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Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation

Section of Advanced Lung Disease and Lung Transplantation, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; and Pulmonary and Critical Care Division, Naval Medical Center, San Diego, California

Correspondence and requests for reprints should be addressed to Robert M. Kotloff, M.D., 838 West Gates, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19027. E-mail: kotloff{at}mail.med.upenn.edu

	ABSTRACT

TOP ABSTRACT CONTENTS SOLID ORGAN TRANSPLANTATION HEMATOPOIETIC STEM CELL... CONCLUSIONS REFERENCES

 
The ability to successfully transplant solid organs and hematopoietic stem cells represents one of the landmark medical achievements of the twentieth century. Solid organ transplantation has emerged as the standard of care for select patients with severe vital organ dysfunction and hematopoietic stem cell transplantation has become an important treatment option for patients with a wide spectrum of nonmalignant and malignant hematologic disorders, genetic disorders, and solid tumors. Although advances in surgical techniques, immunosuppressive management, and prophylaxis and treatment of infectious diseases have made long-term survival an achievable goal, transplant recipients remain at high risk for developing a myriad of serious and often life-threatening complications. Paramount among these are pulmonary complications, which arise as a consequence of the immunosuppressed status of the recipient as well as from such factors as the initial surgical insult of organ transplantation, the chemotherapy and radiation conditioning regimens that precede hematopoietic stem cell transplantation, and alloimmune mechanisms mediating host-versus-graft and graft-versus-host responses. As the population of transplant recipients continues to grow and as their care progressively shifts from the university hospital to the community setting, knowledge of the pulmonary complications of transplantation is increasingly germane to the contemporary practice of pulmonary medicine.

Key Words: hematopoietic stem cell transplantation • organ transplantation • pneumonia

	CONTENTS

TOP ABSTRACT CONTENTS SOLID ORGAN TRANSPLANTATION HEMATOPOIETIC STEM CELL... CONCLUSIONS REFERENCES

 
Solid Organ Transplantation

Infectious Pulmonary Complications

Noninfectious Pulmonary Complications

Hematopoietic Stem Cell Transplantation

Overview

General Risk Factors for Pulmonary Complications

Infectious Pulmonary Complications

Noninfectious Pulmonary Complications

Conclusions

Solid organ transplantation and hematopoietic stem cell (HSC) transplantation emerged in the 1960s as novel therapeutic approaches to human disease. Propelled by advances in basic immunobiology and clinical care, solid organ transplantation is now widely applied in the treatment of vital organ dysfunction, as is HSC transplantation in the treatment of malignant, hematologic, autoimmune, and genetic diseases. Although offering extended survival to many patients with otherwise lethal conditions, these techniques remain fraught with risk. Pulmonary complications, both infectious and noninfectious, are among the most commonly encountered hazards and they contribute significantly to morbidity and mortality. Factors enhancing the risk of pulmonary complications include the immunosuppressed status of the transplant recipient, the surgical techniques used to carry out organ transplantation, and the chemoradiation conditioning regimens employed in HSC transplantation.

The topic of pulmonary complications of transplantation was previously the subject of a State of the Art review in 1991 (1–3). Advances in the diagnosis, treatment, and prevention of these complications, as well as a greater appreciation for their prevalence and natural history, have prompted this update. The past decade has witnessed a continued proliferation of transplant centers, a steady increase in the number of procedures performed, and a progressive shift in the care of recipients from the university hospitals to the community setting. Once esoteric, knowledge of the pulmonary complications of transplantation has become increasingly relevant to the contemporary practice of pulmonary medicine.

The pulmonary complications encountered among solid organ and HSC transplant populations are sufficiently distinct in spectrum, presentation, and clinical course to warrant that they be addressed in separate sections of this review. The section on solid organ transplantation focuses on experience with the four most commonly performed procedures—heart, kidney, lung (including heart–lung), and liver transplantation. Complications limited to specific organ recipient populations are noted in the subheadings.

	SOLID ORGAN TRANSPLANTATION

TOP ABSTRACT CONTENTS SOLID ORGAN TRANSPLANTATION HEMATOPOIETIC STEM CELL... CONCLUSIONS REFERENCES

 
Infectious Pulmonary Complications
Although the incidence of infectious complications after organ transplantation has declined with the introduction of more effective prophylactic strategies and with refinements in immunosuppressive regimens, infection remains a common life-threatening complication faced by these patients. The lungs are particularly vulnerable, representing the leading infectious site in lung and heart transplant recipients (4–6) and the second most common site (after intraabdominal infection) in liver transplant recipients (7). The incidence of pulmonary infection is lowest in kidney transplant recipients, reflecting the less rigorous surgical procedure required to implant the allograft and the decreased level of immunosuppression required to maintain it.

The spectrum of microorganisms responsible for posttransplantation infections is similar among the various solid organ transplantation populations and is discussed in detail in the sections to follow. The sequence in which these different organisms appear in the posttransplantation course is fairly characteristic (Figure 1) (8). The first month is influenced predominantly by infectious risks posed by surgery and intensive care, and to a lesser extent by the initiation of immunosuppressive agents. Nosocomial bacterial infections predominate, similar to that of the general surgical population. The second stage extends from 1 to 6 months, a period of maximum sustained immunosuppression that is characterized by the emergence of opportunistic pathogens. Beyond 6 months, allograft function in the majority of patients is sufficiently stable to permit reduction in the level of immunosuppression. Consequently, infections are largely due to common community-acquired pathogens. Opportunistic infections occur less frequently in this later period but remain especially prevalent among the subset of patients requiring augmentation of immunosuppression for treatment of chronic rejection or recurrent episodes of acute rejection.

View larger version (24K): [in this window] [in a new window]   Figure 1. Timeline of infectious complications (pulmonary and nonpulmonary) after solid organ transplantation. CMV = cytomegalovirus; EBV = Epstein–Barr virus; HSV = herpes simplex virus; PTLD = posttransplant lymphoproliferative disorder; RSV = respiratory syncytial virus; VZV = varicella zoster virus. Reprinted by permission from Fishman and Rubin (N Engl J Med 1998;338:1741–1751) (8).

Community-acquired bacterial pneumonia occurs later in the posttransplantation period. Haemophilus influenzae, Streptococcus pneumoniae, and Legionella species are among the commonly identified organisms (5, 10, 15). Response to therapy is generally excellent, with reported mortality rates of 0–33% (5, 9, 15). Lower respiratory tract infections occurring in the later phases posttransplantation are particularly prevalent among lung transplant recipients who have developed bronchiolitis obliterans syndrome (BOS) (6). These patients typically present with recurrent episodes of purulent bronchitis and pneumonia. Bronchiectasis can be documented on high-resolution computed tomography (CT) in up to one-third of these patients (16, 17). Pseudomonas aeruginosa is identified as the etiologic agent in the majority of cases (6).

In the early era of organ transplantation, Nocardia infections were relatively common, with a prevalence of 2–13% documented in several large series (6, 18, 19). More recent case series have suggested a lower frequency of infection, on the order of 0.2–2.1% (5, 20, 21). This trend has been attributed to the introduction of cyclosporine-based immunosuppressive regimens that have permitted the use of reduced doses of corticosteroids and, more recently, to the widespread use of sulfonamides for Pneumocystis carinii pneumonia (PCP) prophylaxis (5, 11). Nonetheless, clinicians must remain particularly vigilant for this infection in patients in whom trimethoprim–sulfamethoxazole has either not been administered because of allergy or has been discontinued after the first year. Infection due to this aerobic, gram-positive filamentous rod is most common beyond the first month after transplantation. Patients may be asymptomatic or may present in a subacute fashion with fever, nonproductive cough, pleuritic chest pain, dyspnea, hemoptysis, and weight loss. Dissemination to brain, skin, and soft tissue occurs in up to one-third of infected patients. Chest radiographs and CT scans typically demonstrate one or several nodules that may be cavitary (22, 23). Sulfonamides are the treatment of choice; minocycline, amikacin, imipenem, and ceftriaxone are alternative agents for sulfa-allergic patients. Treatment for at least 3 months is recommended for pulmonary infection, and for up to 12 months for disseminated disease. Mortality directly attributable to Nocardia infection ranges from 0 to 30% among the various solid organ transplant populations (11, 20, 21, 24, 25).

Tuberculosis.
Tuberculosis has been reported in about 0.5–2% of organ transplant recipients in the United States and Europe (26–28), but in up to 15% of recipients in endemic areas such as India (29). Although a relatively uncommon posttransplantation infection in developed countries, the annualized rate of infection is 30- to 100-fold higher than that of the general population (26–28).

Reactivation of latent infection is believed to be the predominant mechanism for development of active tuberculosis after transplantation, but this assumption is difficult to verify on the basis of available data. In published series, information about pretransplantation PPD status is available for fewer than half of organ transplant patients who developed active tuberculosis after transplantation. Among this subgroup, only 22% demonstrate a positive response, although one must assume that there is a high false negative skin test rate due to multiple factors present in patients with chronic organ dysfunction (26). In addition, only 5% of transplant recipients with tuberculosis have a pretransplantation history of infection and only 12% demonstrate chest radiographic evidence of prior infection (26). Less common modes of acquisition include nosocomial outbreaks and donor transmission through infected kidney, lung, and liver allografts (26).

An analysis by Singh and Paterson of the published literature, encompassing a total of 511 cases of tuberculosis between 1967 and 1997, provides important insight into the clinical presentation of this infection in solid organ transplant recipients (26). Onset of infection occurred a median of 9 months after transplantation and nearly two-thirds of cases developed within the first year. Fifty-one percent of patients had tuberculosis restricted to the lungs, 16% had focal extrapulmonary infection, and 33% had disseminated disease. Counting both patients with pulmonary tuberculosis and those with lung involvement as part of disseminated disease, the overall rate of lung involvement was 71%. Fever was the most common presenting symptom, occurring in more than 90% of patients with disseminated disease but in only 66% of those with pulmonary tuberculosis. Chest radiographic abnormalities included focal infiltrates in 40%, a miliary pattern in 22%, pleural effusions in 13%, diffuse interstitial infiltrates in 5%, and cavitary lung disease in only 4%.

Treatment of active tuberculosis in organ transplant recipients involves the use of combination therapy as per standard guidelines for the general population. Administration of this regimen to transplant recipients can be challenging, however. The risk of isoniazid-induced hepatotoxicity is markedly enhanced in liver transplant recipients, necessitating discontinuation of this agent in 41–83% of patients (26, 30). Other recipient populations tolerate this agent better, with reported discontinuation rates of less than 5% (26). Administration of rifampin, a potent inducer of the hepatic P-450 microsomal enzyme system, dramatically increases the clearance of cyclosporine and tacrolimus, consequently lowering blood levels of these drugs and enhancing the risk of rejection (31–33). Concurrent use of rifampin mandates frequent monitoring of immunosuppressive drug levels and appropriate adjustment in dosing to maintain therapeutic levels. Because of difficulties in maintaining therapeutic drug levels, some clinicians have advocated avoidance of rifampin in favor of alternative agents (31).

Even in contemporary series, mortality among transplant recipients with tuberculosis remains in the range of 25–40% (26, 31). This high mortality rate reflects not only the direct consequences of the infection but also the impact of enhanced rejection and graft loss among treated but suboptimally immunosuppressed patients and the adverse impact of comorbid conditions that may have contributed to development of tuberculosis. For patients who complete a full course of treatment, response is highly favorable and mortality rates are low (31).

Given the significant morbidity and mortality associated with active tuberculosis in the transplant population, routine skin testing and preemptive treatment of latent infection are recommended (34). Ideally, skin testing should be performed before transplantation, when there is a greater likelihood that the latently infected patient will mount a delayed hypersensitivity response to antigenic challenge. Because waiting times for transplantation often exceed 1 year in all but the most urgent circumstances, the recommended 9-month course of isoniazid instituted at the time of listing can often be completed before transplantation. In this way, interactions with immunosuppressive drugs that could lead to an enhanced risk of hepatotoxicity can be avoided. The approach to liver transplant candidates and liver transplant recipients with latent infection is more problematic. There is an understandable reluctance to use isoniazid before transplantation because of the presence of severe liver disease. However, the feasibility of administering isoniazid to liver transplant candidates was demonstrated in a series of 18 patients, all of whom tolerated a complete course without a significant change in hepatic function (35). The use of isoniazid after liver transplantation is associated with an increased risk of hepatotoxicity, but the risk may be lower when the drug is administered as a single agent rather than as part of a multidrug antituberculous regimen (36). If treatment of latent infection with isoniazid is attempted after liver transplantation, liver biopsy should be considered in the setting of elevated liver enzymes, because etiologies other than drug toxicity (e.g., allograft rejection) may be responsible in up to half of these instances (26). A 4-month course of rifampin is an acceptable alternative to isoniazid and is ideally initiated before transplantation to avoid interactions with the calcineurin inhibitors. The other approved regimen for treatment of latent infection—a 2-month course of rifampin and pyrazinamide—has been associated with frequent and severe hepatotoxicity (37). For this reason, this regimen is absolutely contraindicated in patients with chronic liver disease awaiting transplantation and must be used with extreme caution in liver transplant recipients.

Nontuberculous mycobacterial infection.
Among lung transplant recipients, the nontuberculous mycobacteria may be more common than Mycobacterium tuberculosis as a cause of pulmonary infections. In the largest published series encompassing 261 patients, pulmonary infection due to nontuberculous mycobacteria was documented in 16 patients (6.1%) compared with only 2 cases of pulmonary tuberculosis (0.8%) (38). Thirteen of the 16 cases were due to Mycobacterium avium complex; M. kansasii, M. abscessus, and M. asiaticum each accounted for one case. Pulmonary infection tended to occur late in the posttransplantation course and was associated with preexistent chronic rejection in more than half the cases. Treatment resulted in clinical improvement in approximately half of treated patients and there were no deaths directly attributable to these infections.

Pulmonary infection due to nontuberculous mycobacterial species is considerably less common in other solid organ transplant populations. Published series identify pulmonary involvement in only 8 of 502 heart transplant recipients (1.6%) (39) and 5 of 3,763 renal transplant recipients (0.1%) (40, 41). Only single case reports document this complication after liver transplantation (42). The prevailing pathogens responsible for pulmonary infection in these populations are M. kansasii and M. avium complex (39, 40, 43).

Cytomegalovirus.
Cytomegalovirus (CMV) is the most common viral pathogen encountered in all solid organ recipient populations. Infection can occur by transfer of virus with the allograft or by reactivation of latent virus remotely acquired by the recipient. Seronegative recipients who acquire organs from seropositive donors are at greatest risk for developing infection, and these primary infections tend to be the most severe. The use of antilymphocyte antibody therapy for immunosuppression also enhances the likelihood and severity of infection in susceptible recipients.

CMV infection typically emerges 1 to 3 months after transplantation, although onset may be delayed in patients receiving prophylaxis. Infection is often subclinical, manifested as asymptomatic viremia or shedding of virus in the respiratory tract or urine. Clinical disease can assume a number of forms including a mononucleosis-like "CMV syndrome" with fever, malaise, and leukopenia; and organ-specific involvement of the lungs, gastrointestinal tract, liver, myocardium, and central nervous system. In addition to the direct impact of tissue invasion in producing symptoms and dysfunction of involved organs, CMV infection appears to enhance the overall level of host immunosuppression, possibly accounting for the frequent emergence of other opportunistic infections in its wake. More insidiously, CMV infection has also been linked to the subsequent development of chronic allograft dysfunction and graft loss (44, 45).

Contemporary series employing a variety of antiviral prophylactic strategies document an incidence of CMV pneumonitis of 0–9.2% among liver transplant recipients (46–49), 0.8–6.6% among heart transplant recipients (5, 9, 50, 51), and less than 1% among renal transplant recipients (52, 53). In contrast, an incidence of 15–55% has been reported after lung transplantation (54–58). The higher frequency of CMV pneumonitis in the lung transplant population is consistent with the notion that the lung is a major site of CMV latency and, therefore, that large quantities of CMV can be transmitted in the allograft (59). The high incidence likely also reflects the widespread performance of surveillance bronchoscopy in this population, facilitating detection of subclinical disease. Indeed, surveillance bronchoscopy has demonstrated that about 10–15% of cases of CMV pneumonitis are asymptomatic (56, 60). For the majority of transplant recipients, a prodrome of fever, malaise, and myalgias frequently precedes the onset of pneumonitis, which is heralded by nonproductive cough and dyspnea. Associated laboratory findings of leukopenia, thrombocytopenia, and elevated liver transaminases provide important clues to the presence of CMV. Radiographically, CMV pneumonitis is associated with a number of nonspecific findings including ground glass opacities, airspace consolidation, and nodules (61, 62).

A diagnosis of CMV pneumonitis is unequivocally established only by demonstration of characteristic viral inclusions on histologic or cytologic specimens. Unfortunately, the yield of transbronchial lung biopsy and bronchoalveolar lavage in demonstrating these changes is relatively low and surgical lung biopsy, while definitive, is invasive. This has prompted the development of alternative diagnostic techniques but the clinical limitations of these newer tools must be appreciated. Use of the rapid shell vial culture of bronchoalveolar lavage fluid is extremely efficient in detecting virus in the lung. However, because shedding of virus into the respiratory tract can occur in the absence of tissue invasion, a positive culture in the appropriate clinical setting at best provides only a presumptive diagnosis. Precise quantification of viral load in peripheral blood can now be achieved by means of the pp65 antigenemia assay and by polymerase chain reaction (PCR) techniques. Data on the role of these assays as surrogate diagnostic markers of invasive disease are limited (46, 54). In one preliminary study, Sanchez and colleagues demonstrated that the blood viral load measured by PCR was significantly higher in lung transplant recipients with biopsy-proven CMV pneumonitis compared with those without (54). Nonetheless, using a threshold optimized by receiver operating curve analysis, the positive predictive value of this technique in diagnosing CMV pneumonitis was only 40%, although the negative predictive value was 89%. There is a larger body of literature on the use of peripheral blood viral load quantification not as a diagnostic tool per se, but as a means of identifying patients most likely to progress from subclinical infection to clinical disease (46, 48, 50, 63). These studies suggest that a high or rapidly increasing peripheral blood viral load is a sensitive but nonspecific marker of imminent progression to symptomatic disease, with a positive predictive value of only 49–64% and a negative predictive value in excess of 95%. In the final analysis, viral load quantification is most appropriately employed in targeting patients for preemptive prophylaxis (see below), but its role in diagnosing established or incipient CMV disease (including pneumonitis) is limited.

The efficacy of ganciclovir in the treatment of CMV disease in various solid organ transplant populations has been suggested in uncontrolled clinical series and has become the standard of care (64). In renal transplant recipients, for example, ganciclovir reduced the overall mortality associated with CMV pneumonitis from 50 to 20% and mortality in the subset requiring mechanical ventilation from more than 90 to 60% (1). Standard treatment consists of a 2- to 3-week course of intravenous ganciclovir at a dose of 5 mg/kg twice daily, adjusted for renal insufficiency. Some advocate the addition of CMV hyperimmune globulin in treatment of severe disease, but evidence supporting this practice is scant (65). Although treatment is effective, relapse rates of up to 60% in primary infection and 20% in previously exposed recipients have been reported (66). Administration of a 3-month course of oral ganciclovir after definitive intravenous therapy modestly reduces the risk of relapse (67).

In an attempt to minimize the adverse impact of CMV infection on the posttransplantation course, emphasis has shifted to preventive strategies. Numerous prospective, randomized trials, summarized in several reviews and in one metaanalysis, have documented the efficacy of antiviral prophylaxis in diminishing the risk of CMV infection and invasive disease (45, 68, 69). Ganciclovir, administered orally or intravenously, has been the drug most commonly employed for the various solid organ recipient populations; valacyclovir is an alternative agent whose benefits have been demonstrated principally after kidney transplantation (53). In current practice, oral valganciclovir is emerging as an attractive option due to its excellent bioavailability after oral administration and once-daily prophylactic dosing requirement. Retrospective data as well as a recent prospective, randomized trial suggest that this agent is at least as effective as oral ganciclovir in the prevention of CMV disease in solid organ recipients (52, 70).

Universal prophylaxis of all donor-seropositive/recipient-seronegative patients is recommended as the risk of CMV disease is high (66, 71). Because the risk of disease is significantly lower in seropositive recipients (independent of donor status), it has been argued that universal prophylaxis of this group leads to overtreatment, increasing costs, and unduly exposing patients to the risk of drug toxicity. In this population, preemptive strategies targeting antiviral therapy exclusively to patients demonstrating a rising viral load in peripheral blood are being developed (66, 72).

Emergence of ganciclovir-resistant strains of CMV threatens to unravel the therapeutic gains that have been achieved in the treatment of this infection. Analysis of CMV isolates from various solid organ transplant populations at Loyola University Medical Center (Maywood, IL) documented ganciclovir resistance in 15.2% of lung, 5.3% of heart, 5.6% of liver, and 2.2% of kidney recipients (73). Across all populations, donor-positive/recipient-negative patients are at greatest risk of developing resistance, likely because of the high viral load associated with primary infection (74, 75). Other risk factors that have been identified include the use of potent immunosuppressive agents such as antilymphocyte antibodies and daclizumab, and prolonged exposure to ganciclovir (74, 75). There is particular concern that the low serum levels achieved with use of oral ganciclovir may predispose to development of resistance (8). Foscarnet is the agent of choice for treatment of ganciclovir-resistant disease, but its use may be limited by associated nephrotoxicity. The presence of ganciclovir-resistant disease is associated with decreased survival in lung transplant recipients (75, 76).

