Complications of Lung Transplantation

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Lung Transplantation

Complications of Lung Transplantation Andrew M. Tager, MD Leo C. Ginns, MD

L ung transplantation was reviewed in the Critical Care Nursing Clinics of North America in 1992.61 Even since then, the morbidity and mortality rates of this operation have decreased significantly. The 2-year actuarial survival of lung transplant recipients, which had climbed from 51 % for patients receiving transplants from 1983 to 1989, to 60% for those who received transplants from 1990 to 1991, increased further to 68% for those who received transplants from 1992 to 1994.55 This improvement has come despite the expansion of the candidate pool to include increasingly ill patients. The improvement is owing, in part, to technical refinements of the operation itself. It also is attributable to better prevention, diagnosis, and treatment of posttransplant complications. Complications of lung transplantation can be classified into three broad categories: (1) complications of the operation itself, (2) complications of transplantation-that is, rejection, and (3) complications of the immunosuppressive agents used to prevent rejection, including infection, malignancy, and direct side effects of the medications. The From the Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

accumulation of experience with lung transplant patients has allowed for delineation of the usual clinical presentations of the major complications in each of these categories, as well as their usual times of presentation, which are reported in Table 1. In each of the categories listed, this article describes the clinical presentations of the major transplantrelated complications, as well as strategies for their prevention, early diagnosis, and treatment.

Complications of the Operation Itself In the first 2 weeks following lung transplantation, the greatest cause of morbidity and mortality are complications caused by the transplant operation itself. 55 These early complications include those related to the lung transplant operation specifically, such as the reimplantation response and airway anastomotic complications; and those complications related to thoracic surgical operations generally. Complications of thoracic surgical operations in general include pain, phrenic nerve dysfunction, retained bran-

CRITICAL CARE NURSING CLINICS OF NORTH AMERICA I Volume 8 I Number 3 I September 1996

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Table 1. TIMING OF MAJOR COMPLICATIONS FOLLOWING LUNG TRANSPLANTATION

Time Postoperatively

Oto 4 weeks

Complications of Operation General to Thoracic Surgery

Retained bronchial secretions and mucous plugging Atelectasis Persistent air leaks Pneumothorax Hemorrhage Atrial arrythmias Myocardial infarction Cardiac arrest

Complications of Operation Specific to Lung Transplantation

Reimp lantation response Airway dehiscence Systemic hypotension Adynamic ileus Diaphragmatic hernia

Rejection

Infection

Hyperacute rejection Acute rejection

Bacterial pneumonia Fungal infections Wound and line infections

2 to 3 months 4 to 6 months

> 6 months

Airway stenosis

Acute rejection Chronic rejection

Bacterial pneumonia Fungal infections Viral infections, including CMV, and RSV Pneumocystis carinii pneumonia Mycobacterial infections

Malignancy

Post-transplant lymphoproliferative disorder

COMPLICATIONS OF LUNG TRANSPLANTATION

chial secretions and mucous plugging, atelectasis, pneumonia, persistent air leaks, tension and nontension pneumothoraces, hemorrhage, respiratory failure, and cardiac and hemodynamic complications. 77• 99 Therapies of certain of these general thoracic surgical complications must be modified for the lung transplant recipient. For example, concern about healing of the airway anastomosis limits endotracheal suctioning to the airways proximal to the anastomosis only. Retained bronchial secretions and mucous plugging distal to the anastomosis are treated instead with frequent therapeutic flexible bronchoscopies, usually performed daily or even more frequently in the early postoperative period. Hemorrhage

The underlying pulmonary diseases of lung transplant recipients frequently lead to the formation of dense pleural adhesions and the hypertrophy of the bronchial circulation. These changes can lead to significant hemorrhage following the removal of the recipient's native lung(s). Any degree of hemorrhage that occurs can be exacerbated by the anticoagulation necessary for cardiopulmonary bypass, which is required during some transplant operations. The incidence of significant hemorrhage has been reduced by the use of aprotinin as a hemostatic, and the use of a transverse, or "clamshell," incision rather than a median sternotomy in double-lung transplant recipients, which allows better visualization of the pleural surface and posterior mediastinum.20 The Reimplantation Response

The reimplantation response has been defined broadly as "the morphologic, roentgenographic, and functional changes that occur in a lung transplant in the early postoperative period as a result of surgical trauma, ischemia, denervation, lymphatic interruption, and other injurious processes (exclusive of rejection) that are unavoidable aspects of the transplant operation." 69 The reimplantation response presents with the triad of worsened

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gas exchange, decreased lung compliance, and alveolar and interstitial infiltrates, typically most extensive in perihilar regions. It is extremely common, occurring in the majority of patients, 1• 87 and presents within hours to days of operation. 87 A perihilar infiltrate in the transplanted right lung typical of the reimplantation response is demonstrated in Figure lB, which shows the chest radiograph of a patient on postoperative day (POD) three. The same patient's chest radiograph on POD one, prior to the development of the reimplantation response, is shown in Figure lA for comparison. Treatment is supportive, with mechanical ventilation, and diuretics and fluid restriction as tolerated. Although the reimplantation response can cause severe hypoxemia and prolong the need for mechanical ventilation, the typical course is marked by progressive clearing to complete resolution within several days to several weeks. 1• 87 Figure 1 C shows the chest radiograph of the patient described previously on POD four, demonstrating early resolution of the previously seen reimplantation response with supportive care, including the judicious use of diuretics. A minority of patients who develop the reimplantation response, however, go on to develop adult respiratory distress syndrome attributed to the initial reperfusion injury.12 Development of adult respiratory distress syndrome unilaterally in single-lung transplant recipients can make the ventilatory requirements of the transplanted lung differ dramatically from those of the remaining native lung. Some of these patients have benefited from the use of two separate ventilators to ventilate each lung independently. Airway Anastomotic Complications

