State of the Art Pulmonary Considerations of Organ Transplantation Part 31 , 2
NEIL A. ETTINGER and ELBERT P. TRULOCK Contents Introduction Heart Transplantation Pretransplant Considerations Pulmonary Function Testing Airway Responsiveness Respiration and Sleep Cardiopulmonary Exercise Testing Pleural Effusions Pulmonary Embolism and Infarction Pulmonary Hypertension Other Pulmonary Problems Intraoperative Considerations Orthotopic Heart Transplantation Heterotopic Heart Transplantation Posttransplant Considerations Noninfectious Complications Atelectasis Pleural Effusions Pulmonary Edema Pulmonary Hypertension Malignancy Infectious Complications Bacterial Pneumonia Mediastinitis Cytomegalovirus Pneumonia Fungal Pneumonia Protozoal Pneumonia Heart-Lung Transplantation Pretransplant Considerations Recipient Selection Donor Selection and Donor-Recipient Matching Intraoperative Considerations Posttransplant Considerations Immunosuppression Weaning from Mechanical Ventilation Noninfectious Complications Pulmonary Edema Acute Rejection Obliterative Bronchiolitis Infectious Complications Bacterial Pneumonia Cytomegalovirus Pneumonia Herpes Simplex Pneumonitis Protozoal Pneumonia Fungal Pneumonia Results Survival Pulmonary Function Gas Exchange Exercise Performance Control of Breathing Airway Reactivity AM REV RESPIR DIS 1991; 144:433-451
Introduction During the last decade cardiac transplantation emerged as a standard therapy for end-stage heart disease. Cardiomyopathy and coronary artery disease have been the principal indications; less common reasons have included valvular disease and refractory dysrhythmias (332). In the last 3 yr (1987 through 1989), the number of heart transplants has reached a plateau of approximately 2,500 per yr. Current 5-yr actuarial survival after orthotopic heart transplantation is 72070 (333). Pretransplant Considerations
The purposes of the pretransplant pulmonary evaluation are to detect pulmonary abnormalities secondary to the intrinsic heart disease, to screen for any coexistent primary lung disease, and to assess the risk for cardiac transplant surgery. The majority of heart transplant candidates with ischemic or idiopathic cardiomyopathy present with the clinical syndrome of severe chronic congestive heart failure (CHF) and are in New York Heart Association functional Class 3 or 4. The hemodynamic profile of potential recipients with CHF has usually revealed a mean left ventricular ejection fraction of lessthan 20 or 25%, with a mean cardiac index of approximately 2.0 L/ min/m" and mean pulmonary capillary wedge pressure greater than 25 mm Hg (334, 335).
Pulmonary Function Tests The reduction in vital capacity in patients with heart failure was the earliest recognition of the effect of CHF on pulmonary function. Since then, pulmonary function studies in nonhomogeneous groups of patients with CHF have shown both restrictive and obstructive patterns. Recent investigations of pulmonary function in patients with severe CHF and in candidates for cardiac transplantation
have usually revealed predominantly restrictive physiology; however, the reductions in lung volumes have been relatively mild. Mean vital capacity (VC) has averaged 70 to 80% predicted and TLC 70 to 90% predicted (334-337). Although an inverse relationship between VC (or TLC) and pulmonary capillary wedge pressure has been demonstrated, the correlation was not strong (338). Several factors, including interstitial and alveolar edema, pleural effusions, and cardiomegaly, can contribute to the restrictive physiology. In one group of recipients evaluated before and after transplantation, cardiac volume alone accounted for 69010 of the change in FVC after transplantation (334). In the absence of coexistent primary lung disease, the abnormalities in pulmonary function have been reversed by successful cardiac transplantation (334, 336). The DLco has usually been mildly decreased in potential heart transplant recipients and in nontransplant patients with moderate-to-severe left ventricular dysfunction (335, 337). In a large group of potential cardiac transplant recipients, the Dtco was the most frequently abnormal routine pulmonary function test parameter and had a mean value of 64.5010 predicted (335). It was the only abnormality in 31010 of the patients, and it occurred in conjunction with a spirometric
(Received in original form February 14, 1991 and in revised form April 16, 1991) 1 From the Respiratory and Critical Care Division, Washington University School of Medicine, St. Louis, Missouri. 2 Correspondence and requests for reprints should be addressed to Neil A. Ettinger, M.D., Respiratory and Critical Care Division, Washington UniversitySchool of Medicine, Box 8052,660South Euclid Avenue, St. Louis, MO 63110.
This is Part 3 of three parts; the first part appeared in Vol. 143, Number 6, and the second part appeared in Vol. 144, Number 1 of the Review. 433
ETTINGER AND TRULOCK
abnormality in another 36010 of the recipients. No correlation could be established between diffusion impairment and the pulmonary capillary wedge pressure or the duration of CHF. Pre- and posttransplantation values of OLeo have been reported in one study of 10 recipients (339). The OLeo, corrected for hemoglobin, and the Keo fell significantly after transplantation. A correlation between the cyclosporine blood level and the decline in Keo was noted, and a toxic effect of cyclosporine on the lung was speculated as a plausible explanation in the absence of other obvious causes. Although this postulate is intriguing, cyclosporine pulmonary toxicity has not previously been detected or suspected during its widespread use in solid organ transplantation. Pulmonary function tests (PFTs) are part of the routine pretransplant screening evaluation in most cardiac transplantation centers. Although there are no widely accepted guidelines, a variety of exclusion criteria have been mentioned (334, 340, 341); however, none of them have been rigorously validated. The link between preoperative pulmonary status and outcome after heart transplantation has been the focus of only one study (342). Preoperative PFTs, arterial blood gases, and hemodynamic variables were compared in 33 cardiac transplant recipients. There was no significant difference between the survivors and nonsurvivors in any PFT parameter or in arterial blood gases. Survival was negatively influenced only by older age and higher pulmonary vascular resistance. PFTs must be utilized cautiously as a pretransplantation screening tool. A restrictive pattern and/or a decreased OLeo are not unusual and could be caused solely by CHF. Although less characteristic of chronic CHF, an obstructive pattern can also occur alone or together with other abnormalities (335). Hence, PFTs are less valuable for detecting coexistent primary lung disease but can be helpful when the pattern and severity of abnormalities are synthesized with other clinical information. Furthermore, although unpublished experience and empirically derived guidelines from some centers cannot be discounted, rigid exclusionary criteria regarding pulmonary function for cardiac transplantation have not been strongly supported in the literature.
Airway Responsiveness Studies of airway reactivity by provocation tests with inhaled cholinergic agents
in somewhat heterogeneous groups of patients with chronic CHF have yielded inconsistent results. Although two studies found normal responses to inhaled methacholine (343,344), several others reported some degree of airway hyperreactivity in the majority of patients (345-347). No correlation has been established between various hemodynamic variables and the PC 2 0FEV 1 (345). Many of the patients in these studies have been smokers or exsmokers, but in one comparison PC 2 0FEV 1 was similar in nonsmokers and exsmokers (345). The clinical importance of bronchial hyperresponsiveness in patients with CHF is unclear. The therapeutic focus should remain on CHF itself. However, the methacholine-induced bronchoconstriction is reversed in some patients by treatment with an inhaled ~-agonist (346), and a trial of such therapy might be worthwhile if other conventional treatments of CHF have been exhausted and attacks of cardiac asthma continue.
Respiration and Sleep Only recently has the relationship between sleep and disordered breathing been analyzed in patients with CHF (348, 349). These relatively small studies have found a high incidence of abnormal breathing patterns, especially CheyneStokes respiration and central apnea, and unexpected severe nocturnal oxygen desaturation. The prevalence and implications of sleep-related breathing disorders and nocturnal desaturation in patients with CHF is uncertain at the present time. No adverse events have been detected, but the study groups have been small and the surveillance period short. Nonetheless, the frequent discovery of clinically unsuspected nocturnal desaturation is worrisome. Hypoxemia could aggravate myocardial ischemia and/or trigger cardiac dysrhythmias. Thus, after other medical treatment has been maximized, nocturnal Sao, recording may be worthwhile in selected patients with severe CHF.
Cardiopulmonary Exercise Testing The severity of chronic CHF, including the widely employed New York Heart Association classification, has traditionally been judged in part by the patient's symptomatology. Such a subjective approach has obvious inherent limitations, and more objective measures have been sought to gauge severity, to monitor progression of the disease or response to treatment, and to predict prognosis. The
radionuclide left ventricular ejection fraction has been a valuable parameter, but it has correlated loosely with symptoms and functional class (341). In the past few years cardiopulmonary exercise testing has become a useful adjunct in the management of patients with cardiac failure. Cardiopulmonary exercise testing not only can quantify the severity of cardiac failure (350) but also can help distinguish between cardiac and pulmonary causes of dyspnea and exercise limitation (351, 352). The determination of Vo1max during a graded exercise test has provided a noninvasive, reliable, and reproducible way to categorize cardiac failure (350, 353). Little-to-no cardiac failure is present if Vo1max is greater than 20 ml/kg/ min, mild-to-moderate cardiac failure if Vo2max is 16to 20 mllkg/min, moderateto-severe failure if Vo1max is 10 to 16 mllkg/min, and severe failure if Vo2max is less than 10 ml/kg/min. These categories correspond respectively to a maximal cardiac index during exercise of more than 8 Lzmin/m-, 6 to 8 Lzmin/m", 4 to 6 L/ min/m-, and less than 4 Lzrnin/m- (350). When considering patients with CHF for cardiac transplantation, determination of Vo2max can provide some prognostic guidance. In one comparison patients with a Vo2max less than 10 mIl kg/min had a 1 yr mortality rate of 770/0, whereas those with a Vo2max greater than 10 ml/kg/min had a mortality rate of 21% (354). Thus, cardiopulmonary exercise testing can help identify high-risk patients, and serial evaluations may facilitate detection of clinical deterioration.
Pleural Effusions Heart failure is probably the most common cause of pleural effusion, and pleural effusions occur frequently in CHF. The mechanisms of pleural liquid and solute exchange have been thoroughly reviewed (355, 356). The relationship between central hemodynamics and pleural effusion has not been completely resolved, and questions persist regarding the relative importance of right- versus left-side pressure in experimental models (352). A close association between pulmonary arterial wedge pressure elevation and pleural effusion formation has been established in patients with CHF (357). In contrast, no pleural effusions could be demonstrated in a heterogeneous group of patients with chronic right atrial and/ or pulmonary arterial hypertension caused mostly by either primary pulmonary hypertension or COPO (358).
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
The majority of pleural effusions caused by CHF are bilateral, but unilateral effusions also occur with a 2:1 rightside predominance (355). The pleural fluid is typically a transudate; however, chronicity and diuretic therapy may shift the characteristics into the exudative range (359, 360). In this situation the distinction may be enhanced by using the albumin gradient (albuminserum - albuminfluid), a value greater than 1.2 g/dl corresponding to a transudate (359). Pleural effusions have been observed in as many as 34% of potential heart transplant recipients (335), but no studies of the effusions have been reported. As in other patients with CHF, a thoracentesis is not mandatory in the pretransplant evaluation unless atypical clinical or radiographic features are present, or the cause of the effusion is unclear. If a thoracentesis is performed, some recipients will likely have pleural effusions with equivocal or exudative characteristics because of their chronicity and/or diuretic therapy. The albumin gradient may be useful, but other causes of a pleural exudate should be excluded by appropriate tests.
