State of the Art Pulmonary Considerations of Organ Transplantation Part 2 1 , 2
NEIL A. ETTINGER and ELBERT P. TRULOCK Bone Marrow Transplantation
A growing list of hematologic and malignant diseases have been successfully treated with bone marrow transplantation. Two-yr, disease-free survival currently exceeds 60070 in some forms of leukemias and aplastic anemia (220). In addition, the use of marrow replacement in nonmalignant disorders such as aplastic anemia or Gaucher's disease may restore normal hematologic elements or correct defective metabolic pathways (221). Selection of patients who are in the early stages of their disease process is clearly associated with a more favorable outcome (222). Although the procedure itself is relatively simple, the complications that arise after marrow transplantation reflect a series of insults that begin with the diagnosis of malignant disease and end with the administration of potentially lethal doses of cytotoxic drugs and radiation. The subsequent pancytopenia only amplifies the variety and the severity of the complications. Pulmonary complications occur in 40 to 60070 of marrow recipients (220) and are a major obstacle to the success of this procedure. To understand the genesis of the pulmonary disorders that arise after marrow transplantation, familiarity with the procedure itself is important. In addition, the impact of cytotoxic drugs and radiation on normal tissues, the immune system, and local lung defense mechanisms must be considered.
Pretransplant Considerations Pretransplant pulmonary function. Prior to marrow transplantation, pulmonary function studies should be obtained not only to detect intrinsic, nonmalignant pulmonary disease, but also to serve as a baseline for comparison following the transplant procedure. Marrow transplant candidates usually have had varying AM REV RESPIR DIS 1991; 144:213-223
degrees of exposure to cytotoxic drugs or radiation by the time marrow transplantation is undertaken. Although lung injury may arise as a result of such exposure, the majority of candidates have no obvious pulmonary symptoms and have normal measurements of pulmonary function (223). A small proportion of patients demonstrate either restrictive or obstructive ventilatory changes and/or a reduction in DLCO (224, 225). These abnormalities are usually mild and are generally asymptomatic. However, although spirometry and lung volumes are usually normal, a relatively high proportion of patients may have some degree of underlying airway dysfunction as suggested by the presence of asymptomatic airway hyperreactivity in as many as 40070 of patients before transplantation (226). Occult pulmonary infection. The presence of unexplained pulmonary infiltrates in the marrow transplant candidate warrants further investigation, particularly because previous treatment of an underlying hematologic malignancy enhances the likelihood of opportunistic infection. Prolonged neutropenia or the prior use of corticosteroids should heighten concern for an undiagnosed infectious process. Of particular importance are focal lesions that may represent an unsuspected fungal infection (227). Bronchoscopy and needle aspiration in this setting may be nondiagnostic; surgical resection may be warranted if these or other approaches are not helpful and if pulmonary function permits. Segmental resection of a focal Aspergillus lesion combined with prophylactic antifungal therapy has permitted successful bone marrow transplantation (228).
Intraoperative Considerations Marrow transplantation begins with the "conditioning" or the "preparative" regimen. During this stage 0 f the procedure,
high doses of chemotherapeutic agents are administered in an effort to destroy all malignant cells and to completely eradicate the patient's immune system. Total body irradiation is often used concomitantly to ensure that both these goals are accomplished. Failure to eradicate either residual tumor or the recipient's immune system may result in malignant relapse or rejection of the marrow allograft, respectively. Both the type and the dose of drugs or radiation used in the conditioning regimen is determined by the nature of the underlying disease and by the extent of previous exposure to these agents. An attempt is made to observe dose limitations in order to avoid toxicity to nonhematologic organ systems (229, 230). After conditioning is complete and the peripheral hematologic elements have reached a nadir, the donor marrow is infused. In an allogeneic transplant, the donor marrow is usually obtained from an HLA compatible relative, but such matches are available only 40070 of the time (230). In the case of autologous transplantation, marrow is obtained from the patient during a period of disease remission or before transplantation for a nonhematologic malignancy. Approx(Received in original form October 5, 1990 and in revised form February 14, 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 8052,660 South Euclid Avenue, St. Louis, MO 63110.
This is Part 2 of three parts; the first part appeared in the last issue of the Review (Vol. 143, Number 6). Part 3 will appear in the next issue of the Review. 213
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imately 750 ml of marrow is obtained from 150 to 200 aspirates while the donor is under general anesthesia. The marrow is filtered and, depending on protocol availability, may be pretreated with monoclonal reagents that deplete the marrow of immunocompetent T-cells. This is done in an effort to prevent the subsequent development of graft versus host disease (GVHD). Once infused, the donor marrow lodges in the marrow cavity and grows, resulting in engraftment within 2 to 3 wk (229).
Immunologic impact ofbone marrow transplantation. Unlike solid organ transplantation, where the immune system is suppressed in order to prevent allograft rejection, the goal of immunosuppression in marrow transplantation is the complete eradication of the immune system. Profound neutropenia occurs in all patients, lasting on average 2 to 3 wk. The duration of neutropenia may be prolonged by the use of methotrexate to prevent acute GVHD, by T-depletion of donor marrow and during autologous transplantation (231). Despite neutrophil recovery, profound impairment of nearly all immune function is seen during the first 4 to 5 months after marrow transplantation. The cellular arm of the immune response is impaired for the first 3 months, although lymphocytes may recover some nonspecific proliferative or cytotoxic properties within this time period. The ability of lymphocytes to recruit neutrophils remains significantly diminshed, however, despite recovery of other lymphocytic functions. Impaired immunoglobulin secretion occurs early, most likely as a result of abnormal T-cell suppression of immunoglobulin production. This observation has definite implications regarding vaccination after marrow transplantation. The patient's ability to make antibodies to recall or neoantigens is delayed for at least a year. As a result, vaccination is usually not effective in eliciting an antibody response during this interval (230, 232). Complete recovery of both cellular and humoral immune function may be expected within 1 yr of a successful transplant if GVHD does not develop. The development of either acute or chronic GVHD delays recovery of both arms of the immune response, and treatment further intensifies the degree of immunosuppression. As a result, GVHD is associated with an increased incidence of both bacterial and opportunistic infections (230).