Poor healing of the anastomosis between the donor and recipient airways can lead to significant complications. In the early lung transplant experience, anastomotic complications contributed directly to the death of most of the recipients who survived to POD ten, and were considered to be "the Achilles heel of human lung transplantation." 98

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Figure 1. A, Chest radiograph of a patient on the first postoperative day, following single-lung transplantation of the right lung. The patient's severe underlying emphysema is demonstrated in the hyperexpanded native left lung. The transplanted right lung appears clear. 8, Patient on the third postoperative day, demonstrating the development of a perihilar infiltrate in the transplanted right lung, characteristic of the reimplantation response. C, Patient on the fourth postoperative day, with resolution of the reimplantation response in the transplanted right lung and with supportive care, including the judicious use of diuretics.

The major cause of poor airway healing appears to be an inadequate blood supply to the anastomosis. 83 Increasingly severe ischemia leads to mucosa! ulceration, followed by necrosis of submucosal tissue and cartilage, and ultimately, full-thickness necrosis. Anastomotic necrosis can lead to catastrophic airway dehiscence early after transplantation, or to significant airway stenosis subsequently. Luminal narrowing also can be caused by the growth of granulation tissue, the formation

of a fibrotic stricture, or the development of perianastomotic bronchomalacia. 83 The door to successful lung transplantation was opened by the demonstration that wrapping the airway anastomosis with a protective flap of well-vascularized tissue, such as intestinal omentum, can provide an adequate blood supply for healing.71 The omental wrap was used in the first successful series of singlelung transplants. 71 Subsequently, some transplant centers have reported a low incidence

COMPLICATIONS OF LUNG TRANSPLANTATION

of airway complications using the alternative technique of a telescoping anastomosis, without an omental wrap. 10 Instead of an end-toend anastomosis, the telescoping anastomosis uses the intussuception of the donor bronchus into that of the recipient. Airway anastomotic complications are diagnosed by direct visualization with bronchoscopy.83 Their presence also can be signaled by changes in follow-up spirometry indicative of unilateral mainstem bronchial obstruction. 2· 75 Anastomotic narrowing owing to granulation tissue can be treated with rigid bronchoscopy and surgical debridement or with bronchoscopic Nd: YAG laser ablation.11· 15 Narrowing caused by stricture formation can be managed with bronchoscopic dilatation or stent placement. 15, 23

Cardiac and Hemodynamic Complications Both perioperative myocardial infarctions and cardiac arrests have occurred in lung transplant recipients, though relatively infrequently. 39 More common cardiac and hemodynamic complications are atrial arrhythmias and episodes of systemic hypotension. Postoperative atrial arrhythmias, including atrial fibrillation and flutter, are not unexpected, given that atrial clamps are applied intraoperatively and some handling of the heart is inevitable. Most convert spontaneously or with medical therapy, 39 making the need for direct current cardioversion infrequent. Systemic hypotension requiring vasopressor and inotropic support also is common in the first week following transplant. 20• 6o The hemodynamic profile typically seen includes a severely depressed systemic vascular resistance with a normal or diminished cardiac index.6o This complication has been associated with the reimplantation response.6o Postoperative hemodynamic instability also has been common in patients with underlying pulmonary hypertension. 20 In the first week post-transplantation minimal activity, suctioning, or pain can cause wide swings in pulmonary artery pressures in these patients, which can result in significant episodes of systemic

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hypotension or hypertension, as well as significant oxygen desaturations. 20

Gastrointestinal Complications As has previously been the case with heart

and heart-lung transplant patients, the incidence of gastrointestinal (GI) complications in lung transplant recipients significantly exceeds that observed in patients undergoing nontransplantation thoracic operations.88 Frequent GI complications occurring early after transplantation include the development of a diaphragmatic hernia through the defect created to allow passage of the omental pedicle used to wrap the bronchial anastomosis,88 and the development of a prolonged adynamic ileus, requiring nasogastric suction and parenteral nutritional support. A postoperative ileus developing in a transplant recipient may be potentiated by drug toxicities. GI complications occurring later after transplantation may present atypically. 88 Transplant patients may fail to manifest the usual symptoms and signs of intra-abdominal pathologic processes because of their immunosuppressive medications, which reduce their ability to mount inflammatory responses. This can result in delays in diagnosis and lead to poorer outcomes. For this reason, a high index of suspicion and liberal use of diagnostic studies have been recommended in evaluating abdominal complaints posttransplantation.88 Additionally, pretransplant GI imaging to identify pre-existing abdominal conditions can be extremely helpful in posttransplantation management. A GI complication unique to patients with underlying cystic fibrosis is the development of a meconium ileus equivalent. In this syndrome, inspissated intestinal contents in the distal ileum and proximal colon cause small bowel obstruction, presenting with pain, distention, constipation, and bilious vomiting. 59 The syndrome is likely related to malabsorbtion caused by the exocrine pancreatic insufficiency commonly occurring in cystic fibrosis patients. 59 Preventive strategies center around the resumption of supplemental pancreatic enzymes as soon as bowel function permits.