Pulmonary Embolism and Infarction The risk of pulmonary embolism is increased in patients with heart disease, and the risk is magnified by CHF and atrial fibrillation (361). In a necropsy analysis of 152 patients with idiopathic dilated cardiomyopathy, pulmonary emboli or infarcts were discovered in 66 of 131 autopsies (50070) (362). Right-side, intracardiac thrombi or endocardial plaques were identified in 45 of the 66 cases, but the deep venous system of the legs was not examined. The prevalence of deep venous thrombosis or pulmonary thromboembolism has not been surveyed directly in potential cardiac transplant recipients. Nonetheless, they usually have one or more proven risk factors and, therefore, must be considered a high-risk group. Recent preoperative pulmonary embolism and unresolved pulmonary infarction have been associated with substantial posttransplantation morbidity and are still considered at least temporary contraindications to cardiac transplantation by most centers (340, 341, 363). Secondary infection of the infarcted area in an already immunocompromised recipient has been complicated by sepsis, lung abscess, empyema, and bronchopleural fistula, often necessitating surgical
management (364, 365). Thus, if pulmonary embolism or infarction is suspected during the pretransplant evaluation, the diagnosis should be definitively confirmed or excluded by ventilation-perfusion scintigraphy and/or pulmonary angiography. If the diagnosis is corroborated, standard therapy should be instituted, and cardiac transplantation should be postponed until the problem has been treated and resolved. When dictated by the potential recipient's cardiac status, transplantation can be done in the presence of known or suspected pulmonary embolism or infarction (364, 365); however, the attendant risks should be justified by the recipient's short-term prognosis without transplantation.
management of pulmonary hypertension and the type of transplant procedure are in the province of the transplant cardiologist and surgeon. From the pulmonary perspective, the pulmonary arterial hypertension should not be substantially out of proportion to the pulmonary venous hypertension. If a discrepancy is noted, complications, such as pulmonary embolism, or other coexisting pulmonary processes should be contemplated and evaluated.
Other Pulmonary Problems Other pulmonary problems may be encountered during the pretransplant assessment. In general, these should be handled in the standard fashion. An aggressive approach to diagnosis is generally Pulmonary Hypertension warranted by the potential adverse conPulmonary artery pressure rises pari sequences of overlooking a serious probpassu with pulmonary venous pressure lem in a prospective transplant recipient. in CHF. Although the pulmonary vas- Among the more common of these othcular changes and increased pulmonary er problems are hemoptysis and unexvascular resistance due to left heart fail- plained focal or diffuse pulmonary ure are almost always reversible with infiltrates. definitive treatment such as cardiac transHemoptysis can be caused by CHF. plantation, the normal donor heart will However, many potential cardiac transdevelop right heart failure in the early plant recipients have a significant smokposttransplant period if the afterload on ing history and are at risk for both bronits unadapted right ventricle is too great. chitis and bronchogenic carcinoma as In general, suitable recipients for ortho- well as pulmonary thromboembolism topic heart transplantation should have (vide supra). The chance of bronchogenic a pulmonary vascular resistance (PVR) carcinoma is low if the chest radiograph less than 2.5 to 5 Wood units and a pul- is normal (371); however, an occult lemonary artery systolic pressure less than sion should be excluded by bronchosco45 to 50 mm Hg after receiving optimal py in most patients. Indications for bronmedical management (341, 366, 367). choscopy in nontransplant patients with Strategies for orthotopic transplanta- hemoptysis have been outlined: age more tion in patients with an elevated PVR than 40 yr; any abnormality on chest rahave included oversizing a normal donor diograph; significant smoking history; heart or implanting a domino donor and duration of hemoptysis more than heart with right ventricular hypertrophy 1 wk (371, 372). Bronchoscopy can be from a heart-lung transplant recipient. done safely by carefully monitoring viAlternatively, a heterotopic heart trans- tal signs, cardiac rhythm, and oxygen plant can be performed. Although con- saturation throughout the procedure, and troversy still surrounds the best approach a negative bronchoscopic examination to such patients, recent reports have sug- has implied a good prognosis in nongested that orthotopic transplantation transplant patients with hemoptysis and may be preferable if a suitable donor a normal chest radiograph (373). Comheart can be obtained (368, 369). Regard- puted tomography has augmented the raless of the approach to cardiac transplan- diographic evaluation of hemoptysis, but tation' posttransplantation survival sta- it has not obviated the need for bronchostistics have been worse in recipients with copy and has rarely supplemented the an elevated PVR (342, 369, 370). Some combined diagnostic yield of chest radipatients with primary cardiac disease and ography and bronchoscopy (374). irreversible secondary pulmonary hyperDiffuse interstitial or interstitial/alvetension, usually with PVR >6 to 8 Wood olar infiltrates are the radiographic hallunits, will not be acceptable candidates mark of CHF. In hydrostatic pulmonary for cardiac transplantation. If there are edema, a good correlation has been no contraindications, they may be con- found between radiographic scores and sidered for heart-lung transplantation. indicator dilution measurements of exDecisions about the acceptability and travascular lung water (356). However,
ETTINGER AND TRULOCK
the correlation between pulmonary arterial wedge pressure and radiographic score has shown more variability. A normal wedgepressure with persistent radiographic evidence of edema has not been uncommon in the acute setting and has been attributed to the slow clearance of extravascular lung water, but this discrepancy may be lesslikelyin more chronic, stable CHE Nonetheless, a disparity between the hemodynamics and the chest radiograph may raise the specter of another cause for the radiographic pattern. A further workup is necessary if other possible etiologies are present and the clinical picture is ambiguous. In cardiac transplantation evaluations this dilemma occasionally arises in patients being treated with certain antidysrhythmic drugs. Amiodarone (375,376), procainamide (377), and tocainide (378, 379) have all been associated with druginduced pulmonary syndromes that can mimic CHF and/or infection. However, by integrating clinical features, hemodynamics, and bronchoscopic findings, distinction is usually possible. A trial of drug withdrawal may be helpful, but can carry significant risk in patients with refractory dysrhythmias. Steroids have been used after diagnosis in severecases. Intraoperative Considerations
The technique of orthotopic heart transplantation has undergone very fewmodifications since its early development and application in the 1960s. Differences in the approach to this operation are usually few and reflect relatively minor institutional preferences (380). In general, after institution of cardiopulmonary bypass, the recipient heart is removed by dividing the atria at their midlevel and severing the great vessels above their valves (381). The donor atria are then anastomosed to the remaining cuffs of native atria, and the proximal and distal ends of the great vessels are joined. If the graft ischemic time is kept within accepted limits and implantation is uneventful, the patient is usually weaned from cardiopulmonary bypass without difficulty (380). Heterotopic heart transplantation (HHT) is performed in selected patients who have high pulmonary vascular resistance, who receive an inappropriately small donor organ, or who have acute and potentially reversiblemyocardial dysfunction that is expected to resolve (382). During HHT, the donor heart is placed in the right thoracic cavity and connected to the recipient's heart in such a man-
ner that the native right ventricle provides the majority ofthe right-side cardiac output and the donor left ventricle provides the bulk of the left-side cardiac output. Although this technique is occasionally useful, it has a number of disadvantages. Long-term anticoagulation is required because of the risk of systemic embolization from the recipient's native left ventricle; angina may continue from the recipient's remaining ischemic myocardium, and arrhythmias originating from the native heart may develop or persist (380). Recent evidence suggests that there are fewer indications for this type of procedure and that orthotopic transplantation is preferable wheneverpossible (368). Although most patients are weaned from cardiopulmonary bypass without difficulty, approximately 10,10 of heart transplant recipients are unable to wean, and an additional 2% are weaned only with the aid of mechanical circulatory assistance. Normally, function of the cardiac allograft has been shown to be suboptimal for the first 4 days after transplantation (383), and right ventricular recovery may be delayed even longer (384). In most cases, however, the use of lowdose inotropic support is usually sufficient to maintain adequate cardiac output. As a result of the early myocardial dysfunction, cardiac output is predominantly rate dependent for the first few days; bipolar atrial pacing or chronotropic agents, such as isoproterenol or dobutamine, are often used during this period to maintain adequate cardiac output (384). Posttransplant Considerations
Heart transplant recipients face a number of complications after transplantation that limit the ultimate success of the procedure. Infectious complications, particularly pneumonia, occur in 40 to 80% of the patients (385). Among the noninfectious complications, acute and chronic allograft rejection, accelerated graft atherosclerosis, and malignancies appear to be the most important problems facing long-term survivors (386). The management of many of these complications usually lies in the province of the transplant cardiologist. However, the heart transplant recipient is susceptible to pulmonary complications that are particularly prominent in the early posttransplant period. Noninfectious Complications
The majority of heart transplant recipients develop noninfectious pulmonary complications with a spectrum and fre-
quency similar to that seen in patients undergoing nontransplant cardiac surgery (382). Immediately after transplantation, pericardial effusions; atelectasis; and pleural, mediastinal, or peritoneal air collections are common but are usually not clinically important (382). Mediastinal hemorrhage, although rare, can be life threatening, and any progressive widening of the mediastinal silhouette accompanied by increased bleeding from mediastinal drains warrants prompt investigation (387). Acute cardiac rejection, which is characterized by hemodynamic and radiographic signs of biventricular dysfunction, is rare in the immediate posttransplant period. However, poor ventricular function, especially of the right ventricle, is common in the first few days after transplantation and is usually a result of ischemia or preservation injury (383). Atelectasis. Atelectasis can be expected in 65 to 91% of patients undergoing nontransplant cardiac surgery, and the frequency is probably similar in heart transplant recipients. The vast majority develop left lower lobe atelectasis, although the process may be bilateral in as many as 50% (387, 388). The left-side predominance reflects a variety of preoperative and intraoperative factors. These include retraction of the left lower lobe during surgery, compression of the lobe by the enlarged native heart, poor accessibility to the left lower lobe with routine endobronchial suction catheters, and the effects of topical cooling of the donor heart on the left phrenic nerve (382). Paralysis or paresis of the left phrenic nerve is a well-documented complication of topical cardioplegia that may occur in 55 to 64% of patients (389). The resulting left hemidiaphragmatic dysfunction can last from weeks to months (388, 389). Patients who undergo heterotopic heart transplantation invariably develop right lower lobe atelectasis as a result of compression by the allograft placed in the right thoracic cavity (368). The appearance of atelectasis may be delayed until after extubation, and the routine use of positive end-expiratory pressure during mechanical ventilation does not prevent its development (388). The concurrent presence of pleural effusions may further predispose to atelectasis and delay its resolution. In a study of 92 patients undergoing cardiac surgery, atelectasis resolved within 10 days in one-third of patients but took longer than 10 days in another third. The final third never had radiographic clearing
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
