Lung T Ransplantation

Lung t ransplantation 9 Jonathan E Spahr1 and Keith C Meyer 2 1 Children ’ s Hospital of Pittsburgh and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 2 University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Allotransplantation of the human lung was fi rst per- prevent them have extended survival and provided formed in 1963 by Dr James Hardy at the University most recipients with an improved quality of life after of Mississippi. It did not become successful enough lung transplantation. to achieve acceptance as a treatment for end - stage This chapter focuses on the three main aspects of lung disease (ESLD) until the mid - 1980s to the early optimizing the outcome of lung transplantation: fi rst, 1990s when improved surgical techniques, advances patient selection and appropriate timing and criteria in organ preservation, and the development and clini- for lung transplantation is reviewed; the focus then cal implementation of novel immunosuppressive turns to the technical aspects of the procedure; fi nally, drugs allowed long - term survival of lung allograft attention focuses on perioperative and postoperative recipients. Lung transplantation has evolved consid- complications and strategies to prevent or treat such erably over the past two decades and is now a defi ni- complications. tive treatment for ESLDs that do not respond to other therapeutic interventions. As lung transplantation has become accepted as a life - prolonging therapy for Selection of p atients for ESLD and performed at various centers world - wide, l ung t ransplantation many complications have been identifi ed, and methods Indications and c ontraindications for monitoring and treating those complications have arisen. Despite considerable progress in preventing Indications for lung transplantation include the broad and treating complications, only half of recipients categories of obstructive, restrictive, suppurative, and survive more than 5 years after receiving a lung trans- vascular pulmonary diseases. Older adults undergo plant. The risks and benefi ts of lung transplantation transplantation much more frequently for chronic must be carefully weighed for each patient. In addi- obstructive pulmonary disease (COPD) and intersti- tion, the timing of the procedure is of critical impor- tial lung disease (ILD) than children and young adults, tance. Thus, a great deal of attention has been focused who undergo lung transplantation predominantly for on appropriate referral criteria and timing for this suppurative lung diseases, of which cystic fi brosis procedure in order to maximize its benefi t. (CF) is the most common. Improvements in surgical technique and immunosup- The task of determining eligibility for lung trans- pressive regimens combined with a growing aware- plantation should be the responsibility of a multidis- ness of common complications and the measures to ciplinary team that evaluates both the physiologic and psychosocial characteristics of individuals referred for transplantation. This team typically consists of physi- Primer on Transplantation, 3rd edition. cians (medical and surgical), nurses, pharmacists, Edited by Donald Hricik. © 2011 American Society of mental health specialists, and social workers. Patients Transplantation. and families should be informed of the rigors inherent

205 CHAPTER 9 in undergoing lung transplantation. Candidates for (SLT) and 60 years for bilateral lung transplantation lung transplantation must have the ability to deal (BLT). At the other end of the age spectrum, children with these challenges physically, psychologically, and are limited by the size of their thorax and the size of fi nancially. available donor lungs. In 1998, the American Thoracic Society (ATS) and Of particular importance in deciding whether a the European Respiratory Society (ERS) developed a patient with ESLD is a candidate for lung transplanta- consensus statement for the selection of candidates tion is the status of native lung function. As lung for lung transplantation. This statement, updated in transplantation candidates generally wait an average 2006, considers both general and disease - specifi c of 18– 24 months before they can be transplanted, the factors, which include age, expected survival without referring physician is charged with the diffi cult task lung transplantation, and quality of life. In general, of predicting 2 - year mortality for their patients with most transplant centers would agree that the upper ESLD so that the effectiveness of this potentially life - age limit is 65 years for single lung transplantation prolonging procedure can be optimized. Table 9.1

Table 9.1 Indications for disease- speciﬁ c patient referral and transplantation

Recipient indication Referral Transplantation

Obstructive lung • BODE index > 5 (BODE is a composite Patients with a BODE index of 7– 10 or at least one disease score based on BMI, FEV1 , dyspnea of: index, and exercise capacity) • COPD • history of hospitalization for exacerbation • Criteria used before the creation of the associated with acute hypercapnia • Obliterative/ BODE index: ( P CO > 50 mmHg) constrictive 2 bronchiolitis • Post - bronchodilator FEV1 < 25% of • pulmonary hypertension or cor pulmonale (or predicted normal value both) despite supplemental oxygen therapy

• P aCO2 > 7.3 kPa (55 mmHg) • FEV1 < 20% predicted and either D LCO < 20% predicted or homogeneous distribution of • Associated pulmonary arterial emphysema hypertension/cor pulmonale

Pulmonary fi brosis Histologic or radiologic evidence of UIP IPF or fi brotic NSIP: irrespective of VC • IPF D LCO < 39% predicted (IPF) or < 35% (fi brotic Histologic evidence of fi brotic NSIP NSIP) • Fibrotic NSIP Other characteristic with predictive value ≥ 10% decline in FVC during 6- month follow - up • Sarcoidosis (IPF): (IPF, NSIP) • Other ILD • VC < 60 – 70% predicted Decrease in oxyhemoglobin saturation to < 88% during 6MWT • DLCO < 50 – 60% predicted Honeycomb change on HRCT (fi brosis score > 2) • Resting hypoxemia (P aO 2 < 7.3 kPa [55 mmHg]) Sarcoidosis: NYHA class III/IV and any of:

• Hypercapnia (P aCO2 > 6 kPa [45 mmHg]) • resting hypoxemia

• Desaturation during 6- MWT to < 88% • pulmonary hypertension

• Secondary pulmonary arterial hypertension • right atrial pressure > 15 mmHg

• NYHA functional class III/IV for other • LAM or PLCH: severe impairment in lung function ILD (sarcoidosis, LAM, PLCH) and exercise capacity and/or resting hypoxemia

206 LUNG TRANSPLANTATION

Table 9.1 (Continued)

Recipient indication Referral Transplantation

Septic obstructive Post - bronchodilator FEV1 < 30% (especially • Oxygen - dependent respiratory failure lung disease young females) • Hypercapnia • Cystic ﬁ brosis Exacerbation of pulmonary disease requiring • Pulmonary hypertension ICU stay • Non - CF bronchiectasis Increasing frequency of exacerbations requiring intravenous antibiotics

Refractory and/or recurrent pneumothorax

Recurrent hemoptysis not controlled by embolization

Other factors with predictive value for CF:

• hypercapnia (P aCO 2 > 6 kPa [45 mmHg])

• rapidly progressive decline in lung function

• resting hypoxemia (P aO2 < 7.3 kPa [55 mmHg])

Pulmonary vascular • NYHA class III/IV regardless of ongoing • Persistent NYHA class III/IV on maximal medical disease therapy therapy

• Primary • Rapidly progressive disease (e.g. • Low ( < 350 m) or declining 6MWT pulmonary worsening functional capacity despite • Failing therapy with intravenous epoprostenol or hypertension (PPH) escalating doses of vasodilator therapy) equivalent (PPH) • Chronic • Not a surgical candidate if indication is • Cardiac index < 2 L/min per m2 thromboembolic chronic thromboembolic disease disease • Right atrial pressure > 15 mmHg

Heart and lung • NYHA class III/IV despite optimal therapy • Persistent NYHA class III/IV on maximal medical diseasea therapy • Progressive symptoms • Eisenmenger’ s • Low ( < 350 m) or declining 6MWT distance • Other factors to consider: cor pulmonale, syndrome declining cardiac output, presence of • Other cyanosis cardiopulmonary disease

6MWT, 6 - minute walk test; BODE, body mass index, airfl ow obstruction, dyspnea, and exercise capacity index in COPD; CF, cystic fi brosis; COPD, chronic obstructive pulmonary disease; D LCO, diffusion capacity of the lung for carbon monoxide; FVC, forced vital capacity; FEV1 , forced expiratory volume in 1 s; HRCT, high- resolution computed tomogra- phy of the thorax; ILD, interstitial lung disease; IPF, idiopathic pulmonary fi brosis; LAM, lymphangioleiomyomatosis; NSIP, non - specifi c interstitial pneumonia; NYHA, New York Heart Association; PLCH, pulmonary Langerhans’ cell histiocytosis; PPH, primary pulmonary hypertension; VC, vital capacity; UIP, usual interstitial pneumonia. a Heart – lung transplant usually required. See Orens, et al. J Heart Lung Transplant 2006; 25 :745 – 55.

207 CHAPTER 9 summarizes referral criteria and ideal timing of trans- Non - curable chronic extrapulmonary infection plantation according to specifi c indications for the Signifi cant chest wall and/or spinal deformity procedure. For each indication, guidelines for listing Documented non- adherence or inability to follow are discussed separately below. through with medical therapy and monitoring As the primary goal of lung transplantation is to Untreatable psychiatric or psychologic condition that prolong life rather than to permanently cure an ESLD, will impair compliance with medical therapy consideration of how the patient will benefi t from No reliable social support system lung transplantation must be made. There is ongoing Substance addiction within past 6 months • Relative contraindications debate about the survival benefi t of lung transplanta- Critical or unstable condition tion based on the underlying disease. For the most Severely limited functional status with poor part, individuals with CF, ILD, and pulmonary hyper- rehabilitation potential tension appear to derive a survival benefi t from lung Colonization with highly resistant or highly virulent transplantation. However, studies evaluating survival microorganisms > 2 benefi t for patients with COPD have yielded mixed Severe obesity (BMI 30 kg/m ) Severe or symptomatic osteoporosis results. For many patients with an otherwise untreat- Mechanical ventilation able form of ESLD, lung transplantation can provide Suboptimally treated serious medical condition palliation of symptoms and improved quality of life even when long - term survival is not extended. For a See Orens et al. J Heart Lung Transplant 2006; 25 :745 – 55. example, in patients with Eisenmenger ’ s syndrome, a b In general, a 5- year disease- free interval is prudent. clear survival benefi t of lung transplantation has not been identifi ed. However, most patients with this disorder experience improvement in exercise tolerance and are able to improve their daily function after lung transplantation. The absolute and relative contraindications to lung transplantation vary from center to center (see Key The need for mechanical ventilation at the time of points 9.1 ). In general, absolute contraindications transplantation is an absolute contraindication for include severe extrapulmonary disease, use of tobacco some centers but a relative contraindication at others, or alcohol, impaired functional status, and refractory depending on the underlying ESLD. Adults with CF psychosocial problems. Examples of severe extrapul- should not be excluded from undergoing lung trans- monary disease that would preclude lung transplanta- plantation if they are mechanically ventilated, because tion are infection with human immunodefi ciency mortality rates are not infl uenced by the need for virus (HIV), active tuberculosis, hepatitis B, signifi - ventilation at the time of transplantation. In contrast, cant left ventricular dysfunction, active malignancy the need for mechanical ventilation in children with within 5 years, renal insuffi ciency, hepatic dysfunc- CF is associated with poor short- and long- term out- tion, portal hypertension, diabetes mellitus with end - comes. Many individuals require supplemental organ damage, and osteoporosis with vertebral oxygen and even non - invasive ventilation in the form compression fractures. of bi - level positive airway pressure (BiPAP) as a “ bridge ” to transplantation. Currently available data suggest that posttransplant outcomes are improved for recipients with CF who use BiPAP before lung Key points 9.1 Absolute and relative transplantation. contraindications to lung There are some factors that may make lung trans- transplantationa plantation more challenging and place the patient at • Absolute contraindications considerable risk for suboptimal outcome. Patients Malignancy within 2 years, with the exception of who have had previous chest surgery or pleurodesis b cutaneous squamous and basal cell tumors (chemical or surgical) may have signifi cant pleural Untreatable, advanced dysfunction of another major fi brosis and adhesion of the visceral and parietal organ system pleura. This makes explantation of the native lungs

208 LUNG TRANSPLANTATION extremely diffi cult and prone to hemorrhagic compli- perioperative and postoperative periods and that may cations. Nevertheless, prior surgery or pleurodesis is signifi cantly decrease the likelihood of long - term sur- not considered an absolute contraindication to future vival. Table 9.2 lists both medical and psychosocial lung transplantation. Oral corticosteroids are known evaluations that are helpful in assessing risk in a lung to impair wound healing, and many centers consider transplantation candidate. This list, although exten- a daily dose of prednisone > 20 mg to be a contrain- sive, is not absolute and may not cover all situations. dication, although this is not universal. Subsequent sections will address specifi c disease states and/or comorbidities that may require additional evaluation. Pretransplant e valuation

As there are contraindications to lung transplanta- COPD and α 1 - a ntitrypsin d eﬁ ciency - a ssociated tion, a comprehensive pretransplant evaluation is e mphysema required to identify potential comorbidities that COPD, including the obstructive disease resulting present potentially insurmountable problems in the from α 1 - antitrypsin deﬁ ciency, is the most common

Table 9.2 Evaluation of potential candidates for lung transplantation • Psychosocial evaluation • ? Tobacco use within 6 months • ? Illicit drug use, drug- seeking behavior • Compliance with medical therapies • ? Signifi cant psychiatric illness • Adequate social support • Cardiopulmonary • Full pulmonary function tests • Standardized exercise test (e.g., 6- minute walk test) • Electrocardiogram • Stress echocardiogram (plus coronary catheterization as appropriate) • High - resolution CT scan of thorax • Lipid profi le • Other • Peripheral blood cell survey • Glucose and hemoglobin A1C • 24 - hour creatinine clearance • Bone mineral density scan • Infection specifi c • Quarterly respiratory tract cultures (for suppurative lung disease) • Gram - negative bacilli • Meticillin - resistant Staphylococcus aureus • Mycobacteria • Fungi • Serology • HIV • Hepatitis B and C • Varicella • Cytomegalovirus • Toxoplasmosis • Vaccinations • PPD skin test • Evaluation and treatment of paranasal sinus disease