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In addition to its impact on systemic immunity, marrow transplantation also has a significant effect on local lung defense mechanisms. Early after transplantation, the majority of cell populations present in lavage fluid are of donor origin and are dysfunctional with respect to their usual protective capabilities. Winston and coworkers (233) lavaged seven patients within 4 months of marrow transplantation and observed impaired alveolar macrophage killing of both bacteria and fungi as well as defective phagocytosis and chemotaxis. These functional abnormalities returned to normal within 6 to 12 months (233). Graft versus host disease. GVHD arises as a result of transplantation of immunocompetent donor lymphocytes into the recipient. These lymphocytes are then able to recognize and destroy antigenically distinct host tissues such as skin, liver, and gastrointestinal epithelium. These organs are the most common targets of both acute and chronic GVHD. Treatment usually consists of antilymphocyte preparations, cyclosporine, highdose steroids, or azathioprine. Not surprisingly, infection is the most common cause of death among affected patients (234). Acute GVHD usually occurs between 20 to 100 days after marrow transplantation and affects 30 to 60070 of patients (220). Mortality approaches 10070, and the majority of patients die of infection (230). The development of an exfoliative skin rash, diarrhea, or liver dysfunction are the most common clinical features. A variety of prophylactic regimens are used to prevent acute GVHD and usually consist of combinations of cyclosporine with azathioprine, methotrexate, or steroids. Pretreatment of donor marrow with T-cell specific antibodies (T-cell depletion) has been used with some success. However, T-cell depletion is associated with a higher rate of malignant relapse, possibly caused by a diminished "graft versus tumor" effect (221). The chronic form of GVHD usually occurs more than 100 days after transplantation and affects 35070 of all patients who have survived to this point (230). More than half of these patients previously had acute GVHD and the clinical features resemble a variety of autoimmune diseases such as scleroderma, primary biliary cirrhosis, and Sjogren's syndrome. Skin rash, abnormal gastrointestinal motility, malabsorption, and ophthalmic and sinopulmonary sicca are common
clinical features (234) and the late development of severe airway obstruction is thought to represent a manifestation of this process (235). The incidence of late bacterial and viral pneumonias is increased among affected patients (236). Impact of cytotoxic drugs. The bone marrow transplant recipient may have been exposed to any of a large number of chemotherapeutic agents that directly or indirectly cause lung injury. These drugs may be used during the initial treatment of the underlying malignancy or as part of the conditioning regimen before marrow infusion. Although the majority of cytotoxic drug-induced pulmonary disorders are manifested as interstitial pneumonitis with fibrosis, unusual presentations have also been described (237). Distinguishing the impact of cytotoxic agents from other causes of lung injury is difficult, if not impossible. Familiarity with the effect of these drugs on the lung is important, however. The marrow transplant candidate may have preexisting lung injury as a result of previous treatment with these agents, which should be considered if pulmonary problems arise posttransplantation. It is also possible, although not proven, that previous drug-induced lung injury may increase susceptibility to other pulmonary complications after transplantation. Impact of radiation. The use of total body irradiation (TBI) in marrow transplantation results in a decrease in the incidence of malignant relapse and graft failure (238). In the dose range of radiation used (5 to lOGy), subclinical lung function abnormalities may result, usually within the first 90 days after radiation exposure (239). The most sensitive indicator of radiation-induced lung injury is a reduction in diffusing capacity (224). Changes in lung volumes are relatively uncommon when TBI is used alone (240). However, restrictive ventilatory changes may arise when radiation is combined with high-dose chemotherapy (241). Enhanced pulmonary toxicity is seen when radiation is combined with bleomycin, cyclophosphamide, hydroxyurea, vincristine, actinomycin D, and adriamycin (242). The majority of episodes of clinical radiation pneumonitis have been described in association with therapeutic radiation for solid tumors or lymphomas rather than with the lower, prophylactic doses used with TBI (243). The development of clinical illness as a direct result
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
of TBI is uncommon, but a direct or permissive role for radiation in the development of infectious or idiopathic pneumonitis has been suggested (244).
Posttransplant Considerations A wide variety of infectious and noninfectious complications arise after marrow transplantation, including some disorders that are unique among marrow recipients. In addition to the usual spectrum of infectious complications, the impact of cytotoxic drugs and radiation must be considered among the pulmonary complications, although the precise manner as well as the frequency with which they contribute to lung disease is unknown.
Noninfectious Complications Interstitial pneumonitis. Interstitial pneumonitis is a major limiting factor to the success of bone marrow transplantation and is a significant cause of death among patients who otherwise receive a successful graft (245). The incidence ranges from 35 to 50070 of recipients of allogeneic transplants but is significantly lower « 20070) in recipients of syngeneic or autologous grafts (246, 247). Although bacterial and fungal etiologies are occasionally identified, pneumonitis caused by cytomegalovirus (CMV) or unidentified causes predominate (247, 248). Regardless of the etiology, the clinical presentation is remarkably similar: dyspnea, fever, hypoxemia, and diffuse interstitial infiltrates develop 40 to 75 days after grafting. Mortality is high, ranging from 50 to 90070 depending upon the etiology (246, 249, 250). In approximately 30 to 50070 of patients with interstitial pneumonia, an etiologic agent is not identified, and the term "idiopathic" interstitial pneumonitis is applied. Idiopathic pneumonia is clinically, radiographically, and temporally indistinguishable from pneumonitis caused by CMV or Pneumocystis; mortality ranges from 60 to 78070 (236, 247). Histopathologically, an interstitial mononuclear infiltrate is typically seen although diffuse alveolar damage also is described (251). Exhaustive efforts to implicate a wide variety of pathogens have been uniformly unsuccessful (236, 248). A number of studies have attempted to identify risk factors for the development of idiopathic pneumonia (247). Applebaum and colleagues (250) observed that idiopathic pneumonitis occurs with equal frequency in recipients of both syngeneic and allogeneic transplants, sug-
gesting that it reflects pulmonary toxicity from the conditioning regimen and is probably not related to GVHD (250). However, Weiner and coworkers (247) found that severe GVHD, older age, the use of methotrexate instead of cyclosporine, and high dose rates of radiation were important risk factors. Several investigators have suggested that the incidence of idiopathic pneumonitis may be decreased either by lowering the total dose or the dose rate ofradiation or by fractionating the radiation treatments (238, 239, 245, 248, 249). However, opposite conclusions have been reached by others, and no clear consensus on the optimal approach to radiation administration has emerged (247, 252). Weiner and colleagues (247) reviewed 932 marrow transplant recipients and observed no relationship between interstitial pneumonitis and total lung dose or fractionation schedules. In this study, higher dose rates increased the risk of pneumonitis but only in patients who received methotrexate after transplant. Idiopathic pneumonia following marrow transplantation most likely represents the cumulative effect of radiation and chemotherapy on the lung. The clinical and" histopathologic parallels be-
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tween this entity and radiation pneumonitis are interesting but not sufficient to attribute the phenomenon solely to radiation (245, 248). Rather, the extent of previous chemotherapy may serve to reduce the tolerance of the lung to radiation, making the pulmonary toxicity of drugs and radiation additive or synergistic (242). Treatment of idiopathic pneumonitis is difficult. The use of corticosteroids has not proven beneficial in anecdotal experience (236). Airway complications. Airway complications are among the earliest pulmonary problems that arise after marrow transplantation and are usually a result of the mucosal toxicity of the conditioning regimen (253, 254). High-dose chemotherapy and TBI may cause mucositis of sufficient severity to threaten the airway. The inflammation typically involves the oral and nasopharyngeal mucosa, and may cause severe dysphagia and odynophagia (253). In extreme cases, upper airway inflammation may result in aspiration of blood or secretions (254) or the development of laryngeal edema, which may require intubation to maintain airway patency (figure 6). The use of high-dose narcotic analgesia for relief of mucositis-related pain may fur-
Fig. 6. A 33-year-Old man with acute myelogenous leukemia, 2 wk after allogeneic marrow transplantation, who demonstrates the major types of airway complications that can arise after marrow transplantation. Severe mucositis with glottic edema necessitated intubation for airway protection. After extubation, aspiration of blood from the oropharynx resulted in obstruction and collapse of the right upper lobe. Reexpansion of the right upper lobe was achieved after therapeutic fiberoptic bronchoscopy.