during the 6- to 22-wk follow-up (387). However, the reported incidence has In general, aggressive pulmonary toilet ranged as high as 12070 of autopsied pais the only treatment required, although tients (392). The syndrome usually debronchoscopic clearing of secretions is velops within 24 to 48 h after surgery and occasionally necessary.Pneumonia rarely is associated with an extremely high morsupervenes in the atelectatic segments in tality (390). this setting (382). The mechanisms of increased vascuPleural Effusions. Pleural effusions lar permeability after cardiopulmonary are described in up to 78070 of cardiac sur- bypass are multifactorial and are presentgical patients during the immediate post- ly only partially understood. The interoperative period. The majority are small, action of blood with foreign surfaces durbilateral, and are often associated with ing CPB is associated with the release of atelectasis (387). Formation of pleural vasoactive substances such as C3a and fluid may occur as a result of CHF C5a, which may result in leukoaggluti(20070), minor postsurgical hemorrhage nation within pulmonary capillaries and or pleural irritation during the procedure which may also directly affect vascular (382, 387). However, cardioplegia solu- permeability (393). Ultrastructural studies tion, iced saline, or mediastinal blood after CPB have demonstrated engorgemay also enter the pleural space through ment of the pulmonary vascular bed with unrecognized pleural tears (390). Pre- leukocytes, intracellular edema of puloperative collections of pleural fluid are monary vascular endothelium, and inoften drained at the time of surgery so terstitial edema and hemorrhage (395). that the postoperative development of Recent studies have also confirmed an pleural effusions should prompt an at- increase in extravascular lung water (396, tempt to identify a causative factor. Most 397) immediately after CPB that appears effusions regress within days, but some to be more pronounced in elderly patients organize and leave permanent blunting (398). The methodology in this area, however,remains controversial (399), and of the costophrenic angle (382). Pulmonary Edema. Pulmonary ede- its relevanceto the development of ARDS ma is common in the immediate post- in this setting is unclear. The preoperaoperative period after heart transplanta- tive use of amiodarone has also been astion. This observation often reflects in sociated with the postoperative developpart the existence of preoperative pulmo- ment of ARDS in cardiac surgical panary congestion. However, a number of tients (400). Pulmonary Hypertension. Right venadditional factors exist during both the operation and the early posttransplant tricular failure as a result of irreversible period that favor the formation of inter- pulmonary hypertension remains one of stitial or alveolar edema. Posttransplant the leading causes of early mortality afventricular dysfunction, heparin-prota- ter heart transplantation. This finding is mine interactions, excessive volume ad- true despite careful, invasive hemodyministration during weaning from car- namic assessment of pulmonary vascudiopulmonary bypass (CPB), and the lar resistance during the pretransplant presence of renal insufficiency may all evaluation (401). Hemodynamic decompensation in this contribute to edema formation (390). In addition, CPB itself has been associated setting usually occurs during attempts with changes in both pulmonary epithe- at discontinuing cardiopulmonary bylial and endothelial permeability that pre- pass, although progressive elevations in dispose to the development of pulmonary pulmonary vascular resistance may also occur during the first 24 h postoperativeedema (391). The early developmental period of ly. Rising pulmonary artery pressures, cardiac surgery was marked by an ex- falling cardiac output, and systemic tremely high incidence of fatal, acute lung hypotension are cardinal signs of this injury, often referred to as "postperfu- phenomenon, and the use of inotropic sion pulmonary congestion syndrome" agents and vasopressors have shown (392) or "postpump syndrome" (393). limited utility in maintaining hemodyThe incidence of this complication has namic stability. Exclusion of other causes progressivelydeclined with improvements of pulmonary hypertension, such as pulin surgical technique and reductions in monary artery torsion or thrornboembocardiopulmonary bypass time. Present- li, is important (402). Prostaglandin E 1 (POE 1 ) , adminily, adult respiratory distress syndrome (ARDS) is relatively uncommon after stered through a right heart catheter has cardiac surgery with a generally accept- been used successfully in the treatment ed incidence of less than 2070 (382, 390). of posttransplant pulmonary hyperten-
sion, although the effects of the drug on the systemic blood pressure may require simultaneous vasopressor support (401). Successful use 0 f mechanical circulatory assistance of the right ventricle, in conjunction with POE 1 , has also been described (402). However, in contrast to its proved success after conventional cardiac surgery, the results of mechanical circulatory assistance after heart transplantation have been disappointing. Despite its ability to stabilize the circulation, an extremely high mortality caused by sepsis and pneumonia is reported (404). The lack of consistently effective treatment for right ventricular failure after heart transplantation emphasizes the need for improved methods of pretransplant evaluation of pulmonary vascular resistance. Measurements of reversibility of elevated pulmonary artery pressures may be poor predictors of pulmonary vascular behavior posttransplant (405). In addition, the recognition that both pulmonary vascular resistance and its degree of reversibility may change during the interval between evaluation and transplantation should lead to more frequent assessments of pulmonary vascular resistance prior to transplantation. Malignancy. In a review of 204 heart transplant recipients at Stanford who receivedconventional immunosuppression, 7070 of patients developed lymphoproliferative disorders. The risk of developing lymphoma was highest in patients younger than age 20, those with idiopathic cardiomyopathy, and those who required retransplantation (406). Patients transplanted under immunosuppression with cyclosporine appear to have a similar or even higher incidence of posttransplant lymphomas (407). Starzl* observed these lesions in 6.3070 of heart transplant recipients and found that reduction of immunosuppression was effective therapy in one of three patients. Interestingly, patients undergoing heart or heart-lung transplantation had the highest incidence of lymphoma among all other organ recipients and the only cases of pulmonary involvement. However, these differences probably reflect variability in immunosuppressive protocols and not differences between types of organ recipients (407). The most effective treatment of posttransplant lymphomas remains unclear,
* Detailed in Part 1. Starzl TE, Porter KA, Iwatsuki S, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporine-steroid therapy. Lancet 1984; 1:583-7.
ETTINGER AND TRULOCK
438 TABLE 4 PNEUMONIA FOLLOWING HEART TRANSPLANTATION Causative Pathogens· Study (reference)
Stinson (410) Hofflin (385) Cooper (412) Mammana (411) Copeland (363)
1971 1974-1980 1983 1983 1984
20 38 40 16 32
Hofflin (385) Gorensek (414) Austin (413)
1982-1984 1988 1989
72 50 118
Patients with Pneumonia (%)
10 45 16 10 22
(50) (N/A) (40) (62) (69)
25 (N/A) 12 (24) 35 (30)
Conventional 6 14 7 2 4
Immunosuppression 1 2 2 N/A 7 5 N/A 1 2 0 1 2 5 1 0
Cyclosporine-based Immunosuppression N/A 3 2 2 5 4 6 2 13 11 6 0
4 9 3 0 0
8 1 5
0 1 0 2 6
3 2 1 N/A 0
0 2 3 2 2
2 1 2
4 0 0
3 0 N/A
Definition of abbreviations: NA = not available from published data; G( +) = gram positive; G( -) = gram negative; CMV = cytomegalovirus; PCP species; NOC = nocardia; LEG = Legionella; ANAER = anaerobe; P. BOYOII = Pseudoallerischia boydii; COCCI = Coccidioides immitis; MYCO • Multiple pathogens often present.
largely because of the pathogenic variability of these tumors. Cytotoxic chemotherapy, localized irradiation, and resection have all been tried with mixed results (408). High-dose acyclovirmay be effective in those polyclonallymphomas proved to be related to Epstein-Barr virus infection, but the development of abnormal cellular proliferation may occur independently of and long after active viral replication. Hence, antiviral chemotherapy may not be effective. Reduction of immunosuppression is probably the most effective and the most practical mode of therapy in the heart transplant recipient. Infectious Complications Infectious complications accounted for over 50070 of patient deaths during the early era of heart transplantation*. Although infection continues to be the leading cause of morbidity and mortality, a variety of factors have resulted in a significant reduction in both the incidence and the severity of infections. The introduction of selective immunosuppression with cyclosporine and the widespread use of endomyocardial biopsy to diagnosis rejection and to guide additional immunosuppressive therapy are primarily responsible for these improvements (409). Pulmonary infections are by far the leading infectious complication after heart transplantation, occurring in 40 to 60% of patients in the pre-cyclosporine era (410-412) and in 24 to 40070 of patients in more recent reviews (413. 414).
* Detailed in Part 1. Horn JE, Bartlett JO. Infectious complications following heart transplantation. In: Baumgartner WA, Reitz BA, Achuff se, eds. Heart and heart-lung transplantation. Philadelphia: W.B. Saunders; 1990; 220-36.
The adverse effects of median sternotomy on lung mechanics (415), the development of acute lung injury as a result of cardiopulmonary bypass (416), and prolonged intubation all predispose the heart transplant recipient to pneumonia. In addition, the presence of interstitial pulmonary edema before transplantation may impair pulmonary clearance mechanisms and serve as a medium for bacterial growth (417). A recent multivariate analysis of risk factors for pneumonia after heart transplantation identified posttransplant reintubation and the use of immunosuppressive protocols that include higher doses of steroids as significant risk factors for the development of pneumonia (414). The majority of pulmonary infections occur within the first 3 to 4 months following heart transplantation (413, 418), and it is during this period that most fatal infections occur (418).A wide variety of routine and opportunistic pathogens have been reported, in part reflecting institutional differences in nosocomial flora (table 4). Multiple pathogens are present in 20 to 25% of pulmonary infections (411,413) and are responsible for a large proportion of infection-related deaths (410). Intensification of immunosuppression during periods of allograft rejection further increases the risk of clinically significant infections (419). In addition to pneumonia, mediastinitis and empyema are also well-recognized complications and are often associated with an unfavorable outcome (420). Bacterial Pneumonia. Most episodes of bacterial pneumonia occur within the first 2 to 3 wk after heart transplantation (385) and are usually caused by aerobic, gram-negative pathogens present in the hospital environment. Late episodes of pneumonias, occurring more than 1 yr
(CANDIDA) (Po BOYD", MYCO) (Po BOYD", HSV) (COCCI, P. BOYD II)
4 (HSV, MYCO)
= Pneumocystis carinii; ASP = aspergillus = mycobacterial species; HSV = herpes .
after transplantation, and often of undetermined etiology are also described. These late pneumonias often respond to empiric antibiotic therapy and are presumably bacterial in nature (413). The overall frequency of bacterial pulmonary infections after heart transplantation has declined since the introduction of cyclosporine (413). Legionellapneumophila is increasingly recognized as a common pathogen in compromised hosts and is responsible for 2 to 5070 of cases of bacterial pneumonia after heart transplantation (421). An incidence approaching 20% has been reported by several authors (411, 422), although the lower figures are probably more accurate. The majority of episodes are sporadic in nature, but common source outbreaks are also described (385). The variability in the reported incidence appears to be related in part to the presence or absence of surveillance programs for this pathogen in institutions where heart transplantation is performed (421). The clinical features of Legionella pneumonia in this setting are similar to other bacterial pulmonary infections. Fever and malaise are universally present, cough is often productive and neurologic, or abdominal complaints may occur (423). The process usually begins as a focal, patchy alveolar infiltrate that progresses over several days to either unilateral or bilateral lobar consolidation. Unlike immunocompetent patients, organ transplant recipients often present with nodular infiltrates (10%) that progressto necrotizing pneumonia with cavitation (424). Effusions and bronchopleural fistula with empyema have also been described (423, 425).Treatment with erythromycin is usually successful but may require 6 to 12 months of therapy because relapse is common. Intravenous
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
therapy is preferred during the early stages of treatment as a high rate of treatment failure is seen with early oral therapy. The addition of rifampin is often helpful in patients who do not respond to erythromycin (423, 425). The reported incidence of nocardial pulmonary infection after heart transplantation varies, reflecting the sporadic nature of the infection and an incomplete understanding of its epidemiology and pathogenesis. Of the first 160 heart transplant recipients at Stanford, 13070 developed nocardial pulmonary disease (426,427), a figure that has dropped significantly since the introduction of cyclosporine. More recent series describe an incidence of zero to 6% of patients (385, 413, 418, 424). The impact of routine prophylaxis with trimethoprimsulfamethoxazole (TMP-SMX) on the incidence of these infections is unclear. In the Stanford series, 810,10 of patients with pulmonary nocardiosis presented . radiographically as a solitary nodular lesion. Fever and nonproductive cough were the most common clinical features although 400,10 of all patients wereentirely asymptomatic. The lung was the only site of involvement in 80% of patients. Those with disseminated disease to skin or bone often had extensive local complications that required surgical debridement. Although a few cases were diagnosed during the patients' initial hospitalization, the vast majority occurred months to years after transplantation (median 229, range 43 to 982 days). Treatment with TMP-SMX was successful in all cases, probably reflecting the aggressive approach to early diagnosis and treatment taken in this series (426). The Stanford series also identified an association between nocardial infection and the subsequent development of infection with nontuberculous mycobacteria. Of the 21 heart transplant patients with nocardiosis, five subsequently developed infection with nontuberculous mycobacteria (four Mycobacterium kansasii and one Mycobacterium avium intracellulare) at a median of 902 days after the nocardial infection. Despite strong statistical support for this association, an intensive analysis of a variety of potential predisposing factors failed to identify an explanation for this observation (428).