209 CHAPTER 9 indication for lung transplantation in adults. As the desaturation to 88% or less predicts a survival rate surgical risks are lower for SLT versus BLT in patients of approximately 35% at 4 years. with COPD, SLT is commonly performed for this The progression of other ILDs is quite variable. In lung transplantation indication, which helps to the case of non- specifi c interstitial lung disease (NSIP) expand the donor pool when a single donor can be and sarcoidosis, progression tends to be less rapid used for two recipients. Although there may be an (compared with IPF) and more likely to respond advantage to BLT with regard to outcome and lung to immunomodulatory medications. However, the function, exercise capacity is comparable for SLT fi brotic variant of NSIP, if accompanied by oxyhemo- versus BLT recipients with COPD. globin desaturation to ≤ 88% during a 6MWT, carries Certain criteria must be met to list candidates with a prognosis that is fairly similar to that for IPF. COPD for lung transplantation, and these include a Therefore, recommendations to refer patients with demonstrated ability to abstain from smoking. Most NSIP are based on the aggressiveness of the disease transplant centers require abstinence from cigarette and whether it is characterized by a cellular and/or smoking anywhere from 6 months to 12 months. fi brotic histopathology. Likewise, sarcoidosis may Physiologic parameter thresholds for lung transplan- progress to extensive pulmonary fi brosis, and wait - tation in COPD have included forced expiratory listed patients with severe impairment of lung func- volume at 1 s (FEV 1 ) < 25% predicted without revers- tion have a projected survival that is very similar to ibility and/or P aCO2 ≥ 7.3 kPa (55 mmHg) with or that for wait- listed patients with IPF. without elevated pulmonary artery pressures and pro- In the case of ILD, SLT is more commonly per- gressive deterioration. The most recent recommenda- formed than BLT. However, BLT should be consid- tions from the International Society for Heart and ered if there is signifi cant bronchiectasis in the native Lung Transplantation (ISHLT), however, advocate lungs that would predispose the lungs to a chronic use of the BODE index (body mass index, airfl ow suppurative process. obstruction, dyspnea, and exercise capacity index in COPD) for decision - making (see Table 9.1 ) The Bronchiectasis/Cystic fi brosis American Thoracic Society and European Respiratory BLT is the recommended procedure for severe sup- Society (ATS/ERS) have also made the recommenda- purative lung disease due to bronchiectasis (some- tion that priority for lung transplantation be given to times the result of advanced CF), which is typically patients who require oxygen supplementation and widespread throughout both lungs. Conventional who exhibit progressive deterioration and elevated wisdom dictates that, if only one lung is transplanted,

P aCO2 because mortality is increased for such residual infection in the native lung can spread to the patients. transplanted lung and cause unacceptable complications in the immunocompromised recipient. The sup- Interstitial l ung d isease purative and fl uctuating nature of CF lung disease Idiopathic pulmonary fi brosis (IPF) is the most presents a signifi cant and often vexing challenge to common form of ILD for which lung transplantation physicians in determining the appropriate and optimal is performed. Indications for referral include sympto- time for referral as well as preparing the patient for matic and progressive disease recalcitrant to therapy, referral to a lung transplantation center. signifi cantly impaired lung function with decrease in The presence of multidrug- resistant Pseudomonas forced vital capacity (FVC) to < 60 – 70% of the pre- aeruginosa is not a contraindication for transplanta- dicted normal value and/or diffusion capacity for tion, but persistent carriage of pan - resistant P. aeru- carbon monoxide ( D LCO) < 50 – 60% predicted. As ginosa is considered to be a contraindication at some the median survival after diagnosis of IPF is approxi- centers. However, several studies have shown no dif- mately 2– 3 years, current ISHLT guidelines recom- ference in post - lung transplantation survival for mend referral to a lung transplantation center at the patients infected with pan - resistant P. aeruginosa and time of diagnosis due to the progressive nature of the those with antibiotic - sensitive strains. Additionally in disease. Hemoglobin oxygen desaturation during a vitro sensitivities of P. aeruginosa may not accurately 6 - minute walk test (6MWT) may be helpful in deter- refl ect in vivo sensitivity and should be interpreted mining the degree of lung function decline. Specifi cally, with caution because some individuals have been

210 LUNG TRANSPLANTATION

shown to improve clinically despite the use of criteria or complex scoring systems that utilize mul- anti - pseudomonal antibiotics that would not be tiple parameters have not shown signiﬁ cantly better considered effective according to in vitro susceptibil- predictive value. Determining the optimal time for ity testing. In some cases, the use of aerosolized col- referral and transplantation for children is particu-

istin has been reported to cause a re - emergence of larly diffi cult. Although FEV 1 , P aO 2 , and P aCO 2 con- sensitive P. aeruginosa in CF patients awaiting lung tinue to be important factors in deciding when to transplantation. refer the child with CF for lung transplantation, most Chronic infection with Burkholderia cepacia in centers continue to evaluate on a case - by - case basis. patients with CF is viewed by some centers to be a Pneumothorax and hemoptysis are associated with a contraindication to lung transplantation. One retro- signifi cant increase in 2 - year mortality, even when spective study of patients with cystic fi brosis showed FEV 1 is not severely impaired, and their occurrence that 6- month mortality was signifi cantly increased may indicate a need to consider early referral. In addi- only in cases where genomovar III strains of B. tion, a rapid and sustained decline in lung function, cepacia caused the chronic infection. These data especially when occurring in young females, may indi- suggest that determining the specifi c B. cepacia cate a need to refer for lung transplantation. Lastly, genomovar may be useful in weighing the risk of lung frequent, recurrent exacerbations that require hospi- transplantation for patients who harbor B. cepacia in talizations and/or antibiotic treatment also may their respiratory secretions before transplantation. herald a rapid decline in lung function and impending Aspergillus fumigatus is commonly isolated from need for lung transplantation referral. respiratory secretions of patients with CF. Surprisingly, this fungus is rarely a serious pathogen in the post - Pulmonary h ypertension transplant patient with CF. When aspergillosis occurs Patients with primary pulmonary hypertension who in lung transplant recipients with CF, it is usually in meet criteria for New York Heart Association the form of tracheobronchial aspergillosis in the allo- (NHYA) class III or IV, and who have progressive graft bronchi adjacent to the anastomoses (the injured disease despite medical therapy, meet the criteria epithelium at the anastomosis is susceptible to asper- for lung transplantation. Right heart catheteriza- gillus infection as it heals after reperfusion). tion measurements that show mean pulmonary artery Severe malnutrition with very low body mass index pressure > 55 mmHg, mean right atrial pressure (BMI), which frequently occurs in patients with CF > 15 mmHg, and cardiac index < 2.0 L/min per m 2 and ESLD, may place the patient in a risk category support the decision to refer for lung transplantation. that is too high to safely perform lung transplanta- An important decision when evaluating patients with tion. Supplemental nutrition via enterostomy tube pulmonary hypertension for lung transplantation is may be required before transplantation to improve a whether SLT or BLT should be performed. Although low BMI. Another consideration in patients with CF a well - functioning single lung should have adequate is the presence of signifi cant hepatobiliary disease. As capacitance to prevent right heart strain or failure, survival into adulthood progressively increases, published data do not provide clear guidelines, and advanced liver disease is becoming more prevalent the decision to perform SLT versus BLT should be and may pose a problem after otherwise successful made on a case - by - case basis. Heart and lung trans- lung transplantation. Although combined lung and plantation is necessary when left ventricular function liver transplantation can be considered, relatively few is irreversibly compromised. centers are willing to perform a combined lung – liver Patients with Eisenmenger’ s complex may tolerate transplantation during the same operation. mean pulmonary artery pressures > 55 mmHg and The timing of referral for patients with advanced mean right atrial pressures > 15 mmHg, making their CF lung disease presents a signifi cant challenge to risk of mortality and clinical course more diffi cult referring physicians. The recommended physiologic to predict. For these patients, heart– lung transplanta- parameters that predict respiratory failure within 2 tion appears to confer a better outcome in regard to years and, thus, the basis for referral include post - mortality.

bronchodilator FEV1 < 30% predicted, P aO2 < 7.3 kPa With the advent of new medications (e.g., bosen-

(55 mmHg), and P aCO2 > 6 kPa (45 mmHg). Other tan, prostaglandin infusion, and sildenaﬁ l) to treat

211 CHAPTER 9 pulmonary hypertension, patients are able to live Table 9.3 Lung allocation scoring (LAS ) system in the longer without the need for lung transplantation. In USA contrast to other indications for lung transplantation, the need for donor lungs for this indication has LAS score determinants decreased with the advent of medical therapies that • Specifi c disease indication for lung transplant successfully lower pulmonary arterial pressures and • Forced vital capacity (percent predicted) improve cardiac output. • Pulmonary arterial systolic pressure UNOS a llocation (o ld and n ew s ystems) • Supplemental oxygen requirement (L/min) The United Network for Organ Sharing (UNOS) • Age recently made a signifi cant change to the allocation • Height and weight system for lung donation in the USA, and imple- mented the new system in 2005. Before this change, • Functional status (I, II, III) recipient rank on the lung transplantation wait - list • 6MWT distance was based on waiting time, blood group compatibil- • Ventilator use ity, and size matching. In contrast to policies for heart and liver transplantation, severity of disease was not • Pulmonary capillary wedge pressure a factor in the old system, with the exception of • Serum creatinine patients with IPF, who were automatically credited 90 days of accrued wait - list time due to the relatively • P CO2 severe and progressive nature of their disease. Calculation of the LAS score The new UNOS allocation system does take into account severity of disease and assigns each potential • Waiting list survival probability during next year is recipient a lung allocation score based on medical calculated information. The medical parameters taken into • Calculate wait- list urgency account by the new lung allocation system (LAS) are • Calculate posttransplant survival probability during listed in Table 9.3 . Specifi c types of ESLD are priori- fi rst post - transplantation year tized according to the inherent degree of severity and expected progression of the disease. However, the • Calculate posttransplant survival measure LAS scoring system applies only to individuals aged • Calculate raw allocation score > 12 years. For those aged < 12 years, waiting time is still the most signifi cant factor in determining lung • Raw allocation score is then normalized (0– 100; organ allocation priority. offers go to candidate with highest score within specifi c Once the potential recipient is determined to be a blood group and thoracic dimension category) candidate for lung transplantation, they are registered into the UNet secure internet - based system for organ allocation and data collection, and the data are used to compile a score ranging from 0 to100, with higher scores corresponding to higher priority. This score, plantation center physicians believe that certain along with the ABO blood group compatibility, size patients have exceptional circumstances and their matching, and the patient ’ s distance from the hospi- LAS does not accurately refl ect the patient ’ s situation tal, will determine the order of patient eligibility when and urgency for transplantation, they may petition an offer for a donor lung is received by the lung the Lung Review Board to determine if an adjustment transplantation center where the patient is listed. In can be made. the case of a tie score, time spent on the list is used In the case of pediatric lung allocation, lung size to break the tie. Information must be updated every needs to be taken into account and recipient priority 6 months, but data may be updated at any time to is based on donor age. Those under the age of 12 refl ect changes in the patient’ s status. If lung trans- continue to have their recipient priority determined

212 LUNG TRANSPLANTATION by the time spent on the waiting list. Key points 9.2 transplantation wait - lists. One concern is that this also reﬂ ects how children receive priority over adult shift will tend to select patients who will have a patients for donor lungs. decreased posttransplant survival due to the severity of their illness at the time of transplantation.

Key points 9.2 Pediatric transplantation: Technical c onsiderations matching and prioritization The d onor < + • Donor age 12 12 – 17 18 Careful selection of an organ donor and optimized (years) donor management are crucial determinants of post - < ≥ • First priority Age 12 Age 12 – 17 Age 12 lung transplant outcome. Unfortunately, the rate of recipient donor procurement for lungs remains < 20% (17% in • Second priority Age 12 – 17 Age < 12 Age < 12 the USA and 12% in Europe) and represents the recipient major limiting factor for the number of lung trans- • Third priority Age 18+ Age 18+ plantations performed. Potential donors vary consid- recipient erably in terms of clinical stability and organ function, and signifi cant decline in pulmonary function all too frequently occurs during the critical management period when donors are managed in an intensive care setting. The lungs are particularly prone to injury, Policies for listing and delisting in other countries and maintaining optimal lung function in a potential do not use a LAS scoring system as is done in the donor requires tactics that are counterproductive to USA. The Eurotransplant organization, a suprana- maintaining optimal function of other organs (e.g., tional consortium of numerous European countries, providing high perfusion pressures to maintain ade- still uses time on the wait - list combined with donor– quate intravascular volume for procurement of opti- recipient suitability to match recipients with donor mally functioning kidneys). High central venous organs. However, patients who display imminent pressures may cause the lungs to develop hydrostatic need for invasive mechanical ventilation or other evi- edema, loss of compliance, and impaired gas exchange. dence of rapid decompensation can be granted a high The period of time from the inciting illness, such as urgency status and be given the highest transplant a traumatic brain injury, to the point when brain priority. death is declared poses signifi cant risk for pulmonary Before the change in the US allocation system, time complications that include aspiration, barotrauma, spent on the waiting list ranged from a median of 18 ventilator - associated pneumonia, diffuse lung injury, months to 24 months and the number of wait - listed and non - cardiogenic pulmonary edema. lung transplant candidates continued to rise as the Brain death adversely affects cardiovascular func- donor pool remained static. The goal of the new tion, and donor management includes measures to system is to decrease the number of patients dying achieve optimal hemodynamics by maintaining nor- while awaiting lung transplantation by allocating movolemia, blood pressure, and cardiac output to lungs to those individuals most in need. The new LAS sustain adequate perfusion pressure and blood fl ow, system takes into account the anticipated benefi t and thereby preserve organ function while trying to linked to the underlying cause of ESLD, as well as the limit vasoactive drug requirements. Supportive inter- anticipated mortality without a transplant. However, ventions required to stabilize and maintain optimal the ability to predict mortality from ESLD continues organ function in the donor may include infusion of to be limited due to marked variability across differ- fl uids and red blood cells for hypovolemia and ent patient cohorts and disease processes. Early results anemia, sodium bicarbonate for acidosis, hypotonic indicate that the new allocation system has shifted solutions for hypernatremia, insulin infusions for recipient diagnoses toward pulmonary fi brosis while hyperglycemia, and vasoactive drug support for reducing the overall mortality rate for those on lung hypotension, (see Chapter 3 ).