Community respiratory viruses.
Infections due to the community respiratory viruses—influenza, parainfluenza, adenovirus, and respiratory syncytial virus (RSV)—are common in the general population, typically presenting as mild, self-limited upper respiratory tract illnesses. It is unclear whether the risk of acquiring these viral infections is increased among solid organ transplant recipients, but there is a greater propensity for these pathogens to involve the lower respiratory tract and, therefore, to result in a more severe spectrum of illness (77, 78). Of the various organ transplant populations, the highest rates of infection have been reported in lung transplant recipients, up to 21% of whom develop respiratory viral infections (77–80). The ostensibly higher rate of infection documented after lung transplantation must be interpreted with caution as it could reflect enhanced detection due to the frequent performance of bronchoscopy rather than a true increase in susceptibility.

RSV and influenza virus infections occur seasonally, with epidemics in the winter and spring months, whereas adenovirus and parainfluenza infections are seen throughout the year. Patients with lower respiratory tract involvement, in the form of bronchiolitis or pneumonitis, typically present with fever, dyspnea, cough, and wheezing (78, 79). Chest radiographs may be normal or may show only subtle interstitial changes (77). CT of the chest is more sensitive and findings of ground glass, airspace consolidation, nodules, and tree-in-bud opacities are seen (Figure 2) (81). The diagnosis rests on demonstration of virus in respiratory secretions obtained by nasopharyngeal swabbing, nasal wash, or bronchoalveolar lavage. Viral culture represents the "gold standard" for diagnosis but typically entails a period of 3–14 days before results are available. Rapid diagnostic tests utilizing enzyme-linked immunosorbent assays or immunofluorescence techniques to identify viral antigens are now available, but results should be corroborated by standard viral culture.

View larger version (126K): [in this window] [in a new window]   Figure 2. Respiratory syncytial virus (RSV) infection. (A) High-resolution computed tomography (CT) demonstrating diffuse centrilobular nodules, peripheral tree-in-bud opacities, and focal bronchial wall thickening and dilatation consistent with bronchiolitis. The patient presented with wheezing and dyspnea several months after heart transplantation and had RSV recovered from bronchoalveolar lavage specimens. (B) Standard CT image of another transplant recipient with RSV pneumonia, demonstrating diffuse ground glass opacities and mild reticulation.

Treatment options are limited and largely supportive. The efficacy of antiviral therapy has been convincingly demonstrated only in the treatment of influenza in immunocompetent hosts. In this context, initiation of amantadine or rimantadine within 48 hours of symptom onset shortens the severity and duration of illness due to influenza A (87). Similar results are achieved with the early administration of the neuraminidase inhibitors zanamivir and oseltamivir, which have the added advantage of efficacy against both influenza A and B (88–90). Studies confirming benefit of these agents in organ transplant recipients are notably lacking. There is no established treatment for infections due to the other respiratory viruses although aerosolized ribavirin has been advocated as treatment for RSV and parainfluenza virus infections on the basis of anecdotal reports of success (82, 84, 91).

The limited treatment options have led to an increased focus on prevention. Respiratory viruses are highly contagious and infection control measures that emphasize minimizing contact with infected individuals and frequent hand washing may reduce risk. The inactivated influenza vaccine should be administered to all transplant recipients and close contacts. Although the antibody response appears to be attenuated in the solid organ transplant recipient, many are still able to mount protective antibody responses (92, 93). Case reports suggesting that vaccination may augment the alloimmune response and increase the risk of allograft rejection have not been confirmed in studies and should not prevent routine vaccination (94, 95). Chemoprophylaxis of transplant recipients with amantadine, ramantadine, or one of the neuraminidase inhibitors should be considered in the setting of a major influenza outbreak or after exposure to a sick contact with presumed influenza (96, 97).

Aspergillosis.
Although a number of opportunistic and endemic fungi have been reported to cause pulmonary infections in organ transplant recipients, Aspergillus species are by far the most frequent and lethal fungal pathogens encountered. The incidence of invasive aspergillosis approximates 5% among the liver, heart, and lung transplant populations, but occurs considerably less frequently after kidney transplantation (5, 9, 15, 98, 99). Invasive disease is most commonly diagnosed within the first 6 months and nearly always involves the lung. Dissemination to distant sites, particularly the brain, occurs in a considerable minority of patients (98, 99). Symptoms of invasive aspergillosis are nonspecific and include fever, cough, pleuritic chest pain, and hemoptysis. Radiographically, pulmonary aspergillosis may appear as single or multiple nodular opacities, cavities, or alveolar consolidation. The halo sign, considered a highly characteristic radiographic feature of invasive aspergillosis in the HSC transplant population (see below), is infrequently encountered and considerably less specific in the solid organ transplant populations (61, 100, 101).

Diagnosis of invasive aspergillosis can be problematic. Aspergillus is cultured from sputum in only 8–34% and from bronchoalveolar lavage fluid in 45–62% of patients with invasive disease (98). Conversely, the false positive rate associated with recovery of Aspergillus from respiratory tract cultures ranges from 28 to 55% in organ transplant recipients, with the highest rates of airway colonization seen after lung transplantation (99, 102). In the context of compatible clinical and radiographic features and/or demonstration of Aspergillus in respiratory secretions by culture or cytology, the clinician must exercise judgment in deciding whether to initiate an empiric trial of antifungal therapy or pursue more definitive proof by means of transthoracic needle biopsy or surgical lung biopsy.

Amphotericin B has traditionally been the mainstay of therapy for invasive aspergillosis, but its many side effects and need for intravenous administration have made it a rather unappealing choice. More recently, liposomal amphotericin preparations have been introduced that are less nephrotoxic than the parent compound, an important feature for a drug used concurrently with calcineurin inhibitors (cyclosporine and tacrolimus). The triazoles itraconazole and voriconazole offer the advantages of availability in both oral and intravenous formulations and absence of nephrotoxicity. Voriconazole absorption from the gastrointestinal tract is much more reliable than that of itraconazole, making it the preferred oral agent. Voriconazole was shown to have superior efficacy and less toxicity than amphotericin B in the treatment of invasive aspergillosis, and it may soon emerge as first-line therapy (103). Both of the triazoles are potent inhibitors of the P-450 hepatic enzyme system and can lead to dangerously high blood levels of cyclosporine and tacrolimus if appropriate adjustments in the dosing of these calcineurin inhibitors are not made. Because of particularly profound interactions, the concurrent use of voriconazole and sirolimus is contraindicated. Caspofungin, the first of a new class of echinocandins, has been approved in the United States for treatment of invasive aspergillosis in patients who fail or are intolerant of first-line therapy. Despite the availability of antifungal therapy, mortality in published series is in the range of 30–90%, with the highest mortality rates associated with disseminated disease (11, 98, 99, 103). The therapeutic role of surgical resection remains uncertain, but surgery has been advocated in cases of localized pulmonary infection refractory to medical therapy (104–106).

Endobronchial aspergillosis is uniquely encountered in the lung transplant population, with an observed frequency of about 5% (99). In most cases, infection is localized to the bronchial anastomosis, where devitalized cartilage and foreign suture material create a nurturing environment. Less commonly, infection may present as a more diffuse ulcerative bronchitis with formation of pseudomembranes, typically following in the wake of a severe ischemic injury to the bronchial mucosa. Clustered within the first 6 months posttransplantation, these airway infections are usually asymptomatic and detected only by surveillance bronchoscopy. Although usually responsive to oral itraconazole or to inhaled or intravenous amphotericin, airway infections have rarely progressed to invasive pneumonia or have resulted in fatal erosion into the adjacent pulmonary artery (99, 107). An increased risk of subsequent bronchial stenosis or bronchomalacia has also been reported, but it is unclear whether this is a consequence of the infection or of an underlying ischemic injury to the bronchus that predisposed to infection (108, 109).

Pneumocystis carinii pneumonia.
Before the widespread introduction of chemoprophylaxis, Pneumocystis carinii pneumonia (PCP) was observed to be a common opportunistic infection among solid organ transplant recipients. As documented in older series, organ-specific prevalence rates for at-risk patients (i.e., not receiving prophylaxis) were 4% for kidney and heart transplant recipients, 11% for liver transplant recipients, and up to 33% for heart–lung recipients (110). With the administration of low-dose trimethoprim–sulfamethoxazole or an alternative prophylactic agent, PCP can be effectively prevented. In a large contemporary series from the Cleveland Clinic (Cleveland, OH), PCP was documented in only 25 of 1,299 solid organ transplant recipients and it occurred exclusively in patients who were not receiving prophylaxis (110). The greatest risk of PCP falls between the second and sixth posttransplantation months. The risk declines significantly beyond the first year for all groups except lung transplant recipients (110), prompting many nonlung programs to discontinue prophylaxis beyond this point. Likely because of the need for augmented immunosuppression, patients with refractory acute allograft rejection or with chronic allograft rejection appear to be at increased risk for the late development of PCP and continuation or resumption of PCP prophylaxis may be warranted under these circumstances (110). Indefinite prophylaxis is advocated for lung transplant recipients.

PCP in solid organ transplant recipients typically presents in a subacute fashion, with a mean duration of symptoms before diagnosis of 14 days (110). Dyspnea, fever, and cough are the most common presenting symptoms (110). Radiographic abnormalities are typically bilateral and may appear as interstitial, alveolar, or ground glass opacities, the latter best demonstrated on CT scan. The diagnosis can be established by bronchoalveolar lavage alone in about 90% of cases; performance of transbronchial biopsies modestly enhances the yield (110). High-dose trimethoprim-sulfamethoxazole represents first-line therapy, with intravenous pentamidine typically reserved for patients who fail or cannot tolerate trimethoprim-sulfamethoxazole. Mortality directly attributable to PCP was 18% (5 of 28) in the Cleveland Clinic series (110).

Miscellaneous fungal infections.
Although Aspergillus species account for the majority of invasive fungal infections of the lung in solid organ transplant recipients, a myriad of other fungal organisms can cause pulmonary disease. These include Cryptococcus neoformans, the zygomycetes (especially Mucor species), and the geographically restricted endemic fungi (Histoplasma capsulatum, Coccidioides immitus, and Blastomyces dermatitidis) (111–114). In general, the presenting features of these fungal infections are neither clinically nor radiographically distinct and all have the potential to cause disseminated disease in addition to pneumonia. Candida species are responsible for a number of serious posttransplant infections, including sepsis, intraabdominal abscesses, and urinary tract infections, but involvement of the lungs is conspicuously rare. The one notable exception to this is infection of the bronchial anastomosis that occasionally occurs after lung transplantation (108, 115). An emerging pulmonary pathogen is Scedosporium apiospermum (previously known as Pseudallescheria boydii). This organism has been documented to cause infection in all of the major solid organ transplant populations (116). Invasive pulmonary disease is a feature in about 50% of cases; central nervous system and endovascular involvement as well as widespread dissemination are also common (116). In distinction to the other fungal pathogens discussed above, Scedosporium is frequently resistant to amphotericin B; voriconazole appears to be the preferred agent.

Noninfectious Pulmonary Complications
Perioperative complications: liver transplantation.
Liver transplantation entails the performance of extensive upper abdominal surgery on a population of patients considered by conventional standards to be poor surgical candidates due to malnutrition, debility, and critical illness. Not surprisingly, prolonged ventilatory support is a relatively common feature of the early postoperative period. In a survey of 546 liver transplant patients, Glanemann and colleagues found that 11% of patients required mechanical ventilatory support beyond 24 hours (117). Risk factors for prolonged ventilator support included acute liver failure before transplantation, severe postoperative graft dysfunction, and retransplantation. All patients were eventually extubated but 36% of those who had been ventilated for more than 24 hours and 12% of those ventilated for less than 24 hours required reintubation. The most common indications for reintubation were pneumonia, encephalopathy, and surgical bleeding (118). The need for reintubation was associated with significantly poorer survival.

Acute respiratory distress syndrome is a highly lethal cause of postoperative respiratory failure after liver transplantation. The reported incidence ranges from 4.5 to 15.7%, with a mortality rate approximating 80% (119). Sepsis is the most common risk factor, but other potential risk factors include massive blood transfusions, transfusion-related acute lung injury, aspiration, and the use of OKT3 antilymphocyte therapy.

Perioperative pleural effusions are present in the majority of liver transplant recipients (120). Effusions are transudative and are either right-sided or bilateral, but are never exclusively on the left. Disruption of diaphragmatic lymphatics during hepatectomy is postulated to be the principal mechanism of fluid accumulation (120). Effusions may enlarge over the first postoperative week but typically resolve by the third week. Approximately 10% of patients require therapeutic drainage because of respiratory compromise (120). Effusions that continue to enlarge beyond the first week, and isolated left-sided effusions, should be sampled to rule out other causes.

Right-sided diaphragmatic dysfunction is an underappreciated perioperative complication of liver transplantation that is presumed to result from crush injury to the right phrenic nerve by the suprahepatic vena caval clamp placed during surgery (121). A prospective study of 48 liver transplant recipients detected evidence of delayed or absent right-sided phrenic nerve conduction by transcutaneous electrophysiologic testing in 79% of patients whereas the left phrenic was normal in all cases. In 38% of patients, there was associated right diaphragmatic paralysis documented by ultrasound. Phrenic nerve injury was not associated with increased duration of mechanical ventilatory support or hospital stay. In a subset of patients monitored by serial testing, abnormalities in phrenic nerve conduction and diaphragmatic excursion normalized by 9 months after surgery.

Perioperative complications: lung transplantation.
Mild, transient pulmonary edema ("reimplantation response," "reperfusion pulmonary edema") is a nearly universal feature of the freshly transplanted lung allograft. It is presumed to be a consequence of ischemia–reperfusion injury and the attendant increase in microvascular permeability, but surgical trauma and lymphatic disruption may be contributing factors. In about 12–22% of cases, injury is sufficiently severe to cause a form of acute respiratory distress syndrome termed "primary graft failure" (122–124). Risk factors for development of primary graft failure that have been preliminarily identified include donor female sex, donor African-American ethnicity, donor age (less than 21 or more than 45 years), and a recipient diagnosis of primary pulmonary hypertension (122). An association between prolonged graft ischemic time and primary graft failure has been observed in some studies (125) but not in others (124, 126). The diagnosis of primary graft failure rests on the development of widespread radiographic infiltrates and markedly impaired oxygenation within the initial 72 hours of transplantation, and the exclusion of other causes of early graft dysfunction such as volume overload, pneumonia, rejection, atelectasis, and pulmonary venous outflow obstruction. Histologic examination of lung tissue from patients with primary graft failure reveals a prevailing pattern of diffuse alveolar damage (126). Treatment is supportive, relying on conventional mechanical ventilation utilizing low tidal volume strategies, as well as on such adjunct measures as independent lung ventilation and extracorporeal life support for select patients who otherwise cannot be stabilized (127, 128). The use of nitric oxide in patients with established graft injury has been associated with sustained reduction in pulmonary artery pressures and improvement in oxygenation (129, 130). However, the prophylactic administration of nitric oxide to all recipients at the time of reperfusion does not reduce the incidence of primary graft failure (123). With an associated in-hospital mortality rate of 42–60% (124, 126), primary graft failure is the leading cause of perioperative deaths among transplant recipients (131). Recovery among survivors is often protracted and incomplete, although attainment of normal lung function and exercise tolerance is possible. Results of emergent retransplantation in this setting have been poor (132).

Major dehiscence of the bronchial anastomosis was once a leading cause of perioperative mortality, but refinements in surgical technique, tissue preservation, and immunosuppression have reduced the risk of life-threatening dehiscence to a negligible level. Focal dehiscence, incidentally detected on bronchoscopy or heralded by the appearance of a spontaneous pneumothorax, is still encountered in 1–6% of patients (133–135). Tube thoracostomy may be required for evacuation of pneumothoraces, but focal dehiscence usually heals without surgical intervention. Currently, the most common form of airway complication is anastomotic narrowing, with a reported frequency of 12–24% in contemporary series (133, 136). Some centers have reported a higher rate of anastomotic stenosis associated with the use of the telescoped anastomosis compared with the end-to-end technique (137, 138). Narrowing of the anastomosis can result from ischemia-induced stricture or bronchomalacia, or from the formation of excessive granulation tissue. Independent of the mechanism, anastomotic narrowing typically develops within several weeks of transplantation. Clues to its presence include focal wheezing on the involved side, recurrent bouts of pneumonia or purulent bronchitis, and suboptimal pulmonary function studies demonstrating airflow obstruction. Diagnosis is based on direct bronchoscopic visualization. Techniques employed to address anastomotic narrowing include balloon dilatation, laser debridement, and stent placement, all readily performed through a flexible bronchoscope (133). Endobronchial brachytherapy has been successfully employed as an adjunct in managing recurrent episodes of stenosis due to hyperplastic granulation tissue (139).

Acute hyperinflation of the native lung leading to respiratory and hemodynamic compromise in the immediate postoperative period has been reported in 15–30% of patients with emphysema undergoing single-lung transplantation (140, 141). Although risk factors remain poorly defined, the combination of positive pressure ventilation and significant allograft edema serves to magnify the compliance differential between the two lungs and may predispose to this complication. Acute hyperinflation can be rapidly addressed by initiation of independent lung ventilation, ventilating the native lung with a low respiratory rate and prolonged expiratory time to facilitate complete emptying. Beyond the perioperative period, some single-lung transplant recipients with underlying emphysema demonstrate exaggerated or progressive native lung hyperinflation that more insidiously compromises the function of the allograft. In this setting, surgical volume reduction of the native lung can result in significant functional improvement (142).

Phrenic nerve injury after lung transplantation can result from intraoperative traction or from division of the nerve in the setting of extensive fibrous adhesions and difficult hilar dissection, In two prospective studies, phrenic nerve injury was documented in 7.4 and 29.6% of patients (143, 144). The significantly higher frequency found in the latter study likely relates to the more sensitive screening technique utilized, involving phrenic nerve electrophysiologic testing in addition to radiographic visualization of diaphragmatic motion. The presence of phrenic nerve injury may prolong the stay in the intensive care unit but does not typically compromise long-term outcomes (144, 145).

Perioperative complications: heart transplantation.
Heart transplant recipients are subject to the same generic perioperative pulmonary complications encountered in the general cardiac surgical population. These include atelectasis, pulmonary edema, pleural effusions, and mediastinitis. Diaphragmatic dysfunction was documented in 12% of heart transplant recipients in one small series and was predominantly right-sided (143).

Perioperative complications: kidney transplantation.
Kidney transplantation is performed with relatively few perioperative pulmonary complications, reflecting the use of a lower abdominal incision and the comparative good health of the recipients (1, 146). The vast majority of patients are extubated in the operating room. The most common noninfectious pulmonary complication is pulmonary edema due to impaired salt and water excretion in the setting of early allograft dysfunction or rejection. There appears to be an increased incidence of thromboembolic events, possibly related in part to surgical manipulation of the pelvic veins (1).

Neoplastic disorders.
"Posttransplant lymphoproliferative disorder" (PTLD) is a term applied to a spectrum of abnormal B cell proliferative responses ranging from benign polyclonal hyperplasia to more commonly encountered malignant lymphomas. Epstein–Barr virus (EBV) has been identified as the stimulus for B cell proliferation, which proceeds in an unchecked fashion because of the muted cytotoxic T cell response in the immunosuppressed host. EBV-naive recipients who acquire primary infection at the time of organ transplantation are at greatest risk of developing PTLD (147, 148). A higher intensity of immunosuppression and, in particular, the use of antilymphocyte antibody preparations have also been implicated as risk factors (149). Likely reflecting differences in the magnitude of immunosuppression employed, the incidence of PTLD is only 1–2% among kidney and liver transplant recipients, but is in the range of 5–7% among recipients of hearts and lungs (150, 151). The incidence is greatest within the first year posttransplantation (150, 151). Lung transplant recipients and heart transplant recipients are the most likely to present with intrathoracic involvement, which typically assumes the form of one or multiple pulmonary nodules occasionally accompanied by regional adenopathy or pleural effusions (Figure 3) .

View larger version (126K): [in this window] [in a new window]   Figure 3. Posttransplantation lymphoproliferative disorder. Standard CT image of a lung transplant recipient showing multifocal nodular opacities. Surgical lung biopsy confirmed a diagnosis of posttransplant lymphoproliferative disorder.

The published literature is somewhat ambiguous with respect to prognosis. In a study that encompassed several different organ transplant populations, 45% of patients died during a median follow-up period of approximately 3 years, but it was not stated whether all deaths were a direct consequence of PTLD (152). In multivariate analysis, increased age, elevated lactate dehydrogenase levels, severe organ dysfunction, presence of B symptoms (fever, night sweats, and weight loss), and multiorgan involvement were independent markers of poor prognosis, but the type of transplant was not. A series restricted to lung transplant recipients documented a 37% mortality rate directly attributable to PTLD over a median observation period of 3 years (151). Patients with extrapulmonary involvement had the poorest prognosis. Neither of these two studies included a comparison group of patients without PTLD. In contrast, a study from Stanford composed chiefly of heart transplant recipients demonstrated no difference in survival between patients with and without PTLD (150). To date, there are insufficient data to ascertain the impact of the various treatment regimens on survival.

Other malignancies occasionally present in the lungs after transplantation. Bronchogenic carcinoma has been reported in 1.6–4.1% of heart transplant recipients (155). It may also arise in the native lung of single-lung transplant recipients with underlying chronic obstructive pulmonary disease or pulmonary fibrosis, the vast majority of whom are also smokers. The reported incidence of lung cancer after lung transplantation is 2.0–3.7% for patients with chronic obstructive lung disease and 3.4–4.0% for the pulmonary fibrosis population (156, 157). It is unclear whether the reported frequency of lung cancer in the heart and lung populations represents an increased risk or simply reflects the expected occurrence rate in a population with a high prevalence of cigarette smoking. Among liver transplant recipients with a pretransplantation history of hepatocellular carcinoma, the lung is the most common site of recurrence (22). Recurrence usually occurs within 2 years of transplantation and appears radiographically as single or multiple lung nodules. An elevated -fetoprotein level provides an important clue to the possibility of recurrent disease (22).

