other fungi causing infections in lung transplant recipients include Cryptococcus, Candida species and Aspergillus. Aspergillus i s a ubiquitous environmental fungus that is common in lung transplant recipients, affecting 30 \200\22350%. Despite this only 3% develop invasive disease that presents as pneumonia o ccasionally complicated by systemic dis- semination with mortality rates as high as 60%. Tr eatment is with intravenous or nebulised amphotericin or oral voriconazole and surgical res ection of affected areas in refractory cases. Renal disease Chronic kidney disease (CKD) is common after transplant, eventually affecting up to 90% of patients. Deterioration in S PARKER & A FISHER 424 Gastrointestinal complications Gastrointestinal problems, mainly due to immunosuppres- sive drug toxicity, are common (incidence of up to 50%) in lung transplant recipients, the majo rity are self-limiting and respond to conservative management. Complications include: pepti c ulcer disease, gastritis, gas- troparesis, pseudomembranous colitis, and CMV infection. B owel perforation in an immunosuppressed patient carries a particularly high mortality of up to 75%. Table 17.2.1 International Society of Heart and Lung Transplantation scoring criteria Grade Histology A0 (no rejection) No signi \201 cant abnormality A1 (Minimal) Infrequent perivascular mononuclear cell in \201 ltrates around venules A2 (Mild) More frequent in \201 ltrates, more than a few cells thick, involving veins and arteries. A3 (Moderate) More exuberant mononuclear cell in \201 ltrates from the perivascular space into the alveo lar interstitium. KEY FACT Gastroesophageal re \202 ux disease appears to be a partic- ular problem after lu ng transplant and has been linked to the development of BOS. A4 (Severe) In \201 ltrates extend into the alveolar space with pneumocytes damage: there may be necro sis of vessels and lung parenchyma. Neurological complications Most non-infectious neurological complications are due to calcin eurin inhibitor side effects. Manifestations are usually mild and include tremor, headaches and paraesthesia. Drug-induced leukoencephalopathy is a more serious problem, manifesting as a wide range of possible symptoms including confusion, coma, seizures, cortical blindnes s and quadriplegia. Occipital lobe involvement is common with CT scans showing non-enhancin g areas of reduced attenu- ation in the cerebral white matter. The cause of the injury is n ot clear and may relate to either a direct toxic effect of the drug or possible vasospasm a nd consequent ischaemic injury. Dose reduction or withdrawal of the offending drug is usual ly results in a substantial improvement. small and medium sized airways airways with connective tissue. OB is a histological diagnos is obtained from lung biopsy but patchy distribution of disease results in a low diagnos- t ic sensitivity (15 \200\22328%). This lead to the use of a clinical correlate, the \200 \230bronchiolitis obliterans syndrome \200\231 (BOS) based on the development of air \202 ow limitation with de- cline in FEV1 and reduced FEF25 \200\22375, from a stable post trans plant baseline value. Staging of the disease (BOS level 0 \200\2233) depends on the magnitu de of the decrease in FEV1. The loss of function was considered to be irreversible (present >3 weeks) and requires exclusion of other condi- tions that can alter allograft function s uch as infection or acute rejection. BOS is variable in its clinical presentation and natur al history. Initial symptoms are often non speci \201 c or absent. As the disease progress es patients develop exertional dys- pnoea, cough, and wheezing and can suffer frequent resp i- ratory tract infections. Acute rejection Acute rejection of the transplanted lung affects up to 40% of patients in t he \201 rst 30 days after transplant and its inci- dence markedly declines after 6 months . Acute rejection presents with non speci \201 c symptoms such as fever, cough, breathless ness and malaise and may be as- sociated with in \201 ltrates or pleural effusions on the CXR. Rejection may be clinically silent, particularly later on and as many as 20% of cases are picked up unexpectedly during surveillance transbronchial biopsy. Bronchoscopy and tran sbronchial biopsy is required for diagnosis. Histologically it is characterized by perivasc ular and interstitial mononuclear cell infiltrates that may extend into the alveolar septae and affect the airway depending on severity. Acute rejection is graded according to an ISH LT formulation from A0 (no evidence of rejec- tion) to A4 (severe acute rejection). Early a cute rejection is treated with pulsed IV methylpred- nisolone followed by an augmented dose of oral corticos- teroids tapered over the course of a month. Most patients respond rapidl y with improvements seen as early as 24 hours after treatment is commenced. Acute rejection occurring after the \201 rst month can be adequately treated with augmented oral cortico steroids The frequency and severity of acute rejection episodes are recognized as predispos ing to BOS, the principal cause of late mortality. Table 17.2.2. BOS Scoring System (Estenne, 2002) BOS 0 FEV1 >90% of baseline and FEF25 \200\22375% >75% of baseline FEV1 81 \200\22390% of baseline and/or FEF25 \200\22375% <75% of baseline BOS 0 p ( \200\230potential \200\231 BOS) FEV1 66 \200\22380% of baseline FEV1 51 \200\22365% of baseline FEV1 <50% of baseline BOS 1 BOS 2 BOS 3 The median time from transplantation to initial diagnosis is 16 \200\22320 months, yet the range is very wide. The disease is progressive with a poor long-term survival rate of 30 \200\22340% at 5 years. Progression of BOS tends to follow one of three patterns: \200 Su dden onset of symptoms with a rapid decline in lung function.