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Some centers also add N-acetylcysteine to the enteral feedings of these patients.43

Rejection Placing a donor organ from one individual into a genetically different recipient is referred to as allogeneic transplantation, that is, transplantation between members of the same species who nonetheless possess different copies (alleles) of multiple genes. 42 These genetic differences between donor and recipient result in rejection of the graft by the recipient's immune system. The antigens against which the recipient's immune response is targeted are known as histocompatibility antigens. There are multiple histocompatibility antigens that differ in their ability to cause rejection. Antigens that can cause particularly strong reactions are encoded by the major histocompatibility complex (MHC), and are referred to as MHC antigens. 42 The human MHC is called the human leukocyte antigen (HLA) complex. There are multiple immunologic processes that can produce a spectrum of rejection responses to transplanted organs. This spectrum can be subdivided into hyperacute, acute, and chronic rejection. Each of these categories can be characterized in terms of its causative immunologic mechanism(s), as well its typical mode and timing of clinical presentation. Hyperacute Rejection

Hyperacute rejection, when it occurs, is noted within minutes to hours after transplantation.4 This form of rejection was described in kidney transplant recipients, and although its occurence in lung transplant patients has not been documented, it has been suspected in rare cases.48 It is caused by pre-existing antibodies in a recipient to antigens on donor vascular endothelium, including HLA antigens and ABO blood-group antigens. Such antibodies may be present in a recipient because of prior exposure to these antigens through blood transfusion, pregnancy, or previous trans-

plantation. These antibodies bind to the vascular endothelium of graft and activate inflammatory and coagulation cascades. This results in rapid and extensive thrombosis of graft vessels, which causes graft failure. Fortunately, this form of rejection can be prevented almost entirely by the preventive strategies discussed later. Acute Rejection

Acute rejection typically occurs in the first 3 months following transplantation, although the risk of this form of rejection persists thereafter, and late episodes are not unusual. 19· 78 Acute rejection is caused by the recipient's cellular immune responses against the graft's HLA antigens. Although this response is complex and involves multiple cell types and soluble mediators, the key cell is the Tlymphocyte.54 The T-lymphocyte consequently is the target of both preventive and therapeutic measures for this form of rejection. In keeping with the central role of the lymphocyte in its etiology, the key pathologic feature of acute rejection is a perivascular lymphocytic infiltrate, which also may be accompanied by a lymphocytic bronchitis or bronchiolitis.101 Acute rejection is graded pathologically in terms of severity, from grade one, minimal acute rejection, to grade four, severe acute rejection.101 The lymphocytic infiltrate characteristic of grade one, acute rejection is demonstrated in Figure 2, which shows lung tissue taken from a transbronchial biopsy of a patient during an episode of acute rejection. Symptoms of acute rejection include cough, dyspnea , and fatigue, although a substantial number of patients may be asymptomatic. 94 Physical signs include rales and wheezes. The presence of acute rejection also may be indicated by a rise in temperature greater than 0.5°C above a stable baseline, a fall in oxygenation greater than 10 mm Hg below a stable baseline, or a fall in forced expiratory volume in 1 second (FEV1) of greater than 10% below a stable baseline. 94 Radiographic findings associated with acute rejection include increased septa! lines, new or increased pleural

COMPLICATIONS OF LUNG TRANSPLANTATION

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Figure 2. Lung tissue taken from a transbronchial biopsy of a patient during an episode of acute rejection, demonstrating the lymphocytic infiltrate characteristic of grade one (minimal) rejection.

effusions, and new or increased air-space disease.8 The increased septal lines seen are believed to be the radiographic correlates of the lymphocytic infiltrates that are characteristic

Figure 3. Chest radiograph of the same patient shown in Figure 1 on the twelfth postoperative day. The transplanted right lung now demonstrates a diffuse interstitial and alveolar infiltrate, including increased septal lines, characteristic of acute rejection.

of acute rejection histologically.8 Figure 3 shows the chest radiograph of the same patient shown in Figure 1, during an episode of acute rejection on POD 12. At that time, the patient's chest radiograph demonstrated a diffuse interstitial and alveolar infiltrate, including increased septal lines. Despite this potentially characteristic radiographic appearance, a substantial number of patients with acute rejection may have no chest radiograph abnormalities.67 In some of these patients, an increase in septal lines can still be appreciated on chest CT scan, as demonstrated in Figure 4A, which shows the scan of another patient during an episode of acute rejection in the transplanted right lung. For comparison, Figure 4B shows the chest CT scan appearance of a single-lung transplantation patient doing well at the time of routine follow-up. These chest CT scan findings, however, also can be nonspecific and establishing the diagnosis of acute rejection generally requires ruling out possible infectious complications with bronchoalveolar lavage and transbronchial biopsy. Unfortunately, despite the preventive mea-

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Figure 4. A, Chest CT scan of a patient during an episode of acute rejection in the transplanted right lung. The CT scan demonstrates the increased septal lines characteristic of acute rejection. B, Chest CT scan of a singlelung transplant patient doing well at the time of routine follow-up. The patient's severe underlying emphysema is demonstrated in the native left lung.

sures discussed subsequently, acute rejection is an almost universal occurrence in the first several months following lung transplantation.34· 35 Chronic Rejection