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ther compromise airway patency. This possibility should be considered in the evaluation and treatment of respiratory failure arising in this setting. Pulmonary edema. Pulmonary edema is one of the most common early pulmonary complications following marrow transplantation (255). Twofactors are important when considering the mechanism of pulmonary edema in these patients; first, cardiac or renal function may be abnormal as a result of previous or concomitant chemotherapy. Second, large volumes of fluid are often infused to administer drugs and parenteral nutrition and to minimize the toxicity of the conditioning regimen. The onset of pulmonary edema is usually rapid, and it occurs primarily between the second and third week after transplantation. Hypoxemia with diffuse interstitial infiltrates and effusions are common, and weight gain is usually apparent (256). In a review of 30 consecutive bone marrow transplant recipients, Dickout and colleagues (256) observed acute pulmonary edema in 13 patients, 4 of whom required temporary mechanical ventilation. Considerable weight gain as well as echocardiographic evidence of hypervolemia was present. Aggressive diuresis and a reduction in administered fluid volume at the first sign of weight gain or edema eliminated this complication in a subsequent prospective trial involving 30 additional patients. The fact that a number of chemotherapeutic agents are cardiotoxic is wellrecognized and must be considered in the pathogenesis of pulmonary edema in these patients. The use of adriamycin and daunorubicin is associated with the development of a congestive cardiomyopathy that is dose dependent (> 550 mg/ m') and that is potentiated by prior mediastinal irradiation (257). Cyclophosphamide, which is commonly used in leukemic conditioning regimens, may cause a progressive, fatal hemorrhagic myopericarditis that is associated with pericardial effusions, tamponade, and left ventricular failure. The use of high doses of cytotoxic drugs in combination may be particularly deleterious (258). Although dosage limitations have been recommended for a few chemotherapeutic agents, it is possible that many of these agents may cause myocardial damage at lower than recommended doses. Pulmonary hemorrhage. The increasing diagnostic use of bronchoalveolar lavage has led to the recognition of pulmonary hemorrhage as a significant
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cause of pulmonary disease among marrow recipients (259). The actual incidence of this complication after marrow transplantation is uncertain. The majority of reports include both marrow recipients and other immunocompromised hosts and do not distinguish between patient groups (260, 261). Among the fewreports specifically regarding marrow recipients, diffuse alveolar hemorrhage (DAH) is described in 11 to 21070 of patients, with a mortality that ranges from 50 to 80070 (259, 262, 263).
Various criteria are used to define DAH. Severalinvestigators use quantitative scores of alveolar macrophage hemosiderin content while others rely on clinical and radiographic findings and the gross appearance of the lavage fluid (259, 260). The diagnosis of DAH is usually made by bronchoscopy, but the lavage fluid appearance may be misleading. Alveolar macrophage hemosiderin content correlates with the severity of hemorrhage present in histologic sections, but many patients with elevated hemosiderin scores have grossly normal lavage fluid. Lavage fluid appearance may therefore be an insensitive indicator of alveolar hemorrhage (260). The clinical or prognostic significance of elevated macrophage hemosiderin content in the face of normal appearing lavage fluid is unclear. Hemoptysis is rare in DAH and hemorrhage is often unsuspected. The majority of patients have a constellation of clinical and radiographic findings that are suggestive of infection (figure 7), including high fever, dyspnea, nonproductive cough, hypoxemia, and diffuse alveolar infiltrates (259, 260). Atypical presentations with localized infiltrates of varying distribution have also been described (261). The onset of this syndrome is usually within the first fewweeks after transplantation and often coincides with recovery of peripheral neutrophils. Patients with DAH usually have higher fevers, more severemucositis, and a greater degree of renal insufficiency than those patients who do not develop the syndrome. Nearly all patients are thrombocytopenic, although the platelet count does not appear to predict the development or the severityof this disorder (259). Infection probably plays a permissive role, but this issue is controversial. Kahn and coworkers (260) observed that 50070 of patients with severe DAH had invasive pulmonary aspergillosis; however, Robbins and colleagues (259) failed to detect evidence of any infection in the
majority of 29 autologous marrow transplant patients with DAH. The early reports of "hemorrhagic" pulmonary edema in recipients of mismatched marrow allografts may have represented DAH (263-265). The pathogenesis of this disorder is most likely multifactorial. The finding of diffuse alveolar damage among the patients in the study by Robbins and coworkers (259) suggests that bleeding may arise as a result of nonspecific lung injury that occurs during the conditioning regimen and which is aggravated by the superimposition of thrombocytopenia, infection, or neutrophil recovery (259). Treatment is usually supportive and not particularly effective in most patients. Progression is often observed despite correction of platelet or other clotting abnormalities (259). However, outcome is generally better in those patients who do not have coexistent infections (262, 266). Granulocyte transfusion lung injury. The use of therapeutic or prophylactic granulocyte transfusions has been associated with the development of CMV pneumonia and other, noninfectious pulmonary complications (267). However, the precise role of granulocytes in the pathogenesis of these complications is controversial (268). The use of granulocyte transfusions in combination with amphotericin B or in the setting of endotoxemia has been associated with development of acute respiratory failure, and the use of non-HLA identical granulocytes has been implicated as a cause of idiopathic pneumonitis during the immediate posttransplant period (268, 269). However, the use of granulocyte transfusions has markedly declined in the absence of proved benefit (236). Pulmonary vascular disease. Pulmonary vascular abnormalities are discovered histologically in as many as 50070 of autopsied marrow transplant recipients, although these changes appear to have little clinical importance. Endothelial swelling and thrombosis confined primarily to arterioles, capillaries, and venules are the predominant histopathologic findings (263). The relationship of these changes to the subsequent development of idiopathic pneumonitis or pulmonary hemorrhage is uncertain. Pulmonary thromboembolism is rare after marrow transplantation and is not cited in most reviewsof pulmonary complications in these patients. Robbins and coworkers (259) recently described thromboemboli in 3 of 15 autopsied patients who died of diffuse DAH, but an
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
etiologic connection was not established. Bone fragment emboli are found in a high proportion of patients and presumably arise from bone spicules that escape the initial filtering of the harvested marrow; however, they do not appear to be clinically significant (270). Embolism of marrow fat has been observed in association with alveolar hemorrhage and interstitial pneumonitis, but sufficient information is not available to establish a primary role for fat embolism in posttransplant lung injury (271). Emboli arsing from central venous catheters are probably the most common source of thromboemboli in these patients. Among the more unusual pulmonary vascular complications is pulmonary venoocclusivedisease, which has been described in three marrow recipients between 1 and 2 months after transplantation (272, 273). The clinical picture in these patients is dominated by dyspnea along with signs of pulmonary hypertension and right-sided congestive failure. Although the diagnosis may be suggested by the clinical and hemodynamic presentation, open lung biopsy is required to confirm the fibrous occlusion of small pulmonary venules. Risk factors for the development of this complication appear to include the use of high-dose chemotherapy for aggressiveinduction, consolidation, and transplant preparation as well as multiple marrow transplant procedures (272). Treatment with high-dose corticosteroids was effective in two of the three reported cases. Mediastinal emphysema. Mediastinal emphysema may precede or complicate interstitial pneumonitis in the marrow transplant recipient. Hill and coworkers (274) recently described six cases ofmediastinal emphysema in 146patients transplanted over a 2-yr period. None of the patients were mechanically ventilated, and five of the six cases had or subsequently developed interstitial pneumonitis. Fivepatients died of respiratory failure. The authors noted that this complication coincided with recent increases in the total dose of radiation used in the preparative regimen (9.5 to 11.5 Gy) and postulated that the higher dose of radiation combined with malnutrition and highdose steroids altered the integrity of the pulmonary tissues (274). Posttransplant pulmonary function. Both restrictive and obstructive ventilatory changes occur after marrow transplantation, but the majority of these changes are asymptomatic. Restrictive changes often occur in association with
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Fig. 7. A 26-year-old Hispanic woman who underwent a second allogeneic bone marrow transplant for acute myelogenous leukemia. Engraftment occurred 15 days after marrow infusion. (A) Basilar infiltrates developed within 48 h of engraftment, and 500/0supplemental oxygen was required. Fiberoptic bronchoscopy revealed grossly bloody lavage fluid, and all cultures and stains were negative for routine or opportunistic pathogens. (B) The patient improved and was weaned from supplemental oxygen but deteriorated abruptly 10 days later with fever and progressive hypoxemia. Repeat BAL revealed recurrent alveolar hemorrhage, and CMV was detected by shell vial assay. The patient subsequently died of respiratory failure.