Mediastinitis. Mediastinitis is a serious and life-threatening complication of all forms of cardiovascular surgery, occurring in 0.4 to 4.5% of patients. The clinical constellation of fever, leukocy-
to sis, and sternal wound inflammation or instability usually appears within 2 wk of surgery and clues the clinician to the presence of this infection (7). The most common causative organisms include gram-positive cocci, enterobacteriacae, and Pseudomonas aeruginosa. Mediastinitis may also be caused by fungi, mycoplasma species, or mycobacteria, although such infections are rare (7). The incidence of mediastinitis after heart transplantation has been reported as high as 7 to 8% (385, 420), although several centers have reported no episodes in their patients. Sternal wound infections often predispose to the development of mediastinitis because they may directly extend into the mediastinum (424). As a result, aggressive surgical debridement and systemic antibiotic therapy is required. Other postulated causes of mediastinitis in this setting include prolonged instrumentation of the patient's chest with mediastinal tubes or catheters, emergent reexploration of the chest in a nonoperative setting (424), and inadequate prophylaxis (409). Trento and coworkers (420) observed mediastinitis in six of 80 patients with heart transplants under immunosuppression with cyclosporine. In these patients, the usual clinical signs wereoften absent, possibly as a result of the concurrent immunosuppressive therapy. The onset of infection was delayed more than 4 wk in the majority, and most episodes followed augmented immunosuppression for acute cardiac rejection. The presence of a pericardial effusion was the most consistent clinical finding. Treatment of established mediastinitis consists of reexploration, debridement of the soft tissues and sternum, closure over irrigating catheters and drains, and systemic antibiotics. Trento and coworkers (420) successfully used this approach in five of six patients. Cytomegalovirus Pneumonia. The incidence of cytomegalovirus (CMV) infection after heart transplantation generally ranges from 67 to 100% (385,429-431), with over one-third of infected patients consistently developing symptomatic CMV disease (429, 430, 432). However, the type of immunosuppressive regimen and the CMV serologic status of the recipient have considerable impact upon these figures. In a recent study by Hofflin (385), 55% of heart transplant patients immunosuppressed by conventional regimens (containing antithymocyte globulin, azathioprine, and prednisone) developed CMV infection versus 25% of patients
receiving cyclosporine-based regimens. The rate of primary infection among patients at risk dropped from 44 to 120,10, and the rate of reactivation infection dropped from 67 to 34%. The use of cyclosporine also resulted in a decrease in the rate of symptomatic disease from 57 to 28% of infected patients. Although these observations do not reach statistical significance, similar differences have been found by other investigators. Overall, the risk of symptomatic disease is less in patients with reactivation infection (430, 432).
Animal studies have verified that the donor heart is capable of transmitting latent CMV (434) and that cardiac myocytes, not passenger leukocytes, probably harbor latent virus (435). CMV infection of coronary endothelial cells can also occur and has been shown to cause coronary thrombosis with subsequent myocardial infarction (436). The heart may be directly injured as a result of CMV infection, but this is a rare manifestation of CMV disease (437). CMV pneumonia occurs in 11 to 16% of infected patients (413, 430) and has a clinical presentation similar to that in other organ transplant recipients. Fever is the most common presenting symptom (433), and a diffuse pulmonary infiltrate is the predominant radiographic finding. However, focal infiltrates are described in up to one-third of patients (413, 438). Coinfection with other pathogens, particularly bacteria and fungi, is common and frequently fatal (figure 8) (430). Patients undergoing primary CMV infections have had an increased incidence of bacterial pulmonary superinfections (439). Viremia has been documented in a veryhigh proportion of heart transplant recipients (62 to 79%) and frequently precedes the development of symptomatic disease and pneumonitis (429). Beforethe availability of effective treatment, mortality ranged from 46 to 75% (413,430). Ganciclovir has proved to be very effective in the treatment of CMV pneumonitis in heart transplant recipients, although the number of reported patients treated is small. Keayand coworkers (431) described response rates of 81% among 16 heart transplant patients with symptomatic CMV disease. Mortality for patients with pulmonary involvement was 140/0, which compares favorably with previously published figures. Watson and colleagues (440) also describe successful treatment of CMV pneumonitis in four of four affected patients. Toxicityoccurs in approximately 20% of patients and
ETTINGER AND TRULOCK
Fig. 8. (A) Enlargement of routine follow-up chest radiograph of a 49-yr-old man who had undergone orthotopic heart transplantation 6 wk earlier. A small, 1-cm nodule in the left mid-lung field (arrow) was missed on initial radiologic evaluation (B) chest radiograph of the same patient 1 wk later after the onset of low grade fever. The nodule has increased dramatically in size. Transbronchial lung biopsy revealed both CMV pneumonitis and invasive aspergillus pneumonia. The patient responded to treatment with both amphotericin and ganciclovir.
consists predominantly of reversible neutropenia. Overall, the incidence and the severity of toxicity is less in heart transplant recipients than in marrow recipients or patients with the acquired immunodeficiency syndrome (431). The usefulness of antiviral agents or immunoglobulin as prophylaxis for CMV infection or disease has not been studied in large, well-designed trials in heart transplant recipients. Andreone and coworkers (418) observed a 3070 incidence of symptomatic CMV infections in patients treated with low-dose CSA, azathioprine, and prednisone compared with a 30070 incidence in patients treated with high-dose CSA and a 38070 incidence in patients treated with conventional immunosuppression. They attributed the low incidence in the former group to a combination of factors, including the elimination of antilymphocyte preparations from the treatment protocol, the use of lower doses of prednisone, and the use of seronegative blood products and hyperimmune globulin in patients at risk for primary CMV disease. Fungal Pneumonia. Heart transplant recipients are at risk for fungal infections with both endemically restricted fungi and invasivefungal species. Although not as problematic as in marrow recipients,
mortality, especially with aspergillus pneumonia, remains exceedingly high. Approximately 30070 of the first 206 heart transplant recipients at Stanford developed invasive fungal disease (441), and over half of them died of the infection. The introduction of cyclosporine, however, appears to have diminished the incidence of fungal infections (385). The reported incidence of aspergillus pneumonia in heart transplant recipients ranges from zero to 24070 (median 9070) with a mortality that ranges between 54 and 86070 (409, 441). The variability in incidence between studies is probably related to differences in both environmental factors and efforts directed toward preventing the infection (385). Several new therapeutic strategies for the treatment of aspergillus pneumonia have been evaluated in heart transplant recipients. Liposomal preparations of amphotericin have been shown to achieve nearly 10-fold higher plasma levels than free drug with minimal nephrotoxicity. These preparations have been used successfully in patients with progressive disease who werenot tolerating conventional therapy (424, 442). Itraconazole, a new, oral antifungal agent has also been used successfully in similar circumstances (443). The effectiveness of these agents
has yet to be evaluated in larger, controlled studies. Protozoal Pneumonia - Pneumocystis carinii. Pneumocystis carinii pneumonia is described in 3 to 20070 of heart transplant recipients, usually within the first 6 months after transplantation (413). The use of prophylactic TMP-SMX has probably reduced these figures substantially, but no controlled trials addressing this issue have been performed in this patient population. Immunosuppression with cyclosporine also appears to have lowered the incidence of this infection (385). Pneumocystis pneumonia may progress rapidly and mortality has been reported as high as 34070 in heart recipients (441). However, more recent experience suggests that the outcome is generally good if the diagnosis is made early and specific therapy is instituted and if copathogens are not present (413). Toxoplasma gondii. Of special concern in the heart transplant recipient is pulmonary infection by Toxoplasma gondii. In the normal host, toxoplasma organisms are ingested and then widely disseminate to body tissues, ultimately becoming encysted in the heart and other muscles where they remain dormant but viable. Subsequently, the organisms may be transplanted with the donor heart
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
(444). Immunosuppression may later result in reactivation of a previously latent infection. Although the most frequent clinical manifestations of active toxoplasma infection in immunocompromised patients include fever, chorioretinitis, necrotizing encephalitis, or myocarditis, pulmonary involvement may also occur and may be fatal (445). Transmission of latent toxoplasma and the subsequent clinical expression of infection bear certain similarities to CMV (446). Twelve to 17070 of heart transplant recipients have had no previous exposure to the organism and receive a heart from a seropositive donor. Over 50070 of these patients will develop a symptomatic primary infection (424). Luft and coworkers (445) reviewed 50 heart and heart-lung transplant recipients and found that of four patients at risk for primary infection, three seroconverted and each developed life-threatening toxoplasmosis. Of 19 patients at risk for reactivation infection, 10 had significant increases in antibody titers but none developed clinical disease. Although unusual, reactivation infection may also be life threatening (410). The diagnosis of toxoplasmosis requires the demonstration of tachyzoites in body fluids or tissues, particularly endomyocardial biopsy specimens. Serologic studies may also be useful. Latex agglutination titers and dye test titers will usually begin to rise at 4 to 12 wk after transplantation, at which time clinical illness may appear (7). However, the development of symptoms may be delayed for weeks or months after the appearance of the serologic changes. Prophylaxis with pyrimethamine or TMP-SMX is recommended for patients at risk for primary infection (447), although these agents by themselves are not satisfactory for the treatment of active infection. The combination of pyrimethaminesulfadiazine is considered effective therapy for established toxoplasmosis", Heart-lung nan.plantatlon
Because the lung becomes an allograft, heart-lung transplantation (HLT) adds another dimension to the pulmonary considerations of organ transplantation. In addition to the usual infectious and noninfectious complications described in recipients of other organs, the pulmonary considerations of HLT transplantation are complicated by the possibility of graft rejection. • See footnote on page 438.
According to the 1989 report of the Registry of the International Society for Heart Transplantation, 501 patients had undergone HLT in centers throughout the world (370). After steady growth from 1981 through 1988, HLT activity worldwide plateaued at approximately 200 cases/yr in 1989. The principal indications for HLT have been primary pulmonary hypertension, Eisenmenger's syndrome, and congenital cardiac defects (370). Collectively, these forms of pulmonary vascular disease have accounted for over 50070 of the transplants. Recently, however, annual activity for these indications has trended downward, but this decline has been offset by a rise in annual rates for other pulmonary diseases, particularly cystic fibrosis. During the 1980s, isolated lung transplantation also became a clinical reality. Single (unilateral) lung transplantation was performed for pulmonary fibrosis (448-450), COPD (451, 452), primary pulmonary hypertension (453,454), and selected cases of Eisenmenger's syndrome (454); double (bilateral) lung transplantation was done for CO PO (455, 456), antitrypsin deficiency emphysema (455), and cystic fibrosis (456, 457). Thus, for many indications both HLT and isolated lung transplantation are now feasible, but the optimal transplant operation for each clinical condition has not been determined. Additional experience and longer follow-up studies will be required to address this question. The major advantage of HLT is the ability to transplant organs to patients with combined cardiopulmonary disease. Many of these patients may not be suitable candidates for isolated lung transplantation. The disadvantages of HLT are the scarcity of donor heart-lung organ blocks, especially in the United States, and, consequently, the long waiting period for transplantation. In addition, when either HLT or isolated lung transplantation would work equally well, the available donor organs can be extended to more recipients by utilizing them separately for a heart transplant and one or two lung transplants.