Chronic rejection is a poorly understood process that affects all solid-organ transplants, leading to chronic graft dysfunction and late graft failure . This form of rejection typically occurs greater than 1 year after lung transplantation, but has been described as early as 2 months following operation. 49 The cause of chronic rejection is unclear. Hypothesized causes include the cumulative effect of recurrent episodes of acute rejection, chronic arterial insufficiency and progressive graft

ischemia, and an ongoing subclinical hostimmune response against graft. 93• 94 Pathologically, for all solid-organ transplants, "the common denominator of (chronic rejection) entails development of obliterative fibrosis of hollow structures within the graft, regardless of whether they are vessels, bronchioles, or bile ducts." 93 In the transplanted lung, chronic rejection causes (1) bronchiolitis obliterans, characterized by submucosal scarring of membranous and respiratory bronchioles, which causes subtotal or total obliteration of the bronchiolar lumens, and (2) chronic vascular rejection, characterized by fibrointimal thickening of arteries and veinsrn1 The central feature of chronic rejection is the development of physiologic airway obstruction. Although the diagnosis of chronic

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Figure 5. Chest radiograph on the fifteenth postoperative day. The transplanted right lung now demonstrates complete clearance of the episode of rejection, following "pulse" treatment with high-dose corticosteroids in the interval 3 days.

rejection may be confirmed by a transbronchial biopsy demonstrating the changes described previously, the key diagnostic criterion is a 20% decline in the FEV1 from a previously established post-transplantation baseline, for which no other cause, for example infection or acute rejection, can be found.16 Clinically, chronic rejection often presents insidiously, with the first manifestation typically being a nonproductive or minimally productive cough. Dyspnea is a relatively late manifestation of this form of rejection, occurring up to several months later and reflecting extensive airway disease. 92 Unfortunately, despite the preventive strategies described next, chronic rejection affects approximately one half of lung transplant recipients49 and is a significant cause of late mortality. 13 Preventive Strategies

There are two broad strategies that can be used to prevent rejection. The donor graft can be selected in such a way as to minimize the immune response provoked in the recipient, or the recipient's immune response can be suppressed. Borrowing from experience with kidney transplantation, hyperacute rejection

has been avoided almost completely in lung transplant patients by (1) ABO blood-group matching between donor and recipient, and (2) screening recipients for antibodies against a panel of the most commonly expressed HLA antigens. 94 The occurrence of acute and chronic rejection also can be reduced in kidney transplant patients by matching donor and recipient HLA antigens.4• 24 The limited time that donor lungs can be preserved, however, has precluded HLA matching in lung transplantation. The prevention of acute and chronic rejection in lung transplantation, therefore, relies on the use of agents capable of suppressing the recipient's immune response. Immunosuppressive regimens used in lung transplantation typically use multiple agents. Because the T-lymphocyte is the key agent of cell-mediated rejection, immunosuppressants are used for their ability to reduce Tlymphocyte function or number. Cyclosporine has become the most important immunosuppressive agent for solid-organ transplantation, including lung transplantation. It inhibits antigen-induced production of interleukin-2 (IL-2), a cytokine central to Tlymphocyte activation and proliferation. 9• 46 Other immunosuppressive agents, used in combination with cyclosporine, include azothioprine, a cytotoxic purine analog that

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blocks DNA synthesis and inhibits proliferation of lymphocytes62 ; corticosteroids, which decrease production of multiple inflammatory mediators that promote lymphocyte proliferation, including IL-2 30 ; and antilymphocyte antibodies, which deplete T lymphocytes. These antibodies can be either polyclonal antisera, such as antilymphocyte globulin (ALG) and antithymocyte globulin (ATG ); or monoclonal antibodies such as OKT3, which is directed against the CD3 antigen of T cells. A new immunosuppressive agent, tacrolimus (FK506), inhibits antigen-induced production of IL-2 like cyclosporine, but 50 to 100 times more potently. FK-506 has shown promise when used in place of cyclosporine in other solid organ transplants and is being investigated for use in lung transplant patients. 34

Treatment

Episodes of acute rejection are treated with corticosteroids, and patients almost always respond.94 A 3-day "pulse" of intravenous methylprednisolone, 500 to 1000 mg daily, is sufficient to treat most episodes. Additionally, if maintenance treatment with prednisone recently has been decreased or stopped, then escalating or resuming prednisone treatment, with a taper to the prerejection dose over 2 to 3 weeks, also may be beneficial. Following the development of the episode of acute rejection demonstrated in Figure 3, which shows the patient's POD 12 chest radiograph, the patient received "pulse" treatment with highdose corticosteroids. Complete interval clearing of the acute rejection is demonstrated by the patient's chest radiograph 3 days later, on POD 15, as shown in Figure 5. Some episodes of acute rejection failing to resolve with steroid treatment have been treated successfully with OKT3. 84 • 85 Chronic rejection has been treated by increasing patients' immunosuppressive therapy, with high-dose corticosteroids, azathioprine, or antilymphocyte antibodies , including ALG, ATG , and OKT3. Although beneficial results have been achieved with these measures, patients frequently relapse,

and chronic rejection remains a source of significant late mortality. 94

Infections The immunosuppressive agents used to prevent and treat rejection also suppress transplant patients' immunologic defenses against infection. Consequently, infections are a significant source of morbidity and mortality in recipients of all solid-organ transplants. The rate of infectious complications is even higher in lung transplant patients, however, than in recipients of other solid organs.20 There are multiple factors contributing to this higher infection rate. First, the possibility of organ donation is established by virtue of donors' brain death, and hence donors are by definition intubated and mechanically ventilated. This exposes all donor lungs to aspiration, airway colonization, and parenchymal infection. 45 Second, lung transplant recipients are commonly intubated for longer periods of time after their operation than other solid-organ transplant recipients, further increasing their risk of pneumonia. Third, the lung allograft is unique among organ transplants in that it is exposed continuously to the external environment, and consequently, potential pathogens. Finally, two important pulmonary defense mechanisms , the cough reflex37 and mucociliary clearance, 37 · 82 have been demonstrated to be impaired in transplanted lungs. All of these factors increase lung transplant patients' susceptibility to pulmonary infections and, in fact, the lung is the site of the majority of their post-transplant infections. 64 Bacterial Pneumonia