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a reduction in diffusing capacity. These changes developearly, are partially reversible, and are presumably related to the acute effects of radiation or cytotoxic drugs (224, 241). Over time, however, significant obstructive ventilatory changes appear in a small proportion of patients. In a review of over 300 marrow recipients, Springmeyer and coworkers (241) described functionally mild restrictive changes during the firstyear after transplantation but observed the emergence of progressive airflow obstruction in an increasing proportion of long-term survivors.. The severity of expiratory airflow obstruction that develops after marrow transplantation ranges from asymptomatic involvement of small airways to fulminant and fatal obliterative bronchiolitis (226). Onset is usually 6 to 12months after transplantation (235), and 11 to 17070 of patients without previous evidence of airflow obstruction are affected (235, 275). Several risk factors have been identified. In a review of over 281 adult marrow recipients tested 1 yr following transplantation, Clark and coworkers (235) observed that chronic GVHD and the prolonged use of methotrexate were strongly and independently associated with the subsequent development of expiratory airflow obstruction. Chan and colleagues (275) found that physiologic and morphologic evidence of small airways obstruction were related to both GVHD and viral respiratory infections. The relationship of chronic GVHD to airflow obstruction is strong and has been reported by other investigators (223). No relationship with acute GVHD has been observed (223, 225, 235). A small subset of marrow recipients develop ventilatory obstruction that is rapidly progressive and often fatal. Roca and associates (276) first described this clinical entity and demonstrated obliterative bronchiolitis on histologic examination. Obliterative bronchiolitis has subsequently been confirmed in marrow recipients by a number of other investigators (277-280). Marrow recipients with severe obliterative bronchiolitis develop dyspnea, cough, and wheezing anywhere from 6 wk to over a year after transplantation, often in temporal association with the onset of chronic GVHD (225, 275, 281). The chest radiograph is often normal at the time of the initial presentation (281). A high proportion of patients have evidence of concurrent viral infection, but the significance of infection in promoting bron-
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chiolitis is unclear. The detection of viral pathogens may instead be related to the necessary augmentation of immunosuppression as treatment of chronic GVHD (275). Clark and colleagues observed that less than 50070 of those patients who experienced the early onset of obstructive lung disease had either acute or chronic GVHD, supporting a possible role for infection primarily in the early cases (275, 281). Although open lung biopsy is usually required to make a definitive diagnosis, the presence of bronchiolitis may be suggested by the results of pulmonary function testing after the exclusion of infection by transbronchial biopsy and bronchoalveolar lavage (275). The presence of airway hyperreactivity before transplant is not considered predictive of the subsequent development of obstruction or bronchiolitis (226). The majority of patients have fixed obstruction and do not respond to bronchodilators. Augmentation of immunosuppression in an attempt to ameliorate chronic GVHD is sometimes successful in a small proportion of patients (282, 283). Although lung function may stabilize, patients usually remain severely symptomatic (275). Overall mortality in this group of patients is high, and death from respiratory failure occurs in over 40070 (275, 281). Lymphocytic bronchitis. Beschorner and coworkers (284) observed lymphocytic bronchitis in 25070 of allogeneic marrow recipients at autopsy. Characterized by destruction of the bronchial epithelium by infiltrating small lymphocytes, this disorder is associated with gross inflammation of the tracheobronchial tree as well as superimposed bronchopneumonia. The majority of patients have dyspnea and nonproductive cough, and Pseudomonas aeruginosa is often cultured from respiratory secretions. Histologic comparison of these patients with autopsy findings in other patients who had infectious pulmonary processes has suggested that lymphocytic bronchitis is specific to marrow recipients with advanced degrees of GVHD and therefore represents a pulmonary manifestation of acute GVHD (284). Recent clinical and experimental evidence, however, has questioned the relationship between GVHD and lymphocytic bronchitis. In a clinicopathologic review of autopsies on 128 marrow recipients, histologic evidence of lymphocytic bronchitis was present in 20070 of the cases, but no relationship with acute GVHD could be established (285). Similar his-
topathologic changes were demonstrated in ventilated trauma victims and patients with viral pneumonia. In animal studies, O'Brien and coworkers (286) failed to find a connection between lymphocytic bronchitis and acute GVHD in 46 allografted dogs; furthermore, the prevalence was comparable in both autografted and allografted animals. Thus, the question of direct lung injury during acute GVHD remains unanswered, but these findings imply that the lung is not a direct target of this process. Infectious Complications A large number of infectious pulmonary complications have been identified after marrow transplantation. The diagnostic scheme generally takes advantage of the recipient's unique susceptibility to various pathogens during the evolution of immune recovery (222, 236). However, variability in the rate of immune reconstitution and atypical presentations of common infections require a thorough investigation for infectious disorders at any point in the posttransplant course. Particularly prominent among marrow recipients are respiratory viral and fungal infections both of which are more aggressive and refractory to therapy than in other organ transplant patients. Cytomegalovirus pneumonitis. The incidence of CMV infection after allogeneic bone marrow transplantation ranges from 50 to 70070, and approximately one-third of infected patients subsequently develop CMV pneumonia (236, 287). Overall, CMV pneumonitis occurs in 15070 of all marrow recipients, usually between 50 to 60 days after transplantation. The devastating consequences of this infection are illustrated by the 85070 or greater case fatality rate (287). Several risk factors are associated with the development of CMV pneumonitis following marrow transplantation. An increased incidence is observed among seropositive patients, older patients, patients who receive TBI, and patients with the more severe grades of GVHD (231, 248). In addition, the infusion of marrow or granulocytes from seropositive donors into seronegative recipients is associated with an increased risk of both infection and pneumonitis (288). CMV pneumonia is rare in recipients of autologous or syngeneic grafts, however, despite a similar overall incidence of infection. This observation may reflect the absence of GVHD in these patients, the diminished need for immunosuppression, the presence of residual host cellu-
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STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
lar immunity, or a combination of all these factors (246, 250). However, the recent observation that CMV infection and pneumonitis occur with similar incidence in recipients of T-cell-depleted marrow (low incidence of GVHD) suggests that CMV infection may occur independently of GVHD or that T-cell depletion itself may facilitate the infection (289). The single feature that distinguishes CMV pneumonia in marrow transplant recipients from CMV pneumonia in recipients of solid organ transplants is the high mortality. Vidarabine, interferon, and high-dose acyclovirare uniformly ineffective at improving survival beyond the expected 15070 (290,291). Ganciclovir demonstrates a significant antiviral effect (292), but its antiviral action is not often translated into clinical efficacy when the drug is used alone. In early studies, survival past the first episode of CMV pneumonia was observed in 10 to 17070 of patients, even when ganciclovir was combined with high-dose corticosteroids (292-294). Recent studies, however, have shown 44 to 48070 survival (table 2), reflecting either early diagnosis and therapy or treatment of patients with milder or later-onset disease (195, 196, 295). Ganciclovir toxicity in these patients is appreciable, with an incidence of reversible neutropenia that ranges from 30 to 67070. An alternative drug, foscarnet, has met with mixed results (296, 297). The combination of ganciclovir and high-titer, CMV-specific immune globulin has proved to be a promising approach to the treatment of CMV pneumonia in marrow recipients. Tworecent reports are encouraging, with survival rates ranging from 52 to 70070 (298, 299). However, relapse occurred in nearly one-third of the patients in one of these studies (299).The results of trials using hyperimmune globulin alone are inconclusive; the 67070 survival observed by Blacklock and coworkers was not substantiated in a subsequent study by Reed and colleagues where a 21070 survival was found (300, 301). However, different immune globulin preparations were used, the patients differed in terms of time of onset and severity of illness, and the sample sizes were small. At present, the combined use of CMV-specific immunoglobulin and ganciclovir appears to be the most appropriate treatment strategy for confirmed CMV pneumonitis. Efforts directed toward reducing relapse may further
NEIL A. ETTINGER and ELBERT P. TRULOCK Bone Marrow Transplantation
A growing list of hematologic and malignant diseases have been successfully treated with bone marrow transplantation. Two-yr, disease-free survival currently exceeds 60070 in some forms of leukemias and aplastic anemia (220). In addition, the use of marrow replacement in nonmalignant disorders such as aplastic anemia or Gaucher's disease may restore normal hematologic elements or correct defective metabolic pathways (221). Selection of patients who are in the early stages of their disease process is clearly associated with a more favorable outcome (222). Although the procedure itself is relatively simple, the complications that arise after marrow transplantation reflect a series of insults that begin with the diagnosis of malignant disease and end with the administration of potentially lethal doses of cytotoxic drugs and radiation. The subsequent pancytopenia only amplifies the variety and the severity of the complications. Pulmonary complications occur in 40 to 60070 of marrow recipients (220) and are a major obstacle to the success of this procedure. To understand the genesis of the pulmonary disorders that arise after marrow transplantation, familiarity with the procedure itself is important. In addition, the impact of cytotoxic drugs and radiation on normal tissues, the immune system, and local lung defense mechanisms must be considered.