213 CHAPTER 9

Traditional (“ standard ” ) criteria that were initially adherence to these ideal criteria would exclude most used to deﬁ ne ideal donors included donor age < 55 potential donors, and adequate objective evidence to years, minimal tobacco exposure, normal chest radio- support their value has not been forthcoming. graph, P aO 2 : F iO2 ratio > 300 during ventilation with Therefore, most centers have judiciously relaxed these

5 cmH 2 O of positive end - expiratory pressure (PEEP) requirements to expand the donor pool. Atelectasis and F iO 2 100%, and the absence of aspiration, puru- and excessive ﬂ uid resuscitation are correctable causes lent secretions, or trauma (Table 9.4 ). However, of hypoxemia, and aggressive management protocols that include ventilator manipulation to promote lung expansion, early bronchoscopy and aggressive secre- Table 9. 4 Criteria for acceptability of donor lungs tion clearance, antibiotic administration, and judicious ﬂ uid management have allowed donors who Traditional criteria were initially considered unsuitable by traditional cri- • Age < 50 years teria to become lung donors. Indeed, most centers have relaxed a number of the • Minimal tobacco exposure “ standard” criteria (e.g., age up to 65 years, smoking

• Normal chest radiograph history > 20 years, P aO2 / F iO2 < 300), and the acceptance of extended donor criteria coupled with improve- • P aO > 39.9 kPa (300 mmHg) on 5 cmH O PEEP with 2 2 ments in donor management has contributed to an F iO2 = 100% increase in lung transplantation procedures over the • No evidence of aspiration past decade. Outcomes using allografts with extended Liberalized criteria (marginal/extended donor) donor criteria have not been shown to be signifi cantly different from outcomes when lungs were used from • Age up to 65 candidates who met ideal donor criteria. For certain • Smoking up to 20 pack - years disease states, however, use of lungs with extended donor criteria may lead to poor outcome. SLT for • Severe chest trauma pulmonary hypertension and IPF with secondary • Mechanical ventilation > 4 days hypertension presents situations in which the native lung would be unable to support a marginal donor • Positive Gram stain on tracheobronchial washing and/or lung. In addition, donor conditions that exclude use of BAL a donor lung include uncontrolled sepsis, positive HIV Interventions to improve donor lung function status, viral hepatitis or encephalitis, active tuberculo- • Frequent suctioning to remove secretions sis, Guillain – Barr é syndrome, illicit drug use, malignancy, and signifi cant chronic lung disease. Regardless • Ventilatory manipulation to promote lung expansion of HIV antibody testing, potential donors with signifi - and reverse atelectasis (e.g. alveolar recruitment with cant risk factors for HIV infection should be excluded inspiratory pressures at 25 cmH 2 O and PEEP 15 cmH 2 0 from donation unless the risk to the recipient of not for 2 h) performing the transplantation is perceived to be • Reverse fl uid overload (diuresis and fl uid restriction) greater than the risk of transmitting HIV infection and disease to the recipient. These risk factors include men Absolute criteria required when donor lungs with extended who have had sex with another man within 5 years, criteria utilized use of non- medical drugs via injection within the pre- > • P aO 2 / F iO2 300 ceding 5 years, engaging in sex for money or drugs • No persistent radiographic infi ltrates within 5 years, inmates of a correctional institution, and people having contact with an HIV - infected indi- • No copious purulent secretions vidual within 12 months (sexual, shared needles, open • No bronchoscopic evidence of aspiration wound contact, or mucous membrane contact). In addition to the use of lungs with extended donor BAL, bronchoalveolar lavage; PEEP, positive end- criteria, some centers have expanded the donor pool expiratory pressure. further by considering potential donors who do not

214 LUNG TRANSPLANTATION meet criteria for brain death but have catastrophic, donor lungs has been cut off, minimization of ischemic irreversible illness. Viable lungs can be procured and time is of key importance in preventing graft injury. utilized after life support has been withdrawn and Older donor age and prolonged ischemic time have cardiac arrest has occurred in this setting, and the use been shown to correlate with decreased 1 - year sur- of lungs from donation after cardiac death (DCD) vival, and early graft function is signifi cantly affected donors represents one strategy to increase the donor by prolonged ischemic times with a threshold esti- pool. Another technique that can increase the donor mated at 330 min, although ischemic time may be pool in lung transplantation is the living lobar lung extended to 8 h for young donors. transplantation. Introduced in 1993, living lobar lung Optimal ex vivo preservation of the donor lung and transplantation uses two donors who each provide minimization of ischemic time are critical to postim- one lobe (usually the lower lobe) to supply the recipi- plantation allograft function. Poor initial graft func- ent with adequate lung tissue for the transplant. The tion can have considerable adverse effects upon most common use of this technique is for patients postimplantation recovery and prolong the need for with CF (usually children) with two parents serving invasive mechanical ventilation, thereby predisposing as donors. A recent report of a 10- year experience recipients to nosocomial infections and other compli- with living lobar donation indicated that survival was cations of prolonged intensive care unit (ICU) stays. similar to that of recipients transplanted with deceased Furthermore, poor initial graft function may increase donor grafts, except in cases of re - transplantation or the risk of developing subsequent allograft rejection. when the recipient was intubated and mechanically The ideal preservation solution should prevent intra- ventilated. cellular acidosis, calcium accumulation, and edema while suppressing the generation of oxyradicals and promoting the regeneration of intracellular energy The g raft metabolism. Although intracellular preservation solu- Careful explantation of the lungs, which is done tions (e.g., Euro - Collins, University of Wisconsin together with explantation of the heart, is crucial to [UW] Solution) have been used by many centers, achieving optimal post - transplant physiologic func- experimental and clinical evidence now support the tion. Careful attention to all aspects of excising the use of extracellular solutions, in particular the low - lung from the donor and preserving it ex vivo are potassium dextran – glucose agent, Perfadex, as an crucial for preventing primary graft dysfunction optimal preservation fl uid. Antegrade fl ush of the (PGD), which accounts for a substantial number of lungs is typically performed in concert with infl ation all deaths in lung transplant recipients. of the lungs with an adequate tidal volume (10 mL/ Just before cross- clamping the major vessels to free kg) and maintenance of airway pressures in the range

the lungs from the donor, the explant is typically of 20– 25 cmH 2 O before cross- clamping. Equilibration ﬂ ushed with epoprostadil followed by ﬂ ushing with airway pressures should, however, be limited to 10 –

cold preservation fl uid, and the explanted lungs are 15 cmH 2 O to avoid barotrauma during storage and maintained at 4 – 10 ° C (on ice) until reimplantation is air transport, and fl ushing pressures should be limited performed. Retrograde fl ushing (pulmonary vein to to 10 – 15 mmHg. pulmonary artery) with preservation fl uid can be Other therapies may be administered to optimize done before implantation to try to free any clots that the donor lung. Prostaglandins, which counteract have embolized to the lung before explantation. ischemia - induced vasoconstriction, and corticoster- When retrograde fl ush is performed through the pul- oids, which prevent intense infl ammatory responses, monary veins in situ while the lungs are still ventilated are used to prevent reperfusion injury. Newer inter- (following antegrade fl ush), lung preservation may be ventions that seek to prevent or mitigate primary graft enhanced with better distribution of fl ush solution dysfunction (PGD) include the use of inhaled nitric throughout the vasculature and less impairment of oxide (NO), surfactant replacement, continuous infu-

surfactant function. Retrograde ﬂ ush may also be sion of prostaglandin E 1 into the recipient during performed in vivo when the lung has been partially early stages of reperfusion, preimplantation donor implanted (before construction of vascular anastomo- leukocyte depletion, administration of oxyradical ses) in the recipient. Once in situ perfusion of the scavengers, donor leukocyte infusion, and administer-

215 CHAPTER 9 ing other anti - infl ammatory therapies (inhibition of perfect vascular and bronchial anastomoses is platelet - activating factor, chemokine receptor inhibi- extremely important in maximizing the likelihood of tion, complement antagonists). Although promising, postoperative success. Inhaled NO and cardiac bypass these latter interventions have yet to be adopted in should be available for every procedure. Intraoperative clinical lung transplantation protocols that attempt to cardiopulmonary bypass (CPB) or extracorporeal improve early graft function and prevent PGD. membrane oxygenation (ECMO) may be needed to support the recipient during surgery and should be used as needed to support recipient gas exchange The m atch during the procedure. CPB, when performed intraop- Donor – recipient matching is primarily based on eratively in higher - risk patients, allows controlled donor lung size, which must approximate the pre- initial reperfusion of the graft(s) while using lower dicted lung size of the recipient, and ABO blood inspired oxygen tensions, thus helping to limit reper- group match. With the exception of living donor lung fusion injury. In addition to surgical expertise, expe- transplantation, HLA matching is not feasible. rienced anesthesiologists play a key role in surgical Matching for cytomegalovirus (CMV) status is desir- management. Decisions about the use of double - able but not mandatory with currently used antiviral lumen intubation techniques, ventilation strategies, prophylaxis. the need for cardiac bypass, the role of vasoactive Size matching is done by measuring dimensions on medications such as NO, and hemodynamic support, a standard chest radiograph or computed tomogra- must be addressed jointly by surgeons and anesthesi- phy (CT) of the thorax. Total lung capacity (TLC) of ologists during removal of native lungs and implanta- recipients with pulmonary fi brosis usually approxi- tion of donor organs. mates that of the donor lung post - transplantation when SLT is performed. However, the donor lung Single l ung t ransplantation may be restricted and TLC may be lower than SLT can be performed for all recipient indications expected due to increased compliance of the residual with the exception of suppurative lung diseases (CF native lung when SLT is performed for COPD. TLC and non - CF bronchiectasis). In the case of IPF and should approximate the recipient ’ s predicted value pulmonary hypertension, the graft should have after BLT. For children, size matching varies from optimal appearance and function because the native institution to institution and even within institutions. lung will have little to contribute to respiratory func- Matching recipient and donor within 10 cm or 10% tion. Also, although some centers fi nd SLT acceptable of the body length are two examples of estimations for patients with pulmonary hypertension, there may used for size matching in children. If there is a mis- be specifi c circumstances for which a BLT would be match in the sizing where the donor lung is too large more advantageous. In cases of pulmonary hyperten- for the recipient thoracic cage, the donor lung can be sion with left ventricular dysfunction, heart – lung down - sized via plication or lobectomy. transplantation is indicated. Ventilation – perfusion (V / Q ) scanning in the poten- Case tial recipient plays an important role in determining A suitable donor was identifi ed for a 56 - year - old man which lung should be transplanted. It can demon- with idiopathic pulmonary fi brosis. However, CT of the strate areas of poor ventilation and perfusion and can thorax revealed that the donor lung was 12 cm longer estimate the relative contribution of each lung to res- than the lung of the recipient. Lobectomy was performed piratory function. The native lung with poorest func- to achieve adequate size matching and single lung trans- tion should be chosen for replacement. plantation was performed successfully. Surgical pneumonectomy is typically performed through a posterolateral incision for SLT recipients. However, posterolateral thoracotomy for the left lung The i mplantation p rocedure and anterolateral thoracotomy for the right lung will optimally expose the hilar structures. The procedure A well- coordinated effort that minimizes ischemia can be performed without the need for CPB if the non - time and allows the surgical team to create technically transplanted native lung has residual function that is

216 LUNG TRANSPLANTATION adequate to support the individual during the proce- performed for pulmonary hypertension. Hypoxemia dure. The non - transplanted lung is selectively venti- or hemodynamic instability may occur during cross - lated as the contralateral lung is defl ated and removed. clamping of the fi rst pulmonary artery, after per- If signifi cant hypoxemia occurs due to shunting fusion of the fi rst transplanted lung, or after clamping through the defl ated lung, the pulmonary artery is of the second pulmonary artery. clamped to promote better V / Q matching. If refractory hypoxemia or other manifestations of inadequate Living l obar t ransplantation residual lung function occur, CPB should be used. As previously stated, the living lobar lung transplan- Once the recipient native lung has been explanted, tation represents a technique established to expedite the donor lung is positioned and anastomoses are transplantation and relieve some of the stress on the made between donor and recipient bronchus, donor UNOS donor pool. The donors must be larger than and recipient pulmonary artery, and donor pulmo- the recipient to allow adequate matching of the donor nary veins to recipient left atrium. Precautions must lobe to the dimensions of the recipient thoracic cage. be taken not to disrupt the phrenic and vagus nerves Inadequate donor graft size may result in pleural com- and, in the case of left SLT, the recurrent laryngeal plications and the development of bullae. Blood nerve. Bronchial anastomoses are often performed by group matching must be performed, but donor – telescoping the donor and recipient bronchi because recipient HLA mismatches appear to have no signifi - end - to - end anastomoses tend to require a tissue patch cant infl uence on survival. The operation is performed and are more prone to healing complications. As the similarly to SLT or sequential BLT. Donor morbidity bronchial circulation provides blood fl ow to the generally consists of a prolonged need for thoracot- airways, anastomosis of the donor and recipient omy tubes or a need for additional thoracotomy bronchial arteries may theoretically prevent airway tubes, and donor mortality is quite low. Recipient mucosal ischemia and anastomotic complications. survival has been reported to be comparable to cadav- However, outcomes when the bronchial arteries are eric lung transplant survival at 1, 3 and 5 years anastomosed are not signifi cantly different from out- post - transplantation. comes without bronchial artery anastomosis, and perfusion of the bronchi via retrograde fl ow through the bronchial artery from the pulmonary circulation The p ostoperative p eriod appears to be adequate to promote healing and to The p erioperative p eriod maintain viability of the bronchial mucosa. Initial postoperative management is directed by the Bilateral l ung t ransplantation hemodynamic status of the patient and initiation of Originally performed as an en bloc procedure (double appropriate immunosuppressive and prophylactic lung transplantation) whereby both lungs were trans- therapies. Upon completion of the surgical procedure, planted at once via a single airway anastomosis at the intensive supportive care should start, including trachea, BLT is now most often performed by bilat- hemodynamic monitoring, close attention to allograft eral sequential transplantation of the lungs via an function, use of vasoactive medications as needed to anterior clam - shell incision. The advantage to sequen- maintain appropriate perfusion, assessment of renal tial transplantation is that the patient may not need function, appropriate prophylaxis for peptic ulcer to undergo CPB, and the bilateral bronchial anasto- disease and deep vein thrombosis, and strict glucose moses are more stable than a single tracheal anasto- control and nutritional supplementation. Hemody- mosis. In addition, the transverse thoracosternotomy namic support during the early postoperative period incision used in the sequential technique allows for should focus on avoiding pulmonary edema while better exposure of the pleura when compared with maintaining adequate perfusion pressure. Pulmonary the median sternotomy incision used in the en bloc capillary occlusion pressure should be kept as low as double lung transplant procedure. The contralateral possible while maintaining adequate urine output and lung is selectively ventilated during the transplanta- systemic blood pressure. Vasoactive agents, fl uid tion, and CPB can be utilized in the event of refrac- restriction, and diuretics should be used as needed to tory hypoxemia or when transplantation is being achieve this goal.