The majority of infections in lung transplant recipients are caused by bacteria, and the most common bacterial infection in these patients is pneumonia. 64 Bacterial pneumonias occur most frequently in the early postoperative period, within 2 months of transplant. 64 Gram-negative bacilli are the most common causative organisms.64 Clinically, these infec-

COMPLICATIONS OF LUNG TRANSPLANTATION

tions present with fever, new or increased radiographic infiltrates, and the presence of a new or newly predominant organism by sputum gram stain and culture. 79 The diagnosis frequently is confirmed by bronchoscopy. Patients are treated with culture-directed antibiotics for 2 to 4 weeks, often accompanied by a modest reduction in immunosuppression. Unfortunately, despite therapy, these infections remain a leading cause of mortality. 79

Cytomegalovirus Infections Cytomegalovirus (CMV) is a member of the human herpes virus family. Although CMV usually does not cause clinically significant disease in immunocompetent persons, it is the most important opportunistic infection in lung transplant recipients, and the second most frequent infection in these patients overall. 79 Following a primary infection, CMV is not cleared from the body, but remains present in a latent state. Consequently, CMV disease in lung transplant recipients can result from either (1) reactivation of a latent CMV infection acquired by the recipient prior to transplant, or (2) transmission of CMV to the recipient following transplant, from either the donor lung or transfused blood products, resulting in a new primary infection. The frequency of CMV disease therefore depends on whether the recipient and donor carry latent CMV, which is determined by the presence or absence of antibodies to CMV. Post-transplantation infections are most frequent in recipients positive for CMV antibodies (CMV + ), indicative of prior CMV exposure, regardless of the CMV status of the donor. 79 CMV infections in these patients are felt to be caused by a reactivation of their own latent infections, because of their immunosuppressive therapy. 89 CMV infections are most severe, however, in recipients negative for CMV antibodies (CMV-) who receive lungs from CMV+ donors. 79 CMV infections in these patients are thought to be caused by primary infections with the virus transmitted from the allograft, which has been documented to occur in renal transplant recipi-

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ents. 14 Primary infections have been associated with more severe manifestations of disease and higher mortality rates than reactivation of latent infections. 5• 24 In most cases of CMV disease, the infection is generalized, involving multiple organ systems, although clinically apparent disease may not be present in all organ systems affected. 38 The most significant site of disease is the lung, where CMV pneumonitis can present with fever, dyspnea, hypoxemia, and diffuse radiographic infiltrates. 79 In a significant minority of lung transplant patients, the primary site of clinically apparent disease is the GI tract. These cases present with anorexia, weight loss, epigastric pain, or diarrhea.79 CMV also can present with a nonspecific complex of symptoms and signs, including fevers, chills, malaise, and myalgias, which can be accompanied by leukopenia, with greater than 3% atypical lymphocytes in the peripheral blood smear.18• 79 Prior to the use of ganciclovir preventively, CMV disease typically presented in the second month posttransplantation. In addition to reducing the frequency of CMV disease, the use of ganciclovir preventively has delayed the usual time of presentation of CMV disease until 4 to 6 months post-transplantation. 79 The ability to diagnose the presence of CMV infection rapidly has improved dramatically.38· 72 CMV early antigen can be assayed for in bronchoalveolar lavage fluid and urine, and its presence indicates active CMV replication. A test for the rapid detection of CMV antigenemia in peripheral blood also is now available and appears to be a sensitive early marker for CMV infection. Additionally, positive culture results can be obtained significantly earlier with the use of a shell-vial system in place of traditional viral culture methods. Even in immunosuppressed patients, however, CMV infection can be asymptomatic, and the documentation of clinically significant disease caused by CMV requires a biopsy of the organ(s) suspected to be involved, with demonstration of intracellular inclusions typical of the virus in the biopsy tissue. 79

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Without treatment, the mortality of CMV pneumonitis approaches 100%.72 Fortunately, the introduction of ganciclovir has led to successful treatment outcomes in most cases. 29 Lung transplant patients surviving CMV pneumonitis, however, still appear to be subject to multiple long-term sequelae, including reduced lung function , increased rates of subsequent bacterial or fungal pneumonias, increased rates of chronic rejection, and lower 2-year survival. 27 Other Viral Infections

Herpes simplex virus can cause necrotizing tracheobronchitis and esophagitis and less frequently, pneumonitis in the early weeks post-transplantation, but these infections have become uncommon with the widespread use of prophylactic acyclovir or ganciclovir.5 Epstein-Barr virus (EBY), which can cause pharyngitis and mononucleosis in immunocompetent persons, rarely has been reported to cause fever, malaise, pharyngitis, and adenopathy in lung transplant patients.1s EBY also has been implicated, however, in the pathogenesis of post-transplant lymphoproliferative disorders, a severe complication of transplantation described subsequently. Respiratory syncytial virus, which causes tracheobronchitis, bronchiolitis, and pneumonia in immunocompetent children, recently has been implicated as causing a broad spectrum of respiratory illness in lung and other solid-organ transplant recipients, ranging from isolated rhinitis to fatal adult respiratory distress syndrome. 56 Aerosolized ribavirin and respiratory syncytial virus hyperimmune globulin have been used to treat these infections, with successful outcomes reported.5· 56· 73 Fungal Infections