Pretransplant Considerations RecipientSelection. The principal indications for HLT are congenital heart disease with pulmonary hypertension (Eisenmenger's syndrome); congestive cardiomyopathy with secondary critical, irreversible pulmonary hypertension; and end-stage lung disease with severe cor pulmonale or coexistent severe primary
cardiac disease. Unfortunately, all patients with an indication are not suitable candidates for HLT. Recipient selection guidelines for both HLT and isolated lung transplantation have been relatively stringent (458-462). Some typical criteria are summarized in table 5. Previous major cardiothoracic surgery has been associated with fatal intraoperative and perioperative bleeding complications (463,464); therefore, depending upon the nature of the previous surgery, it may be an absolute or relative contraindication to HLT. As experience has increased, some centers have accepted patients with previous median sternotomy, open lung biopsy, or lobectomy on a caseby-case basis. However, patients with extensive surgery to the pleura (pleurodesis or pleurectomy) are not usually accepted. The normal blood supply to the donor trachea and main bronchi is interrupted by HLT. The donor anastomosis and trachea are dependent on retrograde bronchial blood flow from the pulmonary circulation and on collateral supply from the coronary circulation to prevent airway ischemia (459). High-dose steroids impair bronchial healing (465) and may further jeopardize the integrity of the anastomosis. Thus, while steroidtreated patients have been successfully transplanted, steroid therapy should be minimized or discontinued to decrease the risk of an airway complication. The timing of transplantation is a matter of clinical judgment. The natural history of the patient's disease, the recent clinical course, and the presence of any poor prognostic factors must be weighed in the decision. Given the lengthy waiting period for many recipients, early consideration of appropriate candidates would be reasonable. In contrast, transplantation is not usually an option for moribund, desperate, or emergency cases.
Donor Selection and Donor-recipient Matching. The criteria for choosing donors have varied slightly among transplant centers (459, 460, 463, 466, 467); representative requirements are illustrat-
TABLE 5 RECIPIENT SELECTION GUIDELINES Age: up through 45 and 50 yr Physiologically severe cardiopulmonary disease Limited life expectancy without transplantation Suitable psychosocial profile No systemic disease No significant secondary organ dysfunction No previous major cardiothoracic surgery No high-dose corticosteroid therapy
ETTINGER AND TRULOCK
442 TABLE 6 DONOR SELECTION GUIDELINES Age younger than 35 through 40 years No history of pulmonary disease, including asthma No major thoracic trauma Normal chest radiograph No active systemic or pulmonary infection Normal lung compliance* Normal oxygenation * Normal electrocardiogram Adequate mean systemic arterial pressure* • See comments in text.
ed in table 6. Most of the criteria are selfexplanatory, but a few deserve elaboration. Lung compliance in this setting is usually judged by the peak inspiratory pressure, which at typical ventilator tidal volumes of 10 to 15 ml/kg should be less than 20 to 25 em H 2 0 . Oxygenation should reflect a nearly normal alveolararterial O2 gradient. Specified criteria have included P0 2 > 450 mm Hg at FI0 2 = 1.0 and P0 2 > 150 mm Hg at FIo2 = 0.30 (458, 460, 466). A short period of ventilator support is preferable, but, if other criteria are met, a longer period may be acceptable. Mean systemic arterial pressure should exceed 65 mm Hg with dopamine or dobutamine doses below 10 meg/kg/min. The recipient and donor are matched for ABO blood group compatibility and, within certain tolerances, for thoracic dimensions. If necessary, 0 blood group donor organs can be used in a recipient with another blood type, but alloantibodies formed by passenger B-Iymphocytes in the donor lung may cause a transient graft-versus-host hemolytic anemia 7 to 14 days after transplantation. The size of the donor lungs must be appropriate for the recipient's thoracic cavity. If the donor lungs are too large, the chest could be difficult to close and compressive atelectasis could occur; if the lungs are too small, pleural space problems can develop. Size matching has been accomplished primarily by comparing height and weight or various radiologic thoracic dimensions of the donor and recipient (459, 463, 466). However, the chest radiographs are not truly comparable. The recipient's chest radiograph is usually taken with standard technique (posteroanterior projection; full inspiration), but the donor's chest radiograph has to be done with portable technique (anteroposterior projection; no control over the degree of inflation). Despite this apparent shortcoming, radiographic methods have provided a satisfactory match. An alternative to radiographic dimen-
sions is to compare the recipient's measured pre-HLT TLC to the donor's predicted TLC (468). Exact size matching has not been essential, however, and significant discrepancies between the recipient's measured pre-HLT TLC and the donor's predicted TLC have been well tolerated (468). The size of the donor lung does not have a major influence on the recipient's TLC or chest wall configuration at 1 yr posttransplantation (468, 469). The recipient's TLC at this stage tends towards its pre-HLT value (468), suggesting that it is the pretransplantation compliance and configuration of the recipient's thoracic cage that determines late posttransplantation lung volume. Although HLA typing has been done rather routinely, HLA matching has not been used prospectively in donor selection. In a retrospective analysis of HLA compatibility, two or more mismatches between donor and recipient at HLA locus A were associated with a tendency toward more frequent and more severe obliterative bronchiolitis (OB) (470). Further study will be essential to determine the impact of HLA incompatibility on outcome and the possible role of donorrecipient HLA matching in HLT.
Intraoperative Considerations Although donors were originally transported to the transplant center for organ harvesting, distant procurement is now standard practice. Most centers have devised their own approach to donor organ handling and preservation (463, 471-473). These methods have provided adequate protection with good early graft function for ischemic times up to 4 to 5 h. The recipient's operation at the transplant center is coordinated with the remote organ procurement to minimize the ischemic time. The recipient's operation (459) is performed through a median sternotomy with the patient on cardiopulmonary bypass and fully anticoagulated. The na-' tive heart and lungs are removed separately, taking care not to injure the phrenic, vagus, or recurrent laryngeal nerves. Maintaining hemostasis during this extraction phase can be particularly difficult in patients who have pleuropericardial adhesions from previous procedures or extensive vascular collaterals from Eisenmenger's syndrome. The donor heart-lung block is positioned in the recipient's thoracic cavity to begin the implantation phase of the operation. The donor trachea is trimmed
and anastomosed to the recipient's trachea just above the carina. In general, omentopexy has not been employed in HLT as it has been in isolated lung transplantation, but the anastomosis is sometimes reinforced with mediastinal tissues. The right atrium of the donor is sutured to the right atrial remnant of the recipient, and the aorta is joined about 2 em above the aortic valve. Recently,combined heart and unilaterallung transplantation has been reported in two patients who had previous thoracic procedures in one hemithorax (474). A single lung was transplanted into the unoperated hemithorax, and the contralateral native lung was left in place to avoid dissection in the field of the previous surgery. Although it may be worthy of consideration in selected patients, experience with this strategy is too limited to assess its clinical value. Perioperative (30-day) mortality after HLT was 18.8070 in 1988, down from 26.2070 in 1987 (370). The leading cause of early mortality is infection, which accounts for over 40070 of deaths (370). Other causes of early deaths have included graft failure, cardiac events, rejection, and dehiscence of the tracheal anastomosis (370, 463, 475). Intraoperative hemorrhage, a frequent cause of perioperative death during the early experience (463,475), has been greatly reduced by more stringent recipient selection. The incidence of nonfatal operative complications is difficult to tabulate. Minor selflimited air leaks from the tracheal anastomosis, injuries to the recurrent laryngeal and vagus nerves, and bleeding requiring reexploration have all been mentioned (475-477).
Posttransp/ant Considerations The problems that arise in the early period following HLT are often quite similar to those that arise after routine cardiac or thoracic surgery. Injury to the phrenic nerve with resultant diaphragmatic paralysis, pulmonary edema, and nosocomial infection are possible. The magnitude of these problems may be enhanced by the attendant immunosuppression and the constant possibility of allograft rejection or dysfunction. Immunosuppression. The induction protocol has varied slightly among centers (459, 475, 477, 478). .Cyclosporine and azathioprine are begun immediately after surgery. However, because these drugs do not provide prompt immune suppression, the regimen is usually supplemented with antilymphocyte (or an-
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAfi TRANSPLANTATION
tithymocyte) globulin or OKT3 monoclonal antibody for the first 3 to 10days. Methylprednisolone is given during the first 24 h in some protocols, but otherwise steroids are withheld for the first 14 to 21 days to allow healing of the tracheal anastomosis. Daily prednisone (0.2 to 0.4 mg/kg/day) is introduced after this period, but the protocol at Papworth Hospital has successfully relied on cyclosporine and azathioprine alone as the maintenance drugs (477). Prednisone is tapered over 4 to 8 wk to 0.2 mg/kg/day. Acute rejection is treated at any time, including the first 7 to 10 days, with three successive daily boluses of methylprednisolone. This is sometimes followed by a boost and taper of the daily steroid dose.
Weaningfrom Mechanical Ventilation. Weaning from ventilatory support should proceed as rapidly as feasible; withdrawal is usually successful between 24 to 72 h after transplantation. Early mobilization and chest physiotherapy have been helpful in this process. Epidural catheters and patient-controlled devices for analgesia may expedite the weaning process. Patients who had chronic hypercapnia before transplantation often remain hypercapnic for 1 to 2 wk after transplantation. Extubation may proceed despite COz retention as long as the patient is breathing comfortably and the respiratory acidosis is adequately compensated.