Pulmonary metastatic calcification: kidney and liver transplantation.
Deposition of calcium in the lung parenchyma and other organs is a well documented complication of chronic renal failure and is postulated to relate to alterations in calcium and phosphate balance and parathyroid hormone secretion (158). Although renal transplantation should have a mitigating effect, pulmonary metastatic calcification rarely may progress despite successful transplantation (159, 160) and may accelerate in association with graft failure (161, 162). Pulmonary metastatic calcification has also been described in liver transplant recipients, with a reported incidence in two series of 5.2 and 47% (163, 164). Renal insufficiency was a common but not universal feature of these patients. Secondary hyperparathyroidism, due to transient hypocalcemia induced by large-volume infusion of citrate-containing blood products and, when present, to renal insufficiency, has been offered as a possible mechanism (164).

Metastatic pulmonary calcification is most often clinically silent but rarely may lead to restrictive lung disease or fulminant respiratory failure (161, 162, 165). The major import of this disorder lies in its ability to radiographically mimic more ominous processes such as infection or malignancy. Single or multiple nodular opacities or areas of alveolar consolidation are seen on plain chest radiographs (Figure 4A) , but calcification of these lesions may not be apparent. The demonstration of high attenuation (greater than 100 HU) parenchymal opacities by CT scan (Figure 4B) or of increased uptake of tracer in the lung by technetium bone scintigraphy is helpful in establishing a diagnosis (158). In instances of diagnostic uncertainty, transbronchial or surgical lung biopsy may be necessary. There is no established treatment for pulmonary metastatic calcification but, given the overall favorable prognosis, this is rarely a consideration.

View larger version (110K): [in this window] [in a new window]   Figure 4. Metastatic calcification. (A) Chest radiograph demonstrating multifocal nodular opacities in an asymptomatic liver transplant recipient. (B) Standard CT image of the same patient demonstrating three nodules, each containing areas of high attenuation consistent with calcification.

As a consequence of its inhibitory effects on fibroblast proliferation, sirolimus has the potential to impair wound healing. Fueling concerns about this is a report of an unusually high incidence of serious bronchial anastomotic dehiscence in a small series of lung transplant recipients who received sirolimus immediately postoperatively (171). Pending further study, sirolimus should be used with caution before complete healing of the airway has occurred.

Hepatopulmonary syndrome and portopulmonary hypertension: liver transplantation.
Hepatopulmonary syndrome and portopulmonary hypertension represent two unusual pulmonary complications of advanced liver disease. Although their onset precedes liver transplantation, these disorders do not immediately or invariably correct after this intervention and they can therefore contribute significantly to posttransplantation morbidity and mortality.

Hepatopulmonary syndrome is defined as the triad of liver disease, arterial hypoxemia, and abnormal intrapulmonary vascular dilatation. The vast majority of cases involve diffuse dilatation of the pulmonary microvasculature at the precapillary and capillary level (Type 1 pattern). Rarely, discrete macroscopic arteriovenous communications are present (Type 2 pattern). Proof of the presence of intrapulmonary vascular abnormalities is provided by demonstration of systemic uptake of technetium-labeled macroaggregated albumin on standard radionuclide perfusion imaging or the delayed appearance of bubbles in the left atrium by contrast echocardiography. Diffuse microvascular dilatation is postulated to cause hypoxemia by increasing the distance through which oxygen must diffuse and thereby creating a central stream of inadequately oxygenated red cells. Unlike a true shunt, this process can be partially corrected with administration of 100% oxygen, which serves to increase the pressure gradient favoring transfer of oxygen from the alveolus to the bloodstream. An unusual feature of hepatopulmonary syndrome is the tendency for oxygenation to worsen in the erect as opposed to supine position (orthodeoxia), presumably due to basilar predominance of the vascular abnormalities.

Although hepatopulmonary syndrome was once considered an absolute contraindication to liver transplantation, subsequent demonstration of its resolution after transplantation has led to the reversal of this stance. Nonetheless, because hypoxemia often does not correct immediately and may in fact dramatically worsen in the early postoperative period, excessive morbidity and mortality have been observed among these patients. In a review of 13 published reports encompassing 81 patients with hepatopulmonary syndrome who underwent liver transplantation, refractory hypoxemia contributed significantly to the observed 16% perioperative mortality, and 21% of survivors required prolonged mechanical ventilatory support (172). A prospective study of 24 patients with hepatopulmonary syndrome undergoing liver transplantation at two experienced centers found a 1-year survival of 71%, considerably below the overall 1-year survival of 90% achieved by these centers. Six of the seven patients with hepatopulmonary syndrome who died had persistent postoperative hypoxemia necessitating mechanical ventilation. The vast majority of patients who survive to hospital discharge ultimately achieve normal room air oxygen levels, but the time to resolution of hypoxemia is often measured in months. Late recurrence of hepatopulmonary syndrome coincident with deteriorating allograft function has been reported (173).

Attempts to identify factors predictive of posttransplantation outcome in patients with hepatopulmonary syndrome have yielded conflicting results. Arguedas and colleagues found that a preoperative arterial oxygen tension on room air of less than or equal to 50 mm Hg and an extrapulmonary shunt fraction of greater than or equal to 20% (calculated on the basis of uptake of tracer in the brain on macroaggregated albumin scintigraphy) were both strong predictors of mortality, with positive predictive values of 67 and 64% and negative predictive values of 93 and 100%, respectively (174). In contrast, Taille and colleagues were unable to discern any significant relationship between these parameters and postoperative mortality, although they did find a correlation between the magnitude of preoperative hypoxemia and the length of time to achieve a normal oxygen level posttransplantation (175).

Postoperative care of the patient with persistent hypoxemia due to hepatopulmonary syndrome centers on the administration of supplemental oxygen while awaiting resolution of the disorder. On the basis of the positional nature of hypoxemia discussed above, one group reported improvement in oxygenation in a patient with use of the Trendelenburg position (176). With the demonstration that nitric oxide is an important mediator of the abnormal vascular dilatation that characterizes hepatopulmonary syndrome, attention has turned to the potential therapeutic role of inhibitors of nitric oxide in treating hypoxemia (177). Schenk and colleagues described significant improvement in oxygenation and shunt fraction for up to 10 hours after administration of a single dose of methylene blue to seven patients with advanced cirrhosis and hepatopulmonary syndrome (178). Brussino and coworkers administered nebulized N^G-nitro-L-arginine methyl ester—an inhibitor of nitric oxide synthesis—to a single patient with hepatopulmonary syndrome and demonstrated a marked rise in arterial oxygen tension and a dramatic reduction in the magnitude of bubbles appearing in the left atrium on contrast echocardiography (179). Although these preliminary observations are promising, additional corroborating studies are necessary before the widespread clinical use of these agents can be recommended. In the rare instances in which discrete arteriovenous malformations are present (Type 2 pattern), coil embolization can be an effective treatment strategy (180).

Portopulmonary hypertension describes the development of pulmonary hypertension in patients with advanced liver disease and portal hypertension. The diagnosis rests on demonstration of a mean pulmonary artery pressure exceeding 25 mm Hg and a normal pulmonary capillary wedge pressure. Some authors also include the criterion of a pulmonary vascular resistance exceeding 120 dyn/second per cm^–5 to distinguish this syndrome from the more benign and common finding of elevated pulmonary pressures due solely to increased cardiac output. Histologically, the abnormalities in the pulmonary vascular bed are identical to those seen in primary pulmonary hypertension: medial hypertrophy, intimal fibrosis, and plexiform lesions. Although a mechanistic link has yet to be defined, the observation that the prevalence of pulmonary hypertension in patients with liver disease exceeds that of the general population suggests that there is a connection. Portopulmonary hypertension is encountered in 1–2% of patients with chronic liver disease and in up to 12.5% of patients referred for liver transplant evaluation (181).

Although mild pulmonary hypertension does not appear to adversely impact liver transplantation, more significant elevations in pressure are associated with excessive posttransplantation mortality. Data derived from a large retrospective review and from a multicenter liver transplant database document mortality rates of 60–100% for liver transplant recipients with a preoperative mean pulmonary artery pressure of or exceeding 50 mm Hg, 35–40% for those with mean pressures between 35 and 50 mm Hg, and 0–17% for those whose mean pulmonary artery pressure is below 35 mm Hg. Most deaths occur intraoperatively or in the immediate postoperative period and are largely attributable to progressive right heart failure and hemodynamic collapse. Although the experience with severe portopulmonary hypertension has generally been poor, there are rare reports of improvement in pulmonary hemodynamics after transplantation (181, 182).

The demonstration that intravenous prostacyclin (epoprostenol) significantly improves pulmonary hemodynamics in patients with portopulmonary hypertension provides a strategy for optimizing the condition of some patients who would otherwise be excluded from consideration for transplantation (183). Several case reports document successful transplantation of patients with severe portopulmonary hypertension who responded favorably to the preoperative initiation of prostacyclin (184, 185). In addition, this therapy has been successfully employed in the posttransplantation treatment of progressive or recurrent pulmonary hypertension (182, 186).

Pulmonary allograft rejection: lung transplantation.
Among the solid organ transplant populations, lung transplant recipients are uniquely predisposed to pulmonary injury mediated by alloreactive T lymphocytes in the form of acute allograft rejection. Approximately 55–75% of transplant recipients experience at least one episode of acute rejection within the first year (56, 187). Beyond this period, the frequency of acute rejection declines to a low level (55, 56). Factors that influence the likelihood of developing acute rejection remain poorly defined. The degree of HLA discordance between donor and recipient has been inconsistently identified as a risk factor (188, 189). One study suggests that polymorphisms in toll-like receptor 4 that downregulate recipient innate immune responsiveness may be associated with a lower incidence of acute rejection (188).

Symptoms of acute rejection are nonspecific and include malaise, low-grade fever, dyspnea, and cough. Radiographic infiltrates, a decline in arterial oxygenation at rest or with exercise, and an abrupt fall of greater than 10% in spirometric values are important clues to the possible presence of rejection, but similar findings accompany infectious episodes. Published series employing surveillance lung biopsies have demonstrated that histologically significant acute rejection (i.e., Grade A2 or higher) may be clinically silent in 14–40% of patients (55, 56, 60, 190).

Transbronchial lung biopsy has emerged as the gold standard for diagnosis of acute rejection. The procedure is safe, can be performed in serial fashion over time, and has a sensitivity of 61–94% and specificity in excess of 90% for the diagnosis of acute rejection (191). The histologic hallmark of acute rejection is the presence of perivascular lymphocytic infiltrates that, in more severe cases, spill over into the adjacent interstitium and alveolar airspaces. Lymphocytic bronchitis or bronchiolitis may accompany the parenchymal involvement or may be an independent feature. A histologic classification system has been universally adopted to categorize and grade the severity of acute cellular rejection (192).

Conventional treatment of acute rejection consists of a 3-day pulse of high-dose intravenous methylprednisolone. In most cases, this results in rapid improvement in symptoms, pulmonary function, and radiographic abnormalities, but follow-up biopsies show histologic evidence of persistent rejection in 30% of patients with prior mild acute rejection and 44% of patients with prior moderate acute rejection (190). A transient increase in oral prednisone and subsequent tapering over several weeks is advocated by some clinicians after the intravenous steroid pulse or as primary treatment for histologically mild episodes.

Chronic rejection, in the form of bronchiolitis obliterans, develops in up to two-thirds of lung transplant recipients and represents the major impediment to long-term graft and patient survival (193–195). Bronchiolitis obliterans is a fibroproliferative process characterized by submucosal inflammation and fibrosis of the bronchiolar walls, ultimately leading to complete obliteration of the airway lumen. The functional consequence of this process is progressive and irreversible airflow obstruction. Because the characteristic histology is difficult to demonstrate by transbronchial lung biopsy, a surrogate diagnostic schema based on the magnitude of decline in FEV₁ has evolved, termed "bronchiolitis obliterans syndrome" (BOS) (196).

Acute rejection, particularly when recurrent or severe, and lymphocytic bronchiolitis have been consistently identified as major risk factors for development of BOS, supporting the view that BOS is a consequence of alloimmune injury (193–195, 197–199). Nonimmune factors may also be important in initiating or perpetuating injury, but have been more variably substantiated. These factors include CMV and other respiratory viral infections, a synergistic interaction between older donor age and prolonged ischemic times, and gastroesophageal reflux with occult aspiration (196, 199).

The incidence of BOS is greatest within the first 2 years, but the risk remains considerable and steady beyond this time point (197). Onset of disease is typically insidious but may be abrupt in more aggressive cases. Dyspnea, cough, and recurrent bouts of purulent tracheobronchitis, with recovery of Pseudomonas aeruginosa from sputum cultures, are highly characteristic features. Although chest radiographs are usually unremarkable, high-resolution computed tomography reveals evidence of air trapping on expiratory images in the majority of patients and evidence of bronchiectasis in some (16, 17, 200). Progressive airflow obstruction is the rule, although the pace of decline is highly variable and the course may be interrupted by periods of functional stability. The prognosis is generally poor, with a 40% mortality rate within 2 years of onset (201). Patients with early onset of BOS (i.e., within the first 3 years) appear to experience more rapid decline in lung function and higher mortality (202).

A myriad of immunosuppressive modalities have been employed in the treatment of BOS, including pharmacologic agents, anti-lymphocyte antibodies, photopheresis, and total lymphoid irradiation, but consensus is lacking on the optimal approach (201, 203–207). At best, immunosuppressive measures appear to slow the rate of decline rather than to fully arrest or reverse the process. A potential role for macrolide therapy is suggested by a pilot study documenting improvement in the FEV₁ in five of six patients with BOS treated with azithromycin (208). Macrolides possess antiinflammatory and antipseudomonal properties, either or both of which could account for the observed beneficial effect. The only definitive treatment is retransplantation, but this strategy remains highly controversial in the context of a scarce donor organ pool (209).

The development of strategies to prevent BOS is an area of intense interest but, to date, little substantive progress. In recognition of the established link between acute rejection and BOS, many transplant centers routinely perform surveillance lung biopsies to detect and treat clinically silent acute rejection, but the impact of this strategy on risk of BOS remains uncertain (210, 211). Data from an uncontrolled, retrospective cohort study suggest that the use of statins may be associated with a reduction in the number and severity of acute rejection episodes and a lower incidence of BOS (212).

	HEMATOPOIETIC STEM CELL TRANSPLANTATION

TOP ABSTRACT CONTENTS SOLID ORGAN TRANSPLANTATION HEMATOPOIETIC STEM CELL... CONCLUSIONS REFERENCES

 
Overview
The term "hematopoietic stem cell transplantation" has supplanted the previously employed term "bone marrow transplantation" to reflect the broader range of donor stem cell sources that are now available: bone marrow, fetal cord blood, and growth factor–stimulated peripheral blood. HSC transplantation is further defined by whether the source of stem cells is from the patient himself (autologous), an identical twin (syngeneic), or a nonidentical sibling or unrelated individual (allogeneic). After allogeneic HSC transplantation, the disparities in match between the donor graft and the recipient for the human leukocyte antigens (HLA) mediate graft-versus-host disease (GVHD) and graft rejection (host-versus-graft reactions). Although these reactions are generally detrimental to the recipient, a graft-versus-malignancy effect is thought to improve antileukemic responses (213–215).

Before stem cell infusion, high doses of chemotherapy with or without total body irradiation are typically administered to ablate the bone marrow, maximize tumor cell kill, and, in the case of allogeneic transplantation, induce immunosuppression to prevent rejection of the donor stem cells. This conditioning regimen is similar for both autologous and allogeneic transplantation and is likely responsible for many of the pulmonary complications seen after transplantation. In the allogeneic setting, immunologic injury mediated by host-reactive donor immune cells (i.e., GVHD) may lead to additional pulmonary complications. Attempts to limit the toxicity of the conditioning regimen have led investigators to develop reduced intensity nonmyeloablative regimens for allogeneic transplantation. This strategy depends on the induction of GVHD and the associated graft-versus-malignancy effect, rather than the tumoricidal effects of conventional high-dose chemotherapy and radiation, to eliminate residual tumor. Nonmyeloablative HSC transplantation may have its greatest application among older patients and those with multiple medical problems who may not tolerate more intensive conditioning regimens (213–217).

Traditionally, the main indication for HSC transplantation has been in the treatment of hematologic malignancies and solid tumors, for which the technique serves as a "rescue" therapy to restore marrow function after lethal, marrow-ablating doses of radiation and chemotherapy employed to eradicate malignant cells. More recently, the technique has been used to replace dysfunctional hematopoietic or lymphoreticular precursors involved in nonmalignant disorders such as aplastic anemia, thalassemia, and congenital immune deficiency syndromes. Currently, HSC transplantation is also undergoing study as a treatment for immune-mediated diseases such as systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, for which immune reconstitution may be beneficial (218, 219).

General Risk Factors for Pulmonary Complications
Pulmonary complications, both infectious and noninfectious, occur in up to 60% of HSC transplant recipients and nearly one-third of recipients require intensive care after transplantation (220, 221). In one respect, the HSC transplantation recipient may present a less confusing clinical diagnostic picture than that of other immunocompromised patients because specific complications tend to occur within well defined time periods (Figure 5) (220). The timing and intensity of cytoreductive therapies, the pattern of immune reconstitution that follows, and the use of prophylactic strategies for infectious agents influence the duration of these intervals (222).

View larger version (23K): [in this window] [in a new window]   Figure 5. Timeline of pulmonary complications occurring after hematopoietic stem cell transplantation. ARDS = acute respiratory distress syndrome; BMT = bone marrow transplantation (i.e., hematopoietic stem cell transplantation); BO = bronchiolitis obliterans; CHF = congestive heart failure; DAH = diffuse alveolar hemorrhage; GVHD = graft-versus-host disease. Reprinted by permission from Soubani and colleagues (Chest 1996;109:1066–1077) (220).

The use of alternative hematopoietic precursor sources, such as mobilized peripheral blood stem cells; and cytokines, such as hematopoietic cell colony-stimulating factors, has shortened the time to engraftment (225). Although the shorter period of neutropenia decreases the incidence of infectious pulmonary complications, rapid immune system reconstitution has been hypothesized to contribute to inflammatory complications such as diffuse alveolar hemorrhage and the engraftment syndrome (226–228).

Several studies have suggested that pretransplantation pulmonary function abnormalities may be predictive of subsequent risk of respiratory complications (229–233) and mortality (234, 235). In one of the larger studies, Crawford and Fisher found that both a reduced diffusing capacity and an increased arterial–alveolar oxygen gradient were independently associated with increased early mortality after HSC transplantation, although the risk was less than that associated with other recognized risk factors such as relapse status at time of transplant and donor–recipient HLA nonidentity (235). There is considerable variability in the available studies with respect to the particular pulmonary function parameters that are identified, the outcomes to which they are linked, and the strength of the association with posttransplantation outcomes. For this reason, information derived from pretransplant pulmonary function testing should not be used as absolute exclusion criteria but as a guide to relative risk assessment.

Respiratory failure is the most common cause of critical illness after HSC transplantation. The risk factors for respiratory failure that are present at time of transplantation are receipt of HLA-nonidentical donor marrow, active phase of malignancy, and older age (greater than 21 years) (234, 236). The incidence of respiratory failure increases from about 10% with no risk factors, to more than 50% when all three are present.

Infectious Pulmonary Complications
Despite the introduction of numerous prophylactic strategies and advances in diagnosis and treatment, pneumonia remains the leading infectious cause of death after HSC transplantation. Factors that enhance the vulnerability of the recipient to pneumonia include protracted neutropenia before engraftment, impaired humoral and cellular immunity associated with the administration of exogenous immunosuppressive agents, and GVHD.

Bacterial pneumonia.
Bacterial pneumonia may occur at any time in the posttransplantation period, but is particularly prevalent during the preengraftment period of profound neutropenia. A review of 255 consecutive patients who had undergone allogeneic or autologous HSC transplantation revealed a 15% incidence of bacterial pneumonia (237). Nearly half the cases occurred within the first 100 days, and 22% of cases overall, were fatal. Early bacterial infections may be less frequent after nonmyeloablative HSC transplantation than conventional procedures, because of the shorter duration of neutropenia (238). Gram-negative pathogens, especially Pseudomonas aeruginosa and Klebsiella pneumoniae, predominate in the first 100 days whereas gram-positive organisms such as Streptococcus pneumoniae cause the majority of late infections (237). Legionella species have been reported to be an important cause of nosocomial pneumonia in some centers (239, 240).

Bacterial pneumonia is commonly heralded by fever, but respiratory symptoms and signs may be absent in the neutropenic host. Presumably because of the paucity of neutrophils, chest X-ray abnormalities may be subtle or absent as well. In one series, the use of high-resolution CT imaging revealed evidence of pneumonia in more than 50% of febrile neutropenic patients with normal chest radiographs (241). Broad-spectrum antibiotics (with antipseudomonal activity) should be initiated expeditiously in all suspected cases of bacterial pneumonia and in febrile, neutropenic patients without an identified site of infection. There is currently no consensus on the routine use of prophylactic antibiotics in afebrile, asymptomatic neutropenic patients during the preengraftment period (242). Administration of intravenous immunoglobulin may reduce the risk of bacterial infections in the subset of allogeneic recipients who experience severe hypogammaglobulinemia during the first 100 days (242).

Tuberculosis.
In nonendemic areas, tuberculosis is uncommonly encountered after HSC transplantation, with a frequency of only 0.1–0.25% documented in two large surveys (243, 244). In contrast, a frequency of 5.5% was noted in a series from Hong Kong, a region where the prevalence of tuberculosis in the general population is 10-fold higher than that of other developed countries (245). Risk factors for development of tuberculosis include allogeneic HSC transplantation, total body irradiation, and chronic GVHD (244, 245). Time to onset of infection is highly variable. In two of the largest published series, median time to onset was 150 and 324 days, respectively (244, 245). The majority of patients present with pulmonary disease, marked by fever, cough, and radiographic infiltrates. Treatment with standard regimens is highly effective even in this immunocompromised population.