217 CHAPTER 9

The goals of mechanical ventilation include avoid- Pulmonary edema is almost always present in the ing any additional damage to the reperfused allograft immediate postoperative period. Although usually and using low tidal volume ventilation strategies as mild, severe pulmonary edema may occur as a conse- needed to avoid barotrauma. Inspired oxygen should quence of multiple complications that include fl uid be weaned as rapidly as possible to avoid tissue injury overload, reperfusion injury, massive transfusions, due to hyperoxia. The ultimate goal is to liberate the and acute renal failure. Disruption of lymphatic patient from mechanical ventilation as soon as possi- vessels or vascular anastomoses also may cause pul- ble and thereby avoid complications related to pro- monary edema. longed ventilatory support. In the case of SLT for Reperfusion lung injury (Figure 9.1 ) caused by COPD, PEEP and high airway pressures should be damage of endothelial – alveolar interfaces is a major minimized to avoid overdistension of the native lung. contributor to early respiratory failure and mortality In extenuating circumstances such as severe early graft in patients receiving lung transplantation and is now failure, individual lung ventilation may be needed to termed PGD and graded on the basis of severity of provide appropriate airway pressures for each lung gas exchange impairment (see Key points 9.3 ). PGD and avoid ventilator - induced lung injury. Most recipi- occurs in 13– 25% of lung transplant recipients and ents are weaned from mechanical ventilation within typically has an overwhelmingly negative effect on 48 – 72 h. In the case of lung transplantation for pul- recovery, causing prolonged hospitalization and monary hypertension, the patients may need to be increased mortality. One group has suggested that an sedated for a slightly longer period of time to prevent even higher incidence of primary graft failure (50%) the occurrence of hemodynamic compromise due to can be detected using criteria of radiographic infi l- the relative instability of the pulmonary vascular bed trate in the fi rst 3 days after transplantation with combined with a heart that has been chronically con- P aO2 : F iO2 ratios < 300. A higher incidence of ICU ditioned to high pulmonary artery pressures. mortality occurs in those with PGD versus those Protocols should be in place to begin immunosup- without (29% vs 10.9%, respectively). Four variables pressive therapies and prophylactic antimicrobial predict higher mortality in the setting of PGD: age, agents to prevent rejection and post - lung transplant degree of impaired gas exchange, graft ischemia time, infectious complications. Immunosuppressive regi- and severe early hemodynamic failure. mens are discussed below. Monitoring for hyperacute rejection (a rare occurrence) and acute rejection (AR) is extremely important and is discussed below. Key points 9.3 Classifi cation of primary Complications in the p erioperative p eriod graft dysfunction Perioperative lung transplantation complications include, but are not limited to, pulmonary edema, PGD grade Infi ltrates on chest P aO 2 / F iO 2 ratio immediate graft failure, acute bacterial infection, radiography bleeding, diaphragmatic paresis or paralysis, anasto- ≥ motic stenosis or dehiscence, renal failure, and stroke 0 None 300 ≥ (Table 9.5 ). Size matching is a key issue in transfer- 1 Present 300 ring lungs from one thoracic cavity to another, and 2 Present 200 – 300 < problems may arise from size discrepancy. Undersized 3 Present 200 lungs may over - infl ate, leading to possible graft dysfunction, and pleural effusions may form. Lungs that are too large for the recipient are prone to the development of atelectasis and pneumonia, and oversized lungs may compromise hemodynamic parameters. Bronchial anastomoses may develop ischemia, Although size matching is important, surgical lung dehiscence, ulcerations, malacia, or stenosis. volume reduction can be done to allow a better fi t for Implantation of grafts with smaller airways, par- oversized lungs and has no apparent ill - effects on ticularly lung transplantation performed on children, graft survival or mortality. are more prone to develop signifi cant airway

218 LUNG TRANSPLANTATION

Table 9.5 Post - transplant complications Allograft rejection • hyperacute (humoral) • acute cellular • lymphocytic bronchitis/bronchiolitis • chronic rejection (bronchiolitis obliterans) Primary graft dysfunction Bronchial anastomosis complications (dehiscence, malacia, stenosis) Infection • bacterial (pneumonia, bacterial tracheobronchitis, empyema) • fungal infection (e.g. Aspergillus, Candida spp., tracheobronchial aspergillosis) • viral (e.g. CMV, RSV, infl uenza) • mycobacterial • Pneumocystis spp. • Coagulation/thrombotic events • hemorrhage • hypercoagulability • thrombosis of venous anastomoses • venous thromboembolism • axillary vein thrombosis • heparin - induced thrombocytopenia with thrombosis • Multisystem failure Neurological complications (usually drug induced) • central nervous system dysfunction • tremor Pleural effusion Phrenic nerve injury Vocal fold paralysis Renal dysfunction/insuffi ciency Native lung complications (single lung transplantation) • hyper - infl ation (emphysema) • infection • pneumothorax Cardiovascular • systemic hypertension • cardiac rhythm disturbances • hyperlipidemia Hemolytic– uremic syndrome Diabetes mellitus • new onset • worsened control of established disease Gastrointestinal complications • impaired motility (diarrhea, bezoar) • colonic (diverticulitis, perforation, colitis) • hepatobiliary dysfunction Musculoskeletal complications • Impaired bone metabolism: – osteoporosis – compression fractures – avascular necrosis • Myopathy Myelosuppression Malignancies/lymphoproliferative disease (PTLD, primary lung cancer, other) Menstrual irregularities

CMV, cytomegalovirus; PTLD, post- transplantation lymphoproliferative disease; RSV, respiratory syncytial virus.

219 CHAPTER 9

Figure 9.1 Thoracic imaging of lung transplant recipients. obliterans syndrome. (c) HRCT scan showing allograft (a) Anteroposterior chest radiograph of a recipient with bronchiectasis (arrows). (d) HRCT scan showing a new grade 3 primary graft dysfunction (PGD). (b) High- small cell carcinoma in the ﬁ brotic native lung of a single resolution CT (HRCT) scan showing air trapping in a lung transplant recipient with idiopathic pulmonary bilateral lung transplant recipient with bronchiolitis ﬁ brosis.

complications. Preoperative steroid use, CPB, reper- Infection in the perioperative period is largely caused fusion injury, acute rejection, airway infection, by bacterial organisms, although viral and fungal and administration of postoperative cytolytic drugs infections should not be overlooked. Broad - spectrum have all been linked to anastomotic dysfunction. antibiotics should be given until organisms can be Anastomotic complications arising in the fi rst year identifi ed, and it is important to consider infections after lung transplantation may be increased in recipi- that may have existed in the donor before transplan- ents who are tall or in those receiving organs from tation. Infectious complications are discussed in more donors who had prolonged mechanical ventilation. detail under “ Postoperative period” . Aspergillus infection of tracheobronchial anastomo- Phrenic nerve injury or diaphragmatic dysfunc- ses may occur, especially in CF patients. Risk factors tion can occur due to the transplant procedure. for anastomotic complications in children include Diaphragmatic dysfunction can have signifi cant prolonged mechanical ventilation and infection with effects on weaning from the ventilator and, thus, B. cepacia or fungus. tends to prolong hospitalization. Fortunately, this Infection is a constant concern in the perioperative complication does not seem to have a signifi cant period and can arise from aspiration, surgical sites, impact on long - term outcome. or nosocomial infections. Pediatric recipients appear Pulmonary embolism can be a devastating compli- to have a higher incidence of pneumonia than adults. cation that may occur during the perioperative period,

220 LUNG TRANSPLANTATION

especially during the fi rst postoperative month, with immunosuppressive agents emerge as major issues. an incidence that ranges up to 30%. As with all post- The combinations of immunosuppressive drugs operative patients, lung transplant recipients are at required to prevent graft rejection pose a risk of side high risk for developing deep venous thrombosis effects and toxicities that include renal dysfunction, (DVT) and subsequent pulmonary emboli (PEs). In central nervous system complications, osteoporosis, addition, clot can form at sites of vascular anastomo- hyperlipidemia, and increased risk of malignancy. ses. As a result of the potentially devastating effects Other potential complications include pulmonary dis- of DVT/PE, patients should receive adequate DVT orders that can affect the transplanted lung, such as prophylaxis. In some situations, it may be prudent to acute rejection, allograft infection, recurrence of place an inferior vena cava fi lter to prevent fatal PEs. disease in the transplanted lung (e.g., pulmonary Hyperacute, antibody- mediated rejection may Langerhans ’ cell histiocytosis, lymphangioleiomyo- occur in the immediate postoperative period, although matosis, sarcoidosis), problems with the native lung very few cases have been reported. Hyperacute rejec- that may affect allograft function in recipients of SLT tion is characterized by the development of diffuse (e.g., hyperinfl ation of an emphysematous native infi ltrates within a few hours of lung transplantation. lung, infection, pneumothorax), post - transplant lym- These recipients test positively for panel - reactive anti- phoproliferative disorder (PTLD), and bronchiolitis bodies and retrospective tissue cross - match studies. obliterans (BO). Clinical features of this aggressive clinical syndrome include sudden, rapid increases in airway pressure, Immunosuppression copious amounts of blood - tinged fl uid emanating The goal of immunosuppressive therapy is to promote

from the airways, a precipitous decline in P aO2 : F iO2 , immune tolerance of the lung allograft. Despite seem- and coagulopathy. Treatment includes escalation of ingly adequate immunosuppressive regimens, a high immunosuppressive therapy combined with plas- proportion of lung transplant recipients will develop mapheresis to attenuate the production and the pres- acute rejection, which tends to occur more frequently ence of pre - formed antibodies. in lung transplantation than in other solid organ transplantations. Immunosuppression of the lung transplant recipient must be intense and sustained to The p ostoperative p eriod suppress the numerous factors that promote and drive Patients who survive the perioperative period and allograft rejection. Immune system components that leave the hospital usually experience a signifi cant mediate a rejection cascade include innate immunity, improvement in lung function over the next few adaptive immunity, humoral immunity, and autoim- months. It is imperative that the patient and the mune responses. As a result of the complexity and healthcare team work to ensure the vitality of the overlap in these components of the immune system, transplanted lung to achieve and maintain this there is no simple physiologic “ switch ” that can be improvement in lung function over time. Although shut off to control rejection. The posttransplant there is no consensus for various aspects of postop- immunosuppressive regimen usually consists of a cal- erative surveillance, lung transplantation programs cineurin inhibitor (CNI), a purine synthesis inhibitor, are more likely to succeed if frequent and reasonably and a corticosteroid. In addition, almost 45% of lung intense surveillance is employed to prevent or recog- transplantation centers report that they utilize induc- nize complications. The rigorous post - transplant sur- tion therapy with either anti -thymocyte globulins veillance program and the complex medical regimen (ATGs), monoclonal anti -CD3 antibody (OKT3), or that lung transplant recipients must adhere to as out- anti- interleukin (IL)- 2 - receptor antibodies. The ration- patients underscores one reason why patients must be ale for use of induction antibody therapy in lung trans- carefully screened before listing for lung transplanta- plantation includes the high risk of acute rejection and tion. Nevertheless, even with rigorous surveillance the benefi cial effect of providing time to achieve thera- protocols in place, multiple complications may occur. peutic levels of maintenance agents. Recent data from As the recipient recovers from the transplant pro- the International Society for Heart and Lung cedure and management shifts to long - term ambula- Transplantation (ISHLT) database show a small but tory care, complications associated with long - term statistically signifi cant survival advantage associated

221 CHAPTER 9 with the use of induction antibodies in the early post- Data from the 2007 report of the ISHLT indicate operative period. Unfortunately, adequately powered, that lung transplantation centers prefer tacrolimus prospective, randomized controlled trials are lacking over cyclosporine and mycophenolate over azathio- to support or refute the use of any specifi c induction/ prine. Target of rapamycin (TOR) inhibitors maintenance immunosuppressive regimen to optimize (sirolimus and everolimus) have been touted as CNI - long- term allograft survival after lung transplantation. sparing agents. However, sirolimus therapy has been Adequate maintenance immunosuppressive the- sporadically linked to adverse pulmonary reactions rapy, which is started immediately postoperatively, is and must be monitored carefully. Moreover, new use of key importance in preventing AR. Currently, the of these agents has been associated with impaired CNIs (cyclosporine and tacrolimus) provide the wound healing and, in lung transplant recipients, “ backbone ” for maintenance regimens administered with dehiscence of the tracheal anastomosis. Novel to lung transplant recipients. Although tacrolimus approaches to preventing or treating AR include the may have greater effi cacy for refractory AR, and administration of inhaled cyclosporine. One single - switching from cyclosporine to tacrolimus has been center, randomized, placebo- controlled trial of reported to stabilize or slow declining allograft func- inhaled cyclosporine demonstrated improvement in tion due to “ chronic rejection,” it remains unclear overall allograft survival and chronic rejection - free whether tacrolimus is truly better than cyclosporine survival, although a signifi cant effect on preventing in preventing AR. The purine synthesis inhibitors, AR was not demonstrated. azathioprine or mycophenolate (mycophenolate AR can be treated with high - dose intravenous cor- mofetil or mycophenolate sodium) are generally used ticosteroids and, when applicable, conversion from in combination with a CNI. Although smaller studies cyclosporine to tacrolimus. If this is unsuccessful, have suggested that mycophenolate may have supe- cytolytic therapy with ATG or OKT3 may be used. If rior effi cacy over azathioprine in preventing AR, further treatment is needed, high - dose intravenous results from larger prospective, randomized, multi- immunoglobulin (IVIG) provides another option. center trials have not demonstrated any convincing Chronic rejection should be treated by switching from difference between the two agents in suppressing AR. cyclosporine to tacrolimus for at least 3 – 6 months, Finally, prednisone is the corticosteroid of choice in and high- dose corticosteroids and ATG can also tried most centers and is helpful for preventing as well as if refractory. Finally, other modalities such as total treating AR. As a result of its adverse effects, espe- lung irradiation, photopheresis, or chronic use of azi- cially on blood sugar control and bone mineral thromycin may be helpful in stabilizing lung function density, some centers signifi cantly decrease or discon- in recipients with progressive loss of lung function tinue prednisone dosing over the fi rst year after lung due to chronic rejection. transplantation. Large doses of intravenously administered methylprednisolone followed by a gradual Complications in the p ostoperative p eriod taper of oral prednisone are typically used to treat The major complications that occur beyond the peri- episodes of AR. operative period are predominantly linked to rejec- Strategies to avoid toxicity (e.g., monitoring CNI tion and infection. Successful transplant programs levels in peripheral blood) yet maintain adequate must have systems in place to identify and treat these immunosuppression and avoid opportunistic infec- complications early and effectively, and various meas- tion must be followed. Trough levels (C 0 ) of cyclos- ures should be taken to minimize complications and porine and tacrolimus have traditionally been optimize post - transplant outcomes ( Table 9.6 ) . used for monitoring CNIs. However, in the case of cyclosporine, some centers use C2 levels that may Acute r ejection Malaise, cough, fever, and/or leuko- better refl ect area - under - the - curve (AUC) pharma- cytosis, decrease in FEV 1 , changes on chest radio- cokinetics. Although C2 monitoring has been linked graph, and gastrointestinal complaints should signal to enhanced clinical benefi t in heart, liver, and kidney the possibility of AR. It is graded histologically transplant recipients, data that support improved out- based on a commonly accepted scale that was most comes in association with its use in lung transplanta- recently revised in 2005 (Table 9.7 ) . Perivascular tion remain limited. mononuclear infi ltrates with or without lymphocytic

222 LUNG TRANSPLANTATION

Table 9.6 Measures to optimize Experienced and multidisciplinary transplant team in place (thoracic surgeons, post - transplant outcomes pulmonologists, consultants, coordinators/nursing, pharmacists, nutritionists, health psychologists, social workers) Adequate yearly transplant volume to keep team skills at a high level Careful selection of transplant candidates Optimized pretransplant management • Adequate pharmacologic therapies • Avoidance of debilitation/deconditioning (optimal nutrition, pulmonary rehabilitation) Donor management • Careful selection • Optimal supportive care Use of strategies to avoid/minimize ex vivo allograft preservation injury Aggressive postoperative ICU management • Avoid ventilator - induced injury • Consider early extracorporeal membrane oxygenation for severe, refractory graft dysfunction • Judicious ﬂ uid restriction • Closely monitor graft function Prophylactic/pre- emptive therapies • Adequate immune suppression • Cytomegalovirus • Aspergillus spp. • Pneumocystis spp. Surveillance • Lung allograft – spirometry – radiologic imaging – bronchoscopy (BAL and transbronchial biopsy) • Immunosuppressant monitoring – CNI peripheral blood levels – bone marrow function • Intermittent assessment of non- pulmonary issues – renal function – gastrointestinal function (GER, etc.) – cardiac function – lipid proﬁ le – systemic blood pressure – nutrition – bone metabolism – glucose metabolism – malignancy risk

BAL, bronchoalveolar lavage; CNI, calcineurin inhibitor; GER, gastroesophageal reﬂ ux; ICU, intensive care unit.