Noninfectious Complications - Pulmonary Edema. During the early postoperative period, special attention must be given to managing intravascular volume. Extravascular lung water tends to increase because normal lymphatic drainage has been severed and pulmonary vascular permeability may have been altered by ischemia, preservation, and handling. Pulmonary edema formation can be diminished by lowering pulmonary vascular hydrostatic pressure. However, intravascular volume depletion can compromise cardiac output and aggravate the nephrotoxicity of cyclosporine and other drugs. In general, intravascular volume status, as indicated by body weight, central venous pressure, or pulmonary capillary wedge pressure, should be maintained at a minimally acceptable level during the first several days. Acute Rejection. Acute lung allograft rejection has many clinical manifestations. Criteria for a clinical diagnosis of rejection haveincluded symptoms (cough and dyspnea), signs (fever),physical findings (inspiratory rales), radiographic infiltrates, a fall in POl, and/or a decline
in pulmonary function test parameters. In addition to these, there must be no evidence of infection, and the abnormalities must resolve with steroid therapy. However, the clinical pattern of acute rejection is nonspecific, and it overlaps considerably with pulmonary infection. Acute rejection has been observed as early as 7 days after transplantation (479). Up to 60070 of recipients have a biopsy-proven episode of rejection in the first postoperative month, and approximately 60070 of all rejection episodes in the Papworth Hospital series occurred during the first 3 posttransplant months (477). Although the likelihood of rejection appears to decrease over time, longitudinal follow-up has demonstrated that late episodes are not infrequent (477). Chest radiographs are usually abnormal during rejection episodes in the first posttransplantation month, although a normal radiograph does not exclude rejection during this period (480). The radiographic picture hasusually consisted ofperihilar and lower lung zone interstitial infiltrates, which may coalesce and progress to consolidation, and pleural effusions; however, infiltrates without pleural effusions and pleural effusions alone have also been recorded. After the first posttransplantation month the chest radiograph has been normal in over 75070 of biopsy-proved episodes of rejection (480). When present, the radiographic changes of rejection are not unique; indistinguishable patterns have been seen with infection, especially CMV pneumonia (480, 481). Pulmonary function test parameters and oxygenation can change during acute rejection or infection (479-481). During the first 6 to 8 postoperative wk, PFTs normally show a gradually resolving restrictive pattern related to the surgery, and this underlying abnormality has made changes more difficult to interpret during this period. Thereafter, PFTs usually stabilize in the normal to near-normal range, and a significant decline in any parameter, while nonspecific, requires an explanation. During both rejection and infection FVC, FEV 1, and FEFz5-75fJo often decline and oxygenation may deteriorate (479). The changes in spirometry and oxygenation havenot conclusivelydiscriminated between rejection and infection (480, 482); however, in a recent prospective study, the decrement in FEF25-75'" was significantly greater during rejection than infection (479). Because clinical criteria cannot ac-
curately diagnose rejection, a more definitive diagnostic technique is needed. In other solid organ grafts, biopsy has been the standard method for diagnosing rejection. Initially, it was thought that cardiac and pulmonary rejection would occur together after HLT and that endomyocardial biopsy, which is used extensively after cardiac transplantation, could also be used to monitor rejection in both the heart and lungs (483, 484). However, early clinical experience demonstrated that cardiac and pulmonary rejection were not necessarily concordant (485,486). Thus, a repeatable method of sampling lung tissue became essential in the management of HLT recipients. Although originally deemed inadequate for the diagnosis of lung allograft rejection in the canine model (487),transbronchial lung biopsy (TBB) has emerged as the procedure of choice for diagnosing rejection in HLT recipients (481, 482)*. The histologic features of acute pulmonary rejection have been described and classified using this technique (477). The chief characteristic has been a perivascular, mononuclear cell infiltrate that can extend into the alveolar interstitium in more severe cases. Subepithelial and mucosal inflammation have also been present in some cases. Eosinophils have been variably found in the perivascular or mucosal infiltrate. When performed for clinical indications, TBB has an overalldiagnostic yield for infection or rejection of approximately 85070 (479). For the detection of suspected rejection alone, sensitivities of 84 (481)and 93070 (486) and a specificity of 100070 (481) have been reported. A good diagnostic yield has been achieved with at least four biopsies (477, 480), although 17biopsies have been suggested to reach p < 0.01 for missing rejection (488). The complication rate of TBB has been acceptably low in several series (479, 481, 488), and the procedure has been done safely in critically ill and mechanically ventilated recipients (479, 488). The role ofTBB as a surveillancemethod for rejection or infection in asymptomatic recipients is still being explored. Biopsies taken in clinically stable, asymptomatic recipients have usually shown no evidence of rejection (477, 479). Occasionally, a very mild perivascular infiltrate affecting only a few vesselsin the • Detailed in Part I. Higenbottam T, Stewart S, Penketh A. Wallwork J. The diagnosis of lung rejection and opportunistic infection by transbronchiallung biopsy. Transplant Proc 1987; 19:3777-8.
sample has been discovered, but the significance of this finding has not been established. Serial prospective surveillance TBBs had only a 150/0 overall positivity rate in a recent series (479). If this low yield is confirmed in similar studies and larger numbers of patients, the proper place for TBB in surveillance may be questioned, but the importance of early identification and treatment of infection and rejection, even in a small subset of recipients, must not be underestimated. The immunoreactivity of lymphocytes from the lung allograft and from peripheral blood has been investigated as a less invasivemeans for immunologic diagnosis and monitoring. Bronchoalveolar lavage (BAL) lymphocytes harvested during episodes of acute rejection have manifested increased donor-specific alloreactivity in a primed lymphocyte test (PLT) (489). The sensitivity of a positive PLT response for the detection of acute rejection was 91070, but positive results werealso recordedduring bacterial (33070), CMV (28%), and Pneumocystis carinii (330/0) infections. Using peripheral blood lymphocytes, the same test was positive in only 45% of acute rejection episodes. Thus, although the PLT assay using BAL lymphocytes has excellent sensitivity, it lacks the specificity to exclude infection. Furthermore, the assay requires a supply of donor cells, which must be obtained from the spleen or lymph nodes at the time of organ procurement and stored for subsequent use, and a 72 h incubation with the recipient's BAL lymphocytes. Time constraints and availability of donor cells will likely limit the utility of this methodology in many clinical situations, but these limitations do not detract from its valuein understanding lung rejection and in monitoring the allograft in stable recipients. Obliterative Bronchiolitis. OB has been one of the most problematic late complications of HLT. Although the incidence has declined at some centers with more intensive monitoring, earlier diagnosis, and augmented immunosuppressiveregimens,the incidence has remained in the 10 to 50070 range (475, 490, 491). OB is a clinicopathologic syndrome characterized physiologically by airflow obstruction and histologically by bronchiolitis obliterans. The etiology has not been completely elucidated, but it is probably caused by airway-directed chronic rejection (478, 492). If discovered early, it can be reversed or arrested byescalating the levelof immunosuppression (493,494); however, if diagnosed late, it
ETTINGER AND TRULOCK
has usually followed a relentlessly progressive and ultimately fatal course (475, 478, 495).
OB has developed as early as 2 months and as late as 4 yr after HLT, but the mean time to appearance in the Stanford University recipients has been approximately 8 to 12 months (475). Although the original report (496) emphasized a rather rapid, fulminant clinical course, increased awareness has lead to recognition of a more subtle presentation and a more insidious evolution (497). The initial symptom is usually cough, and the presentation may mimic a mild respiratory tract infection. Such a benign-appearing clinical pattern cannot be discounted in a HLT recipient because it may herald the onset of OB. Any such illnesswhich lasts longer than 7 to 10 days and/or which is associated with a persistent decrement in lung function after the symptoms disappear requires further investigation. Occasionally, the early stage of OB has been asymptomatic and has been detected only by routine surveillance pulmonary function testing. The diagnosis of OB is based on pathophysiologic and histologic criteria. The earliest physiologic abnormality has been a decline in the airflow rate in the mid-vital capacity range, i.e., a fall in FEF15-75Oft (497). Decreases in FEV h FEV l/FVC, and, sometimes, TLC have developed later and have reflected more severe disease. The chest radiograph can be normal in the early stage, but patchy interstitial infiltrates, with or without some pleural thickening, have been present in the later stages (496). Pathologically, OB is an inflammatory process of the distal bronchioles. If unchecked, the bronchiolitis may evolvethrough a series of lesions and culminate in destruction, obstruction, or complete scarring and obliteration of small airways (478, 498, 499).
When OB is suspected, the diagnosis should be confirmed histologically if possible. The role of TBB in the diagnosis of acute rejection has been demonstrated, but its place in the detection of OB has not been as clearly defined. The diagnosis of OB can be made by TBB (497, 5(0), but the sensitivity has not been specified. If the clinical picture and PFT pattern are compatible and if infection has been excluded, open lung biopsy would generally be unnecessary even if TBB is not confirmatory. The alloreactivity of BAL lymphocytes and peripheral blood lymphocytes to donor spleen cells in the primed lympho-
cytetest (PLT) has also been studied during chronic rejection, which was defined by a progressive decrease in pulmonary function in conjunction with histologically proved bronchiolitis obliterans (489). A positive PLT response in BAL lymphocytes was observed in 69070 of chronic rejection episodes, somewhat lowerthan the 91% positivity found during acute rejection. However, the presence of high proportions of polymorphonuclear leukocytes in the BAL fluid of some patients with chronic rejection appeared to have an inhibitory effect on lymphocyte proliferation in the PLT assay, and false negative tests presumably occurred in these cases. Peripheral blood lymphocytes showed a positive PLT response in 60% of chronic rejection episodes, better than the 450/0 positivity rate for acute rejection events. The specificity of a positive response was 80070 for BAL lymphocytes and 840/0 for peripheral blood lymphocytes. Thus, the PLT assay may be a useful adjunct to PFTs and TBB in monitoring the allograft for chronic rejection. The best therapy for OB is prevention, and successful prevention is predicated in part on an optimal maintenance immunosuppressive drug regimen. Recipients from the Stanford University program who were maintained on the original two-drug protocol of cyclosporine and prednisone had a very high incidence of OB; 630/0 of hospital survivors treated in this manner developed OB, and 42070 of those afflicted died of this complication (475). The introduction of azathioprine into the regimen slowedthe rate of decline of lung function in affected recipients (493), and the institution of a three-drug maintenance protocol, along with more vigilant surveillance, has reduced the incidence of OB to 200/0 (475). Azathioprine itself, rather than the number of drugs, may have been the key element in decreasing the incidence of OB. At Papworth Hospital a two-drug maintenance regimen of cyclosporineand azathioprine has been employed for some time, and the incidence of OB in recipients at this center has been approximately 10% (466, 490).