Nontuberculous mycobacterial infection.
Infection with nontuberculous mycobacteria has generally been uncommon among HSC transplant recipients (243, 246). However, a series from the Memorial Sloan-Kettering Cancer Center (New York, NY) reported an infection rate that was 5- to 20-fold higher than that of older series (247). In this series of 571 patients, 16 patients (2.8%) satisfied diagnostic criteria for definite infection while another 34 patients (6%) were deemed to have probable or possible infection. Pulmonary infection was reported in 6 of the 16 patients with definite infection. Two of these patients later died as a direct result of infection despite appropriate antimicrobial therapy. The reasons for increased rates of nontuberculous mycobacterial infections at this center are unclear but may involve differences in environmental and nosocomial factors, improvements in detection techniques, and the use of T cell-depleted marrow grafts.

Cytomegalovirus.
Because of the delayed reconstitution of cytotoxic T cell responsiveness and the need to administer immunosuppressive drugs for GVHD prophylaxis, allogeneic HSC transplant recipients are at high risk for developing CMV pneumonia. In the absence of antiviral prophylaxis, the reported incidence of CMV pneumonia after allogeneic procedures is 20–35% compared with only 1–6% after autologous transplantation (248–250). The vast majority of episodes of CMV disease result from reactivation of latent virus in seropositive recipients. Seronegative patients who receive stem cells from a seropositive donor have a lower risk of posttransplantation CMV disease than do seropositive recipients, a situation that contrasts with that seen after solid organ transplantation.

Two strategies have evolved to reduce the risk of CMV disease among seropositive and mismatched (i.e., donor-positive/recipient-negative) allogeneic HSC transplant recipients. The first strategy, universal prophylaxis, involves administration of antiviral therapy to all high-risk patients for a defined period of time after engraftment. The second approach involves preemptive treatment of patients only after subclinical viremia has been detected by the highly sensitive pp65 antigenemia or PCR assay (248, 251–253). Both approaches have been shown to reduce the risk of early CMV disease, but universal prophylaxis is complicated by a high rate of neutropenia. In a randomized, double-blind study comparing the two strategies, universal ganciclovir prophylaxis administered from engraftment to Day 100 was associated with a lower incidence of CMV disease within the first 100 days (254). However, this was offset by an increased incidence of late disease such that no difference in disease frequency was seen at 180 days. Survival was identical in both treatment arms. At the present time, both strategies have been endorsed in published practice guidelines (242). Emerging immunologic interventions may further reduce the incidence of CMV pneumonia in the future. Walter and colleagues reported that donor-derived CMV-specific cytotoxic T lymphocytes could be expanded in vitro and safely infused into the recipient, resulting in effective reconstitution of cellular immunity against CMV (255). The development of a CMV vaccine is also under active investigation, with the possible strategy of immunizing the donor before transplantation to bolster CMV-specific immunity.

In the preprophylaxis era, onset of CMV pneumonia almost invariably occurred between engraftment and Day 100. The use of prophylaxis has reduced the incidence of CMV pneumonia, but has also shifted the onset of disease to later in the posttransplantation course. Among seropositive allogeneic transplant recipients at the Fred Hutchinson Cancer Research Center (Seattle, WA), introduction of prophylaxis led to a decline in the incidence of CMV disease within the first 100 days, from 35 to 6%, whereas the incidence of disease beyond the first 100 days increased from 4 to 15% (248). In another series from the M.D. Anderson Cancer Center (Houston, TX) in which prophylaxis was employed after allogeneic HSC transplantation, diagnosis of 74% of the patients with CMV pneumonia occurred after Day 100 (256). By suppressing early viral replication, antiviral prophylaxis may actually inhibit the development of a CMV-specific cytotoxic T cell response, accounting in part for the appearance of late CMV disease (248). Patients who develop chronic GVHD appear particularly prone to develop late CMV pneumonia (256).

The clinical presentation of CMV pneumonia is not distinctive. Nonproductive cough, fever, and hypoxemia are typical, with rapid progression to respiratory failure in some cases. The chest radiograph most often demonstrates bilateral interstitial opacities, but focal or diffuse consolidation and nodular opacities may also be seen. Ground glass opacities are commonly demonstrated by high-resolution CT. The diagnosis of CMV pneumonia is most securely established by demonstration of viral inclusion bodies in lung tissue, but bronchoscopically derived biopsy and cytology specimens are often inadequate for this purpose. In association with compatible clinical and radiographic features, detection of virus in bronchoalveolar lavage fluid by rapid culture technique is considered diagnostic in this patient population. However, in cases lacking the classic features, results of rapid culture must be interpreted with caution because viral shedding into the respiratory tract can occur in the absence of invasive disease (257, 258).

Historically, CMV pneumonia in HSC transplant recipients was an inexorable process leading to death in more than 85% of cases. Despite the documented antiviral effects of ganciclovir, its use as single-agent therapy in the treatment of CMV pneumonia did not improve outcomes. In 1988, three uncontrolled studies demonstrated that the combination of ganciclovir and CMV immunoglobulin resulted in vastly improved survival rates of 50–70% compared with 0–15% among historical controls (259–261). This approach has become the standard of care despite the fact that no randomized clinical trials have been performed to confirm these observations. It is distinctly possible that the improved survival rates reported in these trials reflect in part earlier detection and treatment of pneumonia. Even with combination therapy, survival of patients with established respiratory failure at the time of diagnosis remains uncommon (262). Foscarnet, in combination with immunoglobulin, is reserved for patients unable to tolerate ganciclovir and those infected with ganciclovir-resistant strains, although support for this regimen is anecdotal.

Pneumonia due to other viruses.
As a group, the community respiratory viral pathogens—RSV, influenza A and B, and parainfluenza—account for the majority of non-CMV viral respiratory infections in both autologous and allogeneic HSC transplant recipients. Collectively, these pathogens are recovered from up to one-third of HSC transplant recipients hospitalized with acute respiratory illnesses; RSV is most commonly isolated (263, 264). With the exception of parainfluenza virus, which occurs year-round, the other viruses occur predominantly in the late fall, winter, and early spring. Outbreaks among the HSC transplant population tend to coincide with community outbreaks (265, 266). Nosocomial transmission from infected healthcare workers has been documented, highlighting the need for meticulous infection control strategies during high-risk periods. Most patients present initially with upper respiratory illness characterized by fever, coryza, and cough. Progression to pneumonia occurs frequently in association with RSV and parainfluenza infection but considerably less so with influenza, although postinfluenza bacterial pneumonias are a concern (263, 267). Among patients with RSV infection, the risk of pneumonia approaches 80% for those who are less than 1 month posttransplantation or still in the preengraftment stage, but falls to less than 40% for those beyond this critical period (268). Once pneumonia develops, mortality from untreated RSV infection approximates 80%. Uncontrolled trials suggest that a combination of aerosolized ribavirin and intravenous immunoglobulin may decrease pneumonia-related mortality when initiated before the onset of respiratory failure (269, 270) and may diminish the risk of progression to pneumonia when administered preemptively at the earliest stage of upper respiratory illness (268). Mortality associated with parainfluenza and influenza pneumonia is considerably lower. Early administration of the neuraminidase inhibitors zanamivir and oseltamivir shortens the duration and severity of influenza infection in immunocompetent hosts, but their efficacy in HSC transplant recipients has not been established (89, 90, 271).

In addition to CMV, other members of the herpesvirus family may occasionally cause pneumonia in HSC transplant recipients. Herpes simplex virus pneumonia typically arises from aspiration or contiguous spread from an oropharyngeal site of infection whereas herpes zoster pneumonia occurs in the setting of disseminated infection and viremia. With the advent of acyclovir, progression to pneumonia is rare with both of these infections. Human herpesvirus 6, the cause of childhood roseola, has been detected in the lungs of some patients with idiopathic pneumonia (272). It is unclear whether this virus is a cause of pneumonia or merely latently reactivated, because virtually all adults are seropositive for the virus.

Adenovirus infection is an uncommon cause of pneumonia that almost invariably develops within the first 3 months of transplantation, an observation that has led to the suggestion that reactivation of latent virus rather than person-to-person spread is the likely pathogenic mechanism. Mortality associated with pulmonary involvement may exceed 50% (273). Although there is no proven treatment, a favorable response to the nucleotide analog cidofovir was reported in one observational study (274).

Aspergillosis.
Invasive aspergillosis stands as one of the most devastating complications of HSC transplantation, principally but not exclusively affecting allogeneic recipients and representing the leading cause of infectious deaths in this group (275). In contrast to bacterial, CMV, and Pneumocystis carinii infections, for which effective prophylactic strategies have decreased the incidence of disease, the incidence of invasive aspergillosis appears to be increasing among allogeneic recipients and currently approximates 10–15% (275, 276). There is a bimodal distribution of cases and risk factors for each period are somewhat distinct (275, 277). Both allogeneic and autologous recipients are at increased risk for invasive aspergillosis during the preengraftment phase, when neutropenia is the prevailing risk factor. Allogeneic marrow transplant recipients experience a second, postengraftment period of vulnerability coincident with the development of chronic GVHD and the attendant need to administer immunosuppressive agents (276–278). There has been a notable decline in preengraftment infections, likely due to the shortened period of neutropenia afforded by use of hematopoietic growth factors and peripheral blood stem cell donation. In contrast, there has been a corresponding increase in the frequency of postengraftment Aspergillus infections and these now constitute the majority of infections occurring after allogeneic transplantation (275–277).

Invasive aspergillosis is confined to the lungs in the majority of cases, but sinusitis and central nervous system involvement also occur with some frequency. Cough and dyspnea are the most common presenting symptoms. Pleuritic chest pain and hemoptysis are important albeit nonspecific clues to the presence of invasive aspergillosis, reflecting the tendency of the organism to invade blood vessels and cause pulmonary infarction. Fever may be absent in up to two-thirds of patients (279). Seizures and hemiparesis are ominous signs signifying central nervous system involvement.

Initial radiographic findings include single or multiple nodules, cavities, and subsegmental or segmental consolidation. In the later stages of infection, a sequestrum of necrotic lung tissue may separate from the surrounding parenchyma, resulting in the air crescent sign—a central nodule partially or circumferentially surrounded by air (Figure 6) (280). CT imaging is more sensitive in detecting abnormalities and can do so at an earlier stage of infection. A highly characteristic CT finding is the halo sign, a rim of low attenuation representing edema or hemorrhage that surrounds a pulmonary nodule (Figure 7) . Caillot and colleagues found that the halo sign was present in more than 90% of neutropenic patients with invasive pulmonary aspergillosis when CT scans were performed at the onset of fever (281).

View larger version (111K): [in this window] [in a new window]   Figure 6. Air crescent sign. Standard CT image of a hematopoietic stem cell transplant recipient with invasive aspergillosis. A nodular soft tissue opacity, representing a necrotic sequestrum of lung, has separated from the surrounding parenchyma in the left upper lobe and is now surrounded by a crescent of air. Several other areas of dense nodular consolidation are seen bilaterally, also representing invasive disease. The air crescent sign is a late finding in invasive aspergillosis, often occurring after recovery from neutropenia.

View larger version (112K): [in this window] [in a new window]   Figure 7. Halo sign. High-resolution CT image of a patient with invasive aspergillosis, demonstrating a nodular opacity surrounded by a rim (i.e., halo) of ground glass attenuation representing edema or hemorrhage.

Intravenous amphotericin B is considered to be standard treatment for invasive aspergillosis, but response to therapy is suboptimal and reported mortality is in the range of 70–90% (277, 287, 288). Newer liposomal formulations are associated with less nephrotoxicity and are indicated for patients who have baseline renal insufficiency and those who develop significant azotemia while receiving standard amphotericin B (289). An attractive alternative to amphotericin is the triazole voriconazole. This drug was shown to have superior efficacy and less toxicity than amphotericin B in a large randomized trial involving immunocompromised patients, many of whom were HSC transplant recipients (103). Caspofungin, the first of the new class of echinocandins to be released, has been approved for salvage therapy of invasive aspergillosis (290). In addition to its role in treatment of proven or suspected infection, systemic antifungal therapy should be administered empirically to all neutropenic patients who remain febrile after 4 days of broad-spectrum antibacterial therapy and for whom all clinical and laboratory studies (including blood cultures) remain negative (242).

Surgical resection of localized disease has been proposed as an adjunct to antifungal therapy and as a means of preventing massive hemoptysis, which has been reported as a complicating factor in up to 15% of patients at the time of resolution of neutropenia (291). A review of seven retrospective case series involving neutropenic patients with hematologic disorders (only a minority of whom were HSC transplantation recipients) documented an average perioperative mortality rate of 17% and successful eradication of fungus in more than 90% of survivors (283). Other than as emergency treatment for massive hemoptysis, there is currently no consensus on the role of surgery in management of invasive aspergillosis.

Effective prophylaxis of Aspergillus infections in the HSC transplant population remains an elusive goal. Low-dose intravenous amphotericin B, aerosolized amphotericin, and itraconazole have all been employed, but none of these strategies has consistently been shown to decrease the incidence of invasive aspergillosis. Measures to minimize environmental exposure to Aspergillus spores, including use of high-efficiency particulate air filters and laminar airflow in patient rooms and avoidance of areas of hospital construction or renovation, are currently emphasized (242).

Pneumocystis carinii pneumonia.
In the absence of prophylaxis, PCP complicates the course of as many as 16% of allogeneic HSC transplant recipients (292). Among patients receiving prophylaxis with oral trimethoprim–sulfamethoxasole, the risk of infection is reduced to a negligible level (293). However, trimethoprim–sulfamethoxasole is often poorly tolerated by this patient population, chiefly because of associated marrow suppression and an allergic rash that can mimic acute GVHD. Adverse reactions requiring discontinuation of the drug have been reported in 30–60% of patients in this population (294). Dapsone and inhaled pentamidine are commonly employed alternatives to trimethoprim–sulfamethoxasole, but appear to be somewhat less effective in preventing PCP (293–295). Atovaquone is an additional consideration, although there are only limited data on the efficacy and safety of this agent in the HSC transplant population (296). Prophylaxis is recommended from the time of engraftment until 6 months posttransplantation for all allogeneic recipients, but should be extended beyond this point for those receiving ongoing immunosuppressive therapy and those with chronic GVHD (297). Although the overall risk of PCP after autologous HSC transplantation is quite low, prophylaxis should be considered for patients who have underlying hematologic malignancies, have received intense conditioning regimens, or have recently received fludarabine or 2-chlorodeoxyadenosine (297).

The median onset of PCP is 60 days after transplantation. The clinical signs and symptoms are not distinct from other causes of diffuse pneumonia. Compared with patients with the acquired immunodeficiency syndrome, HSC transplant recipients generally display a more fulminant onset and course. Chest radiographs usually reveal bilateral interstitial-alveolar infiltrates, although isolated nodules, lobar consolidation, and even normal radiographs have also been reported (298). The diagnostic yield of bronchoalveolar lavage approaches 90%, obviating the need for biopsy in most cases (298). High-dose trimethoprim–sulfamethoxasole for at least 14–21 days is the treatment of choice. Allergic or intolerant patients can be treated with intravenous pentamidine. The use of corticosteroids as an adjunct to antimicrobial therapy, of proven efficacy in acquired human immunodeficiency syndrome-related PCP, is of uncertain benefit in the HSC transplant population. Despite effective therapy, mortality rates as high as 90% for infections within the initial 6 months and 40% for late-onset infections have been reported (298).

Miscellaneous fungal infections.
The zygomycetes, including Mucor and Rhizopus, are an uncommon cause of invasive fungal infection after HSC transplantation, with a prevalence of up to 1.9% (299, 300). In contrast to diabetics, who classically manifest the rhinocerebral form of infection, HSC transplant recipients are most prone to develop pneumonia. Identified risk factors include severe neutropenia, corticosteroid-treated acute or chronic GVHD, and severe, transfusion-related iron overload (300). Similar to Aspergillus, the zygomycetes are angioinvasive, leading to thrombosis, pulmonary infarction, and extensive hemorrhage and accounting for the cavitation and halo sign often seen radiographically. Amphotericin B, often in conjunction with surgical resection of devitalized lung tissue, is the mainstay of therapy but mortality rates in the range of 60–80% have been reported (299, 300).

Other emerging fungal pathogens that occasionally cause pulmonary infections include Fusarium and Scedosporium species (299).

Noninfectious Pulmonary Complications
As the incidence of infectious complications has diminished as a result of effective prophylaxis, noninfectious pulmonary insults have emerged as a major cause of post-HSC transplantation morbidity and mortality (301). Pulmonary edema is the most common early posttransplantation complication. Administration of large volumes of intravenous fluid as well as chemotherapy- and radiation-induced cardiac dysfunction are important etiologic factors in the genesis of hydrostatic pulmonary edema. Noncardiogenic pulmonary edema can result from drug-induced pulmonary toxicity, sepsis, aspiration, transfusion of blood products, or acute GVHD. Several acute lung injury syndromes—idiopathic pneumonia syndrome, engraftment syndrome, and diffuse alveolar hemorrhage—have now been well characterized. Although possessing somewhat distinct clinical features, these syndromes likely share common but poorly understood pathogenic mechanisms involving activation of inflammatory cascades by chemoradiation conditioning regimens and T cell alloreactivity. Bronchiolitis obliterans has emerged as the most common late manifestation of lung injury, but parenchymal and vascular disorders may also develop.

Idiopathic pneumonia syndrome.
Diffuse pneumonia is a common complication after HSC transplantation; no infectious etiology is identified in up to half of these "idiopathic" cases. A National Institutes of Health workshop addressed the issues of definitions and diagnostic criteria for this apparently noninfectious form of acute lung injury (302). The term "idiopathic pneumonia syndrome" (IPS) was suggested to reflect the diversity of clinical presentations and likely multifactorial etiologies. IPS was defined as "diffuse lung injury occurring after marrow transplant for which an infectious etiology is not identified" (302). Bronchoalveolar lavage, rather that lung biopsy, was recommended as the primary diagnostic approach to exclude infection. The specific diagnostic criteria that emerged from this workshop are delineated in Table 1 . Applying these criteria in a retrospective review of 1,165 consecutive patients at the Fred Hutchinson Cancer Research Center, Kantrow and colleagues found that the incidence of IPS in the first 120 days was 7.6% after allogeneic HSC transplantation and 5.7% after autologous procedures (224). Others have reported a more pronounced trend toward increased occurrence after allogeneic transplantation (301). A study focusing exclusively on allogeneic recipients found that the incidence of IPS was significantly lower after nonmyeloablative versus conventional high-dose conditioning regimens (2.2 versus 8.4%), lending support to the belief that IPS is the result of toxicity from intensive chemotherapy and radiation (303). Risk factors for development of IPS include transplantation for a malignancy other than leukemia, high-intensity conditioning regimens, older patient age, and high-grade acute GVHD (224, 301, 303).

IPS likely arises from diverse etiologies. The occurrence of IPS after both allogeneic and autologous HSC transplantation argues strongly that shared conditioning-related toxicities, rather than immune-mediated injury, are principally involved. On the other hand, the association of IPS with acute GVHD after allogeneic transplantation suggests that alloreactive T cell injury may be a contributing factor in this setting. It is also possible that some cases of "idiopathic" pneumonia actually represent episodes of occult infection. Murine models of IPS have begun to shed light on pathogenic mechanisms (304–309). Taken in sum, these models suggest a sequence of events that involves chemokine-driven recruitment of inflammatory and immune-effector cells to the lung, release of oxidants and proinflammatory cytokines, and, in the case of allogeneic transplantation, a second wave of injury mediated by alloreactive T lymphocytes.

Beyond supportive care, there is no proven treatment for IPS. High-dose corticosteroid therapy does not appear to be of benefit (224). The administration of etanercept, a soluble tumor necrosis factor-–binding protein, was well tolerated by three pediatric allogeneic HSC transplant recipients with IPS and was associated with significant improvement in pulmonary dysfunction within the first week of therapy (310). In combination with evidence that antitumor necrosis factor therapy mitigates acute lung injury in murine models of IPS (307), these anecdotal clinical successes should prompt initiation of clinical trials, but they do not yet permit endorsement of etanercept as a treatment.

Diffuse alveolar hemorrhage.
The development of diffuse alveolar hemorrhage (DAH) as a noninfectious complication after HSC transplantation was first brought to light by Robbins and colleagues who, in a retrospective review of 141 consecutive autologous transplant recipients at the University of Nebraska (Lincoln, NE), identified 29 patients (21%) with this disorder (311). The hallmark of the syndrome was the finding of progressively bloodier return from bronchoalveolar lavage in the absence of an identifiable respiratory tract infection. Since the initial description, DAH has been reported by multiple other groups, albeit with a significantly lower incidence approximating 5% (228). The incidence among autologous and allogeneic recipients appears to be equivalent (228). Age greater than 40 years; total body irradiation; transplantation for solid tumors; and the presence of high fevers, severe mucositis, and renal insufficiency have been identified as risk factors for DAH (311). Although thrombocytopenia is common, platelet counts are not lower than those found in patients without DAH and aggressive platelet transfusion does not result in improvement in respiratory status (311).

Diagnostic criteria for DAH are listed in Table 2 . Although demonstration of progressively bloodier bronchoalveolar lavage fluid from at least three lobes is considered a key diagnostic feature, data from a small postmortem study of allogeneic bone marrow transplant recipients illustrate the limitations of this criterion. In this study, Agusti and colleagues found that four of eight patients with autopsy-proven DAH had nonbloody bronchoalveolar lavage fluid (312). Conversely, 7 of 13 patients without histologic evidence of DAH had bloody lavage fluid. The presence of greater than 20% hemosiderin-laden macrophages in bronchoalveolar lavage fluid is an alternative diagnostic criterion, but because it may take 48–72 hours for this finding to appear, the absence of hemosiderin does not exclude a fresh bleeding episode (228, 313).