223 CHAPTER 9

Table 9.7 Grading of acute rejection and bronchiolitis obliterans syndrome

Disorder Grade Findings/Severity Comments

Acute rejection (perivascular A0 None Adequate specimen requires ﬁ ve or more pieces and interstitial inﬂ ammation) A1 Minimal of alveolated parenchyma A2 Mild Routine H & E processing at three levels required A3 Moderate Special stains for microorganisms (GMS, AFB) A4 Severe required Connective tissue stain (e.g. elastic) recommended

Lymphocytic bronchiolitis B0 None Lymphocytic bronchitis/bronchiolitis (LBB) is also (airway inﬂ ammation) B1 Low grade a form of acute rejection B2 High grade BX Ungradable

a Bronchiolitis obliterans BOS 0 FEV1 ≥ 80% of baseline Other causes of lung function decline must be syndrome BOS 1 FEV1 66 – 80% of baseline excluded: BOS 2 FEV 51 – 65% of baseline 1 • acute rejection BOS 3 FEV1 ≤ 50% of baseline • infection

• native lung problems (single lung transplant recipients)

• excessive recipient weight gain

• anastomotic dysfunction

• respiratory muscle dysfunction

• technical problems a Baseline deﬁ ned as the average of the two best FEV1 determinations post- lung transplantation. AFB, acid - fast bacilli; GMS, Gomori methenamine silver; H& E, hematoxylin and eosin.

bronchitis/brochiolitis in the absence of infection is been considered to be clinically insignifi cant, it has the histologic hallmark of AR ( Figure 9.2 ) . Acute been associated with increased risk for developing cellular rejection is by far the most common rejection BO. However, no clear benefi t has been demonstrated response. Hyperacute rejection is rare. However, with intensifying immunosuppression for recipients another form of AR, characterized by alveolar with A1 rejection detected via surveillance bronc- septal capillary injury that lacks the lymphocyte infi l- hoscopy (SB). AR of grade A2 or higher requires tration characterizing cellular AR, has been reported intensifi ed immunosuppression because it is usually to be associated with anti - endothelial antibodies accompanied by worsening lung function and oxy- specifi c for non - major histocompatibility (MHC) genation. One of the main reasons why surveillance antigens. TBLB is performed is because some patients may have The grading for AR ranges from A0 to A4. Grade grade A2 or even A3 AR that is clinically occult A2 or greater is generally considered to be clinically without a perceptible decline in lung function or gas signifi cant and requiring intervention. Grade A1 exchange. A follow - up TBLB should be performed (minimal) is commonly seen on surveillance trans- after the intensifi cation of immunosuppression and bronchial lung biopsy (TBLB) and is of unclear sig- corticosteroid burst to verify that the rejection episode nifi cance. Although grade A1 rejection has generally has been adequately treated and suppressed.

224 LUNG TRANSPLANTATION

Figure 9.2 Histopathology of acute and chronic rejection. note the presence of eosinophils (arrows). (c) ISHLT grade (Images provided courtesy of Henry Tazelaar, MD . ) B1 with mild bronchiolar lymphocytic inﬁ ltrate. (d) (a) International Society for Heart and Lung Chronic airway rejection (obliterative bronchiolitis), with Transplantation (ISHLT) grade A2 acute rejection with complete airway scarring. The right panel shows an one dense perivascular mononuclear inﬁ ltrate and no adjacent section stained with an elastic stain, highlighting interstitial extension. (b) ISHLT grade A3 acute rejection; the internal elastic lamina (arrows).

Case predisposes individuals to ventilator- associated bacte- A 23 - year - old woman developed fever and leukocytosis rial pneumonia, and impaired cough refl exes and 9 weeks after bilateral lung transplantation for cystic mucociliary clearance combined with immunosup- fi brosis. THE FEV1 was 15% lower than a baseline value pression sustain this risk after extubation. Undetected obtained 1 month earlier. Transbronchial lung biopsy infection may be present in the lung allograft before revealed grade A2 acute rejection and no evidence of donor explantation. Ischemic mucosa in the peri - infection. She was treated with high doses of intravenous anastomotic areas and impaired lymphatic drainage methylprednisolone. Cyclosporine was switched to tac- contribute to the risk of bacterial pneumonia. Fever, rolimus. Fever and leukocytosis resolved. Repeat trans- radiographic infi ltrate, and culture - positive lower bronchial biopsy 1 month later showed no evidence of airway secretions can be diagnostic of pneumonia in acute rejection. the transplanted patient, but bronchoscopy with bronchoalveolar lavage (BAL) may be needed to make Infection Infection can occur at any time after lung the diagnosis. transplantation. The incidence of bacterial pneumo- Gram - negative organisms, especially P. aeruginosa , nia is approximately 16% in the fi rst month after lung are the predominant organisms followed by transplantation. Prolonged mechanical ventilation Staphylococcus aureus , which may be meticillin

225 CHAPTER 9 resistant. Empyema occasionally complicates lung chain reaction (PCR) methodologies has greatly transplantation and may be diffi cult to distinguish enhanced the ability to rapidly detect CMV in BAL from postoperative pleural effusions which frequently fl uid, but CMV infection must be distinguished occur as a consequence of disrupted lymphatic drain- from CMV disease, which is characterized by a age. Although pneumonia usually occurs in the trans- cytopathologic process in the lung allograft. The dem- planted lung in single lung transplant recipients, onstration of inclusion bodies in cytomegalic cells on pneumonia can occasionally occur in the residual TBLB specimens is diagnostic of CMV pneumonitis. native lung. Antimicrobial prophylaxis and aggressive However, obtaining diagnostic TBLB may be diffi - treatment of infection in the early postoperative cult, and a presumptive diagnosis of CMV disease can period can decrease the incidence or progression of be made on the basis of clinical features and positive lung infection and, ultimately, improve early graft culture or PCR results. function. In the case of recipients transplanted for There is no consensus as to the timing, duration, suppurative lung disease (CF or non - CF bronchiecta- or optimal dose of prophylactic agents for CMV. sis), pathogens isolated from pre- lung transplantation Some centers employ universal prophylaxis with sputum cultures or pathogens typically isolated from either ganciclovir or valganciclovir, whereas others these individuals are usually the causative pathogens utilize pre - emptive treatment that is based on screen- when post- lung transplantation bacterial pneumonia ing and early identifi cation of CMV infection. occurs. In addition, the paranasal sinuses continue to Disadvantages of universal prophylaxis include cost, harbor organisms that can infect the lower respira- toxicity, and the possible emergence of resistant tory tract after lung transplantation. As a result of organisms, while disadvantages of the pre - emptive this possibility, paranasal sinus disease should be method are the cost of screening and the possibility optimally managed in the pre - and perioperative of failure to identify individuals with CMV infection period. Some centers perform endoscopic sinus before they develop a serious form of CMV disease. surgery to enhance sinus drainage, although there are Nevertheless, signifi cant CMV infection during the no convincing data that such intervention has a sig- early post- lung transplantation period is now rare, nifi cant impact on post- lung transplantation outcome. and most centers continue prophylactic therapy for CMV can cause serious infection that can be life the fi rst year after lung transplantation. Although the threatening, and patients are at greatest risk during appearance of drug - resistant CMV is a concern and the fi rst 3 months post- transplantation. Although has been estimated to range in frequency from 3% to most patients have been exposed before transplanta- 16% in solid organ transplant recipients, such tion, recipients with negative CMV serology at the approaches appear to have signifi cantly decreased the time of transplantation are particularly at risk, espe- morbidity and mortality of CMV infection in lung cially if they receive a graft from a CMV - positive transplant recipients. When CMV pneumonitis or donor. Other risk factors for CMV disease include CMV affecting other organ systems occurs, treatment blood transfusions, immunosuppressive induction with ganciclovir or valganciclovir is usually effective. regimens that deplete lymphocytes, co - infection with In addition, CMV- specifi c or polyvalent immune human herpesviruses 6 or 7, and bronchiolitis oblit- globulin may be used to augment the treatment erans syndrome (BOS). regimen in recipients with CMV disease. Infection with CMV may manifest as a pulmonary Most opportunistic fungal infections are caused by syndrome, with increased shortness of breath and Candida and Aspergillus spp. Pneumonia caused by decreased graft function mimicking AR. In addition, Candida spp. is rare, but surgical site infection and CMV may involve other organ systems and cause dissemination can occur. Aspergillosis is a common extrapulmonary disease including pancytopenia, gas- post - transplantation opportunistic infection that can trointestinal dysfunction, or dermatologic reactions. cause pulmonary and/or extrapulmonary disease, and As pulmonary CMV infection may be diffi cult to invasive disease occurs in approximately 5% of recip- distinguish from AR (and both may be present simul- ients. Aspergillus spp. can cause infection at the anas- taneously), bronchoscopy with TBLB is usually tomotic site and may cause dehiscence in the early required to make a defi nitive diagnosis. The advent post - transplant time period. In addition, aspergillosis of rapid shell- vial culture techniques and polymerase can affect the lung parenchyma and cause angioinva-

226 LUNG TRANSPLANTATION sive disease with cavitating lesions, and sometimes nous ganciclovir for 1 week, oral valganciclovir for 3 involves other organ systems. Prophylactic regimens, weeks) and the syndrome resolved. especially when used for patients with known pre - transplant colonization, may decrease the risk of Bronchiolitis o bliterans The development of BO, post - transplant aspergillosis. A confi dent diagnosis of which is widely perceived to occur as a consequence aspergillosis is made by obtaining biopsy specimens of chronic rejection, continues to be the major factor that show tissue invasion. However, Aspergillus spp. that limits long - term survival and quality of life after growing in culture, combined with the appropriate lung transplantation. Despite improvements in immu- clinical picture, may be suffi cient to make a presump- nosuppression and other elements of patient manage- tive diagnosis and commence therapy. ment, BO still occurs in more than half of all lung Aspergillus spp. can produce devastating, life - transplant recipients who survive to 5 years after lung threatening illness if not identifi ed rapidly and treated transplantation. As BO is diffi cult to diagnose by appropriately. When aspergillosis is suspected, imme- radiologic imaging or transbronchial biopsy, the sur- diate evaluation of the patient for the extent of organ rogate marker of FEV 1 (see Table 9.7 ) is used to system involvement, combined with the administra- detect and grade BO, which is then termed BO syn- tion of intense, multiagent, appropriate antifungal drome. However, when this diagnosis is made, other therapy, is required. Treatment has traditionally con- potentially reversible causes of a decline in lung func- sisted of intravenous amphotericin B, but newer tion (e.g., AR, infection, native lung problems for approaches include the administration of voricona- single lung transplant recipients, excessive recipient zole and caspofungin, depending on the site and weight gain that impairs lung function) must be ruled severity of disease. Many programs administer anti- out as causes of chronic allograft dysfunction. BOS fungal agents (e.g., inhaled, nebulized amphotericin rarely occurs in the fi rst 6 months post - lung trans- B, oral itraconazole, oral voriconazole) for prophy- plantation, and median time to diagnosis is 16 – 20 laxis, especially to patients known to be colonized months. Some patients may not display symptoms at with Aspergillus spp. pretransplantation. all and may be identifi ed only by screening lung func- Many other infectious complications can occur in tion tests. the lung transplant recipient. Possible viral infections Risk factors that have been linked to the develop- include herpes simplex virus, adenovirus, respiratory ment of BOS include episodes of AR, HLA mismatch- syncytial virus (RSV), infl uenza, and parainfl uenza. ing, and an autoimmune reaction to the lung matrix Other fungal infections include Cryptococcus and component, collagen V. However, alloimmune - Coccidioides spp. Mycobacterial infections with both independent factors such as inhaled irritants, airway Mycobacterium tuberculosis and non- tuberculous ischemia, viral infections (e.g., CMV and respiratory mycobacteria may also occur. Finally, other agents viruses including infl uenza virus, RSV, parainfl uenza such as Pneumocystis jiroveci can cause life- threatening virus, adenovirus, and rhinovirus), gastroesophageal illness in the intensely immunosuppressed lung trans- refl ux (GER), and donor factors (underlying asthma, plant recipient. Trimethoprim – sulfamethoxazole (or smoking, and head injury as the cause of death) may other agent if true allergy exists) is used routinely as also cause or contribute to the pathogenesis of BOS. prophylaxis for Pneumocystis spp. Recipients who have three or more episodes of acute rejection in the fi rst 6 – 12 months have a three- to fourfold increased risk of developing BO. However, Case some recipients do not develop BO despite multiple A 55 - year - old man with a history of end- stage lung disease from COPD developed fever and exertional episodes of AR, and recipients who have never had dyspnea 8 months after a single lung transplantation. AR may develop BO. In the pediatric lung transplant Chest radiograph revealed new bilateral interstitial infi l- population, GER appears to be quite prevalent, and trates. Hybrid capture DNA for CMV was previously most pediatric lung transplant centers are very aggres- negative, but CMV prophylaxis had been discontinued sive about identifying and treating GER. Finally, one 6 months post- transplantation. Transbronchial biopsy must consider non - adherence to the medical regimen revealed inclusion bodies consistent with CMV. The when evaluating rejection in the lung transplant patient completed a 4 - week course of therapy (intrave- recipient.