Successfulpreventionof OB also hinges on prompt diagnosis and treatment of acute rejection and infection. Rigorous monitoring of pulmonary function and clinical status are crucial; significant changes should be investigated, usually by fiberoptic bronchoscopy with TBB and BAL. The role of routine bronchoscopy with TBB and BAL as part of a
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
comprehensive posttransplantation surveillance protocol deserves further study. In a recent prospective study, 15070 of routine biopsies in asymptomatic recipients were unexpectedly positive for acute rejection or infection (479). To the extent that these have been hypothesized as precursors of chronic rejection (490, 491), their early detection and eradication could prevent more serious problems later. OB has been treated by augmenting the immunosuppressive drug regimen with high-dose steroids, azathioprine (if not already prescribed), antithymocyte globulin (ATG), and/or OKT3 monoclonal antibody (478, 489, 493, 495, 497). Three types of response to therapy have been described - reversal, stabilization, and progression (493-495). Early detection and treatment appears to give the best chance of reversal, whereas later intervention is more apt either to stabilize the process or to fail entirely. None of the described therapies has emerged as superior, and in refractory cases all of them have often been tried. Many potential etiologies of OB have been speculated. These have included rejection, infection, denervation, decreased mucociliary clearance, and bronchial ischemia (497). These factors and others may all somehow contribute directly or indirectly, but the preponderance of evidence has implied that OB is the consequence of chronic rejection (478, 492, 497). The pathogenesis has not been elucidated. One leading hypothesis has suggested that upregulation of Class II major histocompatibility antigens on airway epithelium leads to activation of recipient T lymphocytes and an airway-directed immunologic reaction (492). This hypothesis is consistent with the observation that infections, which cause airway inflammation and/or enhance cell surface antigen expression through the stimulation of gamma interferon or other mediators, have frequently preceded chronic rejection (491, 500, 501). An alternative theory has proposed that fibrotic repair, which is a sequela of acute rejection, occurs around vessels and airways and is the likely mechanism of OB (502). This theory is supported by the high incidence of antecedent acute rejection in recipients who subsequently develop OB (490, 491). Several risk factors for OB have been recognized. Pulmonary infection has frequently been a forerunner of OB. In the University of Pittsburgh study, OB ulti-
mately developed in 83070 of recipients operative period, the prevalance of bacafter Epstein-Barr virus infection, in 56070 terial pneumonia was rather uniform at after CMV infection, and in 50070 after approximately 35070 throughout three Pneumocystis carinii infection (491). selected posttransplant follow-up periods However, OB also has developed in re- (zero to 2 wk, 2 wk to 1 yr; > 1 yr). Since cipients without antecedent CMV or oth- 1988, however, the prevalence of early er types of infections (464). Acute rejec- bacterial pneumonia has been reduced tion has also been a precursor of OB. In to only 13070 by instituting broad specthe Pittsburgh series, OB was ultimately trum antibacterial antibiotic prophylaxdiagnosed in 77070 of recipients at risk is with ceftazidime and clindamycin and after acute rejection (491). Frequent epi- by promptly adjusting the drug regimen sodes of acute rejection may increase the to treat any bacteria isolated from airrisk of chronic rejection (490). Recipients way secretions during the first 7 to 10 with zero or one donor-recipient mis- days. matches at HLA locus A tended to have The diagnosis of bacterial pneumonia less OB, less severe OB, and fewer deaths has been made by the usual criteria of from OB than recipients with two or more a pulmonary infiltrate, fever, and isolamismatches (470). Thus, HLA compati- tion of a pathogen from a lower respirability at this locus may be yet another tory tract specimen. Expectorated spufactor which influences the recipient's tum or suctioned secretions in intubated susceptibility to OB. patients can provide an adequate speciInfectiousComplications. In the latest men for Gram stain and culture. If not, report of the Registry, infection was the samples can be obtained bronchoscopileading cause of mortality after HLT cally. Bronchial washings are probably (370), accounting for 48070 of the early sufficient for bacterial cultures, but BAL postoperative « 30days)deaths and 73070 fluid and/or protected brush specimens of the late (> 30 days) deaths. Infection can also be submitted. Quantitative culhas also been the source of substantial ture of BAL fluid and protected brush morbidity. Although many sites can be- specimens have been used in other pacome infected in HLT recipients, the lung tient groups to determine the significance allograft has been the principal focus. of bacteria isolated by bronchoscopy The spectrum of pathogens has includ- (504-506). However, these methods have ed bacteria, viruses, fungi, and protozoa, not been verified in HLT recipients, and but bacterial pneumonia and CMV pneu- the results are invalidated by preadminismonitis have been the most problematic. tration of antibiotics (505), a rather comImmunosuppression places all organ mon circumstance. When bacterial pneumonia is a contransplant recipients at an increased risk of opportunistic and nonopportunistic cern, empirical antibiotic therapy should pneumonia. However, the lung as an al- be prescribed while the diagnosis is clarlograft may be more vulnerable to infec- ified. Although fever and infiltrates may tion. Even when procured from an ac- have alternative explanations, especially ceptable donor, the lung is often colo- in the early postoperative period, the mornized with bacteria before implantation bidity and mortality associated with bac(467). Handling, ischemia, preservation, terial pneumonia dictate aggressive treatand reimplantation are other insults that ment. Gram-negative organisms (Pseudocould alter lung defensesin the early post- monasaeruginosa, Serratia marcescens, transplantation period. After HLT, the Escherichia coli, enterobacter species, normal cough reflex has been ablated by acinetobacter species, and Haemophilus denervation, and mucociliary clearance influenzaei, Staphylococcus aureus, and has been markedly reduced (503). This Legionella pneumophi/a have been the combination decreasesclearance of secre- most frequent isolates (501, 507, 508). tions and predisposes to lower respirato- Pending identification of a pathogen and antimicrobial susceptibility test results, ry tract infection. Bacterial Pneumonia. Bacterial pneu- antibiotic coverage should be directed at monia is common after HLT. An overall this group of organisms or selected on prevalence of 66070 has recently been the basis of prior local experience. Cytomegalovirus Pneumonitis. HLT reported in the University of Pittsburgh recipients followed between 1982 and donors and recipients are routinely 1989(501). In this same group, bacterial screened for serologic evidence of previpneumonia was the direct cause or a ma- ous CMV infection. As with other organ jor contributory factor in 42070 of all fa- transplant recipients, posttransplant talities. Although the risk of bacterial CMV infection can be acquired de novo pneumonia was highest in the early post- by transmission with the donor organ,
ETTINGER AND TRULOCK
by transfusion of blood products from a seropositive blood donor, or by reactivation of latent infection in a seropositive recipient. The prevalence of CMV infection in seronegative recipients (R- ) of seropositive donor (D +) organs has been in the 67 to 100070 range, similar to other organ transplant recipients (501, 509)*. In the Papworth Hospital recipients, the attack rate of CMV pneumonia during such primary infection has been 60070, and the case fatality rate of the pneumonia 67070 (509). Becauseof the associated morbidity and mortality, the program at Papworth Hospital stopped transplanting D + /RCMV serologic mismatches (464, 509). While a rigid matching policy will not be feasible at most centers in the United States because of the donor shortage, seronegative recipients should be transplanted with organs from seronegative donors (D - /R- match) whenever possible, and D + /R- mismatches should be avoided if circumstances permit. Blood products from CMV seropositive blood donors can transmit CMV infection, and this route may be particularly important in CMV seronegative recipients (501). The prevalence of primary CMV infection in seronegative recipients at the University of Pittsburgh declined from 71 to 10010 when blood products from seronegative blood donors only were transfused into seronegative HLT recipients. The prevalence of CMV infection in seropositive recipients has also been high, usually in the 50 to 75070 range, regardless of the donor's CMV status (10, 501, 509). Most infections in seropositive recipients probably represent reactivation of latent infection, but reinfection with a different CMV strain cannot be excluded without more sophisticated studies than are routinely done. Perhaps because of their preexisting immunity, CMV infection in seropositiverecipients has more often been asymptomatic, and CMV disease has been milder than in seronegative recipients", Mortality from CMV infection in seropositive recipients has been low, ranging from 6010 in (D + /R + ) patients to 13070 in (D-/R+) patients (509). CMV infection typically occurs 2 to 12 wk after HLT. In the Papworth Hospital series the mean time to diagnosis of primary disease was 3.7 wk and to dis-
covery of reactivation/reinfection was 6.2 wk. CMV infection can cause disease in many organ systems, but in HLT recipients, pulmonary and gastrointestinal involvement have been identified most frequently. CMV pneumonitis poses a special problem because its clinical profile is so similar to acute rejection, but its therapy is quite different. Therefore, a definitive diagnosis must be established when this differential diagnosis arises. Although a rise in CMV titer or the detection of concurrent or antecedent CMV viremia are useful markers of active CMV infection, the diagnosis of CMV pneumonitis requires cytologic or histologic confirmation. Fiberoptic bronchoscopy with BAL and TBB has a good diagnostic yield and a low complication rate in this setting (481, 501). Conventional culture of BAL fluid has a high sensitivity and negative predictive value; however, the cultures must be incubated for several weeks, and a positive culture lacks specificity. The BAL fluid may also be cultured in the shell-vial method and stained after 24 to 48 h incubation for expression of early CMV antigen. This method has not been reported in HLT recipients, but it has been valuable in other patient populations (510). Although more rapid than conventional culture, an analogously high sensitivity but low specificity would be anticipated. Nonetheless, if its negative predictive value proved comparable with conventional culture, it could be valuable in ruling out CMV pneumonitis. Standard cytologic examination of BAL fluid for cells with viral inclusions has had a low sensitivity (21070) but a high specificity (98%) (449)t. BAL cells can also be stained directly for the presence of viral antigen. A sensitivity of 86070, a specificity of 84070, and a negative predictive value of 96% for CMV pneumonia have been reported with this technique (501). The sensitivity ofTBB for the diagnosis of CMV pneumonia in HLT recipients cannot be readily ascertained. However, its role in the diagnosis of CMV pneumonitis in this population is well documented (479, 481). When tissue is needed to distinguish infection from rejection, TBB should be the first step. Open lung biopsy is rarely necessary for this pur-
• Detailed in Part 1. Glenn J. Cytomegalovirus infections following renal transplantation. Rev Infect Dis 1981; 3:1151-78.
• Detailed in Part 1. Paradis IL, Grgurich WF, Drummer JS, Dekker A, Dauber JH. Rapid detection of cytomegalovirus pneumonia by evaluation ofbronchoalveolar cells. Am Rev Respir Dis 1988; 138:697-702.
pose and should be reserved for special situations. The current standard therapy for CMV pneumonitis or other significant CMV disease is ganciclovir. No controlled trial with this agent has been conducted in HLT recipients. However, other treatments have been disappointing, and ganciclovir has been effective in some cases (466,495). In HLT recipients, the limited experience with ganciclovir plus hyperimmune globulin has been favorable. Therefore, a combination of ganciclovir and immune globulin might be considered in refractory or severe cases. The risk of CMV infection should be minimized by matching CMV seronegative recipients with seronegative donors and by transfusing them with blood products from seronegative blood donors whenever possible. However, D + /R-, D + /R +, and D - /R + serological combinations all have a significant risk of CMV infection. No prophylactic regimen has been thoroughly studied in HLT recipients. CMV hyperimmune globulin has been recommended by the Papworth Hospital group based on their limited experience (10),but the hyperimmune globulin preparation is not currently available in the United States. High-dose acyclovir prophylaxis has been adopted by some HLT centers, but no results have been published. Herpes Simplex Pneumonitis. In the absence of prophylaxis, the HLT recipient appears to be at significant risk for herpes simplex virus (HSV) pneumonitis. Smyth and colleagues (511) at Papworth Hospital observed six cases of HSV pneumonitis in five HLT recipients. All of the patients were seropositive for HSV prior to transplant, all had intraoral mucosal lesions, and four of the six had concomitant CMV infection. In addition, the majority had immunosuppression augmented for treatment of rejection during the 10-day period before the onset of pneumonitis. On the basis of this report and observations made in other organ transplant recipients, the use of prophylactic acyclovir appears warranted in seropositive recipients, although the optimal duration of prophylaxis has not been determined (511). Pneumocystis carinii pneumonia. The prevalence of Pneumocystis carinii infection has been low in recipients who have received prophylactic therapy (466, 508), but the risk ofinfection is quite high (501, 507, 512). Prior to instituting routine prophylaxis, 75010 of recipients at risk in the Pittsburgh series were afflicted. Interestingly, the majority (approximately 70070)
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
of these infections wereasymptomatic or subclinical and were discovered incidentally in BAL specimens obtained during routine follow-up bronchoscopies. Typical Pneumocystis carinii pneumonia (PCP) developed less frequently in this series and has been rather rare in others (512). Prophylaxis does not absolutely prevent Pneumocystis carinii infection or pneumonia, and fatal cases still occur. Hence, PCP must remain in the differential diagnosis if the clinical picture is compatible. The diagnosis can be made easily and reliably by bronchoscopy with BAL and/or TBB; the sensitivity of sputum analysis has not been determined in HLT recipients. PCP should be treated in the conventional manner with TMP-SMX or pentamidine. Asymptomatic and/or subclinical infections have responded wellto less intense oral treatment with TMP-SMX (501). Although TMP-SMX prophylaxis is widely prescribed, most centers have not specified their protocol, and some intercenter variation in the regimen is likely. Nonetheless, based on the low incidence of PCP in recipients receiving prophylaxis, all of these have presumably been efficacious. In recipients who are allergic to sulfa drugs, aerosolized pentamidine would be the logical alternative. Although there is no published experience in HLT recipients, this method has been effective in HIV-infected patients (513). FungalPneumonia. Deep-seated fungal infections have been an uncommon infectious complication after HLT, but infections with Candida, Aspergillus, and Cryptococcus have been reported (456, 475, 501, 507, 508). These fungal infections may be localized or disseminated, are often associated with serious complications, and have frequently been implicated in the death of the infected recipient. Candida has been the most frequent fungal infection, perhaps because colonization is so common in the donor lung (467, 501) and in hospitalized, immunosuppressed recipients. The candida infections are often disseminated, but intrathoracic presentations have been important. The most dramatic have been candida infections involving the aortic anastomosis, leading to a mycotic aneurysm and fatal rupture (475, 501). Although isolation of Candida from respiratory tract specimens is not unusual, candida pneumonitis occurs infrequently (475, 508).