Pretransplant Considerations Pretransplant pulmonary function. Prior to marrow transplantation, pulmonary function studies should be obtained not only to detect intrinsic, nonmalignant pulmonary disease, but also to serve as a baseline for comparison following the transplant procedure. Marrow transplant candidates usually have had varying AM REV RESPIR DIS 1991; 144:213-223
degrees of exposure to cytotoxic drugs or radiation by the time marrow transplantation is undertaken. Although lung injury may arise as a result of such exposure, the majority of candidates have no obvious pulmonary symptoms and have normal measurements of pulmonary function (223). A small proportion of patients demonstrate either restrictive or obstructive ventilatory changes and/or a reduction in DLCO (224, 225). These abnormalities are usually mild and are generally asymptomatic. However, although spirometry and lung volumes are usually normal, a relatively high proportion of patients may have some degree of underlying airway dysfunction as suggested by the presence of asymptomatic airway hyperreactivity in as many as 40070 of patients before transplantation (226). Occult pulmonary infection. The presence of unexplained pulmonary infiltrates in the marrow transplant candidate warrants further investigation, particularly because previous treatment of an underlying hematologic malignancy enhances the likelihood of opportunistic infection. Prolonged neutropenia or the prior use of corticosteroids should heighten concern for an undiagnosed infectious process. Of particular importance are focal lesions that may represent an unsuspected fungal infection (227). Bronchoscopy and needle aspiration in this setting may be nondiagnostic; surgical resection may be warranted if these or other approaches are not helpful and if pulmonary function permits. Segmental resection of a focal Aspergillus lesion combined with prophylactic antifungal therapy has permitted successful bone marrow transplantation (228).
Intraoperative Considerations Marrow transplantation begins with the "conditioning" or the "preparative" regimen. During this stage 0 f the procedure,
high doses of chemotherapeutic agents are administered in an effort to destroy all malignant cells and to completely eradicate the patient's immune system. Total body irradiation is often used concomitantly to ensure that both these goals are accomplished. Failure to eradicate either residual tumor or the recipient's immune system may result in malignant relapse or rejection of the marrow allograft, respectively. Both the type and the dose of drugs or radiation used in the conditioning regimen is determined by the nature of the underlying disease and by the extent of previous exposure to these agents. An attempt is made to observe dose limitations in order to avoid toxicity to nonhematologic organ systems (229, 230). After conditioning is complete and the peripheral hematologic elements have reached a nadir, the donor marrow is infused. In an allogeneic transplant, the donor marrow is usually obtained from an HLA compatible relative, but such matches are available only 40070 of the time (230). In the case of autologous transplantation, marrow is obtained from the patient during a period of disease remission or before transplantation for a nonhematologic malignancy. Approx(Received in original form October 5, 1990 and in revised form February 14, 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 8052,660 South Euclid Avenue, St. Louis, MO 63110.
This is Part 2 of three parts; the first part appeared in the last issue of the Review (Vol. 143, Number 6). Part 3 will appear in the next issue of the Review. 213
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imately 750 ml of marrow is obtained from 150 to 200 aspirates while the donor is under general anesthesia. The marrow is filtered and, depending on protocol availability, may be pretreated with monoclonal reagents that deplete the marrow of immunocompetent T-cells. This is done in an effort to prevent the subsequent development of graft versus host disease (GVHD). Once infused, the donor marrow lodges in the marrow cavity and grows, resulting in engraftment within 2 to 3 wk (229).
Immunologic impact ofbone marrow transplantation. Unlike solid organ transplantation, where the immune system is suppressed in order to prevent allograft rejection, the goal of immunosuppression in marrow transplantation is the complete eradication of the immune system. Profound neutropenia occurs in all patients, lasting on average 2 to 3 wk. The duration of neutropenia may be prolonged by the use of methotrexate to prevent acute GVHD, by T-depletion of donor marrow and during autologous transplantation (231). Despite neutrophil recovery, profound impairment of nearly all immune function is seen during the first 4 to 5 months after marrow transplantation. The cellular arm of the immune response is impaired for the first 3 months, although lymphocytes may recover some nonspecific proliferative or cytotoxic properties within this time period. The ability of lymphocytes to recruit neutrophils remains significantly diminshed, however, despite recovery of other lymphocytic functions. Impaired immunoglobulin secretion occurs early, most likely as a result of abnormal T-cell suppression of immunoglobulin production. This observation has definite implications regarding vaccination after marrow transplantation. The patient's ability to make antibodies to recall or neoantigens is delayed for at least a year. As a result, vaccination is usually not effective in eliciting an antibody response during this interval (230, 232). Complete recovery of both cellular and humoral immune function may be expected within 1 yr of a successful transplant if GVHD does not develop. The development of either acute or chronic GVHD delays recovery of both arms of the immune response, and treatment further intensifies the degree of immunosuppression. As a result, GVHD is associated with an increased incidence of both bacterial and opportunistic infections (230).