The pathogenesis of DAH in HSC transplant recipients remains obscure. Postmortem investigations have shown that the majority of patients with DAH have evidence of diffuse alveolar damage (311, 312). It is likely that DAH, like IPS, is part of a spectrum of acute lung injury induced by conditioning chemotherapy, radiation, and occult infection. The fact that many cases occur at the time of engraftment suggests that neutrophil influx into the lung may accentuate the injury and in some way precipitate hemorrhage.

Engraftment syndrome.
Engraftment syndrome describes a clinical entity characterized in its full expression by a combination of fever, erythrodermatous rash, and noncardiogenic pulmonary edema occurring coincident with neutrophil recovery (227). The syndrome has been described as occurring most frequently after autologous HSC transplantation, with an incidence of 7–11% when stringent diagnostic criteria are utilized (317). A similar presentation after allogeneic transplantation has been described, but must be distinguished from acute GVHD. The etiology of this syndrome is poorly understood; release of proinflammatory cytokines during engraftment is postulated to play a principal role. Analysis of risk factors has yielded inconsistent results (227). The use of granulocyte colony-stimulating factor may increase the incidence and severity of the engraftment syndrome and discontinuation of this agent is recommended for patients who develop this complication (318, 319). For patients with significant pulmonary involvement, a prompt response to corticosteroid administration has been reported, although mortality is high among those who progress to respiratory failure before treatment (227, 320).

Delayed pulmonary toxicity syndrome.
The term "delayed pulmonary toxicity syndrome" describes a form of mild to moderate pulmonary injury observed after high-dose chemotherapy and autologous HSC transplantation for breast cancer (321, 322). In contrast to IPS, this syndrome presents at a later time point, is generally responsive to corticosteroid therapy, and has a better prognosis. In a study by Wilczynski and colleagues of 45 consecutive women who received high-dose chemotherapy with cyclophosphamide, cisplatin, and bischloroethylnitrosourea (BCNU) followed by autologous HSC transplantation, 26 patients (58%) developed symptomatic pulmonary toxicity with a mean onset of 10 weeks after transplantation (322). Symptoms are nonspecific and include dyspnea on exertion, nonproductive cough, and fever. Pulmonary function testing reveals a marked reduction in the diffusing capacity associated with a mild to moderate restrictive pattern. Ground glass opacities are the most common radiographic abnormalities demonstrated on CT imaging, but abnormalities may be absent or delayed in up to one-third of patients (322). Response to corticosteroids is generally favorable. In the Wilczynski study, treatment was associated with a mean improvement in diffusing capacity of 17%. In addition, none of the patients in this study died from pulmonary toxicity (322).

Delayed pulmonary toxicity syndrome likely represents a manifestation of chemotherapy-induced lung injury. In support of this, lung pathology specimens in 10 patients with this syndrome demonstrated findings consistent with drug toxicity, including alveolar septal thickening, interstitial fibrosis, and Type II pneumocyte hyperplasia (321). Moreover, in a study that randomized patients to high-dose versus standard chemotherapy before autologous HSC transplantation, the incidence of delayed pulmonary toxicity syndrome was 72% in the high-dose group and only 4% in the group receiving standard therapy (323). Two of the chemotherapeutic agents used in the conditioning regimen administered to patients with this syndrome—BCNU and cyclophosphamide—have been associated with lung toxicity. Although the high-dose chemotherapy regimens associated with delayed pulmonary toxicity syndrome utilized doses of BCNU below the threshold typically associated with pulmonary toxicity, it is likely that the risk of toxicity is enhanced by synergism with concurrently administered cyclophosphamide.

Chronic airflow obstruction/bronchiolitis obliterans.
Chronic airflow obstruction is the most common late complication of allogeneic HSC transplantation, typically occurring beyond the third month and associated with underlying chronic GVHD in the majority of cases (232, 324). The incidence in the allogeneic population varies between 6 and 26% in published series, depending in part on the definition of airflow obstruction that is employed (232, 325). The underlying process accounting for airflow obstruction in the majority of cases is bronchiolitis obliterans (326). In contrast to the relatively high frequency of this disorder among allogeneic recipients, bronchiolitis obliterans is exceptionally rare after autologous transplantation and documentation is at a case report level (327).

In addition to chronic GVHD, risk factors for development of chronic airflow obstruction include increasing recipient age, pretransplantation reduction in the ratio of FEV₁ to forced vital capacity, low serum immunoglobulin levels, use of methotrexate, and history of a respiratory viral infection within the first 100 days (232). The etiology remains obscure. However, the strong association with chronic GVHD and the presence of underlying bronchiolitis obliterans suggest that the bronchial epithelium may be the target of immune-mediated injury induced by donor cytotoxic T cells (328). The reported association with the administration of methotrexate raises the possibility of direct drug-related injury to the pulmonary bronchial epithelium.

Onset is typically insidious rather than abrupt. Presenting symptoms include nonproductive cough, dyspnea, and wheezing. Fever is uncommon. The chest radiograph is commonly normal, but high-resolution CT often demonstrates evidence of air trapping, hypoattenuation, and bronchial dilatation (Figure 8) . The diagnosis is established by demonstration of persistent airflow obstruction on simple spirometry and exclusion of other causes (e.g., viral bronchiolitis, asthma). Because of the patchy nature of the process and the small samples obtained, the yield of transbronchial biopsies is low and the utility of bronchoscopy is limited to its role in excluding infectious causes. Surgical lung biopsy is rarely indicated.

View larger version (116K): [in this window] [in a new window]   Figure 8. Bronchiolitis obliterans. Expiratory high-resolution CT image of a patient who developed progressive, irreversible airflow obstruction 9 months after hematopoietic stem cell transplantation. There is a mosaic perfusion pattern with multiple areas of low attenuation posteriorly that represent air trapping, consistent with a diagnosis of bronchiolitis obliterans.

Pulmonary venoocclusive disease.
Pulmonary venoocclusive disease is a rare complication after HCS transplantation (331–334). This process is characterized by intimal proliferation and fibrosis of the pulmonary venules and small veins, leading to progressive vascular obstruction and increased pulmonary arterial and capillary pressures. Patients typically present several months after transplantation with progressive dyspnea on exertion and fatigue. The triad of pulmonary arterial hypertension, radiographic signs of pulmonary edema, and a normal pulmonary artery occlusion pressure strongly suggests the diagnosis, but it may not be present concurrently in all patients (335).

Because pulmonary venoocclusive disease has been reported in nontransplant patients who have received radiation and chemotherapy and in patients with viral infections, it has been hypothesized that its occurrence after HSC transplantation is a result of an infectious or toxic injury to the endothelium. BCNU, mitomycin C, and bleomycin have been most commonly associated with this process (336).

Arterial vasodilatation in the setting of fixed pulmonary venous resistance can markedly increase transcapillary hydrostatic pressure and precipitate or worsen pulmonary edema. Treatment of pulmonary venoocclusive disease with vasodilators is therefore potentially dangerous and must be initiated under close observation. Response to high-dose corticosteroid therapy has been anecdotally reported (332).

Posttransplant lymphoproliferative disorder.
PTLD is an infrequent but serious complication of allogeneic HSC transplantation. It represents an uncontrolled expansion of donor-derived, EBV-infected B lymphocytes, because of loss of cytotoxic T cell immunity. Major risk factors for development of PTLD include the use of unrelated or HLA-mismatched related donors, T cell-depleted donor stem cells, and anti-thymocyte globulin or monoclonal anti-T cell antibodies for the prevention or treatment of GVHD. Although the overall incidence of PTLD is only 1%, the incidence increases to 8% for those with two risk factors and to 22% for those with three (337). Onset is typically within the first 6 months and is most often characterized by involvement of lymph nodes, liver, and spleen. Pulmonary involvement occurs in about 20% of cases (338). Definitive diagnosis requires biopsy but quantitative EBV DNA monitoring by PCR techniques is emerging as a noninvasive diagnostic technique (339). Treatment includes the administration of anti-B cell monoclonal antibodies combined with a reduction in the dose of immunosuppressive agents (338, 340). The potential benefits of the infusion of in vitro–generated EBV-specific cytotoxic T cells are under investigation (340). Survival among HSC transplantation recipients with PTLD is considerably lower than that of solid organ transplant recipients and is particularly poor for those who had received HSC transplantation for hematologic malignancies (338).

Respiratory failure.
Respiratory failure after HSC transplantation is a relatively frequent and ominous complication. In a review of more than 1,400 consecutive patients who underwent HSC transplantation at the Fred Hutchinson Cancer Research Center between 1986 and 1990, Crawford and Petersen documented the need for mechanical ventilation in 23% of the patients (341). Older age, active malignancy at the time of transplantation, and receipt of an HLA-nonidentical allogeneic transplant were identified as independent risk factors for respiratory failure. Only 4% of ventilated patients in this series survived to discharge, a figure similar to that cited in other studies from this era (221, 342, 343). More recent reports have provided a more favorable perspective, documenting survival rates of 16–26% in mechanically ventilated patients (344–347). To some extent, the improved survival may reflect trends toward use of peripheral stem cell transplantation. One study noted that peripheral stem cell transplant recipients with respiratory failure had a survival rate of 31% compared with only 4% among those who had received conventional bone marrow transplants (345). In another study, 26% of autologous peripheral stem cell recipients who required intubation survived to hospital discharge (348). Improvement in survival has also been documented with early institution of noninvasive mechanical ventilatory support (349). On the other hand, the presence of multisystem organ failure, particularly involving renal and hepatic dysfunction, defines an almost uniformly fatal outcome in HSC transplant recipients with respiratory failure (345, 346, 348).

Despite the trend toward improving outcomes, the generally negative results justify a standard of care for mechanically ventilated patients that restricts prolonged intensive care, particularly for recipients of conventional allogeneic bone marrow transplants and for those with multiorgan failure. The available information should be used to counsel patients and families on the expected outcomes of critical illness and the rational use of life-sustaining modalities.

	CONCLUSIONS

TOP ABSTRACT CONTENTS SOLID ORGAN TRANSPLANTATION HEMATOPOIETIC STEM CELL... CONCLUSIONS REFERENCES

 
Although pulmonary complications remain a leading cause of morbidity and mortality after both solid organ and HSC transplantation, substantial progress is being made. Development of effective prophylactic strategies has reduced the lethal impact that CMV pneumonia and PCP once had on all transplant recipients. In HSC transplantation, use of nonmyeloablative conditioning regimens, although limited in application, has lessened the period of neutropenia and mitigated the toxicities of chemotherapy and radiation on the lung. The next major advance will likely arise from current research efforts to effect immune tolerance, a state of graft-specific alloimmune hyporesponsiveness that preserves host immune responses to infection (350). Successful induction of tolerance after solid organ transplantation would render superfluous the long-term administration of immunosuppressive agents to prevent allograft rejection and would thereby avoid the global immunosuppressed state that accompanies use of these agents. Induction of selective donor T cell hyporesponsiveness after allogeneic HSC transplantation would greatly diminish the risk of GVHD (351), similarly obviating the need for long-term administration of immunosuppressive therapy and presumably lessening the risk of pulmonary complications that are mediated by alloimmunity. It is anticipated that future application of this strategy will ultimately lead to a marked reduction in infectious, neoplastic, and alloimmune pulmonary complications.

	Acknowledgments

 
The authors thank Drs. Warren Gefter, Drew Torigian, and Wallace Miller, Jr. for providing representative radiographic images. The assistance of Marissa Fox in the preparation of the manuscript is also gratefully acknowledged.

	FOOTNOTES

 
Supported in part by the Craig and Elaine Dobbin Pulmonary Research Fund of the University of Pennsylvania Medical Center.

The views stated within are not necessarily those of the United States Navy or the Department of Defense.

Conflict of Interest Statement: R.M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. V.N.A. is currently the local principal investigator of a multicenter study sponsored by Fujisawa Healthcare, Inc., and the University of Pennsylvania School of Medicine receives $6,600 from Fujisawa for each patient enrolled in the study; to date 13 patients have been enrolled and this money is used to support research activities only, and V.N.A. has not directly received any financial award for his participation in the study. S.W.C. received $2,000 as a consultant for Pharmacia, $3,000 in 2002 as an advisor to Aventis, and is currently an advisor to Cubist and has received $4,000 since 2001; he has received $10,000 from Aventis for lectures in 2001 and $4,000 from Ortho-Biotech for lectures in 2000–2002.

Received in original form September 24, 2003; accepted in final form April 6, 2004

	REFERENCES

TOP ABSTRACT CONTENTS SOLID ORGAN TRANSPLANTATION HEMATOPOIETIC STEM CELL... CONCLUSIONS REFERENCES

 