Deep-seated infection with Candida should be treated with amphotericin B in standard therapeutic doses; fluconazole may be a suitable alternative if the nephrotoxicity of amphotericin limits treatment. Response to treatment has usually been disappointing. Because of a significant incidence of early candida infection and its attendant morbidity and mortality, prophylactic amphotericin (as much as 0.3 mg/kg/day for 14 days) has been administered to 15recent recipients with adequate renal function at the University of Pittsburgh. This low-dose regimen eliminated clinically relevant infection and produced minimal toxicity in this group of recipients (501). Only a few cases of aspergillus infection and one case of Cryptococcus infection have been recorded (466, 501, 507). The case fatality rate for aspergillosis was very high in these patients, although in some cases aspergillus infection was not the sole cause of death. Furthermore, diagnosis can be difficult; in at least three cases of. aspergillus infection and the solitary case of cryptococcal infection, the diagnosis was not made antemortem (501). When a diagnosis is established, amphotericin is the treatment of choice for these fungal infections. However, itraconazole has been effective against invasiveaspergillus infection in other settings (514), and may be considered if amphotericin cannot be given.
The greatest mortality is in the first year after transplantation, and a substantial portion of the deaths have occurred in the first 30 days. After rising from 22.5070 in 1985 to 26.2070 in 1987, 30-day mortality decreased to 18.8070 in 1988 (370). Infection has been the leading cause of death, accounting for 48070 of early postoperative mortality and 74070 of later deaths; rejection has caused approximately 20% of both early and late mortality (370). PulmonaryFunction. During the first month after HLT, a significant fall in TLC occurs in most recipients and has been attributed to postoperative alterations in the thoracic cage (468, 515). Thereafter, TLC recovers toward its preHLT value (468). FEV 1 and FVC are decreasedin proportion to the lung volumes and concomitantly return toward normal as TLC increases. As lung function stabilizes, TLC tends towardits pretransplantation valueregardless of the donor lung size (468). Although a mild restrictiveabnormality has been found in some groups of HLT recipients, this finding has been explained by their pretransplantation thoracic volume rather than an intrinsic abnormality in the elastic properties of the allograft (516). Indeed, using radiographic analysis the thoracic configuration has not significantly changed 1 yr after HLT (469), and, when compared, the ratio of TLC post-HLT to TLC pre-HLT has been near unity (468, 516). GasExchange. Oxygenation is usualResults ly normal after recuperation from HLT Survival. In the last report of the Regis- (515, 517, 518). In the early postoperatry of the International Society for Heart tive period arterial Pco, can remain Transplantation the 5-yr actuarial sur- elevated in recipients with preoperative vival for HLT was 55.4070 with n = 16 hypercapnia. In one group of patients at 5 yr (370). For patients having had with bronchopulmonary disease and a transplants between 1981 and 1986, the mean pretransplantation Pco, of 61 mm l-yr actuarial survivalwas 55.7070, but this Hg, the average time to normalization increased to 61.1070 for 1987 recipients. of Pco, was 15 days (519). However, afResults somewhat better than these com- ter recovery Pco, values should return to bined statistics havebeen reported recent- the normal or mildly hypocapnic range ly from some centers. Since the institu- in all recipients regardless of their pretion of a standard three-drug immuno- transplantation condition. Exercise Performance. The functionsuppressive regimen, survival rates in the Stanford University program have risen al capacity of the transplanted cardiopulto 73070 at 1 yr, 73070 at 2 yr, and 65070 monary unit is more than adequate for at 3 yr - a significant improvement over the recipient to lead a normal, active lifethe previous rates of 60070, 50070, and 43070 style.When measured approximately 1 yr at 1, 2, and 3 yr respectively with a two- posttransplantation, the mean maximum drug protocol (475). The Papworth Hos- oxygenuptake reached 52.8% of predictpital group, an early advocate of TBB ed maximal VOl on a treadmill during a for the diagnosis of infection and rejec- maximum tolerable constant work rate tion, has reported l-yr survival of 78070 protocol (517) and 57% of predicted maxand 2-yr survival of 70070 in their recipi- imal VOl on a cycle ergometer during an incremental work rate protocol (518). The ents (466).
mean anaerobic threshold was detected at 43070 of predicted maximal V02 during the incremental protocol (normal = 56070 of predicted maximal V02 ) (518). The average maximum heart rate attained was well below the predicted maximum value for age (517, 518). No evidence of ventilatory limitation to exercise has been discerned (517,518). Values for VE/maximal voluntary ventilation respiratory rate, and VT/VC at peak exercise were all consistent with an adequate breathing reserve. However, the breathing pattern at any level of VEduring exercise was characterized by a higher tidal volume at a lower respiratory rate in HLT recipients than in a comparable group of cardiac transplant recipients (518). The absence of feedback from pulmonary stretch receptors in the denervated lung ofthe HLT recipients was postulated as the explanation for this pattern (518). Gas exchange during exercise is usually undisturbed (517, 518), and no arterial oxygen desaturation usually occurs. The Pe02 response to exercise and to exercise-induced metabolic acidosis is normal, and Vn/VT decreases appropriately between rest and maximum exercise. Hence, ventilation-perfusion matching is not perceptibly affected by pulmonary denervation. The major limitation to exercise after HLTis cardiovascular in origin (517,518). Several factors could impose a circulatory constraint, but the restricted chronotropic response of the denervated heart has been the most clearly delineated. Heart rates at peak exercise have consistently been sub maximal for the HLT recipients' age (517, 518). Chronic anemia related to immunosuppressive drugs, physical deconditioning, steroid myopathy, and systemic hypertension from cyclosporine treatment are other potentially contributory factors. Control of Breathing. HLT provides a unique opportunity to investigate the denervated lung. The afferent and efferent nerve supply to the lung is completely severed during extraction of the heartlung organ block from the donor, and no reinnervation has occurred in longterm survivors (520). Studies of the ventilatory response to hypercapnia have yielded conflicting results. The ventilatory response in HLT recipients was significantly blunted in comparison to normal control subjects in one study (521) but was not significantly different from normal controls (522) or from heart transplant recipients in other studies (523). The breathing frequency response to hypercapnia in HLT
ETTINGER AND TRULOCK
recipients was depressed in comparison to both normal controls (521) and cardiac recipients (523). Mouth occlusion pressure (P 0.1) was significantly greater in HLT recipients than in normal controls and suggested an increased neuromuscular output to sustain equivalent ventilation (523). The response in HLT recipients is not altered by upper airway anesthesia (524). Thus, the data regarding the ventilatory response have been inconclusive, but the results have tended to support a decreased breathing frequency response to hypercapnia (521, 523). The breathing pattern during both hypercapnia and exercise, if not the overall ventilatory response, seems to be modified after HLT, probably by disruption of vagaIly mediated feedback (518, 521). In contrast, no significant differences between HLT recipients and normal subjects have been detected in the response to isocapnic hypoxia (521). Other than the subtle changes in breathing pattern, denervation has no effect on respiration during sleep (521). During formal polysomnography, HLT recipients have not had an increased frequency or severity of apneas, hypopneas or oxyhemoglobin desaturation, and sleep architecture has not been distorted in comparison with normal subjects. Airway Reactivity. Many, but not all, HLT recipients exhibit bronchial hyperreactivity to inhaled methacholine and histamine (525-528); however, bronchial responsiveness to exercise appears to be normal (529). The responses to methacholine and histamine have generally been strongly correlated with each other (526, 527). No relationship has been found between methacholine responsiveness and airway inflammation in endobronchial biopsies, clinical or histologic allograft rejection, time since transplantation, or baseline FEV 1 (525). Denervation hypersensitivity of airway smooth muscle muscarinic receptors has been posed as the mechanism of the enhanced methacholine responsiveness (525, 526), and recent evidence that ipratropium bromide blocks methacholine-induced bronchoconstriction in the transplanted lung has supported the hypothesis that the bronchial hyperreactivity is mediated through muscarinic receptors (530). However, the reaction to histamine after denervation has not been easily explainable in the context of current understanding of the control of airway caliber. Modest responsiveness (fall in FEV 1 > 10070) to ultrasonically nebulized distilled water is present in some HLT recipients (520). It has not been associated with methacholine hyperreactivity or
airway inflammation, but it appears to be common in recipients with histologic rejection. The mechanism of this reaction was uncertain, but, because denervation precludes a reflex pathway, a local, vascular-mediated cause was speculated. References 332. Kriett JM, Kaye MP. The registry of the International Society for Heart Transplantation: seventh official report -1990. J Heart Transplant 1990; 9:323-30. 333. Copeland JG, Mammana RB, Fuller JK, Campbell OW,McAleerMJ, Sailer JA. Heart transplantation: four year's experiencewith conventional immunosuppression. JAMA 1984; 251:1563-6. 334. Hosenpud JD, Stibolt TA, Atwal K, Shelley D. Abnormal pulmonary function specificallyrelated to congestive heart failure: comparison of patients before and after cardiac transplantation. Am J Med 1990; 88:493-6. 335. Wright RS, Levine MS, Bellamy PE, et a/. Ventilatory and diffusion abnormalities in potential heart transplant recipients. Chest 1990; 98: 816-20. 336. Ravenscraft SA, Kubo SH, Olivari MT, et al. Resolution of pulmonary function test abnormalities after successful heart transplantation (abstract). Am Rev Respir Dis 1990; 141:A685. 337. Siegel JL, Miller A, Brown LK, DeLuca A, Teirstein AS. Pulmonary diffusing capacity in left ventricular dysfunction. Chest 1990; 98:550-3. 338. Ries AL, Gregaratos G, Friedman PJ, Clausen JL. Pulmonary function tests in the detection of left heart failure: correlation with pulmonary artery wedgepressure. Respiration 1986; 49:241-50. 339. Casan P, Sanchis J, Cladellas M, Amengual MJ, Caralps JM. Diffusing lung capacity and cyclosporinein patients with heart transplants. J Heart Transplant 1987; 6:54-6. 340. Stevenson LW, MacAlpin RN, Drinkwater 0, Clark S, Dracup K, Laks H. Heart transplantation at UCLA: selection and survival.J Heart Transplant 1986; 5:62-4. 341. Vagelos R, Fowler MB. Selection of patients for cardiac transplantation. Cardiol Clin 1990; 8:23-38. 342. Bussieres LM, Cardella CJ, Daly PA, David TE, Feindel CM, Rebuck AS. Relationship between preoperative pulmonary status and outcome after heart transplantation. J Heart 'Iransplantation 1990; 9:124-8. 343. Seibert AF, Allison RC, Bryers CH, Kirkpatrick MB. Normal airway responsiveness to methacholine in cardiac asthma. Am Rev Respir Dis 1989; 140:1805-6. 344. Eichacker PQ, Seidelman MJ, Rothstein MS, Lejemtel T. Methacholine bronchial reactivity testing in patients with chronic congestive heart failure. Chest 1988; 93:336-8. 345. Sasaki F, Ishizaki T, Mifune J, Fujimura M, Nishioka S, Miyabo S. Bronchial hyperresponsiveness in patients with chronic congestive heart failure. Chest 1990; 97:534-8. 346. Cabanes LR, Weber SN, Matran R, et at. Bronchial hyperresponsiveness to methacholine in patients with impaired left ventricular function. N Engl J Med 1989; 320:1317-22. 347. Pison C, Malo J, Rouleau J, Chalaoui J, Ghezzo H, Malo J. Bronchial hyperresponsiveness to inhaled methacholine in subjects with chronic left heart failure at a time of exacerbation and after increasingdiuretic therapy.Chest 1989; 96:230-5. 348. Dark 0, Pingleton SK, Kerby GR, et a/. Breathing pattern abnormalities and arterial oxygen desaturation during sleep in the congestiveheart failure syndrome. Chest 1987; 91:833-6.
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