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In addition to its impact on systemic immunity, marrow transplantation also has a significant effect on local lung defense mechanisms. Early after transplantation, the majority of cell populations present in lavage fluid are of donor origin and are dysfunctional with respect to their usual protective capabilities. Winston and coworkers (233) lavaged seven patients within 4 months of marrow transplantation and observed impaired alveolar macrophage killing of both bacteria and fungi as well as defective phagocytosis and chemotaxis. These functional abnormalities returned to normal within 6 to 12 months (233). Graft versus host disease. GVHD arises as a result of transplantation of immunocompetent donor lymphocytes into the recipient. These lymphocytes are then able to recognize and destroy antigenically distinct host tissues such as skin, liver, and gastrointestinal epithelium. These organs are the most common targets of both acute and chronic GVHD. Treatment usually consists of antilymphocyte preparations, cyclosporine, highdose steroids, or azathioprine. Not surprisingly, infection is the most common cause of death among affected patients (234). Acute GVHD usually occurs between 20 to 100 days after marrow transplantation and affects 30 to 60070 of patients (220). Mortality approaches 10070, and the majority of patients die of infection (230). The development of an exfoliative skin rash, diarrhea, or liver dysfunction are the most common clinical features. A variety of prophylactic regimens are used to prevent acute GVHD and usually consist of combinations of cyclosporine with azathioprine, methotrexate, or steroids. Pretreatment of donor marrow with T-cell specific antibodies (T-cell depletion) has been used with some success. However, T-cell depletion is associated with a higher rate of malignant relapse, possibly caused by a diminished "graft versus tumor" effect (221). The chronic form of GVHD usually occurs more than 100 days after transplantation and affects 35070 of all patients who have survived to this point (230). More than half of these patients previously had acute GVHD and the clinical features resemble a variety of autoimmune diseases such as scleroderma, primary biliary cirrhosis, and Sjogren's syndrome. Skin rash, abnormal gastrointestinal motility, malabsorption, and ophthalmic and sinopulmonary sicca are common
clinical features (234) and the late development of severe airway obstruction is thought to represent a manifestation of this process (235). The incidence of late bacterial and viral pneumonias is increased among affected patients (236). Impact of cytotoxic drugs. The bone marrow transplant recipient may have been exposed to any of a large number of chemotherapeutic agents that directly or indirectly cause lung injury. These drugs may be used during the initial treatment of the underlying malignancy or as part of the conditioning regimen before marrow infusion. Although the majority of cytotoxic drug-induced pulmonary disorders are manifested as interstitial pneumonitis with fibrosis, unusual presentations have also been described (237). Distinguishing the impact of cytotoxic agents from other causes of lung injury is difficult, if not impossible. Familiarity with the effect of these drugs on the lung is important, however. The marrow transplant candidate may have preexisting lung injury as a result of previous treatment with these agents, which should be considered if pulmonary problems arise posttransplantation. It is also possible, although not proven, that previous drug-induced lung injury may increase susceptibility to other pulmonary complications after transplantation. Impact of radiation. The use of total body irradiation (TBI) in marrow transplantation results in a decrease in the incidence of malignant relapse and graft failure (238). In the dose range of radiation used (5 to lOGy), subclinical lung function abnormalities may result, usually within the first 90 days after radiation exposure (239). The most sensitive indicator of radiation-induced lung injury is a reduction in diffusing capacity (224). Changes in lung volumes are relatively uncommon when TBI is used alone (240). However, restrictive ventilatory changes may arise when radiation is combined with high-dose chemotherapy (241). Enhanced pulmonary toxicity is seen when radiation is combined with bleomycin, cyclophosphamide, hydroxyurea, vincristine, actinomycin D, and adriamycin (242). The majority of episodes of clinical radiation pneumonitis have been described in association with therapeutic radiation for solid tumors or lymphomas rather than with the lower, prophylactic doses used with TBI (243). The development of clinical illness as a direct result
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
of TBI is uncommon, but a direct or permissive role for radiation in the development of infectious or idiopathic pneumonitis has been suggested (244).
Posttransplant Considerations A wide variety of infectious and noninfectious complications arise after marrow transplantation, including some disorders that are unique among marrow recipients. In addition to the usual spectrum of infectious complications, the impact of cytotoxic drugs and radiation must be considered among the pulmonary complications, although the precise manner as well as the frequency with which they contribute to lung disease is unknown.
Noninfectious Complications Interstitial pneumonitis. Interstitial pneumonitis is a major limiting factor to the success of bone marrow transplantation and is a significant cause of death among patients who otherwise receive a successful graft (245). The incidence ranges from 35 to 50070 of recipients of allogeneic transplants but is significantly lower « 20070) in recipients of syngeneic or autologous grafts (246, 247). Although bacterial and fungal etiologies are occasionally identified, pneumonitis caused by cytomegalovirus (CMV) or unidentified causes predominate (247, 248). Regardless of the etiology, the clinical presentation is remarkably similar: dyspnea, fever, hypoxemia, and diffuse interstitial infiltrates develop 40 to 75 days after grafting. Mortality is high, ranging from 50 to 90070 depending upon the etiology (246, 249, 250). In approximately 30 to 50070 of patients with interstitial pneumonia, an etiologic agent is not identified, and the term "idiopathic" interstitial pneumonitis is applied. Idiopathic pneumonia is clinically, radiographically, and temporally indistinguishable from pneumonitis caused by CMV or Pneumocystis; mortality ranges from 60 to 78070 (236, 247). Histopathologically, an interstitial mononuclear infiltrate is typically seen although diffuse alveolar damage also is described (251). Exhaustive efforts to implicate a wide variety of pathogens have been uniformly unsuccessful (236, 248). A number of studies have attempted to identify risk factors for the development of idiopathic pneumonia (247). Applebaum and colleagues (250) observed that idiopathic pneumonitis occurs with equal frequency in recipients of both syngeneic and allogeneic transplants, sug-
gesting that it reflects pulmonary toxicity from the conditioning regimen and is probably not related to GVHD (250). However, Weiner and coworkers (247) found that severe GVHD, older age, the use of methotrexate instead of cyclosporine, and high dose rates of radiation were important risk factors. Several investigators have suggested that the incidence of idiopathic pneumonitis may be decreased either by lowering the total dose or the dose rate ofradiation or by fractionating the radiation treatments (238, 239, 245, 248, 249). However, opposite conclusions have been reached by others, and no clear consensus on the optimal approach to radiation administration has emerged (247, 252). Weiner and colleagues (247) reviewed 932 marrow transplant recipients and observed no relationship between interstitial pneumonitis and total lung dose or fractionation schedules. In this study, higher dose rates increased the risk of pneumonitis but only in patients who received methotrexate after transplant. Idiopathic pneumonia following marrow transplantation most likely represents the cumulative effect of radiation and chemotherapy on the lung. The clinical and" histopathologic parallels be-
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tween this entity and radiation pneumonitis are interesting but not sufficient to attribute the phenomenon solely to radiation (245, 248). Rather, the extent of previous chemotherapy may serve to reduce the tolerance of the lung to radiation, making the pulmonary toxicity of drugs and radiation additive or synergistic (242). Treatment of idiopathic pneumonitis is difficult. The use of corticosteroids has not proven beneficial in anecdotal experience (236). Airway complications. Airway complications are among the earliest pulmonary problems that arise after marrow transplantation and are usually a result of the mucosal toxicity of the conditioning regimen (253, 254). High-dose chemotherapy and TBI may cause mucositis of sufficient severity to threaten the airway. The inflammation typically involves the oral and nasopharyngeal mucosa, and may cause severe dysphagia and odynophagia (253). In extreme cases, upper airway inflammation may result in aspiration of blood or secretions (254) or the development of laryngeal edema, which may require intubation to maintain airway patency (figure 6). The use of high-dose narcotic analgesia for relief of mucositis-related pain may fur-
Fig. 6. A 33-year-Old man with acute myelogenous leukemia, 2 wk after allogeneic marrow transplantation, who demonstrates the major types of airway complications that can arise after marrow transplantation. Severe mucositis with glottic edema necessitated intubation for airway protection. After extubation, aspiration of blood from the oropharynx resulted in obstruction and collapse of the right upper lobe. Reexpansion of the right upper lobe was achieved after therapeutic fiberoptic bronchoscopy.