Both Candida and Aspergillus can cause invasive pneumonias, as well as disseminated infections in lung transplant recipients. These infections typically arise in the allograft, usually presenting within the first several months after transplantation.79 The donor trachea ap-

pears to be the most common source of Candida infections. 18An ulcerative trancheobronchitis, due to Aspergillus and involving the anastomotic site and large airways , also has been described and appears to be highly specific to lung and heart-lung transplantation. 52 Unfortunately, symptoms are often minimal or absent in these infections initially, which can lead to a delay in diagnosis. Consequently, fungal infections are frequently disseminated at the time of recognition and are associated with high mortality rates. 52·79 Treatment has typically been with intravenous amphotericin B in full therapeutic doses. The problem of synergistic nephrotoxicity of amphotericin B with cyclosporine has led, however, in some cases, to the use of fluconazole for Candida infections, and itraconazole for Aspergillus infections.is, 52· 79 Pneumocystis Carinii Pneumonia

Infection with Pneumocystis carinii initially was extremely common in lung transplant recipients, but the frequency of this infection has been reduced markedly by the adoption of prophylactic therapy with oral trimethoprimsulfamethoxazole.18Interestingly, many transplant patients from whom P. carinii has been recovered have been asymptomatic, and clinically significant pneumonias, with fever, cough, dyspnea, hypoxia, and radiographic infiltrates have represented the minority of cases.18 • 36 Treatment of clinically significant pneumonias with standard high-dose regimens of intravenous trimethoprim-sulfamethoxazole has been largely successful. The incidence of this infection peaks 3 to 6 months after transplantation but cases have occurred greater than 1 year following transplantation, in the setting of recently increased immunosuppressive therapy with high-dose corticosteroids for the treatment of rejection. 53 Mycobacterial Infections

Immunosuppression also makes lung transplant recipients prone to infection with Mycobacterium tuberculosis.66 Although reported cases have been infrequent to date, the recent

COMPLICATIONS OF LUNG TRANSPLANTATION

resurgence of tuberculosis in the general population may make this a more common problem in transplant patients in the future. Tuberculosis can occur in transplant patients due to (1) reactivation of latent infections acquired pretransplantation, (2) transmission from donor lungs, or (3) post-transplant exposures to persons with active tuberculosis. 66 The time of presentation of reported cases has ranged from 3 to 20 months posttransplantation. Most cases have been pulmonary infections, presenting with fevers, constitutional symptoms, and chest radiographic abnormalities, including parenchymal infiltrates, pulmonary nodules, hilar adenopathy, and pleural effusions.66 These cases have responded well to antituberculous antibiotics. One case of disseminated tuberculosis has been reported, which was fatal. A fatal case of infection with the nontuberculous Mycobacterium chelonei also has been reported in a heart-lung transplant recipient. 95 Preventive Strategies

The frequency of many post-transplant infections has been reduced through the adoption of preventive antibiotic therapies. The incidence of bacterial pneumonias has been reduced by treatment of recipients with empiric antibacterial antibiotics in the immediate postoperative period, with the choice of antibiotics subsequently being adjusted as per the results of preoperative cultures taken from both recipient and donor airways. 79• 102 Strategies for preventing CMV disease depend on the serologic status of the recipient and donor. Transmission of CMV to CMV - recipients who receive lungs from CMV- donors is prevented by ensuring that these patients receive only CMV- blood products. All other recipient/ donor combinations are treated with ganciclovir, or ganciclovir followed by acyclovir, which has successfully reduced the frequency of CMV disease. 25• 26• 40• 79 At some centers, CMV- recipients who receive lungs from CMV + donors also are treated with CMV hyperimmune globulin, given their high risk of developing severe disease. The use of ganciclovir and acyclovir prophylaxis also has

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virtually eliminated post-transplant herpes simplex virus disease. 79 The incidence of fungal infections has been reduced with the prophylactic use of fluconazole, itraconzole, and amphotericin B. 79 The use of oral trimethoprim-sulfamethoxazole for 1 year following transplantation has markedly reduced the frequency of P. carinii pneumonia. 53 The occurrence of late cases of P. carinii pneumonia associated with increased immunosuppression has led to the recommendation to reinstitute trimethoprim-sulfamethoxazole prophylaxis any time immunosuppression is augmented thereafter. 53 Patients who develop allergic reactions to trimethoprim-sulfamethoxazole can be desensitized, or receive alternative prophylactic antibiotics, such as dapsone. M. tuberculosis is treated preventively by treating recipients with positive PPD skin tests with isoniazide,79 before or after transplant. Special consideration has been given to preventing post-transplant infections in patients with underlying cystic fibrosis (CF).31 Pulmonary infections occur repeatedly in these patients before transplant, often with bacteria progressively resistant to antibiotics. Some centers consider the presence of respiratory pathogens resistant to all antibiotics to be a contraindication to transplantation. Although the underlying abnormalities of CF do not recur in transplanted lungs, they persist in transplanted CF patients' paranasal sinuses,31 which can remain colonized with pretransplant bacterial flora. Sinus drainage in these patients therefore represents a potential source of post-transplant pneumonias with resistant organisms. This has led some centers to perform prophylactic sinus surgery, with subsequent antibiotic irrigation, in CF transplant recipients. 58 Other centers perform such procedures only if clinically significant sinus infections occur in these patients after transplantation.79

Malignancies In addition to the increased risk of infections described previously, immunosuppression