1. Ettinger NA, Trulock EP. Pulmonary considerations of organ transplantation. Part 1. Am Rev Respir Dis 1991;143:1386–1405.[Medline]
2. Ettinger NA, Trulock EP. Pulmonary considerations of organ transplantation. Part 2. Am Rev Respir Dis 1991;144:213–223.[Medline]
3. Ettinger NA, Trulock EP. Pulmonary considerations of organ transplantation. Part 3. Am Rev Respir Dis 1991;144:433–451.
4. Maurer JR, Tullis E, Grossman RF, Vellend H, Winton TL, Patterson GA. Infectious complications following isolated lung transplantation. Chest 1992;101:1056–1059.[Abstract/Free Full Text]
5. Cisneros JM, Munoz P, Torre-Cisneros J, Gurgui M, Rodriguez-Hernandez MJ, Aguado JM, Echaniz A, Spanish Transplantation Infection Study Group. Pneumonia after heart transplantation: a multi-institutional study. Clin Infect Dis 1998;27:324–331.[Medline]
6. Kramer MR, Marshall SE, Starnes VA, Gamberg P, Amitai Z, Theodore J. Infectious complications in heart–lung transplantation: analysis of 200 episodes. Arch Intern Med 1993;153:2010–2016.[Abstract/Free Full Text]
7. Kusne S, Dummer JS, Singh N, Iwatsuki S, Makowka L, Esquivel C, Tzakis AG, Starzl TE, Ho M. Infections after liver transplantation: an analysis of 101 consecutive cases. Medicine (Baltimore) 1988;67:132–143.[Medline]
8. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741–1751.[Free Full Text]
9. Lenner R, Padilla ML, Teirstein AS, Gass A, Schilero GJ. Pulmonary complications in cardiac transplant recipients. Chest 2001;120:508–513.[Abstract/Free Full Text]
10. Torres A, Ewig S, Insausti J, Guergue JM, Xaubet A, Mas A, Salmeron JM. Etiology and microbial patterns of pulmonary infiltrates in patients with orthotopic liver transplantation. Chest 2000;117:494–502.[Abstract/Free Full Text]
11. Montoya JG, Giraldo LF, Efron B, Stinson EB, Gamberg P, Hunt S, Giannetti N, Miller J, Remington JS. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 2001;33:629–640.[CrossRef][Medline]
12. Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas-Chanoin MH, Wolff M, Spencer RC, Hemmer M, EPIC International Advisory Committee. The prevalence of nosocomial infection in intensive care units in Europe: results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA 1995;274:639–644.[Abstract/Free Full Text]
13. Singh N, Paterson DL, Chang FY, Gayowski T, Squier C, Wagener MM, Marino IR. Methicillin-resistant Staphylococcus aureus: the other emerging resistant gram-positive coccus among liver transplant recipients. Clin Infect Dis 2000;30:322–327.[CrossRef][Medline]
14. Weill D, Dey GC, Hicks RA, Young KR Jr, Zorn GL Jr, Kirklin JK, Early L, McGiffin DC. A positive donor gram stain does not predict outcome following lung transplantation. J Heart Lung Transplant 2002;21:555–558.[CrossRef][Medline]
15. Singh N, Gayowski T, Wagener M, Marino IR, Yu VL. Pulmonary infections in liver transplant recipients receiving tacrolimus: changing pattern of microbial etiologies. Transplantation 1996;61:396–401.[Medline]
16. Leung AN, Fisher K, Valentine V, Girgis RE, Berry GJ, Robbins RC, Theodore J. Bronchiolitis obliterans after lung transplantation: detection using expiratory HRCT. Chest 1998;113:365–370.[Abstract/Free Full Text]
17. Lee ES, Gotway MB, Reddy GP, Golden JA, Keith FM, Webb WR. Early bronchiolitis obliterans following lung transplantation: accuracy of expiratory thin-section CT for diagnosis. Radiology 2000;216:472–477.[Abstract/Free Full Text]
18. Wilson JP, Turner HR, Kirchner KA, Chapman SW. Nocardial infections in renal transplant recipients. Medicine (Baltimore) 1989;68:38–57.[Medline]
19. Chapman SW, Wilson JP. Nocardiosis in transplant recipients. Semin Respir Infect 1990;5:74–79.[Medline]
20. Husain S, McCurry K, Dauber J, Singh N, Kusne S. Nocardia infection in lung transplant recipients. J Heart Lung Transplant 2002;21:354–359.[CrossRef][Medline]
21. Roberts SA, Franklin JC, Mijch A, Spelman D. Nocardia infection in heart–lung transplant recipients at Alfred Hospital, Melbourne, Australia, 1989–1998. Clin Infect Dis 2000;31:968–972.[CrossRef][Medline]
22. Paterson DL, Singh N, Gayowski T, Marino IR. Pulmonary nodules in liver transplant recipients. Medicine (Baltimore) 1998;77:50–58.[CrossRef][Medline]
23. Munoz P, Palomo J, Guembe P, Rodriguez-Creixems M, Gijon P, Bouza E. Lung nodular lesions in heart transplant recipients. J Heart Lung Transplant 2000;19:660–667.[CrossRef][Medline]
24. Simpson GL, Stinson EB, Egger MJ, Remington JS. Nocardial infections in the immunocompromised host: a detailed study in a defined population. Rev Infect Dis 1981;3:492–507.[Medline]
25. Forbes GM, Harvey FA, Philpott-Howard JN, O'Grady JG, Jensen RD, Sahathevan M, Casewell MW, Williams R. Nocardiosis in liver transplantation: variation in presentation, diagnosis and therapy. J Infect 1990;20:11–19.[CrossRef][Medline]
26. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998;27:1266–1277.[Medline]
27. Meyers BR, Halpern M, Sheiner P, Mendelson MH, Neibart E, Miller C. Tuberculosis in liver transplant patients. Transplantation 1994;58:301–306.[Medline]
28. Korner MM, Hirata N, Tenderich G, Minami K, Mannebach H, Kleesiek K, Korfer R. Tuberculosis in heart transplant recipients. Chest 1997;111:365–369.[Abstract/Free Full Text]
29. John GT, Shankar V, Abraham AM, Mukundan U, Thomas PP, Jacob CK. Risk factors for post-transplant tuberculosis. Kidney Int 2001;60:1148–1153.[CrossRef][Medline]
30. Meyers BR, Papanicolaou GA, Sheiner P, Emre S, Miller C. Tuberculosis in orthotopic liver transplant patients: increased toxicity of recommended agents; cure of disseminated infection with nonconventional regimens. Transplantation 2000;69:64–69.[CrossRef][Medline]
31. Aguado JM, Herrero JA, Gavalda J, Torre-Cisneros J, Blanes M, Rufi G, Moreno A, Gurgui M, Hayek M, Lumbreras C, Spanish Transplantation Infection Study Group, GESITRA. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Transplantation 1997;63:1278–1286.[CrossRef][Medline]
32. Modry DL, Stinson EB, Oyer PE, Jamieson SW, Baldwin JC, Shumway NE. Acute rejection and massive cyclosporine requirements in heart transplant recipients treated with rifampin. Transplantation 1985;39:313–314.[Medline]
33. Offermann G, Keller F, Molzahn M. Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am J Nephrol 1985;5:385–387.[Medline]
34. American Thoracic Society/Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221–S247.[Free Full Text]
35. Singh N, Wagener MM, Gayowski T. Safety and efficacy of isoniazid chemoprophylaxis administered during liver transplant candidacy for the prevention of posttransplant tuberculosis. Transplantation 2002;74:892–895.[CrossRef][Medline]
36. Schluger LK, Sheiner PA, Jonas M, Guarrera JV, Fiel IM, Meyers B, Berk PD. Isoniazid hepatotoxicity after orthotopic liver transplantation. Mt Sinai J Med 1996;63:364–369.[Medline]
37. American Thoracic Society/Centers for Disease Control and Prevention. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations: United States, 2001. Am J Respir Crit Care Med 2001;164:1319–1320.[Free Full Text]
38. Malouf MA, Glanville AR. The spectrum of mycobacterial infection after lung transplantation. Am J Respir Crit Care Med 1999;160:1611–1616.[Abstract/Free Full Text]
39. Novick RJ, Moreno-Cabral CE, Stinson EB, Oyer PE, Starnes VA, Hunt SA, Shumway NE. Nontuberculous mycobacterial infections in heart transplant recipients: a seventeen-year experience. J Heart Transplant 1990;9:357–363.[Medline]
40. Queipo JA, Broseta E, Santos M, Sanchez-Plumed J, Budia A, Jimenez-Cruz F. Mycobacterial infection in a series of 1261 renal transplant recipients. Clin Microbiol Infect 2003;9:518–525.[CrossRef][Medline]
41. Vandermarliere A, Van Audenhove A, Peetermans WE, Vanrenterghem Y, Maes B. Mycobacterial infection after renal transplantation in a Western population. Transpl Infect Dis 2003;5:9–15.[Medline]
42. Neau-Cransac M, Dupon M, Carles J, Le Bail B, Saric J. Disseminated Mycobacterium avium infection after liver transplantation. Eur J Clin Microbiol Infect Dis 1998;17:744–746.[CrossRef][Medline]
43. Patel R, Roberts GD, Keating MR, Paya CV. Infections due to nontuberculous mycobacteria in kidney, heart, and liver transplant recipients. Clin Infect Dis 1994;19:263–273.[Medline]
44. Duncan SR, Paradis IL, Yousem SA, Similo SL, Grgurich WF, Williams PA, Dauber JH, Griffith BP. Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients. Am Rev Respir Dis 1992;146:1419–1425.[Medline]
45. Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev 2000;13:83–121.[Abstract/Free Full Text]
46. Humar A, Gregson D, Caliendo AM, McGeer A, Malkan G, Krajden M, Corey P, Greig P, Walmsley S, Levy G, et al. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation 1999;68:1305–1311.[CrossRef][Medline]
47. Gane E, Saliba F, Valdecasas GJ, O'Grady J, Pescovitz MD, Lyman S, Robinson CA, Oral Ganciclovir International Transplantation Study Group. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. Lancet 1997;350:1729–1733.[CrossRef][Medline]
48. Rayes N, Seehofer D, Schmidt CA, Oettle H, Muller AR, Steinmuller T, Settmacher U, Bechstein WO, Neuhaus P. Prospective randomized trial to assess the value of preemptive oral therapy for CMV infection following liver transplantation. Transplantation 2001;72:881–885.[CrossRef][Medline]
49. Falagas ME, Snydman DR, George MJ, Werner B, Ruthazer R, Griffith J, Rohrer RH, Freeman R, Boston Center for Liver Transplantation CMVIG Study Group. Incidence and predictors of cytomegalovirus pneumonia in orthotopic liver transplant recipients. Transplantation 1996;61:1716–1720.[CrossRef][Medline]
50. Senechal M, Dorent R, du Montcel ST, Fillet AM, Ghossoub JJ, Dubois M, Pavie A, Gandjbakhch I. Monitoring of human cytomegalovirus infections in heart transplant recipients by pp65 antigenemia. Clin Transplant 2003;17:423–427.[CrossRef][Medline]
51. Kocher AA, Bonaros N, Dunkler D, Ehrlich M, Schlechta B, Zweytick B, Grimm M, Zuckermann A, Wolner E, Laufer G. Long-term results of CMV hyperimmune globulin prophylaxis in 377 heart transplant recipients. J Heart Lung Transplant 2003;22:250–257.[CrossRef][Medline]
52. Akalin E, Sehgal V, Ames S, Hossain S, Daly L, Barbara M, Bromberg JS. Cytomegalovirus disease in high-risk transplant recipients despite ganciclovir or valganciclovir prophylaxis. Am J Transplant 2003;3:731–735.[CrossRef][Medline]
53. Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, Norman D, Mendez R, Keating MR, Coggon GL, International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N Engl J Med 1999;340:1462–1470.[Abstract/Free Full Text]
54. Sanchez JL, Kruger RM, Paranjothi S, Trulock EP, Lynch JP, Hicks C, Shannon WD, Storch GA. Relationship of cytomegalovirus viral load in blood to pneumonitis in lung transplant recipients. Transplantation 2001;72:733–735.[CrossRef][Medline]
55. Baz MA, Layish DT, Govert JA, Howell DN, Lawrence CM, Davis RD, Tapson VF. Diagnostic yield of bronchoscopies after isolated lung transplantation. Chest 1996;110:84–88.[Abstract/Free Full Text]
56. Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Plit ML, Rainer SP, Glanville AR. Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant 2002;21:1062–1067.[CrossRef][Medline]
57. Hertz MI, Jordan C, Savik SK, Fox JM, Park S, Bolman RM III, Dosland-Mullan BM. Randomized trial of daily versus three-times-weekly prophylactic ganciclovir after lung and heart–lung transplantation. J Heart Lung Transplant 1998;17:913–920.[Medline]
58. Soghikian MV, Valentine VG, Berry GJ, Patel HR, Robbins RC, Theodore J. Impact of ganciclovir prophylaxis on heart–lung and lung transplant recipients. J Heart Lung Transplant 1996;15:881–887.[Medline]
59. Balthesen M, Messerle M, Reddehase MJ. Lungs are a major organ site of cytomegalovirus latency and recurrence. J Virol 1993;67:5360–5366.[Abstract/Free Full Text]
60. Trulock EP, Ettinger NA, Brunt EM, Pasque MK, Kaiser LR, Cooper JD. The role of transbronchial lung biopsy in the treatment of lung transplant recipients. Chest 1992;102:1049–1054.[Abstract/Free Full Text]
61. Collins J, Muller NL, Kazerooni EA, Paciocco G. CT findings of pneumonia after lung transplantation. AJR Am J Roentgenol 2000;175:811–818.[Abstract/Free Full Text]
62. Franquet T, Lee KS, Muller NL. Thin-section CT findings in 32 immunocompromised patients with cytomegalovirus pneumonia who do not have AIDS. AJR Am J Roentgenol 2003;181:1059–1063.[Abstract/Free Full Text]
63. Emery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 2000;355:2032–2036.[CrossRef][Medline]
64. Harbison MA, De Girolami PC, Jenkins RL, Hammer SM. Ganciclovir therapy of severe cytomegalovirus infections in solid-organ transplant recipients. Transplantation 1988;46:82–88.[Medline]
65. D'Alessandro AM, Pirsch JD, Stratta RJ, Sollinger HW, Kalayoglu M, Belzer FO. Successful treatment of severe cytomegalovirus infections with ganciclovir and CMV hyperimmune globulin in liver transplant recipients. Transplant Proc 1989;21:3560–3561.[Medline]
66. Rubin RH. Prevention and treatment of cytomegalovirus disease in heart transplant patients. J Heart Lung Transplant 2000;19:731–735.[CrossRef][Medline]
67. Turgeon N, Fishman JA, Doran M, Basgoz N, Tolkoff-Rubin NE, Cosimi AB, Rubin RH. Prevention of recurrent cytomegalovirus disease in renal and liver transplant recipients: effect of oral ganciclovir. Transpl Infect Dis 2000;2:2–10.[CrossRef][Medline]
68. Griffiths PD. The treatment of cytomegalovirus infection. J Antimicrob Chemother 2002;49:243–253.[Abstract/Free Full Text]
69. Couchoud C, Cucherat M, Haugh M, Pouteil-Noble C. Cytomegalovirus prophylaxis with antiviral agents in solid organ transplantation: a meta-analysis. Transplantation 1998;65:641–647.[CrossRef][Medline]
70. Paya C, Humer A, Dominguez E, Washburn K, Blumberg H, Alexander B, Freeman R, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004;4:611–620.[CrossRef][Medline]
71. Singh N. Preemptive therapy versus universal prophylaxis with ganciclovir for cytomegalovirus in solid organ transplant recipients. Clin Infect Dis 2001;32:742–751.[CrossRef][Medline]
72. van der Bij W, Speich R. Management of cytomegalovirus infection and disease after solid organ transplantation. Clin Infect Dis 2001;33:S33–S37.[CrossRef]
73. Lurain NS, Bhorade SM, Pursell KJ, Avery RK, Yeldandi VV, Isada CM, Robert ES, Kohn DJ, Arens MQ, Garrity ER, et al. Analysis and characterization of antiviral drug-resistant cytomegalovirus isolates from solid organ transplant recipients. J Infect Dis 2002;186:760–768.[CrossRef][Medline]
74. Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 2000;356:645–649.[CrossRef][Medline]
75. Bhorade SM, Lurain NS, Jordan A, Leischner J, Villanueva J, Durazo R, Creech S, Vigneswaran WT, Garrity ER. Emergence of ganciclovir-resistant cytomegalovirus in lung transplant recipients. J Heart Lung Transplant 2002;21:1274–1282.[CrossRef][Medline]
76. Kruger RM, Shannon WD, Arens MQ, Lynch JP, Storch GA, Trulock EP. The impact of ganciclovir-resistant cytomegalovirus infection after lung transplantation. Transplantation 1999;68:1272–1279.[CrossRef][Medline]
77. Wendt CH. Community respiratory viruses: organ transplant recipients. Am J Med 1997;102:31–36.[Medline]
78. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002;21:559–566.[CrossRef][Medline]
79. Palmer SM Jr, Henshaw NG, Howell DN, Miller SE, Davis RD, Tapson VF. Community respiratory viral infection in adult lung transplant recipients. Chest 1998;113:944–950.[Abstract/Free Full Text]
80. Vilchez RA, McCurry K, Dauber J, Lacono A, Griffith B, Fung J, Kusne S. Influenza virus infection in adult solid organ transplant recipients. Am J Transplant 2002;2:287–291.[CrossRef][Medline]
81. Ko JP, Shepard JA, Sproule MW, Trotman-Dickenson B, Drucker EA, Ginns LC, Wain JC, McLoud TC. CT manifestations of respiratory syncytial virus infection in lung transplant recipients. J Comput Assist Tomogr 2000;24:235–241.[CrossRef][Medline]
82. Wendt CH, Fox JM, Hertz MI. Paramyxovirus infection in lung transplant recipients. J Heart Lung Transplant 1995;14:479–485.[Medline]
83. Pohl C, Green M, Wald ER, Ledesma-Medina J. Respiratory syncytial virus infections in pediatric liver transplant recipients. J Infect Dis 1992;165:166–169.[Medline]
84. McCurdy LH, Milstone A, Dummer S. Clinical features and outcomes of paramyxoviral infection in lung transplant recipients treated with ribavirin. J Heart Lung Transplant 2003;22:745–753.[CrossRef][Medline]
85. Garantziotis S, Howell DN, McAdams HP, Davis RD, Henshaw NG, Palmer SM. Influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome. Chest 2001;119:1277–1280.[Abstract/Free Full Text]
86. Vilchez RA, Dauber J, McCurry K, Iacono A, Kusne S. Parainfluenza virus infection in adult lung transplant recipients: an emergent clinical syndrome with implications on allograft function. Am J Transplant 2003;3:116–120.[CrossRef][Medline]
87. Douglas RG Jr. Prophylaxis and treatment of influenza. N Engl J Med 1990;322:443–450.[Medline]
88. Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG, Bohnen AM, Hirst HM, Keene O, Wightman K, GG167 Influenza Study Group. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. N Engl J Med 1997;337:874–880.[Abstract/Free Full Text]
89. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG, US Oral Neuraminidase Study Group. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA 2000;283:1016–1024.[Abstract/Free Full Text]
90. Lalezari J, Campion K, Keene O, Silagy C. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Arch Intern Med 2001;161:212–217.[Abstract/Free Full Text]
91. Doud JR, Hinkamp T, Garrity ER Jr. Respiratory syncytial virus pneumonia in a lung transplant recipient: case report. J Heart Lung Transplant 1992;11:77–79.[Medline]
92. Fraund S, Wagner D, Pethig K, Drescher J, Girgsdies OE, Haverich A. Influenza vaccination in heart transplant recipients. J Heart Lung Transplant 1999;18:220–225.[CrossRef][Medline]
93. Blumberg EA, Albano C, Pruett T, Isaacs R, Fitzpatrick J, Bergin J, Crump C, Hayden FG. The immunogenicity of influenza virus vaccine in solid organ transplant recipients. Clin Infect Dis 1996;22:295–302.[Medline]
94. Blumberg EA, Fitzpatrick J, Stutman PC, Hayden FG, Brozena SC. Safety of influenza vaccine in heart transplant recipients. J Heart Lung Transplant 1998;17:1075–1080.[Medline]
95. Kimball P, Verbeke S, Flattery M, Rhodes C, Tolman D. Influenza vaccination does not promote cellular or humoral activation among heart transplant recipients. Transplantation 2000;69:2449–2451.[CrossRef][Medline]
96. Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982;307:580–584.[Abstract]
97. Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, Sharp SJ, Ossi MJ, Zanamivir Family Study Group. Inhaled zanamivir for the prevention of influenza in families. N Engl J Med 2000;343:1282–1289.[Abstract/Free Full Text]
98. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore) 1999;78:123–138.[CrossRef][Medline]
99. Mehrad B, Paciocco G, Martinez FJ, Ojo TC, Iannettoni MD, Lynch JP III. Spectrum of Aspergillus infection in lung transplant recipients: case series and review of the literature. Chest 2001;119:169–175.[Abstract/Free Full Text]
100. Montoya JG, Chaparro SV, Celis D, Cortes JA, Leung AN, Robbins RC, Stevens DA. Invasive aspergillosis in the setting of cardiac transplantation. Clin Infect Dis 2003;37:S281–S292.
101. Patterson TF. Approaches to fungal diagnosis in transplantation. Transpl Infect Dis 1999;1:262–272.[CrossRef][Medline]
102. Horvath JA, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996;100:171–178.[CrossRef][Medline]
103. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–415.[Abstract/Free Full Text]
104. Mayer JM, Nimer L, Carroll K. Isolated pulmonary aspergillar infection in cardiac transplant recipients: case report and review. Clin Infect Dis 1992;15:698–700.[Medline]
105. Sandur S, Gordon SM, Mehta AC, Maurer JR. Native lung pneumonectomy for invasive pulmonary aspergillosis following lung transplantation: a case report. J Heart Lung Transplant 1999;18:810–813.[CrossRef][Medline]
106. Robinson LA, Reed EC, Galbraith TA, Alonso A, Moulton AL, Fleming WH. Pulmonary resection for invasive Aspergillus infections in immunocompromised patients. J Thorac Cardiovasc Surg 1995;109:1182–1196.
107. Kessler R, Massard G, Warter A, Wihlm JM, Weitzenblum E. Bronchial–pulmonary artery fistula after unilateral lung transplantation: a case report. J Heart Lung Transplant 1997;16:674–677.[Medline]
108. Nunley DR, Gal AA, Vega JD, Perlino C, Smith P, Lawrence EC. Saprophytic fungal infections and complications involving the bronchial anastomosis following human lung transplantation. Chest 2002;122:1185–1191.[Abstract/Free Full Text]
109. Nathan SD, Shorr AF, Schmidt ME, Burton NA. Aspergillus and endobronchial abnormalities in lung transplant recipients. Chest 2000;118:403–407.[Abstract/Free Full Text]
110. Gordon SM, LaRosa SP, Kalmadi S, Arroliga AC, Avery RK, Truesdell-LaRosa L, Longworth DL. Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clin Infect Dis 1999;28:240–246.[Medline]
111. Patel R, Paya CV. Infections in solid-organ transplant patients. Clin Microbiol Rev 1997;10:86–124.[Abstract]
112. Vilchez RA, Fung J, Kusne S. Cryptococcosis in organ transplant recipients: an overview. Am J Transplant 2002;2:575–580.[CrossRef][Medline]
113. Nicod LP, Pache JC, Howarth N. Fungal infections in transplant recipients. Eur Respir J 2001;17:133–140.[Abstract/Free Full Text]
114. Blair JE, Logan JL. Coccidioidomycosis in solid organ transplantation. Clin Infect Dis 2001;33:1536–1544.[CrossRef][Medline]
115. Palmer SM, Perfect JR, Howell DN, Lawrence CM, Miralles AP, Davis RD, Tapson VF. Candidal anastomotic infection in lung transplant recipients: successful treatment with a combination of systemic and inhaled antifungal agents. J Heart Lung Transplant 1998;17:1029–1033.[Medline]
116. Castiglioni B, Sutton DA, Rinaldi MG, Fung J, Kusne S. Pseudallescheria boydii (anamorph Scedosporium apiospermum): infection in solid organ transplant recipients in a tertiary medical center and review of the literature. Medicine (Baltimore) 2002;81:333–348.[CrossRef][Medline]
117. Glanemann M, Langrehr J, Kaisers U, Schenk R, Muller A, Stange B, Neumann U, Bechstein WO, Falke K, Neuhaus P. Postoperative tracheal extubation after orthotopic liver transplantation. Acta Anaesthesiol Scand 2001;45:333–339.[CrossRef][Medline]
118. Glanemann M, Kaisers U, Langrehr JM, Schenk R, Stange BJ, Muller AR, Bechstein WO, Falke K, Neuhaus P. Incidence and indications for reintubation during postoperative care following orthotopic liver transplantation. J Clin Anesth 2001;13:377–382.[CrossRef][Medline]
119. O'Brien JD, Ettinger NA. Pulmonary complications of liver transplantation. Clin Chest Med 1996;17:99–114.[CrossRef][Medline]
120. Judson MA, Sahn SA. The pleural space and organ transplantation. Am J Respir Crit Care Med 1996;153:1153–1165.[Abstract]