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ther compromise airway patency. This possibility should be considered in the evaluation and treatment of respiratory failure arising in this setting. Pulmonary edema. Pulmonary edema is one of the most common early pulmonary complications following marrow transplantation (255). Twofactors are important when considering the mechanism of pulmonary edema in these patients; first, cardiac or renal function may be abnormal as a result of previous or concomitant chemotherapy. Second, large volumes of fluid are often infused to administer drugs and parenteral nutrition and to minimize the toxicity of the conditioning regimen. The onset of pulmonary edema is usually rapid, and it occurs primarily between the second and third week after transplantation. Hypoxemia with diffuse interstitial infiltrates and effusions are common, and weight gain is usually apparent (256). In a review of 30 consecutive bone marrow transplant recipients, Dickout and colleagues (256) observed acute pulmonary edema in 13 patients, 4 of whom required temporary mechanical ventilation. Considerable weight gain as well as echocardiographic evidence of hypervolemia was present. Aggressive diuresis and a reduction in administered fluid volume at the first sign of weight gain or edema eliminated this complication in a subsequent prospective trial involving 30 additional patients. The fact that a number of chemotherapeutic agents are cardiotoxic is wellrecognized and must be considered in the pathogenesis of pulmonary edema in these patients. The use of adriamycin and daunorubicin is associated with the development of a congestive cardiomyopathy that is dose dependent (> 550 mg/ m') and that is potentiated by prior mediastinal irradiation (257). Cyclophosphamide, which is commonly used in leukemic conditioning regimens, may cause a progressive, fatal hemorrhagic myopericarditis that is associated with pericardial effusions, tamponade, and left ventricular failure. The use of high doses of cytotoxic drugs in combination may be particularly deleterious (258). Although dosage limitations have been recommended for a few chemotherapeutic agents, it is possible that many of these agents may cause myocardial damage at lower than recommended doses. Pulmonary hemorrhage. The increasing diagnostic use of bronchoalveolar lavage has led to the recognition of pulmonary hemorrhage as a significant
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cause of pulmonary disease among marrow recipients (259). The actual incidence of this complication after marrow transplantation is uncertain. The majority of reports include both marrow recipients and other immunocompromised hosts and do not distinguish between patient groups (260, 261). Among the fewreports specifically regarding marrow recipients, diffuse alveolar hemorrhage (DAH) is described in 11 to 21070 of patients, with a mortality that ranges from 50 to 80070 (259, 262, 263).
Various criteria are used to define DAH. Severalinvestigators use quantitative scores of alveolar macrophage hemosiderin content while others rely on clinical and radiographic findings and the gross appearance of the lavage fluid (259, 260). The diagnosis of DAH is usually made by bronchoscopy, but the lavage fluid appearance may be misleading. Alveolar macrophage hemosiderin content correlates with the severity of hemorrhage present in histologic sections, but many patients with elevated hemosiderin scores have grossly normal lavage fluid. Lavage fluid appearance may therefore be an insensitive indicator of alveolar hemorrhage (260). The clinical or prognostic significance of elevated macrophage hemosiderin content in the face of normal appearing lavage fluid is unclear. Hemoptysis is rare in DAH and hemorrhage is often unsuspected. The majority of patients have a constellation of clinical and radiographic findings that are suggestive of infection (figure 7), including high fever, dyspnea, nonproductive cough, hypoxemia, and diffuse alveolar infiltrates (259, 260). Atypical presentations with localized infiltrates of varying distribution have also been described (261). The onset of this syndrome is usually within the first fewweeks after transplantation and often coincides with recovery of peripheral neutrophils. Patients with DAH usually have higher fevers, more severemucositis, and a greater degree of renal insufficiency than those patients who do not develop the syndrome. Nearly all patients are thrombocytopenic, although the platelet count does not appear to predict the development or the severityof this disorder (259). Infection probably plays a permissive role, but this issue is controversial. Kahn and coworkers (260) observed that 50070 of patients with severe DAH had invasive pulmonary aspergillosis; however, Robbins and colleagues (259) failed to detect evidence of any infection in the
majority of 29 autologous marrow transplant patients with DAH. The early reports of "hemorrhagic" pulmonary edema in recipients of mismatched marrow allografts may have represented DAH (263-265). The pathogenesis of this disorder is most likely multifactorial. The finding of diffuse alveolar damage among the patients in the study by Robbins and coworkers (259) suggests that bleeding may arise as a result of nonspecific lung injury that occurs during the conditioning regimen and which is aggravated by the superimposition of thrombocytopenia, infection, or neutrophil recovery (259). Treatment is usually supportive and not particularly effective in most patients. Progression is often observed despite correction of platelet or other clotting abnormalities (259). However, outcome is generally better in those patients who do not have coexistent infections (262, 266). Granulocyte transfusion lung injury. The use of therapeutic or prophylactic granulocyte transfusions has been associated with the development of CMV pneumonia and other, noninfectious pulmonary complications (267). However, the precise role of granulocytes in the pathogenesis of these complications is controversial (268). The use of granulocyte transfusions in combination with amphotericin B or in the setting of endotoxemia has been associated with development of acute respiratory failure, and the use of non-HLA identical granulocytes has been implicated as a cause of idiopathic pneumonitis during the immediate posttransplant period (268, 269). However, the use of granulocyte transfusions has markedly declined in the absence of proved benefit (236). Pulmonary vascular disease. Pulmonary vascular abnormalities are discovered histologically in as many as 50070 of autopsied marrow transplant recipients, although these changes appear to have little clinical importance. Endothelial swelling and thrombosis confined primarily to arterioles, capillaries, and venules are the predominant histopathologic findings (263). The relationship of these changes to the subsequent development of idiopathic pneumonitis or pulmonary hemorrhage is uncertain. Pulmonary thromboembolism is rare after marrow transplantation and is not cited in most reviewsof pulmonary complications in these patients. Robbins and coworkers (259) recently described thromboemboli in 3 of 15 autopsied patients who died of diffuse DAH, but an
STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
etiologic connection was not established. Bone fragment emboli are found in a high proportion of patients and presumably arise from bone spicules that escape the initial filtering of the harvested marrow; however, they do not appear to be clinically significant (270). Embolism of marrow fat has been observed in association with alveolar hemorrhage and interstitial pneumonitis, but sufficient information is not available to establish a primary role for fat embolism in posttransplant lung injury (271). Emboli arsing from central venous catheters are probably the most common source of thromboemboli in these patients. Among the more unusual pulmonary vascular complications is pulmonary venoocclusivedisease, which has been described in three marrow recipients between 1 and 2 months after transplantation (272, 273). The clinical picture in these patients is dominated by dyspnea along with signs of pulmonary hypertension and right-sided congestive failure. Although the diagnosis may be suggested by the clinical and hemodynamic presentation, open lung biopsy is required to confirm the fibrous occlusion of small pulmonary venules. Risk factors for the development of this complication appear to include the use of high-dose chemotherapy for aggressiveinduction, consolidation, and transplant preparation as well as multiple marrow transplant procedures (272). Treatment with high-dose corticosteroids was effective in two of the three reported cases. Mediastinal emphysema. Mediastinal emphysema may precede or complicate interstitial pneumonitis in the marrow transplant recipient. Hill and coworkers (274) recently described six cases ofmediastinal emphysema in 146patients transplanted over a 2-yr period. None of the patients were mechanically ventilated, and five of the six cases had or subsequently developed interstitial pneumonitis. Fivepatients died of respiratory failure. The authors noted that this complication coincided with recent increases in the total dose of radiation used in the preparative regimen (9.5 to 11.5 Gy) and postulated that the higher dose of radiation combined with malnutrition and highdose steroids altered the integrity of the pulmonary tissues (274). Posttransplant pulmonary function. Both restrictive and obstructive ventilatory changes occur after marrow transplantation, but the majority of these changes are asymptomatic. Restrictive changes often occur in association with
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Fig. 7. A 26-year-old Hispanic woman who underwent a second allogeneic bone marrow transplant for acute myelogenous leukemia. Engraftment occurred 15 days after marrow infusion. (A) Basilar infiltrates developed within 48 h of engraftment, and 500/0supplemental oxygen was required. Fiberoptic bronchoscopy revealed grossly bloody lavage fluid, and all cultures and stains were negative for routine or opportunistic pathogens. (B) The patient improved and was weaned from supplemental oxygen but deteriorated abruptly 10 days later with fever and progressive hypoxemia. Repeat BAL revealed recurrent alveolar hemorrhage, and CMV was detected by shell vial assay. The patient subsequently died of respiratory failure.