227 CHAPTER 9

Although the pathogenesis of BO is not completely to control groups and appears to have relatively little understood, both animal and human data suggest morbidity. Laparoscopic fundoplication can also be that there is an initial injury to airway epithelium that performed safely on patients with ESLD before lung leads to a signifi cant recruitment of infl ammatory transplantation. cells. Prominent among these infl ammatory cells are BO has a devastating effect on long- term survival neutrophils which accumulate in airspace secretions with only 30 – 40% of recipients with BOS surviving and may orchestrate the activation of the immune 5 years after its onset, and management of BOS is system. Proinfl ammatory cytokines and chemokines diffi cult and usually ineffective. Treatment of BOS mediate and potentiate this infl ammatory response, must take into consideration the delicate balance eventually leading to progressive airway damage, of immunosuppression and risk of opportunistic fi brosis, and airway smooth muscle proliferation with infection. Although increasing immunosuppressive bronchiolar scarring and obliteration – all culminat- therapy would be benefi cial to control the immune/ ing in irreversible airfl ow obstruction. However, it infl ammatory response, it also places the patient at should be emphasized that BO is a heterogeneous increased risk of infection. Nevertheless, both infec- disorder with causes and immune/infl ammatory tion and infl ammation must be aggressively treated in responses that may vary from one lung transplant an attempt to prevent the progression of BOS. Patients recipient to another. with BOS after transplantation may have increased One of the fi rst clues to the presence of BO is a sputum production, grow P. aeruginosa on sputum decrease in small airway function (forced expiratory culture, and show signs of bronchiectasis and end -

fl ow at 25– 75% – FEF25 – 75% ), which may precede expiratory air trapping on chest CT. Chronic azithro- symptoms of cough, mucus production and dyspnea. mycin administration has been associated with Transbronchial lung biopsy has a disappointingly low stabilization or improvement in lung function in some sensitivity (17%) for detecting BO, necessitating recipients. Use of HMG - CoA (hydroxymethylglutaryl adoption of the FEV 1 as a surrogate marker for BOS, coenzyme A) reductase inhibitors ( “ statins ” ) also has with a sustained decline in FEV 1 to < 80% of the best been associated with a decreased risk of developing value post- transplantation indicating the onset of BOS. Total lymphoid irradiation (TLI), initiated early BOS. Revision in the BOS staging system in 2002 in the course of chronic rejection that is refractory to included a decline in FEF 25 – 75% to < 75% of the best conventional medical management, has been associ- post - lung transplantation value as indicating the ated with an attenuation of the rate of decline in lung probable onset of BOS, because this parameter may function, and extracorporeal photopheresis may also identify airway obliteration earlier in the disease help stabilize declining graft function in recipients process. As AR (especially if it occurs early, is high with early BOS. Newer approaches that can prevent grade, and recurrent) is thought to be a major risk for or effectively treat BOS are desperately needed. Re - developing BOS, most lung transplantation centers transplantation may be considered, but survival sta- use frequent monitoring to identify and treat AR early tistics for re - transplantation are signifi cantly worse and hopefully prevent the development of BOS. than that for recipients of primary lung transplanta- Existing data support the use of intensive induction tion. Candidates for re - transplantation due to pro- immunosuppression post - lung transplantation, com- gressive, refractory BOS must be evaluated with bined with aggressive treatment of AR detected via intense scrutiny. frequent surveillance bronchoscopy (SB), with TBLB as a way of decreasing the risk of developing chronic Other c omplications rejection precipitated by episodes of AR. In addition, as GER is highly prevalent in patients with advanced Gastrointestinal A number of gastrointestinal com- lung disease and has been linked to chronic allograft plications can occur at any time after lung transplan- dysfunction and BOS, some investigators have taken tation and affect approximately 50% of lung a more aggressive approach to its management. transplant recipients. GER is highly prevalent in Fundoplication performed early after lung transplan- patients with advanced lung disease and has been tation has been reported to be associated with both linked to declines in lung function and the develop- improved lung function and survival in comparison ment of BO. Refl ux can occur for a variety of reasons

228 LUNG TRANSPLANTATION that include postoperative changes to the lower and peripheral blood lipid profi les should be moni- esophageal sphincter and diaphragmatic crura, dys- tored frequently to facilitate the detection and treat- motility associated with diabetes mellitus, and changes ment of these complications. in body habitus (e.g., from corticosteroid - associated weight gain). Non - acid GER occurs in many patients Bone metabolism There is a very high prevalence of and must be detected via impedance/pH monitoring. osteopenia and osteoporosis in patients with advanced Ideally, all candidates and recipients should be lung disease, and lung transplantation can accelerate screened (pH and impedance measurements) for GER bone loss. All recipients should have bone mineral and receive appropriate medical or surgical therapies density checked frequently (e.g., 6 – 12 months post - as needed to prevent signifi cant refl ux. Recipients transplantation and then yearly) via bone mineral with CF are particularly predisposed to gastrointesti- density scanning and receive appropriate therapies if nal complications due to disease - related intestinal T - scores indicate the presence of osteopenia. tract dysfunction. Patients with CF can develop bezoars that often form in the early post - transplant Glucose i ntolerance Corticosteroids and other trans- period and that can inhibit absorption of orally plant medications often disrupt glucose metabo- administered drugs. Recipients with CF are also at lism. Patients with CF are particularly at risk and risk for distal intestinal obstruction, biliary tract com- have a relatively high pretransplant prevalence of plications (cholecystitis, signifi cant biliary stasis, diabetes mellitus that increases signifi cantly post - ascending cholangitis), and intestinal neoplasm (espe- transplantation. Frequent monitoring should be per- cially colon cancer). formed to assess glycemic control and to detect new onset of glucose intolerance. Renal d ysfunction Recipients are at a major risk for developing renal dysfunction after lung transplanta- Malignancy The profound immunosuppression tion, and renal function should be checked frequently required for lung transplant recipients places them at in the fi rst post - transplant months and then at regular increased risk for developing dermatologic malignan- intervals thereafter. Blood levels of CNIs need to be cies and PTLD. The latter occurs in approximately monitored closely and doses adjusted to ensure an 5% of lung transplant recipients, and nearly all cases adequate (but not excessive) level that will give the of PTLD are associated with the Epstein – Barr virus desired degree of immunosuppression. Other electro- (EBV). Recipients who are EBV seronegative seem to lytes that can affect renal function (e.g., magnesium) be at highest risk for developing PTLD in the postop- or rise to dangerous levels (e.g., potassium) also need erative period. Peripheral blood semi- quantitative to be frequently monitored. When serum creatinine EBV PCR may identify recipients at increased risk for rises irreversibly > 1.5 g/dL (or estimated glomerular PTLD and may warrant cautious reduction of immu- fi ltration rate [GF]R < 50 mL/min), or if signifi cant nosuppression and continued prophylactic antiviral proteinuria is detected on urinalysis, referral to a agents to prevent CMV as a cofactor in the pathogen- nephrologist who is familiar with transplant issues esis of PTLD. Treatment consists of decreasing the should be considered. level of immunosuppression to attempt to restore immunity against EBV. Other modalities, such as Cardiovascular Common cardiovascular complica- rituximab, have been used with some success. Overall, tions include systemic hypertension, rhythm distur- the mortality rate attributed to PTLD for recipients bances (e.g., atrial fi brillation), and hyperlipidemia. who develop this complication after lung transplanta- Systemic hypertension has been linked to corticoster- tion is 37 – 50%. oids, CNI administration, and weight gain. Hyperlipi- Primary lung neoplasms may arise in the native demia is also linked to immunosuppressive agents, lung of single lung transplant recipients, and other and the administration of statins for hyperlipidemia neoplasms such as bladder and colon cancer have has been linked to improved survival and decreased been reported. Patients and their care providers need risk of developing BO. Systemic hypertension and to maintain vigilance for any skin changes that may hyperlipidemia will eventually develop in most lung herald the development of a cutaneous malignancy, transplant recipients, and systemic blood pressure and internal malignancy must be considered when

229 CHAPTER 9 unexplained symptoms or signs arise in the post - accurate diagnosis of rejection and/or infection. For transplant setting. Cancer screening, including routine recipients with CF, extrapulmonary problems such as skin examinations, mammography, cervical cancer CF - related diabetes mellitus, CF liver disease, various screening and colonoscopy, must be maintained in the other gastrointestinal complications, and paranasal post - transplant setting. sinus disease must be managed intensively. Frequent clinic visits at a CF center allow the patient to be Long - t erm s urveillance evaluated for nutritional status, pulmonary status, The goal of a surveillance program is to identify any and identifi cation of early complications including acute or evolving issue that is related to an infectious medical and psychosocial problems. process, acute rejection, or other potential complica- Bronchoscopy with TBLB and BAL is an important tions, and to intervene before graft function is irre- tool for the detection of rejection and infection and versibly affected or other complications occur. A is performed when clinically indicated. Examination typical surveillance program should include monitor- of BAL fl uid is particularly helpful in identifying bac- ing of allograft function, evaluation for infectious terial, viral, and fungal infections, whereas TBLB is complications, intermittent laboratory testing and especially useful for identifying AR and/or CMV drug monitoring, monitoring of other organ system pneumonia. Quantitative bacterial cultures and function (renal, cardiovascular function, and gas- stains, cultures for fungi and mycobacteria, and viral trointestinal function), intermittent assessment of studies are typically obtained on BAL fl uid, and trans- bone and glucose metabolism, and attention to risk bronchial biopsies are obtained to evaluate allograft for malignancy. Most centers require frequent per- tissue for evidence of rejection and/or infection. The formance of home spirometry to detect declining sensitivity and specifi city of TBLB in identifying AR

FEV1 values once the recipient has been discharged are approximately 72% and 90 – 100%, respectively. from the hospital, and patients should be educated to Sensitivity and specifi city for the detection of CMV recognize changing symptoms including increased pneumonitis are approximately 91% and 70%, shortness of breath, fever, chills, or decline in exer- respectively. Follow - up bronchoscopy with TBLB is tional capacity. typically performed 4 weeks after the detection and Lung transplant recipients require close and fre- treatment of signifi cant acute rejection to ensure that quent evaluation in the postoperative period to detect enhanced immunosuppression has effectively elimi- allograft dysfunction, particularly rejection and infec- nated the process. tion. As a result of their high prevalence in lung Scheduled SB can detect occult infection or AR in transplant recipients, there are a number of signifi cant patients who appear to be stable and lack radio- complications (hyperlipidemia, diabetes mellitus, graphic or physiologic manifestations of rejection. osteoporosis, renal insuffi ciency, GER, and systemic However, the routine use of SB is controversial, and hypertension) for which screening should be per- SB is routinely performed in only two - thirds of lung formed. Most of these complications are linked to the transplantation centers in the USA. For those institu- intense immunosuppressive regimens initiated at the tions that perform SB, schedules differ from center to time of lung transplantation, and frequent monitoring center and are usually determined by the lung trans- of immunosuppression, especially blood levels of plantation center’ s previous experience. Nevertheless, cyclosporine and tacrolimus, should be performed to SB is an important tool that allows inspection of guide treatment and avoid toxicities. airways and anastomoses, and retrieval of diagnostic Heart rate, blood pressure, temperature, and specimens via TBLB and BAL for the detection of spirometry should be measured on a regular basis to occult rejection and/or infection. Occult infection detect complications. Most lung transplantation and AR are often detected when SB is performed, centers provide their patients with home spirometers especially during the fi rst 6 months post- and monitor lung function on a daily or even twice - transplantation, and the benefi t of detecting and daily basis. Fever and signifi cant decline in lung func- treating AR are thought to be improved survival and tion (decrease in FEV 1 > 10% over 48 h) require decreased risk of developing BO. A signifi cant limita- immediate evaluation, and bronchoscopy with trans- tion of SB is the very limited ability to diagnose bronchial biopsy is usually performed to establish an chronic rejection because of the limited ability to

230 LUNG TRANSPLANTATION

sample tissue that demonstrates histologic changes that affect lung function. For patients receiving SLT

consistent with BO. for COPD, FEV 1 increases from 20% pre- lung trans- Thoracic CT scanning can be a useful tool to evalu- plantation to 45 – 60% 1 year after transplantation. ate the lung allograft. By using end - expiratory, thin- Patients with COPD who receive a BLT can expect section CT scanning (high- resolution CT [HRCT]) in normal or near - normal lung function 1 year postop- the postoperative period, changes consistent with eratively. Patients with CF who receive BLT display

BOS may be detected relatively early (see Figure 9.1 ). an increase in FEV 1 from a mean of 20% predicted When using air trapping as a marker for detecting before lung transplantation to 70 – 80% predicted at BOS, studies have shown a sensitivity ranging from 1 year post- lung transplantation. Finally, normaliza- 74% to 91% and a specifi city ranging from 67% to tion of pulmonary pressures, right ventricular func- 94%. Although HRCT with inspiratory and expira- tion, and cardiac output is expected for patients who tory views may be useful in detecting and assessing receive a BLT for pulmonary hypertension, although the severity of BOS in recipients who are suspected single lung transplant recipients should also experi- of having developed it, HRCT is not recommended ence normalization of hemodynamic parameters. as a routine surveillance test. It can, however, detect Exercise tolerance improves greatly and allows most changes in addition to air trapping (e.g., small recipients to perform activities of daily living without nodules, bronchiectasis) in the lung allograft as well limitation or need for supplemental oxygen. However, as complications in the native lung of single lung cardiopulmonary exercise testing reveals that transplant recipients (e.g., opportunistic infection or maximum oxygen consumption is limited to 50– 60% malignancy) that cannot be detected on routine chest predicted at peak exercise. Deconditioning, and a radiographic imaging (see Figure 9.1 ). possible myopathy that is linked to the immunosuppressant regimen or other factors, likely accounts for Outcomes this limited exercise capacity, because cardiopulmo- The 5 - year survival rate (Kaplan– Meier) is approxi- nary reserve appears to be maintained. Recipients of mately 50% for both adults and children and remains heart, liver and kidney transplants have similar limi- signifi cantly lower than survival for other solid organ tations on cardiopulmonary exercise, suggesting that transplantations. A steep, early decline in survival factors other than organ function may account for the that levels off at 1 – 3 months post- lung transplanta- subnormal maximum oxygen consumption at peak tion refl ects the impact of early events such as surgi- exercise. cal complications, PGD, and thromboembolism. BO Quality of life and cost- effectiveness have been and infection appear to have the greatest impact on scrutinized as important outcome factors in lung long- term survival, and constant exposure to ambient transplantation. Recently, a plethora of research has air as well as aspiration of upper airway and/or been published on QoL in lung transplant recipients. refl uxed gastroesophageal secretions are likely the Most patients who have undergone lung transplanta- major contributors to graft failure and death. As a tion have been found to be happy with their decision result of its signifi cant prevalence and tendency to to undergo the procedure. The recipient approval relentlessly progress, BO claims the lives of most rating of their lung transplantation is approximately individuals who survive the early postoperative 75%, and over 90% of those who have had the pro- period. cedure would elect to have it again. Over 80% of Fortunately, most lung transplant recipients experi- survivors at 1, 3, and 5 years post - transplantation ence signifi cant improvements in lung function, exer- have no activity limitations. However, only 20% of cise tolerance and quality of life (QoL). Average recipients are working full - time at 1 year post- values for vital capacity increase from 43% predicted transplantation despite their lack of activity limita- pre - lung transplantation to 65% and 69% predicted tion. Improvements in QoL appear to have a lasting at 3 months and 1 year, respectively, for patients effect even at 7 years post - transplantation, and there receiving a SLT for IPF. The greatest improvement in does not seem to be a difference in QoL when com- lung function usually occurs in the fi rst 3 months after paring single with bilateral lung transplant recipients. lung transplantation and slowly reaches a plateau at Cost - effectiveness data are relatively scarce, and about 1 year, barring any signifi cant complications results inconclusive.