121. McAlister VC, Grant DR, Roy A, Brown WF, Hutton LC, Leasa DJ, Ghent CN, Veitch JE, Wall WJ. Right phrenic nerve injury in orthotopic liver transplantation. Transplantation 1993;55:826–830.[Medline]
122. Christie JD, Kotloff RM, Pochettino A, Arcasoy SM, Rosengard BR, Landis JR, Kimmel SE. Clinical risk factors for primary graft failure following lung transplantation. Chest 2003;124:1232–1241.[Abstract/Free Full Text]
123. Meade MO, Granton JT, Matte-Martyn A, McRae K, Weaver B, Cripps P, Keshavjee SH. A randomized trial of inhaled nitric oxide to prevent ischemia–reperfusion injury after lung transplantation. Am J Respir Crit Care Med 2003;167:1483–1489.[Abstract/Free Full Text]
124. King RC, Binns OA, Rodriguez F, Kanithanon RC, Daniel TM, Spotnitz WD, Tribble CG, Kron IL. Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg 2000;69:1681–1685.[Abstract/Free Full Text]
125. Thabut G, Vinatier I, Stern JB, Leseche G, Loirat P, Fournier M, Mal H. Primary graft failure following lung transplantation: predictive factors of mortality. Chest 2002;121:1876–1882.[Abstract/Free Full Text]
126. Christie JD, Bavaria JE, Palevsky HI, Litzky L, Blumenthal NP, Kaiser LR, Kotloff RM. Primary graft failure following lung transplantation. Chest 1998;114:51–60.[Abstract/Free Full Text]
127. Meyers BF, Sundt TM III, Henry S, Trulock EP, Guthrie T, Cooper JD, Patterson GA. Selective use of extracorporeal membrane oxygenation is warranted after lung transplantation. J Thorac Cardiovasc Surg 2000;120:20–26.[Abstract/Free Full Text]
128. Gavazzeni V, Iapichino G, Mascheroni D, Langer M, Bordone G, Zannini P, Radrizzani D, Damia G. Prolonged independent lung respiratory treatment after single lung transplantation in pulmonary emphysema. Chest 1993;103:96–100.
129. Ardehali A, Laks H, Levine M, Shpiner R, Ross D, Watson LD, Shvartz O, Sangwan S, Waters PF. A prospective trial of inhaled nitric oxide in clinical lung transplantation. Transplantation 2001;72:112–115.[CrossRef][Medline]
130. Date H, Triantafillou AN, Trulock EP, Pohl MS, Cooper JD, Patterson GA. Inhaled nitric oxide reduces human lung allograft dysfunction. J Thorac Cardiovasc Surg 1996;111:913–919.[Abstract/Free Full Text]
131. Trulock EP, Edwards LB, Taylor DO, Boucek MM, Mohacsi PJ, Keck BM, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: twentieth official adult lung and heart–lung transplant report—2003. J Heart Lung Transplant 2003;22:625–635.[CrossRef][Medline]
132. Novick RJ, Stitt LW, Al-Kattan K, Klepetko W, Schafers HJ, Duchatelle JP, Khaghani A, Hardesty RL, Patterson GA, Yacoub MH, Pulmonary Retransplant Registry. Pulmonary retransplantation: predictors of graft function and survival in 230 patients. Ann Thorac Surg 1998;65:227–234.[Abstract/Free Full Text]
133. Chhajed PN, Malouf MA, Tamm M, Spratt P, Glanville AR. Interventional bronchoscopy for the management of airway complications following lung transplantation. Chest 2001;120:1894–1899.[Abstract/Free Full Text]
134. Schmid RA, Boehler A, Speich R, Frey HR, Russi EW, Weder W. Bronchial anastomotic complications following lung transplantation: still a major cause of morbidity? Eur Respir J 1997;10:2872–2875.[Abstract]
135. Schroder C, Scholl F, Daon E, Goodwin A, Frist WH, Roberts JR, Christian KG, Ninan M, Milstone AP, Loyd JE, et al. A modified bronchial anastomosis technique for lung transplantation. Ann Thorac Surg 2003;75:1697–1704.[Abstract/Free Full Text]
136. Herrera JM, McNeil KD, Higgins RS, Coulden RA, Flower CD, Nashef SA, Wallwork J. Airway complications after lung transplantation: treatment and long-term outcome. Ann Thorac Surg 2001;71:989–993.[Abstract/Free Full Text]
137. Anderson MB, Kriett JM, Harrell J, Smith C, Kapelanski DP, Tarazi RY, Perricone A, Jamieson SW. Techniques for bronchial anastomosis. J Heart Lung Transplant 1995;14:1090–1094.[Medline]
138. Garfein ES, Ginsberg ME, Gorenstein L, McGregor CC, Schulman LL. Superiority of end-to-end versus telescoped bronchial anastomosis in single lung transplantation for pulmonary emphysema. J Thorac Cardiovasc Surg 2001;121:149–154.
139. Halkos ME, Godette KD, Lawrence EC, Miller JI Jr. High dose rate brachytherapy in the management of lung transplant airway stenosis. Ann Thorac Surg 2003;76:381–384.[Abstract/Free Full Text]
140. Weill D, Torres F, Hodges TN, Olmos JJ, Zamora MR. Acute native lung hyperinflation is not associated with poor outcomes after single lung transplant for emphysema. J Heart Lung Transplant 1999;18:1080–1087.[CrossRef][Medline]
141. Yonan NA, el-Gamel A, Egan J, Kakadellis J, Rahman A, Deiraniya AK. Single lung transplantation for emphysema: predictors for native lung hyperinflation. J Heart Lung Transplant 1998;17:192–201.[Medline]
142. Venuta F, De Giacomo T, Rendina EA, Della Rocca G, Flaishman I, Guarino E, Ricci C. Thoracoscopic volume reduction of the native lung after single lung transplantation for emphysema. Am J Respir Crit Care Med 1998;157:292–293.
143. Dorffner R, Eibenberger K, Youssefzadeh S, Wisser W, Zuckermann A, Grabenwoger F, Metz VM. Diaphragmatic dysfunction after heart or lung transplantation. J Heart Lung Transplant 1997;16:566–569.[Medline]
144. Sheridan PH Jr, Cheriyan A, Doud J, Dornseif SE, Montoya A, Houck J, Flisak ME, Walsh JM, Garrity ER Jr. Incidence of phrenic neuropathy after isolated lung transplantation. J Heart Lung Transplant 1995;14:684–691.[Medline]
145. Maziak DE, Maurer JR, Kesten S. Diaphragmatic paralysis: a complication of lung transplantation. Ann Thorac Surg 1996;61:170–173.[Abstract/Free Full Text]
146. Heino A, Orko R, Rosenberg PH. Anaesthesiological complications in renal transplantation: a retrospective study of 500 transplantations. Acta Anaesthesiol Scand 1986;30:574–580.[Medline]
147. Aris RM, Maia DM, Neuringer IP, Gott K, Kiley S, Gertis K, Handy J. Post-transplantation lymphoproliferative disorder in the Epstein–Barr virus-naive lung transplant recipient. Am J Respir Crit Care Med 1996;154:1712–1717.[Abstract]
148. Walker RC, Paya CV, Marshall WF, Strickler JG, Wiesner RH, Velosa JA, Habermann TM, Daly RC, McGregor CG. Pretransplantation seronegative Epstein–Barr virus status is the primary risk factor for posttransplantation lymphoproliferative disorder in adult heart, lung, and other solid organ transplantations. J Heart Lung Transplant 1995;14:214–221.[Medline]
149. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ, Pifarre R, Fisher RI. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990;323:1723–1728.[Abstract]
150. Gao SZ, Chaparro SV, Perlroth M, Montoya JG, Miller JL, DiMiceli S, Hastie T, Oyer PE, Schroeder J. Post-transplantation lymphoproliferative disease in heart and heart–lung transplant recipients: 30-year experience at Stanford University. J Heart Lung Transplant 2003;22:505–514.[CrossRef][Medline]
151. Paranjothi S, Yusen RD, Kraus MD, Lynch JP, Patterson GA, Trulock EP. Lymphoproliferative disease after lung transplantation: comparison of presentation and outcome of early and late cases. J Heart Lung Transplant 2001;20:1054–1063.[CrossRef][Medline]
152. Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Oltoff KM, Somer BG, Schuster SJ, Porter DL, Montone KT, Stadtmauer EA. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation 2001;71:1076–1088.[CrossRef][Medline]
153. Oertel SH, Anagnostopoulos I, Bechstein WO, Liehr H, Riess HB. Treatment of posttransplant lymphoproliferative disorder with the anti-CD20 monoclonal antibody rituximab alone in an adult after liver transplantation: a new drug in therapy of patients with posttransplant lymphoproliferative disorder after solid organ transplantation? Transplantation 2000;69:430–432.[Medline]
154. Reams BD, McAdams HP, Howell DN, Steele MP, Davis RD, Palmer SM. Posttransplant lymphoproliferative disorder: incidence, presentation, and response to treatment in lung transplant recipients. Chest 2003;124:1242–1249.[Abstract/Free Full Text]
155. Dorent R, Mohammadi S, Tezenas S, Silvaggio G, Ghossoub JJ, Leger P, Vaissier E, Leprince P, Carnot F, Riquet M, et al. Lung cancer in heart transplant patients: a 16-year survey. Transplant Proc 2000;32:2752–2754.[CrossRef][Medline]
156. Collins J, Kazerooni EA, Lacomis J, McAdams HP, Leung AN, Shiau M, Semenkovich J, Love RB. Bronchogenic carcinoma after lung transplantation: frequency, clinical characteristics, and imaging findings. Radiology 2002;224:131–138.[Abstract/Free Full Text]
157. Arcasoy SM, Hersh C, Christie JD, Zisman D, Pochettino A, Rosengard BR, Blumenthal NP, Palevsky HI, Bavaria JE, Kotloff RM. Bronchogenic carcinoma complicating lung transplantation. J Heart Lung Transplant 2001;20:1044–1053.[CrossRef][Medline]
158. Chan ED, Morales DV, Welsh CH, McDermott MT, Schwarz MI. Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med 2002;165:1654–1669.[Abstract/Free Full Text]
159. Breitz HB, Sirotta PS, Nelp WB, Ott S, Figley MM. Progressive pulmonary calcification complicating successful renal transplantation. Am Rev Respir Dis 1987;136:1480–1482.[Medline]
160. Murris-Espin M, Lacassagne L, Didier A, Voigt JJ, Cisterne JM, Giron J, Durand D, Leophonte P. Metastatic pulmonary calcification after renal transplantation. Eur Respir J 1997;10:1925–1927.[Abstract]
161. Giacobetti R, Feldman SA, Ivanovich P, Huang CM, Levin ML. Sudden fatal pulmonary calcification following renal transplantation. Nephron 1977;19:295–300.[Medline]
162. Kuhlman JE, Ren H, Hutchins GM, Fishman EK. Fulminant pulmonary calcification complicating renal transplantation: CT demonstration. Radiology 1989;173:459–460.[Abstract/Free Full Text]
163. Libson E, Wechsler RJ, Steiner RM. Pulmonary calcinosis following orthotopic liver transplantation. J Thorac Imaging 1993;8:305–308.[Medline]
164. Munoz SJ, Nagelberg SB, Green PJ, Angstadt JD, Yang SL, Jarrell BE, Maddrey WC. Ectopic soft tissue calcium deposition following liver transplantation. Hepatology 1988;8:476–483.[Medline]
165. Justrabo E, Genin R, Rifle G. Pulmonary metastatic calcification with respiratory insufficiency in patients on maintenance haemodialysis. Thorax 1979;34:384–388.[Abstract/Free Full Text]
166. Morelon E, Stern M, Israel-Biet D, Correas JM, Danel C, Mamzer-Bruneel MF, Peraldi MN, Kreis H. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 2001;72:787–790.[CrossRef][Medline]
167. Singer SJ, Tiernan R, Sullivan EJ. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med 2000;343:1815–1816.[Free Full Text]
168. Lennon A, Finan K, FitzGerald MX, McCormick PA. Interstitial pneumonitis associated with sirolimus (rapamycin) therapy after liver transplantation. Transplantation 2001;72:1166–1167.[CrossRef][Medline]
169. McWilliams TJ, Levvey BJ, Russell PA, Milne DG, Snell GI. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. J Heart Lung Transplant 2003;22:210–213.[CrossRef][Medline]
170. Haydar AA, Denton M, West A, Rees J, Goldsmith DJ. Sirolimus-induced pneumonitis: three cases and a review of the literature. Am J Transplant 2004;4:137–139.[CrossRef][Medline]
171. King-Biggs MB, Dunitz JM, Park SJ, Kay Savik S, Hertz MI. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003;75:1437–1443.[Medline]
172. Krowka MJ, Porayko MK, Plevak DJ, Pappas SC, Steers JL, Krom RA, Wiesner RH. Hepatopulmonary syndrome with progressive hypoxemia as an indication for liver transplantation: case reports and literature review. Mayo Clin Proc 1997;72:44–53.[Abstract]
173. Krowka M, Wiseman GA, Steers JL, Wiesner RH. Late recurrence and rapid evolution of severe hepatopulmonary syndrome after liver transplantation. Liver Transpl 1999;5:451–453.[CrossRef]
174. Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 2003;37:192–197.[CrossRef][Medline]
175. Taille C, Cadranel J, Bellocq A, Thabut G, Soubrane O, Durand F, Ichai P, Duvoux C, Belghiti J, Calmus Y, et al. Liver transplantation for hepatopulmonary syndrome: a ten-year experience in Paris, France. Transplantation 2003;75:1482–1489.[CrossRef][Medline]
176. Meyers C, Low L, Kaufman L, Druger G, Wong LL. Trendelenburg positioning and continuous lateral rotation improve oxygenation in hepatopulmonary syndrome after liver transplantation. Liver Transpl Surg 1998;4:510–512.[CrossRef][Medline]
177. Nunes H, Lebrec D, Mazmanian M, Capron F, Heller J, Tazi KA, Zerbib E, Dulmet E, Moreau R, Dinh-Xuan AT, et al. Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am J Respir Crit Care Med 2001;164:879–885.[Abstract/Free Full Text]
178. Schenk P, Madl C, Rezaie-Majd S, Lehr S, Muller C. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med 2000;133:701–706.[Abstract/Free Full Text]
179. Brussino L, Bucca C, Morello M, Scappaticci E, Mauro M, Rolla G. Effect on dyspnoea and hypoxaemia of inhaled N^G-nitro-L-arginine methyl ester in hepatopulmonary syndrome. Lancet 2003;362:43–44.[CrossRef][Medline]
180. Poterucha JJ, Krowka MJ, Dickson ER, Cortese DA, Stanson AW, Krom RA. Failure of hepatopulmonary syndrome to resolve after liver transplantation and successful treatment with embolotherapy. Hepatology 1995;21:96–100.[CrossRef][Medline]
181. Kuo PC, Plotkin JS, Gaine S, Schroeder RA, Rustgi VK, Rubin LJ, Johnson LB. Portopulmonary hypertension and the liver transplant candidate. Transplantation 1999;67:1087–1093.[CrossRef][Medline]
182. Kett DH, Acosta RC, Campos MA, Rodriguez MJ, Quartin AA, Schein RM. Recurrent portopulmonary hypertension after liver transplantation: management with epoprostenol and resolution after retransplantation. Liver Transpl 2001;7:645–648.[CrossRef][Medline]
183. Krowka MJ, Frantz RP, McGoon MD, Severson C, Plevak DJ, Wiesner RH. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999;30:641–648.[CrossRef][Medline]
184. Tan HP, Markowitz JS, Montgomery RA, Merritt WT, Klein AS, Thuluvath PJ, Poordad FF, Maley WR, Winters B, Akinci SB, et al. Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol. Liver Transpl 2001;7:745–749.[CrossRef][Medline]
185. Ramsay MA, Spikes C, East CA, Lynch K, Hein HA, Ramsay KJ, Klintmalm GB. The perioperative management of portopulmonary hypertension with nitric oxide and epoprostenol. Anesthesiology 1999;90:299–301.[Medline]
186. Rafanan AL, Maurer J, Mehta AC, Schilz R. Progressive portopulmonary hypertension after liver transplantation treated with epoprostenol. Chest 2000;118:1497–1500.[Abstract/Free Full Text]
187. Zuckermann A, Reichenspurner H, Birsan T, Treede H, Deviatko E, Reichart B, Klepetko W. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg 2003;125:891–900.[Abstract/Free Full Text]
188. Palmer SM, Burch LH, Davis RD, Herczyk WF, Howell DN, Reinsmoen NL, Schwartz DA. The role of innate immunity in acute allograft rejection after lung transplantation. Am J Respir Crit Care Med 2003;168:628–632.[Abstract/Free Full Text]
189. Schulman LL, Weinberg AD, McGregor C, Galantowicz ME, Suciu-Foca NM, Itescu S. Mismatches at the HLA-DR and HLA-B loci are risk factors for acute rejection after lung transplantation. Am J Respir Crit Care Med 1998;157:1833–1837.
190. Guilinger RA, Paradis IL, Dauber JH, Yousem SA, Williams PA, Keenan RJ, Griffith BP. The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients. Am J Respir Crit Care Med 1995;152:2037–2043.[Abstract]
191. Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997;155:789–818.[Medline]
192. Yousem SA, Berry GJ, Cagle PT, Chamberlain D, Husain AN, Hruban RH, Marchevsky A, Ohori NP, Ritter J, Stewart S, Lung Rejection Study Group. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection. J Heart Lung Transplant 1996;15:1–15.[Medline]
193. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002;166:440–444.[Free Full Text]
194. Reichenspurner H, Girgis RE, Robbins RC, Yun KL, Nitschke M, Berry GJ, Morris RE, Theodore J, Reitz BA. Stanford experience with obliterative bronchiolitis after lung and heart–lung transplantation. Ann Thorac Surg 1996;62:1467–1473.[Abstract/Free Full Text]
195. Girgis RE, Tu I, Berry GJ. Risk factors for the development of obliterative bronchiolitis after lung transplantation. J Heart Lung Transplant 1996;15:1200–1208.[Medline]
196. Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, Mallory GB, Snell GI, Yousem S. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310.[CrossRef][Medline]
197. Bando K, Paradis IL, Similo S, Konishi H, Komatsu K, Zullo TG, Yousem SA, Close JM, Zeevi A, Duquesnoy RJ, et al. Obliterative bronchiolitis after lung and heart–lung transplantation: an analysis of risk factors and management. J Thorac Cardiovasc Surg 1995;110:4–14.[Abstract/Free Full Text]
198. Heng D, Sharples LD, McNeil K, Stewart S, Wreghitt T, Wallwork J. Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. J Heart Lung Transplant 1998;17:1255–1263.[Medline]
199. Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant 2002;21:271–281.[CrossRef][Medline]
200. Bankier AA, Van Muylem A, Knoop C, Estenne M, Gevenois PA. Bronchiolitis obliterans syndrome in heart–lung transplant recipients: diagnosis with expiratory CT. Radiology 2001;218:533–539.[Abstract/Free Full Text]
201. Date H, Lynch JP, Sundaresan S, Patterson GA, Trulock EP. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J Heart Lung Transplant 1998;17:869–875.[Medline]
202. Brugiere O, Pessione F, Thabut G, Mal H, Jebrak G, Leseche G, Fournier M. Bronchiolitis obliterans syndrome after single-lung transplantation: impact of time to onset on functional pattern and survival. Chest 2002;121:1883–1889.[Abstract/Free Full Text]
203. Iacono AT, Keenan RJ, Duncan SR, Smaldone GC, Dauber JH, Paradis IL, Ohori NP, Grgurich WF, Burckart GJ, Zeevi A, et al. Aerosolized cyclosporine in lung recipients with refractory chronic rejection. Am J Respir Crit Care Med 1996;153:1451–1455.[Abstract]
204. Snell GI, Esmore DS, Williams TJ. Cytolytic therapy for the bronchiolitis obliterans syndrome complicating lung transplantation. Chest 1996;109:874–878.[Abstract/Free Full Text]
205. Kesten S, Chaparro C, Scavuzzo M, Gutierrez C. Tacrolimus as rescue therapy for bronchiolitis obliterans syndrome. J Heart Lung Transplant 1997;16:905–912.[Medline]
206. Dusmet M, Maurer J, Winton T, Kesten S. Methotrexate can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996;15:948–954.[Medline]
207. O'Hagan AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999;115:1459–1462.[Abstract/Free Full Text]
208. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168:121–125.[Abstract/Free Full Text]
209. Kotloff RM. Lung retransplantation: all for one or one for all? Chest 2003;123:1781–1782.[Free Full Text]
210. Tamm M, Sharples LD, Higenbottam TW, Stewart S, Wallwork J. Bronchiolitis obliterans syndrome in heart–lung transplantation: surveillance biopsies. Am J Respir Crit Care Med 1997;155:1705–1710.[Abstract]
211. Swanson SJ, Mentzer SJ, Reilly JJ, Bueno R, Lukanich JM, Jaklitsch MT, Kobzik L, Ingenito EP, Fuhlbrigge A, Donovan C, et al. Surveillance transbronchial lung biopsies: implication for survival after lung transplantation. J Thorac Cardiovasc Surg 2000;119:27–37.[Abstract/Free Full Text]
212. Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003;167:1271–1278.[Abstract/Free Full Text]
213. Baron F, Beguin Y. Nonmyeloablative allogeneic hematopoietic stem cell transplantation. J Hematother Stem Cell Res 2002;11:243–263.[CrossRef][Medline]
214. Mielcarek M, Sandmaier BM, Maloney DG, Maris M, McSweeney PA, Woolfrey A, Chauncey T, Feinstein L, Niederwieser D, Blume KG, et al. Nonmyeloablative hematopoietic cell transplantation: status quo and future perspectives. J Clin Immunol 2002;22:70–74.[CrossRef][Medline]
215. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998;91:756–763.[Abstract/Free Full Text]
216. Champlin R, Khouri I, Komblau S, Molidrem J, Giralt S. Reinventing bone marrow transplantation: nonmyeloablative preparative regimens and induction of graft-vs-malignancy effect. Oncology 1999;13:621–628.[Medline]
217. Little MT, Storb R. History of haematopoietic stem-cell transplantation. Nat Rev Cancer 2002;2:231–238.[CrossRef][Medline]
218. Jantunen E, Myllykangas-Luosujarvi R. Stem cell transplantation for treatment of severe autoimmune diseases: current status and future perspectives. Bone Marrow Transplant 2000;25:351–356.[CrossRef][Medline]
219. Gratwohl A, Passweg J, Gerber I, Tyndall A. Stem cell transplantation for autoimmune diseases. Best Pract Res Clin Haematol 2001;14:755–776.[Medline]
220. Soubani AO, Miller KB, Hassoun PM. Pulmonary complications of bone marrow transplantation. Chest 1996;109:1066–1077.[Free Full Text]
221. Afessa B, Tefferi A, Hoagland HC, Letendre L, Peters SG. Outcome of recipients of bone marrow transplants who require intensive-care unit support. Mayo Clin Proc 1992;67:117–122.[Medline]
222. Matulis M, High KP. Immune reconstitution after hematopoietic stem-cell transplantation and its influence on respiratory infections. Semin Respir Infect 2002;17:130–139.[CrossRef][Medline]
223. Wick MR, Moore SB, Gastineau DA, Hoagland HC. Immunologic, clinical, and pathologic aspects of human graft-versus-host disease. Mayo Clin Proc 1983;58:603–612.[Medline]
224. Kantrow SP, Hackman RC, Boeckh M, Myerson D, Crawford SW. Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 1997;63:1079–1086.[Medline]
225. Hansen F. Hemopoietic growth and inhibitory factors in treatment of malignancies: a review. Acta Oncol 1995;34:453–468.[Medline]
226. Weisdorf DJ. Diffuse alveolar hemorrhage: an evolving problem? Leukemia 2003;17:1049–1050.[CrossRef][Medline]
227. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;27:893–898.[CrossRef][Medline]
228. Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME, Peters SG. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:641–645.[Free Full Text]
229. Clark JG, Crawford SW. Diagnostic approaches to pulmonary complications of marrow transplantation. Chest 1987;91:477–479.[Free Full Text]
230. Ghalie R, Szidon JP, Thompson L, Nawas YN, Dolce A, Kaizer H. Evaluation of pulmonary complications after bone marrow transplantation: the role of pretransplant pulmonary function tests. Bone Marrow Transplant 1992;10:359–365.[Medline]
231. Carlson K, Backlund L, Smedmyr B, Oberg G, Simonsson B. Pulmonary function and complications subsequent to autologous bone marrow transplantation. Bone Marrow Transplant 1994;14:805–811.[Medline]
232. Chien JW, Martin PJ, Gooley TA, Flowers ME, Heckbert SR, Nichols WG, Clark JG. Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003;168:208–214.[Abstract/Free Full Text]
233. Horak DA, Schmidt GM, Zaia JA, Niland JC, Ahn C, Forman SJ. Pretransplant pulmonary function predicts cytomegalovirus-associated interstitial pneumonia following bone marrow transplantation. Chest 1992;102:1484–1490.[Abstract/Free Full Text]
234. Crawford SW, Pepe M, Lin D, Benedetti F, Deeg HJ. Abnormalities of pulmonary function tests after marrow transplantation predict nonrelapse mortality. Am J Respir Crit Care Med 1995;152:690–695.[Abstract]