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also causes an increased risk of certain malignancies in recipients of solid-organ transplants. This increased risk is confined to specific cancers, including non-Hodgkin's lymphomas and other post-transplant lymphoproliferative disorders, squamous cell cancers of the lip and skin, Kaposi's sarcomas, soft-tissue sarcomas, carcinomas of the vulva and perineum, carcinomas of the kidney, and hepatobiliary tumors.B1 Transplant recipients, however, have no increased risk of most cancers common in the general population, including carcinomas of the lung, breast, colon, and prostate, and invasive carcinomas of the uterine cervix.Bl A clinically and morphologically diverse group of B-cell lymphoid proliferations may occur in immunosuppressed patients after transplantation. These proliferations were initially believed to be malignant non-Hodgkin's lymphomas. They do not always meet the criterion of monoclonality necessary to be classified as such, however, and hence have become referred to by the broad term of post-transplant lymphoproliferative disorders (PTLDs).51 These disorders represent a significant source of morbidity and mortality in lung transplant recipients, and in some series, represent the third leading cause of mortality outside of the perioperative period, after infections and rejection.3 Their hypothesized mechanism of pathogenesis relates to EBY infection of B-lymphocytes whose subsequent proliferation is increased due to patients' immunosuppression. A causative role of EBY is supported by serologic evidence of EBY infection in almost all patients with PTLDs, 74 and DNA evidence of EBY infection in lymphoid cells in almost all pathologic specimens of PTLDs.7 Clinically, a distinction can be made between PTLDs presenting early, defined as less than 1 year after transplantation and those presenting later than 1 year after transplantation. 3 PTLDs occurring early tend to present with localized disease, respond favorably to reductions in immunosuppression as their sole treatment, and are associated with lower rates of mortality. PTLDs occurring late frequently present with dissemi-

nated disease, do not respond to reductions in immunosuppression (requiring cytotoxic chemotherapy for treatment), and are associated with higher mortality rates.3 In a large series of thoracic organ transplant patients, all PTLDs occurring in lung transplant patients occurred early, between 2 and 4 months post-transplantation. 3

Direct Toxicities of lmmunosuppressive Medications In addition to increasing patients' risks of infection and malignancy, immunosuppressive medications also have direct toxicities potentially affecting almost all organ systems. These toxicities can be a source of significant morbidity, and even mortality, for lung transplant recipients.

Neph rotoxicity Impaired renal function is the most significant toxicity of cyclosporine. 63 In a study of patients with non-renal diseases, cyclosporine treatment was shown to cause significant decreases in renal blood flow, glomerular filtration rate, and creatinine clearance, associated with significant elevations in serum creatinine. 91 There is evidence that these effects are reversible up to 12 months after the initiation of cyclosporine treatment, but eventually irreversible anatomic damage occurs. 90 Renal function with these chronic changes can remain compromised but stable for prolonged periods of time, but renal deterioration can progress to end-stage renal disease requiring dialysis, and death from renal failure has been reported in one lung transplant patient over 6 years post- transplantation. 21 Multiple drugs have been demonstrated to exacerbate cyclosporine nephrotoxicity, including furosemide , amphotericin B, ganciclovir, acyclovir, trimethoprim-sulfamethoxazole, and the aminoglycosides. 57 • 63 Prevention and treatment of cyclosporine nephrotoxicity requires careful monitoring of both renal function and cyclosporine levels. If a decline in renal func-

COMPLICATIONS OF LUNG TRANSPLANTATION

tion is noted, it generally can be ameliorated by a reduction in cyclosporine dose. Additionally, treatment with misoprostol, a prostaglandin E1 analogue, has been shown to improve renal function in cyclosporine-treated kidney transplant patients. 70 Cyclosporine nephrotoxicity also can cause hypertension, at least in part by causing sodium retention and subsequent extracellular volume expansion. 90 Corticosteroids also cause sodium retention, and thus also can contribute to hypertension in transplant patients. Dietary sodium restriction has been shown to reduce the blood pressure of cyclosporine-treated patients with hypertension significantly.17 A minority of Jung transplant patients, however, will require medication(s) to control their blood pressure adequately. 63 Cyclosporine also induces renal magnesium wasting, which results in moderate to severe hypomagnesemia, requiring chronic replacement therapy in almost one half of lung transplant patients.63 Finally, cyclosporine causes potassium retention. 90 This results in hyperkalemia in only a minority of patients, however, which has been managed successfully with dietary modification and avoidance of potassium-sparing diuretics.63

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dose corticosteroids, and possibly cyclosporine, also can cause pancreatitis. 47 Musculoskeletal Toxicity

Corticosteroids can cause a significant myopathy that can involve both respiratory and proximal limb muscles. 22 This weakness is fully reversible when steroids are discontinued or when dosages are reduced. Rehabilitative conditioning programs appear to be the most effective treatment. 41 Corticosteroids also cause reduced bone formation and increased bone resorption, which can lead to osteoporosis. 44 Steroidinduced osteoporosis affects trabecular bone more than cortical bone, typically resulting in fractures of the vertebrae, ribs, distal radius, and proximal femur. The incidence of fractures in steroid-treated individuals ranges from 11% to 20%. 44 Bone mineral density is determined in lung transplant candidates prior to transplant to identify those with low bone mass who will be particularly at risk for steroid-induced osteoporosis. Multiple therapies are being investigated to determine their ability to prevent or treat osteoporosis, but the optimal management of this problem has not yet been established.44 Central Nervous System Toxicity