231 CHAPTER 9

Recurrence of lung disease is very unusual. Angel LF , Levine DJ , Restrepo MI , et al. Impact of lung Sarcoidosis and lymphangioleiomyomatosis are dis- transplantation donor- management protocol on lung eases that may recur after lung transplantation. In donation and recipient outcomes. Am J Respir Crit Care addition, there have been case reports of recurrence Med 2006 ; 174 : 710 – 16 . Anonymous. Lung Allocation Score System for Transplant in recipients transplanted for Langerhans ’ cell histio- Professionals . United Network for Organ Sharing, 2005 . cytosis, giant cell interstitial pneumonitis, pulmonary Available at: www.unos.org. alveolar proteinosis, and diffuse panbronchioloitis. Arcasoy SM , Hersh C , Christie JD , et al. Bronchogenic carcinoma complicating lung transplantation. J Heart Re - t ransplantation Lung Transplant 2001 ;20 : 1044 – 53 . Aris RM , Gilligan PH , Neuringer IP , Gott KK , Rea J , PGD, severe airway complications, refractory acute Yankaskas JR . The effects of panresistant bacteria in rejection, and progressive BOS can lead to irreversible cystic fi brosis patients on lung transplant outcome. Am J allograft dysfunction and respiratory failure after Respir Crit Care Med 1997 ; 155 : 1699 – 1704 . lung transplantation. Re - transplantation can be per- Aris RM , Neuringer IP , Weiner MA , et al. Severe osteoporo- formed to treat these complications if refractory to all sis before and after lung transplantation. Chest 1996 ; other interventions, but outcomes after re - 109 : 1176 – 83 . transplantation have been signifi cantly worse than Aris RM , Routh JC , LiPuma JJ , Heath DG , Gilligan PH. outcomes after primary lung transplantation. Due to Lung transplantation for cystic fi brosis patients with ethical concerns about proper organ distribution Burkholderia cepacia complex. Survival linked to genomovar type . Am J Respir Crit Care Med 2001 ; 164 : 2102 – 6 . when an overall organ scarcity prevents successful Bando , K , Armitage, JM , Paradis , IL , et al. Indications for transplantation of many wait - listed candidates and and results of single, bilateral, and heart- lung transplanta- various reports of poor outcome after re - tion for pulmonary hypertension . J Thorac Cardiovasc transplantation, the value of retransplantation has Surg 1994 ; 108: 1056 – 65 . been open to question. More recent data suggest that Bankier AA , Muylem AV , Knoop C , Estenne M , Gevenois survival after retransplantation for certain recipient PA . BOS in heart- lung transplant recipients: diagnosis groups approaches that for primary lung transplanta- with expiratory CT. Radiology 2001 ; 218 : 533 – 9 . tion, and outcomes after lung retransplantation have Barraclough K , Menahem SA , Bailey M , Thomson NM . generally improved. Early re - transplantation (within Predictors of decline in renal function after lung trans- 30 days) and re - transplantation for PGD have the plantation . J Heart Lung Transplant 2006 ; 25 : 1431 – 5 . worst outcomes, whereas re - transplantation for BOS Bartz R , Will L , Welter D , Love R , Meyer K . Outcome following lung transplantation for mechanically ventilated appears to provide survival rates that are similar to patients with cystic fi brosis . Am J Respir Crit Care Med long- term survival rates for primary lung transplanta- 2001 ; 163 : A335 . tion. Re- transplantation should be considered on a Benden C , Aurora P , Curry J , Whitmore P , Priestley L , case - by - case basis for recipients of primary lung Elliott MJ . High prevalence of gastroesophageal refl ux in transplantation whose allografts have developed children after lung transplantation. Pediatr Pulmonol severe dysfunction that is refractory to non - surgical 2005 ; 40 : 68 – 71 . interventions. Blondeau K , Mertens V , Vanaudenaerde BA , et al. Acid, non - acid GER and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J Further reading 2007 ; 37 : 625 – 30 . Boehler A , Estenne . Post - transplant bronchiolitis obliterans . Aboyoun CL , Tamm M , Chhajed PN , et al. Diagnostic value Eur Respir J 2003 ; 22: 1007 – 18 . of follow - up transbronchial lung biopsy after lung rejec- Botha P , Fisher AJ , Dark JH . Marginal lung donors: a tion . Am J Respir Crit Care Med 2001 ; 164 : 460 – 3 . diminishing margin of safety? Transplantation 2006 ;82 : Aigner C , Jaksch P , Taghavi S , et al. Pulmonary retransplan- 1273 – 9 . tation: is it worth the effort? A long- term analysis of 46 Bowdish ME , Arcasoy SM , Wilt JS , et al. Surrogate markers cases. J Heart Lung Transplant 2008 ; 27 : 60 – 5 . and risk factors for chronic lung allograft dysfunction . Amital A , Shitrit D , Raviv Y , et al. Development of malig- Am J Transplant 2004 ; 4 : 1171 – 8 . nancy following lung transplantation. Transplantation Braith RW , Conner JA , Fulton MN , et al. Comparison of 2006 ; 81 : 547 – 551 . alendronate vs alendronate plus mechanical loading as

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prophylaxis for osteoporosis in lung transplant recipients: bilevel positive pressure ventilation in cystic fi brosis . Lung a pilot study . J Heart Lung Transplant 2007 ; 26 : 32 – 137 . 2007 ; 185 : 73 – 9 . Canales M , Youssef P , Spong R , et al. Predictors of chronic Egan TM. Non - heart - beating donors in thoracic transplan- kidney disease in long- term survivors of lung and heart- tation . J Heart Lung Transplant 2004 ;23 : 3 – 10 . lung transplantation . Am J Transplant 2006 ; 6 : 2157 – 63 . Egan TM , Edwards LB , Coke MA , et al. Lung allocation in Caplan - Shaw CE , Arcasoy SM , Shane E , et al. Osteoporosis the United States . In: Lynch JP III , Ross DJ (eds), Lung in diffuse parenchymal lung disease. Chest 2006 ; 129 : Biology in Health and Disease , Vol 217 . Lung and Heart - 140 – 6 . Lung Transplantation New York, Taylor & Francis, Chakinala MM , Ritter J , Gage BF , et al. Yield of surveillance 2006 : 285 – 300 . bronchoscopy for acute rejection and lymphocytic Elizur A , Sweet SC , Huddleston CB, et al. Pre - transplantation bronchitis/bronchiolitis after lung transplantation. J Heart mechanical ventilation increases short- term morbidity and Lung Transplant 2004 ;23 : 1396 – 404 . mortality in pediatric patients with cystic fi brosis . J Heart Chamberlain D , Maurer J , Chaparro C , Idolor L . Evaluation Lung Transplant 2007 ;26 : 127 – 31 . of transbronchial lung biopsy specimens in the diagnosis Estenne M , Maurer JR , Boehler A , et al. Bronchiolitis oblit- of bronchiolitis obliterans after lung transplantation. erans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 1994 ; 13 : 963 – 71 . J Heart Lung Transplant 2002 ; 21 : 297 – 310 . Chatila WM , Furukawa S , Gaughan JP , Criner , GJ. Ettinger NA , Bailey TC , Trulock EP , et al. Cytomegalovirus Respiratory failure after lung transplantation. Chest infection and pneumonitis: impact after isolated lung 2003 ; 123 : 165 – 73 . transplantation . Am Rev Respir Dis 1993 ; 147 : 1017 – 23 . Choong CK , Meyers BF . Quality of life after lung transplan- Fischer S , Bohn D , Rycus P , et al. Extracorporeal membrane tation . Thorac Surg Clin 2004 ; 14 : 385 – 407 . oxygenation for primary graft dysfunction at lung trans- Christie JD , Bavaria JE , Palevsky HI , et al. Primary graft plantation: analysis of the Extracorporeal Life Support failure following lung transplantation. Chest 1998 ; 114 : Organization (ELSO) registry. J Heart Lung Transplant 51 – 60 . 2007 ; 26 : 472 – 7 . Christie JD , Kotloff RM , Ahya VN , et al. The effect of Flume PA , Egan TM , Paradowski LJ , Detterbeck FC , primary graft dysfunction on survival after lung trans- Thompson JT , Yankaskas JR . Infectious complications of plantation. Am J Respir Crit Care Med 2005 ; 171 : lung transplantation: impact of cystic fi brosis . Am J 1312 – 16 . Respir Crit Care Med 1994 ; 149 : 1601 – 7 . Cooper JD , Billingham M , Egan T , et al. A working formu- Gammie JS , Keenan RJ , Pham SM , et al. Single - versus lation for the standardization of nomenclature and for double - lung transplantation for pulmonary hypertension. clinical staging of chronic dysfunction in lung allografts. J Thorac Cardiovasc Surg 1998 ; 115 : 397 . J Heart Lung Transplant 1993 ; 12 : 713 – 16 . George I , Xydas S , Topkara VK , et al. Clinical indication Corris P , Glanville A , McNeil K , et al. One year analysis of for use and outcomes after inhaled nitric oxide therapy. an ongoing international randomized study of mycophe- Ann Thorac Surg 2006 ; 82 : 2161– 9 . nolate mofetil (MMF) vs azathioprine (AZA) in lung Gerbase MW , Spiliopoulos A , Rochat T , Archinard M , transplantation . J Heart Lung Transplant 2001 ; 20 : 149 – Nicod LP . Health - related quality of life following single 50 . or bilateral lung transplantation: a 7- year comparison to Daud SA , Yusen RD , Meyers BF , et al. Impact of immediate functional outcome. Chest 2005 ;128 : 1371 – 8 . primary lung allograft dysfunction on bronchiolitis oblit- Glanville AR. The role of bronchoscopic surveillance moni- erans syndrome. Am J Respir Crit Care Med 2007 ; 175 : toring in the care of lung transplant recipients. Semin 507 – 13 . Respir Crit Care Med 2006 ; 27 : 480 – 91 . deJong PA , Dodd JD , Coxson HO , et al. Bronchiolitis oblit- Glanville AR , Estenne M . Indications, patient selection and erans following lung transplantation: early detection using timing of referral for lung transplantation . Eur Respir J computed tomographic scanning. Thorax 2006 ; 61 : 799 – 2003 ; 22 : 845 – 52 . 804 . Glanville AR , Aboyoun CL , Morton JM , et al. Cyclosporine Dellon ES , Morgan DR , Mohanty SP , Davis K , Aris RM . C2 target levels and acute cellular rejection after lung High incidence of gastric bezoars in cystic fi brosis patients transplantation . J Heart Lung Transplant 2006 ; 25 : 928 – after lung transplantation. Transplantation 2006 ; 81 : 34 . 1141 – 6 . Groetzner J , Kur F , Spelsberg F , et al., Munich Lung DeMeo DL , Ginns LC. Clinical status of lung transplanta- Transplant Group. Airway anastomosis complications tion . Transplantation 2001 ; 72 : 1713 – 24 . in de novo lung transplantation with sirolimus - based Efrati O , Kremer MR , Barak A , et al. Improved survival immunosuppression. J Heart Lung Transplant 2004 ; 23 : following lung transplantation with long- term use of 632 – 8 .

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Hadijiliadis D , Madill J , Chaparro C , et al. Incidence and chiolitis obliterans syndrome after lung transplantation . prevalence of diabetes mellitus in patients with cystic J Thorac Cardiovasc Surg 1997 ;114 : 195 – 202 . fi brosis undergoing lung transplantation before and after Lama VN , Flaherty KR , Toews GB , et al. Prognostic value lung transplantation. Clin Transplant 2005 ; 19 : 773 – 8 . of desaturation during 6- minute walk test in idiopathic Hadjiliadis D , Angel LF . Controversies in lung transplanta- interstitial pneumonia. Am J Respir Crit Care Med 2003 ; tion: Are two lungs better than one? Semin Respir Crit 168 : 1084 – 90 . Care Med 2007 ; 27 : 561 – 6 . Leblond V , Sutton L , Dorent R , et al. Lymphoproliferative Hardy JD , Webb WR , Dalton ML , Walker GR . Lung homo- disorders after organ transplantation: A report of 24 cases transplantation in man: report of the initial case . JAMA observed at a single center. J Clin Oncol 1995 ; 13 : 961 – 8 . 1963 ; 186 : 1065 – 74 . Lee E - S , Gotway MB , Reddy GP , Golden JA , Keith FM , Helmi M , Welter D , Cornwell RD , Love RB , Meyer KC . Webb WR. Early bronchiolitis obliterans following lung Tracheobronchial aspergillosis in lung transplant recipi- transplantation: accuracy of expiratory thin- section CT ents with cystic fi brosis; risk factors and outcome com- for diagnosis . Radiology 2000 ; 216 : 472 – 7 . parison to other transplant recipients . Chest 2003 ; 123 : Levy G , Thervet E , Lake J , et al. Patient management by 800 – 8 . Neoral C2 monitoring: an international consensus state- Horning NR , Lynch JP , Sundaresan SR , Patterson GA , ment . Transplantation 2002 ; 73 : S12 – 18 . Trulock EP . Tacrolimus therapy for persistent or recur- Levy RD , Ernst P , Levine SM , et al. Exercise performance rent acute rejection after lung transplantation . J Heart after lung transplantation . J Heart Lung Transplant 1993 ; Lung Transplant 1998 ;17 : 761 – 7 . 12 : 27 – 33 . Husain S , Paterson DL , Studer S , et al. Voriconazole prophy- Lu BS , Garrity ER Jr , Bhorade SM . Immunosuppressive laxis in lung transplant recipients . Am J Transplant drugs: cyclosporine, tacrolimus, sirolimus, azathioprine, 2006 ; 6 : 3008 – 16 . mycophenolate mofetil, and corticosteroids. In: Lynch JP Iacono AT , Johnson BA , Grgurich B , et al. A randomized III , Ross DJ (eds), Lung Biology in Health and Disease , trial of inhaled cyclosporine in lung- transplant recipients. Vol 217 . Lung and Heart- Lung Transplantation . New N Engl J Med 2006 ; 354 : 141 – 50 . York : Taylor & Francis , 2006 : 363 – 99 . Ishani A , Erturk S , Hertz MI , Matas AJ , Savik K , Rosenberg McAnally KJ , Valentine VG , LaPlace SG , McFadden PM , ME . Predictors of renal function following lung or heart - Seoane L , Taylor DE. Effect of pretransplantation pred- lung transplantation . Kidney Int 2002 ; 61 : 2228 – 34 . nisone on survival after lung transplantation. J Heart Kahan ES , Petersen G , Gaughan JP , Criner GJ . High inci- Lung Transplant 2006 ;25 : 67 – 74 . dence of venous thromboembolic events in lung transplant Martinez , FJ , Safrin S , Weycker D , et al. The clinical course recipients. J Heart Lung Transplant 2007 ; 26 : 339 – 44 . of patients with idiopathic pulmonary fi brosis . Ann Intern Kaneda H , Waddell TK , de Perrot M , et al. Pre - implantation Med 2004 ; 142 : 963 – 7 . multiple cytokine mRNA expression analysis of donor Maurer JR , Frost AE , Estenne M , et al. International lung grafts predicts survival after lung transplantation in Guidelines for the Selection of Lung Transplant humans . Am J Transplant 2006 ; 6 : 544 – 51 . Candidates . J Heart Lung Transplant 1998 ; 17 : 703 – 9 . Kawut SM , Lederer DJ , Keshavjee S , et al. Outcomes after Maurer JR. Metabolic bone disease in lung transplant recipi- lung retransplantation in the modern era. Am J Respir ents . In: Lynch JP III , Ross DJ (eds), Lung Biology in Crit Care Med 2008 ; 177 : 114 – 20 . Health and Disease , Vol 217 . Lung and Heart- Lung Kerem E , Reisman J , Corey M , Canny GJ , Levison H . Transplantation . New York: Taylor & Francis, 2006 : Prediction of mortality in patients with cystic fi brosis. 895 – 9 . New Engl J Med 1992 ; 326 : 1187 – 91 . Mayer - Hamblett N , Rosenfeld M , Emerson J , et al. Knoop C , Thiry P , Saint- Marcoux F , Rousseau A , Marquet Developing cystic fi brosis lung transplant referral criteria P , Estenne M. Tacrolimus pharmacokinetics and dose using predictors of 2- year mortality. Am J Respir Crit monitoring after lung transplantation for cystic fi brosis Care Med 2002 ; 166 : 1550 – 5 . and other conditions. Am J Transplant 2005 ; 5 : 1477 – 82 . Meade MO , Granton JT , Matte - Martyn A , et al. A rand- Knoop C , Vervier I , Thiry P , et al. Cyclosporine pharma- omized trial of inhaled nitric oxide to prevent ischemia - cokinetics and dose monitoring after lung transplantation: reperfusion injury after lung transplantation. Am J Respir comparison between cystic fi brosis and other conditions. Crit Care Med 2003 ; 167 : 1483 – 9 . Transplantation 2003 ; 76 : 683 – 8 . Meyer K. Allogeneic recognition and immune tolerance in Kotloff RM , Ahya VN . Medical complications of lung trans- lung transplantation. In: Lynch JP III , Ross DJ (eds), Lung plantation . Eur Respir J 2004 ; 23 : 334 – 42 . Biology in Health and Disease , Vol 217 . Lung and Heart - Kroshus TJ , Kshettry VR , Savik K , John R , Hertz MI , Lung Transplantation . New York: Taylor & Francis, Bolman RM III . Risk factors for the development of bron- 2006 : 47 – 60 .