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a reduction in diffusing capacity. These changes developearly, are partially reversible, and are presumably related to the acute effects of radiation or cytotoxic drugs (224, 241). Over time, however, significant obstructive ventilatory changes appear in a small proportion of patients. In a review of over 300 marrow recipients, Springmeyer and coworkers (241) described functionally mild restrictive changes during the firstyear after transplantation but observed the emergence of progressive airflow obstruction in an increasing proportion of long-term survivors.. The severity of expiratory airflow obstruction that develops after marrow transplantation ranges from asymptomatic involvement of small airways to fulminant and fatal obliterative bronchiolitis (226). Onset is usually 6 to 12months after transplantation (235), and 11 to 17070 of patients without previous evidence of airflow obstruction are affected (235, 275). Several risk factors have been identified. In a review of over 281 adult marrow recipients tested 1 yr following transplantation, Clark and coworkers (235) observed that chronic GVHD and the prolonged use of methotrexate were strongly and independently associated with the subsequent development of expiratory airflow obstruction. Chan and colleagues (275) found that physiologic and morphologic evidence of small airways obstruction were related to both GVHD and viral respiratory infections. The relationship of chronic GVHD to airflow obstruction is strong and has been reported by other investigators (223). No relationship with acute GVHD has been observed (223, 225, 235). A small subset of marrow recipients develop ventilatory obstruction that is rapidly progressive and often fatal. Roca and associates (276) first described this clinical entity and demonstrated obliterative bronchiolitis on histologic examination. Obliterative bronchiolitis has subsequently been confirmed in marrow recipients by a number of other investigators (277-280). Marrow recipients with severe obliterative bronchiolitis develop dyspnea, cough, and wheezing anywhere from 6 wk to over a year after transplantation, often in temporal association with the onset of chronic GVHD (225, 275, 281). The chest radiograph is often normal at the time of the initial presentation (281). A high proportion of patients have evidence of concurrent viral infection, but the significance of infection in promoting bron-
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chiolitis is unclear. The detection of viral pathogens may instead be related to the necessary augmentation of immunosuppression as treatment of chronic GVHD (275). Clark and colleagues observed that less than 50070 of those patients who experienced the early onset of obstructive lung disease had either acute or chronic GVHD, supporting a possible role for infection primarily in the early cases (275, 281). Although open lung biopsy is usually required to make a definitive diagnosis, the presence of bronchiolitis may be suggested by the results of pulmonary function testing after the exclusion of infection by transbronchial biopsy and bronchoalveolar lavage (275). The presence of airway hyperreactivity before transplant is not considered predictive of the subsequent development of obstruction or bronchiolitis (226). The majority of patients have fixed obstruction and do not respond to bronchodilators. Augmentation of immunosuppression in an attempt to ameliorate chronic GVHD is sometimes successful in a small proportion of patients (282, 283). Although lung function may stabilize, patients usually remain severely symptomatic (275). Overall mortality in this group of patients is high, and death from respiratory failure occurs in over 40070 (275, 281). Lymphocytic bronchitis. Beschorner and coworkers (284) observed lymphocytic bronchitis in 25070 of allogeneic marrow recipients at autopsy. Characterized by destruction of the bronchial epithelium by infiltrating small lymphocytes, this disorder is associated with gross inflammation of the tracheobronchial tree as well as superimposed bronchopneumonia. The majority of patients have dyspnea and nonproductive cough, and Pseudomonas aeruginosa is often cultured from respiratory secretions. Histologic comparison of these patients with autopsy findings in other patients who had infectious pulmonary processes has suggested that lymphocytic bronchitis is specific to marrow recipients with advanced degrees of GVHD and therefore represents a pulmonary manifestation of acute GVHD (284). Recent clinical and experimental evidence, however, has questioned the relationship between GVHD and lymphocytic bronchitis. In a clinicopathologic review of autopsies on 128 marrow recipients, histologic evidence of lymphocytic bronchitis was present in 20070 of the cases, but no relationship with acute GVHD could be established (285). Similar his-
topathologic changes were demonstrated in ventilated trauma victims and patients with viral pneumonia. In animal studies, O'Brien and coworkers (286) failed to find a connection between lymphocytic bronchitis and acute GVHD in 46 allografted dogs; furthermore, the prevalence was comparable in both autografted and allografted animals. Thus, the question of direct lung injury during acute GVHD remains unanswered, but these findings imply that the lung is not a direct target of this process. Infectious Complications A large number of infectious pulmonary complications have been identified after marrow transplantation. The diagnostic scheme generally takes advantage of the recipient's unique susceptibility to various pathogens during the evolution of immune recovery (222, 236). However, variability in the rate of immune reconstitution and atypical presentations of common infections require a thorough investigation for infectious disorders at any point in the posttransplant course. Particularly prominent among marrow recipients are respiratory viral and fungal infections both of which are more aggressive and refractory to therapy than in other organ transplant patients. Cytomegalovirus pneumonitis. The incidence of CMV infection after allogeneic bone marrow transplantation ranges from 50 to 70070, and approximately one-third of infected patients subsequently develop CMV pneumonia (236, 287). Overall, CMV pneumonitis occurs in 15070 of all marrow recipients, usually between 50 to 60 days after transplantation. The devastating consequences of this infection are illustrated by the 85070 or greater case fatality rate (287). Several risk factors are associated with the development of CMV pneumonitis following marrow transplantation. An increased incidence is observed among seropositive patients, older patients, patients who receive TBI, and patients with the more severe grades of GVHD (231, 248). In addition, the infusion of marrow or granulocytes from seropositive donors into seronegative recipients is associated with an increased risk of both infection and pneumonitis (288). CMV pneumonia is rare in recipients of autologous or syngeneic grafts, however, despite a similar overall incidence of infection. This observation may reflect the absence of GVHD in these patients, the diminished need for immunosuppression, the presence of residual host cellu-
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STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION
lar immunity, or a combination of all these factors (246, 250). However, the recent observation that CMV infection and pneumonitis occur with similar incidence in recipients of T-cell-depleted marrow (low incidence of GVHD) suggests that CMV infection may occur independently of GVHD or that T-cell depletion itself may facilitate the infection (289). The single feature that distinguishes CMV pneumonia in marrow transplant recipients from CMV pneumonia in recipients of solid organ transplants is the high mortality. Vidarabine, interferon, and high-dose acyclovirare uniformly ineffective at improving survival beyond the expected 15070 (290,291). Ganciclovir demonstrates a significant antiviral effect (292), but its antiviral action is not often translated into clinical efficacy when the drug is used alone. In early studies, survival past the first episode of CMV pneumonia was observed in 10 to 17070 of patients, even when ganciclovir was combined with high-dose corticosteroids (292-294). Recent studies, however, have shown 44 to 48070 survival (table 2), reflecting either early diagnosis and therapy or treatment of patients with milder or later-onset disease (195, 196, 295). Ganciclovir toxicity in these patients is appreciable, with an incidence of reversible neutropenia that ranges from 30 to 67070. An alternative drug, foscarnet, has met with mixed results (296, 297). The combination of ganciclovir and high-titer, CMV-specific immune globulin has proved to be a promising approach to the treatment of CMV pneumonia in marrow recipients. Tworecent reports are encouraging, with survival rates ranging from 52 to 70070 (298, 299). However, relapse occurred in nearly one-third of the patients in one of these studies (299).The results of trials using hyperimmune globulin alone are inconclusive; the 67070 survival observed by Blacklock and coworkers was not substantiated in a subsequent study by Reed and colleagues where a 21070 survival was found (300, 301). However, different immune globulin preparations were used, the patients differed in terms of time of onset and severity of illness, and the sample sizes were small. At present, the combined use of CMV-specific immunoglobulin and ganciclovir appears to be the most appropriate treatment strategy for confirmed CMV pneumonitis. Efforts directed toward reducing relapse may further