GI Toxicity

Irnrnunosuppressive medications have multiple potential GI toxicities. Corticosteroids disrupt the cytoprotective gastric mucosa! barrier and can thereby contribute to the development of gastroduodenal ulceration and bleeding.32 Cyclosporine has been associated with gastric atony, causing anorexia, nausea, vomiting, and erratic drug absorption in at least one third of lung transplant patients. 63· 68 Both cyclosporine and azathioprine can cause elevations in serum bilirubins and transaminases.50 The prevalence of cholelithiasis in heart transplant patients has been noted to be more than twice that expected for age- and gender-matched controls, and the cholestatic properties of cyclosporine and azathioprine may be contributory. 32 Azathioprine, high-

Fifteen to forty percent of patients treated with cyclosporine experience neurologic side effects. 80 The most common of these is tremor. A variety of other motor syndromes, including hemiparesis, paraparesis, and quadraparesis have been reported. Cyclosporine is also epileptogenic, causing seizures in 2% to 6% of patients treated with it. A variety of encephalopathies can be caused by cyclosporine, with two syndromes being described most frequently. The first of these is characterized by a depressed level of consciousness, confusion, cortical blindness, and visual hallucinations. The second syndrome is characterized by ataxia, cerebellar tremor, focal weakness, and an altered mental status. Finally, cyclosporine can cause peripheral neuralgias and neuropathies, particularly paresthesias, dysesthesias,

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and hyperesthesias of the distal extremities, especially the hands. Fortunately, nearly all of these neurologic side effects are reversible with discontinuation or reduction in dosage of cyclosporine.80 Psychiatric Toxicity

In addition to the neurologic tox1c1t1es described in the preceding section, cyclosporine also has been associated with an organic anxiety disorder.96· 97 Corticosteroids have been associated with delirium, organic mood disturbances (particularly euphoria, mania, and depression), and psychotic reactions, characterized by delusions, hallucinations, stupor, and catatonia. 65 • 96 Lithium and clonazepam have been reported to be helpful in managing mania secondary to steroid use in transplant recipients 96 ; phenothiazines have been reported to be effective in treating psychiatric side effects of steroid use in general patient populations. 65 These side effects typically resolve without specific psychiatric therapy if steroids can be discontinued. 65 Hematologic Toxicity

Azathioprine causes bone marrow suppression, which can result in leukopenia, and less frequently, anemia and thrombocytopenia.68 These effects on patients' peripheral blood counts are delayed, typically being noted 7 to 14 days after the initiation of treatment. Leukopenia, when it occurs, further increases patients' risk for opportunistic infections. It is reversible with discontinuation or reduction in dosage of azathioprine. Ganciclovir, as well as CMV infection, also can cause bone marrow suppression.68 Finally, chronic anemia associated with depressed levels of erythropoietin has been reported in solid-organ transplant recipients, possibly due to cyclosporine. 33 This form of anemia has been ameliorated in lung transplant patients with treatment with recombinant erythropoietin.28 Endocrine Toxicity

Corticosteroids can cause both hypercholesterolemia and hyperglycemia. Hypercholes-

terolernia has been noted in the majority of patients following lung transplantation. 63 Hyperglycemia has been noted most commonly when high doses of steroids are used, both in the early postoperative period and with treatment of episodes of acute rejection. 86 Animal studies indicate that cyclosporine is also diabetogenic. Hyperglycemia is usually controlled adequately by diet or oral hypoglycemic agents, but occasionally requires treatment with insulin.

Dermal Toxicity

Corticosteroids can cause acne , dermal atrophy, and a redistribution of subcutaneous fat. Steroid-induced dermal atrophy can result in skin so thin and fragile that even slight trauma may cause significant bruising. 76 Steroidinduced redistribution of subcutaneous fat causes the typical cushingoid appearance of central obesity and moon facies . Cyclosporine frequently causes gingival hyperplasia 100 and hypertrichosis. 6 Cyclosporine-induced hypertrichosis is characterized by thick, pigmented hair developing on the trunk, back, shoulders, arms, neck, ears, forehead, and malar areas of the face .

Conclusion Organ transplantation has been one of the great successes of modern medicine. Lung transplantation has allowed for the treatment of many end-stage lung diseases that otherwise would be uniformly fatal. As noted, the morbidity and mortality rates of lung transplantation have been decreasing as experience with this procedure has accumulated. Ongoing refinements in surgical technique, it is hoped, will continue to reduce the frequency and severity of complications related to the operation itself. Development of new immunosuppressive medications will continue to reduce the frequency and severity of rejection, as well as the infections, malignancies, and direct toxicities caused by immunosuppression. Ultimately, development of the ability to induce antigen-specific tolerance, an

COMPLICATIONS OF LUNG TRANSPLANTATION

area of extremely active and exciting transplantation research, may eliminate the problem of rejection without the need for subsequent global immunosuppression. 4 For the present, ongoing improvements in preventive

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strategies, techniques for early diagnosis, and therapies for the complications of lung transplantation described in this article will continue to improve survival rates following this lifesaving procedure.

SUMMARY

This article summarizes the complications of lung transplantation. Complications discussed are categorized into (1) complications of the operation itself, including hemorrhage, the reimplantation response, airway anastomotic complications, cardiac and hemodynamic complications, and gastrointestinal complications; (2) complications of transplantation, including acute and chronic rejection; and (3) complications of the immunosuppressive agents used to prevent rejection, including infection, malignancy, and direct toxicities of the medications. This article describes the usual presenting features of these complications and summarizes strategies used by transplant providers for their prevention, early diagnosis, and treatment.

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