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Moro J , Almenar L , Martinez - Dolz L , et al. mTOR inhibi- Studer SM , Levy RD , McNeil K , Orens JB. Lung transplant tors: do they help preserve renal function? Transplant outcomes: a review of survival, graft function, physiology, Proc 2007 ; 39 : 2135 – 7 . health - related quality of life and cost - effectiveness. Eur Orens JB , Boehler A , de Perrot M , et al. A review of lung Respir J 2004 ; 24 : 674 – 85 . transplant donor acceptability criteria. J Heart Lung Swanson SJ , Mentzer SJ , Reilly JJ , et al. Surveillance trans- Transplant 2003 ; 22 : 1183 – 200 . bronchial lung biopsies: implication for survival after lung Orens JB , Estenne M , Arcasoy S , et al. International guide- transplantation . J Thorac Cardiovasc Surg 2000 ; 119 : lines for the selection of lung transplant candidates: 2006 27 – 37 . update – a consensus report from the Pulmonary Scientifi c Thabut G , Mal H , Cerrina J , Dartevelle P , et al. Graft Council of the International Society for Heart and Lung ischemic time and outcome of lung transplantation . Am J Transplantation. J Heart Lung Transplant 2006 ; 25 : 745 – Respir Crit Care Med 2005 ; 171 : 786 – 91 . 55 . Thabut G , Vinatier I , Stern JB , et al. Primary graft failure Palmer SM , Miralles AP , Howell DN , et al. Gastroesophageal following lung transplantation: Predictive factors of mor- refl ux as a reversible cause of allograft dysfunction after tality . Chest 2002 ; 121 : 1876 – 82 . lung transplantation. Chest 2000 ; 118 : 1214 – 7 . Trulock EP , Ettinger NA , Brunt EM , Pasque MK , Kaiser Patterson GA. Historical development of pulmonary LR , Cooper JD . The role of transbronchial lung biopsy transplantation. Semin Respir Crit Care Med 1996 ; 17 : in the treatment of lung transplant recipients. An analysis 103 – 7 . of 200 consecutive procedures. Chest 1992 ;102 : 1049 – Pierre F , Keshavjee S . Lung transplantation: donor and 54 . recipient critical care aspects. Curr Opin Crit Care 2005 ; Trulock , EP . Lung Transplantation. Am J Respir Crit Care 11 : 339 – 44 . Med 1997 ; 155 : 789 – 815 . Pilcher DV , Scheinkestel CD , Snell GI , et al. A high central Van De Wauwer C , Van Raemdonck D , Verleden GM , venous pressure is associated with prolonged mechanical et al. Risk factors for airway complications within the fi rst ventilation and increased mortality following lung trans- year after lung transplantation . Eur J Cardiothorac Surg plantation. J Thoracic Cardiovasc Surg 2005 ; 129 : 912 – 8 . 2007 ; 31 : 703 – 10 . Ramalingam P , Rybicki L , Smith MD , et al. Posttransplant Venuta F , De Giacomo T , Rendina EA , et al. Recovery of lymphoproliferative disorders in lung transplant patients: chronic renal impairment with sirolimus after lung trans- the Cleveland Clinic experience. Mod Pathol 2002 ; 15 : plantation . Ann Thorac Surg 2004 ; 78 : 1940 – 3 . 647 – 56 . Verleden GM , Dupont LJ . Azithromycin therapy for patients Reams BD , McAdams HP , Howell DN , et al. Posttransplant with bronchiolitis obliterans syndrome after lung trans- lymphoproliferative disorder: incidence, presentation, and plantation . Transplantation 2004 ; 77 : 1465 – 7 . response to treatment in lung transplant recipients . Chest Verschuuren EA , Stevens S , Pronk I , et al. Frequent monitor- 2003 ; 124 : 1242 –9 . ing of Epstein – Barr virus DNA load in unfractionated Ross DJ , Waters PF , Levine M , Kramer M , Ruzevich S , Kass whole blood is essential for early detection of post- RM . Mycophenolate mofetil versus azathioprine immu- transplant lymphoproliferative disease in lung transplant nosuppressive regimens after lung transplantation: pre- patients . J Heart Lung Transplant 2001 ; 20 : 199 – 200 . liminary experience. J Heart Lung Transplant 1998 ; 17 : Weigt SS , Lynch JP III , Langer LR , et al. Lymphoproliferative 768 – 74 . disorders complicating solid organ transplantation . In: Shumway , SJ , Hertz , MI , Petty , MG , Bolman , RM. Lynch JP III , Ross DJ (eds), Lung Biology in Health and Liberalization of donor criteria in lung and heart- lung Disease , Vol 217 . Lung and Heart- Lung Transplantation . transplantation . Ann Thorac Surg 1994 ;57 : 92 – 5 . New York : Taylor & Francis , 2006 : 901 – 34 . Smeritschnig B , Jaksch P , Kocher A , et al. Quality of life Wigfi eld CH , Lindsey JD , Steffens TG , et al. Early institution after lung transplantation: a cross- sectional study. J Heart of extracorporeal membrane oxygenation for primary Lung Transplant 2005 ;24 : 474 – 80 . graft dysfunction after lung transplantation improved Snyder LD , Palmer SM . Immune mechanisms of lung allo- outcome . J Heart Lung Transplant 2007 ; 26 : 331 – 8 . graft rejection. Semin Respir Crit Care Med 2006 ; 27 : Williams TJ , Patterson GA , McClean PA , Zamel N , Maurer 534 – 43 . JR. Maximal exercise testing in single and double lung Starnes VA , Barr ML , Cohen RG . Lobar transplantation: transplant recipients. Am Rev Respir Dis 1992 ; 145 : indications, technique and outcome. J Thorac Cardiovasc 101 – 5 . Surg 1994 ; 108 : 403 – 10 . Wood KE , Becker BN , McCartney JG , et al. Care of the Starnes VA , Bowdish ME , Woo MS , et al. A decade of living potential organ donor. N Engl J Med 2004 ; 351 : 2730 – 9 . lobar lung transplantation: recipient outcomes. J Thorac Yates B , Murphy DM , Forrest IA , et al. Azithromycin Cardiovasc Surg 2004 ; 127 : 114 – 22 . reverses airfl ow obstruction in established bronchiolitis

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obliterans syndrome. Am J Respir Crit Care Med 2005 ; Bronchiectasis: chronic dilation of bronchi. It can be 172 : 772 – 5 . the result of infl ammation, infection, and/or lung Young LR , Hadjiliadis D , David D , et al. Lung transplanta- tissue fi brosis (traction bronchiectasis). tion exacerbates gastroesophageal refl ux disease . Chest 2003 ; 124 : 1689 – 93 . Bronchoscopy: the direct visualization of the trachea Yousem SA , Berry GJ , Cagle PT , et al Revision of the 1990 and bronchi through a rigid or fl exible tube working formulation for the classifi cation of pulmonary (bronchoscope). allograft rejection: Lung Rejection Study Group . J Heart CPB: cardiopulmonary bypass – to surgically insert Lung Transplant 1996 ;15 : 1 – 15 . Zamora MR , Davis RD , Leonard C , et al. Management of a shunt to bypass a chamber of the heart to carry cytomegalovirus infection in lung transplant recipients: blood directly to the aorta. evidence- based recommendations. Transplantation 2005 ; COPD: Chronic obstructive pulmonary disease – a 80 : 157 – 63 . progressive lung disease process characterized by Zuckermann A , Klepetko W , Birsan T , et al. Comparison diffi culty breathing, wheezing, and a chronic cough. between mycophenolate mofetil- and azathioprine- based Airfl ow obstruction usually does not improve after immunosuppressions in clinical lung transplantation. J Heart Lung Transplant 1999 ; 18 : 432 – 40 . inhaled bronchodilator medications. CF: cystic fi brosis – an inherited disease (autosomal recessive) that affects the lungs, exocrine pancreas Addendum: g lossary and gastrointestinal system resulting in chronic lung disease. α - Antitrypsin defi ciency: a defi ciency of a protein 1 DVT: deep venous thrombosis – blockage of the deep produced in the liver that blocks the destructive veins; particularly common in the leg. effects of certain enzymes.This inherited condition can be associated with emphysema and/or liver Diffuse panbronchiolitis: an idiopathic chronic disease. obstructive airway disease more commonly affecting Japanese individuals. Lymphocytic and plasma Atelectasis: absence of gas from a part or the whole cell infi ltration of bronchial walls occurs. of the lungs, due to failure of expansion or resorp- tion of gas from the alveoli. DIOS: distal intestinal obstructive syndrome – inspis- sation of intestinal contents in the terminal ileum, ARDS: acute respiratory distress syndrome – a mal- cecum, and proximal colon in patients with CF. function of the lung resulting from injury to the small air sacs and the capillaries of the lungs. Upon ECMO: extracorporeal membrane oxygenation – a injury, blood and fl uid leak into the air sacs, making technique that is used to oxygenate blood by breathing diffi cult. The condition can be fatal. passing it through an external membrane. BAL: Bronchoalveolar lavage – a technique that Eisenmenger’ s syndrome: the process in which a left- allows the recovery of both cellular and non - to - right shunt in the heart causes increased fl ow cellular components from the epithelial surface of through the pulmonary vasculature, resulting in the lower respiratory tract and differs from bron- pulmonary hypertension, which causes increased chial washings, which refer to the aspiration of pressures in the right side of the heart and reversal either secretions or small amounts of instilled saline of the shunt into a right - to - left shunt. from the large airways. Empyema: the presence of pus in a body cavity, espe- BiPAP: bilevel positive airway pressure – a non- cially the pleural cavity.

invasive means to deliver both inspiratory and FEV 1 : forced expiratory volume in 1 s – the volume expiratory pressure for ventilatory support. of air that can be exhaled during the ﬁ rst second of a forced exhalation. BO/BOS: bronchiolitis obliterans/bronchiolitis obliterans syndrome – irreversible scarring of the terminal FVC/VC: forced vital capacity/vital capacity – the and respiratory bronchioles which may either par- maximum volume of air that can be (forcibly) tially or totally obliterate the lumen of the airway. expired from the lungs.

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ILD: interstitial lung disease – a disorder resulting in tion in respiratory function. PEs often originate in scarring of lung tissue or the lining of the air sacs the deep leg veins and travel to the lungs through (alveolus); often results in poor oxygen diffusion the blood circulation. Symptoms include sudden from the alveolus into the bloodstream. shortness of breath, chest pain, and rapid heart and respiratory rates. IVC fi lter: inferior vena cava fi lter – a device placed in the inferior vena cava intended to disrupt the PGD primary graft dysfunction: reperfusion injury fl ow of a blood clot from the lower extremities to that occurs after implantation and causes paren- the lungs. chymal infi ltrates and impaired gas exchange. IPF: idiopathic pulmonary fi brosis – scarring or thick- Pulmonary hypertension: elevated blood pressure in ening of lung parenchyma of unknown etiology. the pulmonary circulation. Primary pulmonary NO: nitric oxide – a free radical gas synthesized from hypertension indicates that the etiology is not sec- arginine by nitric oxide synthase. It is one of the ondary to diseases of the heart or lungs. endothelium - dependent relaxing factors released Sarcoidosis: a multisystem disorder characterized in by the vascular endothelium and mediates vasodila- affected organs by a type of granulomatous infl am- tion. It also inhibits platelet aggregation, induces mation. The etiology is unknown. disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Six - minute walk test: 6MWT – a test that measures the distance that a patient can quickly walk on a PCR: polymerase chain reaction – a technique for fl at, hard surface in a period of 6 min. It evaluates amplifying DNA sequences in vitro by separating the global and integrated responses of all the the DNA into two strands and incubating it with systems involved during exercise, including the pul- nucleotide triphosphates. monary and cardiovascular systems, systemic circu- Pleuredesis: the surgical or medical creation of a lation, peripheral circulation, blood, neuromuscular fi brous adhesion between the visceral and parietal units, and muscle metabolism. layers of the pleura, thus obliterating the pleural TBLB: transbronchial lung biopsy – a lung biopsy cavity. obtained during bronchoscopy in which tiny PE: pulmonary embolism – lodging of a blood clot in forceps are passed to the distal bronchi and air sacs the lumen of a pulmonary artery, causing dysfunc- to obtain tissue.

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