235. Crawford SW, Fisher L. Predictive value of pulmonary function tests before marrow transplantation. Chest 1992;101:1257–1264.[Abstract/Free Full Text]
236. Crawford SW. Using outcomes research to improve the management of blood and marrow transplant recipients in the intensive care unit. New Horiz 1998;6:69–74.[Medline]
237. Lossos IS, Breuer R, Or R, Strauss N, Elishoov H, Naparstek E, Aker M, Nagler A, Moses AE, Shapiro M, et al. Bacterial pneumonia in recipients of bone marrow transplantation: a five-year prospective study. Transplantation 1995;60:672–678.[Medline]
238. Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Chauncey T, McSweeney PA, Storb R. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 2002;8:512–520.[CrossRef][Medline]
239. Oren I, Zuckerman T, Avivi I, Finkelstein R, Yigla M, Rowe JM. Nosocomial outbreak of Legionella pneumophila serogroup 3 pneumonia in a new bone marrow transplant unit: evaluation, treatment and control. Bone Marrow Transplant 2002;30:175–179.[CrossRef][Medline]
240. Harrington RD, Woolfrey AE, Bowden R, McDowell MG, Hackman RC. Legionellosis in a bone marrow transplant center. Bone Marrow Transplant 1996;18:361–368.[Medline]
241. Heussel CP, Kauczor HU, Heussel G, Fischer B, Mildenberger P, Thelen M. Early detection of pneumonia in febrile neutropenic patients: use of thin-section CT. AJR Am J Roentgenol 1997;169:1347–1353.[Abstract/Free Full Text]
242. Sullivan KM, Dykewicz CA, Longworth DL, Boeckh M, Baden LR, Rubin RH, Sepkowitz KA. Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation practice guidelines and beyond. Hematology (Am Soc Hematol Educ Program) 2001:392–421.
243. Roy V, Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant 1997;19:467–470.[CrossRef][Medline]
244. de la Camara R, Martino R, Granados E, Rodriguez-Salvanes FJ, Rovira M, Cabrera R, Lopez J, Parody R, Sierra J, Fernandez-Ranada JM, et al., Spanish Group on Infectious Complications in Hematopoietic Transplantation. Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Bone Marrow Transplant 2000;26:291–298.[CrossRef][Medline]
245. Ip MS, Yuen KY, Woo PC, Luk WK, Tsang KW, Lam WK, Liang RH. Risk factors for pulmonary tuberculosis in bone marrow transplant recipients. Am J Respir Crit Care Med 1998;158:1173–1177.[Abstract/Free Full Text]
246. Gaviria JM, Garcia PJ, Garrido SM, Corey L, Boeckh M. Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: characteristics of respiratory and catheter-related infections. Biol Blood Marrow Transplant 2000;6:361–369.[CrossRef][Medline]
247. Weinstock DM, Feinstein MB, Sepkowitz KA, Jakubowski A. High rates of infection and colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;31:1015–1021.[CrossRef][Medline]
248. Boeckh M. Current antiviral strategies for controlling cytomegalovirus in hematopoietic stem cell transplant recipients: prevention and therapy. Transpl Infect Dis 1999;1:165–178.[CrossRef][Medline]
249. Konoplev S, Champlin RE, Giralt S, Ueno NT, Khouri I, Raad I, Rolston K, Jacobson K, Tarrand J, Luna M, et al. Cytomegalovirus pneumonia in adult autologous blood and marrow transplant recipients. Bone Marrow Transplant 2001;27:877–881.[CrossRef][Medline]
250. Machado CM, Dulley FL, Boas LS, Castelli JB, Macedo MC, Silva RL, Pallota R, Saboya RS, Pannuti CS. CMV pneumonia in allogeneic BMT recipients undergoing early treatment of pre-emptive ganciclovir therapy. Bone Marrow Transplant 2000;26:413–417.[CrossRef][Medline]
251. Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, Finke J, Cordonnier C, Link H, Ljungman P. Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood 2002;99:1159–1164.[Abstract/Free Full Text]
252. Kanda Y, Mineishi S, Saito T, Seo S, Saito A, Suenaga K, Ohnishi M, Niiya H, Nakai K, Takeuchi T, et al. Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan. Bone Marrow Transplant 2001;27:437–444.[CrossRef][Medline]
253. Vij R, Khoury H, Brown R, Goodnough LT, Devine SM, Blum W, Adkins D, DiPersio JF. Low-dose short-course intravenous ganciclovir as pre-emptive therapy for CMV viremia post allo-PBSC transplantation. Bone Marrow Transplant 2003;32:703–707.[CrossRef][Medline]
254. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996;88:4063–4071.[Abstract/Free Full Text]
255. Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995;333:1038–1044.[Abstract/Free Full Text]
256. Nguyen Q, Champlin R, Giralt S, Rolston K, Raad I, Jacobson K, Ippoliti C, Hecht D, Tarrand J, Luna M, et al. Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis 1999;28:618–623.[Medline]
257. Schmidt GM, Horak DA, Niland JC, Duncan SR, Forman SJ, Zaia JA, City of Hope-Stanford-Syntex CMV Study Group. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. N Engl J Med 1991;324:1005–1011.[Abstract]
258. Ruutu P, Ruutu T, Volin L, Tukiainen P, Ukkonen P, Hovi T. Cytomegalovirus is frequently isolated in bronchoalveolar lavage fluid of bone marrow transplant recipients without pneumonia. Ann Intern Med 1990;112:913–916.
259. Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med 1988;109:783–788.
260. Emanuel D, Cunningham I, Jules-Elysee K, Brochstein JA, Kernan NA, Laver J, Stover D, White DA, Fels A, Polsky B, et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med 1988;109:777–782.
261. Schmidt GM, Kovacs A, Zaia JA, Horak DA, Blume KG, Nademanee AP, O'Donnell MR, Snyder DS, Forman SJ. Ganciclovir/immunoglobulin combination therapy for the treatment of human cytomegalovirus-associated interstitial pneumonia in bone marrow allograft recipients. Transplantation 1988;46:905–907.[Medline]
262. Enright H, Haake R, Weisdorf D, Ramsay N, McGlave P, Kersey J, Thomas W, McKenzie D, Miller W. Cytomegalovirus pneumonia after bone marrow transplantation: risk factors and response to therapy. Transplantation 1993;55:1339–1346.[Medline]
263. Bowden RA. Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med 1997;102:27–30.[CrossRef][Medline]
264. Whimbey E, Champlin RE, Couch RB, Englund JA, Goodrich JM, Raad I, Przepiorka D, Lewis VA, Mirza N, Yousuf H, et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996;22:778–782.[Medline]
265. Harrington RD, Hooton TM, Hackman RC, Storch GA, Osborne B, Gleaves CA, Benson A, Meyers JD. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis 1992;165:987–993.[Medline]
266. Hertz MI, Englund JA, Snover D, Bitterman PB, McGlave PB. Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine (Baltimore) 1989;68:269–281.[Medline]
267. Wendt CH, Weisdorf DJ, Jordan MC, Balfour HH Jr, Hertz MI. Parainfluenza virus respiratory infection after bone marrow transplantation. N Engl J Med 1992;326:921–926.[Abstract]
268. Ghosh S, Champlin RE, Englund J, Giralt SA, Rolston K, Raad I, Jacobson K, Neumann J, Ippoliti C, Mallik S, et al. Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplant 2000;25:751–755.[CrossRef][Medline]
269. Whimbey E, Champlin RE, Englund JA, Mirza NQ, Piedra PA, Goodrich JM, Przepiorka D, Luna MA, Morice RC, Neumann JL, et al. Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant 1995;16:393–399.[Medline]
270. Ghosh S, Champlin RE, Ueno NT, Anderlini P, Rolston K, Raad I, Kontoyiannis D, Jacobson K, Luna M, Tarrand J, et al. Respiratory syncytial virus infections in autologous blood and marrow transplant recipients with breast cancer: combination therapy with aerosolized ribavirin and parenteral immunoglobulins. Bone Marrow Transplant 2001;28:271–275.[CrossRef][Medline]
271. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, Rode A, Kinnersley N, Ward P, Neuraminidase Inhibitor Flu Treatment Investigator Group. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 2000;355:1845–1850.[CrossRef][Medline]
272. Cone RW, Hackman RC, Huang ML, Bowden RA, Meyers JD, Metcalf M, Zeh J, Ashley R, Corey L. Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation. N Engl J Med 1993;329:156–161.[Abstract/Free Full Text]
273. Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD. Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med 1985;312:529–533.[Abstract]
274. Ljungman P, Ribaud P, Eyrich M, Matthes-Martin S, Einsele H, Bleakley M, Machaczka M, Bierings M, Bosi A, Gratecos N, et al. Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2003;31:481–486.[CrossRef][Medline]
275. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997;175:1459–1466.[Medline]
276. Grow WB, Moreb JS, Roque D, Manion K, Leather H, Reddy V, Khan SA, Finiewicz KJ, Nguyen H, Clancy CJ, et al. Late onset of invasive Aspergillus infection in bone marrow transplant patients at a university hospital. Bone Marrow Transplant 2002;29:15–19.[CrossRef][Medline]
277. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002;100:4358–4366.[Abstract/Free Full Text]
278. Jantunen E, Ruutu P, Niskanen L, Volin L, Parkkali T, Koukila-Kahkola P, Ruutu T. Incidence and risk factors for invasive fungal infections in allogeneic BMT recipients. Bone Marrow Transplant 1997;19:801–808.[CrossRef][Medline]
279. Jantunen E, Piilonen A, Volin L, Parkkali T, Koukila-Kahkola P, Ruutu T, Ruutu P. Diagnostic aspects of invasive Aspergillus infections in allogeneic BMT recipients. Bone Marrow Transplant 2000;25:867–871.[CrossRef][Medline]
280. Kim MJ, Lee KS, Kim J, Jung KJ, Lee HG, Kim TS. Crescent sign in invasive pulmonary aspergillosis: frequency and related CT and clinical factors. J Comput Assist Tomogr 2001;25:305–310.[CrossRef][Medline]
281. Caillot D, Casasnovas O, Bernard A, Couaillier JF, Durand C, Cuisenier B, Solary E, Piard F, Petrella T, Bonnin A, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997;15:139–147.[Abstract/Free Full Text]
282. Denning DW. Early diagnosis of invasive aspergillosis. Lancet 2000;355:423–424.[Medline]
283. Reichenberger F, Habicht J, Kaim A, Dalquen P, Bernet F, Schlapfer R, Stulz P, Perruchoud AP, Tichelli A, Gratwohl A, et al. Lung resection for invasive pulmonary aspergillosis in neutropenic patients with hematologic diseases. Am J Respir Crit Care Med 1998;158:885–890.[Abstract/Free Full Text]
284. Crawford SW, Hackman RC, Clark JG. Biopsy diagnosis and clinical outcome of persistent focal pulmonary lesions after marrow transplantation. Transplantation 1989;48:266–271.[Medline]
285. Jantunen E, Piilonen A, Volin L, Ruutu P, Parkkali T, Koukila-Kahkola P, Ruutu T. Radiologically guided fine needle lung biopsies in the evaluation of focal pulmonary lesions in allogeneic stem cell transplant recipients. Bone Marrow Transplant 2002;29:353–356.[CrossRef][Medline]
286. Maertens J, Verhaegen J, Lagrou K, Van Eldere J, Boogaerts M. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 2001;97:1604–1610.[Abstract/Free Full Text]
287. Ribaud P, Chastang C, Latge JP, Baffroy-Lafitte L, Parquet N, Devergie A, Esperou H, Selimi F, Rocha V, Derouin F, et al. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis 1999;28:322–330.[Medline]
288. Jantunen E, Ruutu P, Piilonen A, Volin L, Parkkali T, Ruutu T. Treatment and outcome of invasive Aspergillus infections in allogeneic BMT recipients. Bone Marrow Transplant 2000;26:759–762.[CrossRef][Medline]
289. White MH, Anaissie EJ, Kusne S, Wingard JR, Hiemenz JW, Cantor A, Gurwith M, Du Mond C, Mamelok RD, Bowden RA. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis 1997;24:635–642.[Medline]
290. Pacetti SA, Gelone SP. Caspofungin acetate for treatment of invasive fungal infections. Ann Pharmacother 2003;37:90–98.[Abstract/Free Full Text]
291. Albelda SM, Talbot GH, Gerson SL, Miller WT, Cassileth PA. Pulmonary cavitation and massive hemoptysis in invasive pulmonary aspergillosis: influence of bone marrow recovery in patients with acute leukemia. Am Rev Respir Dis 1985;131:115–120.[Medline]
292. Meyers JD, Pifer LL, Sale GE, Thomas ED. The value of Pneumocystis carinii antibody and antigen detection for diagnosis of Pneumocystis carinii pneumonia after marrow transplantation. Am Rev Respir Dis 1979;120:1283–1287.[Medline]
293. Souza JP, Boeckh M, Gooley TA, Flowers ME, Crawford SW. High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis. Clin Infect Dis 1999;29:1467–1471.[CrossRef][Medline]
294. Marras TK, Sanders K, Lipton JH, Messner HA, Conly J, Chan CK. Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation. Transpl Infect Dis 2002;4:66–74.[CrossRef][Medline]
295. Vasconcelles MJ, Bernardo MV, King C, Weller EA, Antin JH. Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections. Biol Blood Marrow Transplant 2000;6:35–43.[CrossRef][Medline]
296. Colby C, McAfee S, Sackstein R, Finkelstein D, Fishman J, Spitzer T. A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1999;24:897–902.[CrossRef][Medline]
297. Dykewicz CA. Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients. Clin Infect Dis 2001;33:139–144.[CrossRef][Medline]
298. Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Transplant 1992;10:267–272.[Medline]
299. Jahagirdar BN, Morrison VA. Emerging fungal pathogens in patients with hematologic malignancies and marrow/stem-cell transplant recipients. Semin Respir Infect 2002;17:113–120.[CrossRef][Medline]
300. Maertens J, Demuynck H, Verbeken EK, Zachee P, Verhoef GE, Vandenberghe P, Boogaerts MA. Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant 1999;24:307–312.[CrossRef][Medline]
301. Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;28:425–434.[CrossRef][Medline]
302. Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L, Peavy HH. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 1993;147:1601–1606.[Medline]
303. Fukuda T, Hackman RC, Guthrie KA, Sandmaier BM, Boeckh M, Maris MB, Maloney DG, Deeg HJ, Martin PJ, Storb RF, et al. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative compared to conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood 2003;102:2777–2785.[Abstract/Free Full Text]
304. Bhalla KS, Folz RJ. Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice. Am J Respir Crit Care Med 2002;166:1579–1589.[Abstract/Free Full Text]
305. Panoskaltsis-Mortari A, Strieter RM, Hermanson JR, Fegeding KV, Murphy WJ, Farrell CL, Lacey DL, Blazar BR. Induction of monocyte- and T-cell–attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation. Blood 2000;96:834–839.[Abstract/Free Full Text]
306. Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte J Jr, Crawford JM, Ferrara JL. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation. I. The roles of minor H antigens and endotoxin. Blood 1996;88:3230–3239.[Abstract/Free Full Text]
307. Cooke KR, Hill GR, Gerbitz A, Kobzik L, Martin TR, Crawford JM, Brewer JP, Ferrara JL. Tumor necrosis factor-alpha neutralization reduces lung injury after experimental allogeneic bone marrow transplantation. Transplantation 2000;70:272–279.[Medline]
308. Cooke KR, Krenger W, Hill G, Martin TR, Kobzik L, Brewer J, Simmons R, Crawford JM, van den Brink MR, Ferrara JL. Host reactive donor T cells are associated with lung injury after experimental allogeneic bone marrow transplantation. Blood 1998;92:2571–2580.[Abstract/Free Full Text]
309. Panoskaltsis-Mortari A, Taylor PA, Yaeger TM, Wangensteen OD, Bitterman PB, Ingbar DH, Vallera DA, Blazar BR. The critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients are due to donor T cell infusion and potentiated by cyclophosphamide. J Clin Invest 1997;100:1015–1027.[Medline]
310. Yanik G, Hellerstedt B, Custer J, Hutchinson R, Kwon D, Ferrara JL, Uberti J, Cooke KR. Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2002;8:395–400.[CrossRef][Medline]
311. Robbins RA, Linder J, Stahl MG, Thompson AB III, Haire W, Kessinger A, Armitage JO, Arneson M, Woods G, Vaughan WP, et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med 1989;87:511–518.[Medline]
312. Agusti C, Ramirez J, Picado C, Xaubet A, Carreras E, Ballester E, Torres A, Battochia C, Rodriguez-Roisin R. Diffuse alveolar hemorrhage in allogeneic bone marrow transplantation: a postmortem study. Am J Respir Crit Care Med 1995;151:1006–1010.[Abstract]
313. Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:1364–1368.[Abstract/Free Full Text]
314. Chao NJ, Duncan SR, Long GD, Horning SJ, Blume KG. Corticosteroid therapy for diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Ann Intern Med 1991;114:145–146.
315. Metcalf JP, Rennard SI, Reed EC, Haire WD, Sisson JH, Walter T, Robbins RA, University of Nebraska Medical Center Bone Marrow Transplant Group. Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. Am J Med 1994;96:327–334.[CrossRef][Medline]
316. Raptis A, Mavroudis D, Suffredini A, Molldrem J, Rhee FV, Childs R, Phang S, Barrett A. High-dose corticosteroid therapy for diffuse alveolar hemorrhage in allogeneic bone marrow stem cell transplant recipients. Bone Marrow Transplant 1999;24:879–883.[CrossRef][Medline]
317. Maiolino A, Biasoli I, Lima J, Portugal AC, Pulcheri W, Nucci M. Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant 2003;31:393–397.[CrossRef][Medline]
318. Lee CK, Gingrich RD, Hohl RJ, Ajram KA. Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. Bone Marrow Transplant 1995;16:175–182.[Medline]
319. Marin D, Berrade J, Ferra C, Mateu A, Berlanga J, Salar A, Torrado H, Granena A, Ventura JL. Engraftment syndrome and survival after respiratory failure post-bone marrow transplantation. Intensive Care Med 1998;24:732–735.[CrossRef][Medline]
320. Capizzi SA, Kumar S, Huneke NE, Gertz MA, Inwards DJ, Litzow MR, Lacy MQ, Gastineau DA, Prakash UB, Tefferi A. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;27:1299–1303.[CrossRef][Medline]
321. Todd NW, Peters WP, Ost AH, Roggli VL, Piantadosi CA. Pulmonary drug toxicity in patients with primary breast cancer treated with high-dose combination chemotherapy and autologous bone marrow transplantation. Am Rev Respir Dis 1993;147:1264–1270.[Medline]
322. Wilczynski SW, Erasmus JJ, Petros WP, Vredenburgh JJ, Folz RJ. Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med 1998;157:565–573.
323. Bhalla KS, Wilczynski SW, Abushamaa AM, Petros WP, McDonald CS, Loftis JS, Chao NJ, Vredenburgh JJ, Folz RJ. Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support. Am J Respir Crit Care Med 2000;161:17–25.[Abstract/Free Full Text]
324. Clark JG, Crawford SW, Madtes DK, Sullivan KM. Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course. Ann Intern Med 1989;111:368–376.
325. Curtis DJ, Smale A, Thien F, Schwarer AP, Szer J. Chronic airflow obstruction in long-term survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant 1995;16:169–173.[Medline]
326. Chan CK, Hyland RH, Hutcheon MA, Minden MD, Alexander MA, Kossakowska AE, Urbanski SJ, Fyles GM, Fraser IM, Curtis JE, et al. Small-airways disease in recipients of allogeneic bone marrow transplants: an analysis of 11 cases and a review of the literature. Medicine (Baltimore) 1987;66:327–340.[Medline]
327. Paz HL, Crilley P, Patchefsky A, Schiffman RL, Brodsky I. Bronchiolitis obliterans after autologous bone marrow transplantation. Chest 1992;101:775–778.[Abstract/Free Full Text]
328. Holland HK, Wingard JR, Beschorner WE, Saral R, Santos GW. Bronchiolitis obliterans in bone marrow transplantation and its relationship to chronic graft-v-host disease and low serum IgG. Blood 1988;72:621–627.[Abstract/Free Full Text]
329. Sanchez J, Torres A, Serrano J, Roman J, Martin C, Perula L, Martinez F, Gomez P. Long-term follow-up of immunosuppressive treatment for obstructive airways disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1997;20:403–408.[CrossRef][Medline]
330. Rabitsch W, Deviatko E, Keil F, Herold C, Dekan G, Greinix HT, Lechner K, Klepetko W, Kalhs P. Successful lung transplantation for bronchiolitis obliterans after allogeneic marrow transplantation. Transplantation 2001;71:1341–1343.[Medline]
331. Williams LM, Fussell S, Veith RW, Nelson S, Mason CM. Pulmonary veno-occlusive disease in an adult following bone marrow transplantation: case report and review of the literature. Chest 1996;109:1388–1391.[Abstract/Free Full Text]
332. Hackman RC, Madtes DK, Petersen FB, Clark JG. Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation 1989;47:989–992.[Medline]
333. Troussard X, Bernaudin JF, Cordonnier C, Fleury J, Payen D, Briere J, Vernant JP. Pulmonary veno-occlusive disease after bone marrow transplantation. Thorax 1984;39:956–957.[Free Full Text]
334. Salzman D, Adkins DR, Craig F, Freytes C, LeMaistre CF. Malignancy-associated pulmonary veno-occlusive disease: report of a case following autologous bone marrow transplantation and review. Bone Marrow Transplant 1996;18:755–760.[Medline]
335. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med 2000;162:1964–1973.[Free Full Text]
336. Doll DC, Yarbro JW. Vascular toxicity associated with antineoplastic agents. Semin Oncol 1992;19:580–596.[Medline]
337. Curtis RE, Travis LB, Rowlings PA, Socie G, Kingma DW, Banks PM, Jaffe ES, Sale GE, Horowitz MM, Witherspoon RP, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 1999;94:2208–2216.[Abstract/Free Full Text]
338. Benkerrou M, Jais JP, Leblond V, Durandy A, Sutton L, Bordigoni P, Garnier JL, Le Bidois J, Le Deist F, Blanche S, et al. Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome. Blood 1998;92:3137–3147.[Abstract/Free Full Text]
339. Stevens SJ, Verschuuren EA, Verkuujlen SA, Van Den Brule AJ, Meijer CJ, Middeldorp JM. Role of Epstein–Barr virus DNA load monitoring in prevention and early detection of post-transplant lymphoproliferative disease. Leuk Lymphoma 2002;43:831–840.[CrossRef][Medline]
340. Gottschalk S, Heslop HE, Roon CM. Treatment of Epstein–Barr virus-associated malignancies with specific T cells. Adv Cancer Res 2002;84:175–201.[Medline]
341. Crawford SW, Petersen FB. Long-term survival from respiratory failure after marrow transplantation for malignancy. Am Rev Respir Dis 1992;145:510–514.[Medline]
342. Paz HL, Crilley P, Weinar M, Brodsky I. Outcome of patients requiring medical ICU admission following bone marrow transplantation. Chest 1993;104:527–531.[Abstract/Free Full Text]
343. Faber-Langendoen K, Caplan AL, McGlave PB. Survival of adult bone marrow transplant patients receiving mechanical ventilation: a case for restricted use. Bone Marrow Transplant 1993;12:501–507.[Medline]
344. Huaringa AJ, Leyva FJ, Giralt SA, Blanco J, Signes-Costa J, Velarde H, Champlin RE. Outcome of bone marrow transplantation patients requiring mechanical ventilation. Crit Care Med 2000;28:1014–1017.[CrossRef][Medline]
345. Price KJ, Thall PF, Kish SK, Shannon VR, Andersson BS. Prognostic indicators for blood and marrow transplant patients admitted to an intensive care unit. Am J Respir Crit Care Med 1998;158:876–884.[Abstract/Free Full Text]
346. Rubenfeld GD, Crawford SW. Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: a case for evidence-based guidelines. Ann Intern Med 1996;125:625–633.[Abstract/Free Full Text]
347. Shorr AF, Moores LK, Edenfield WJ, Christie RJ, Fitzpatrick TM. Mechanical ventilation in hematopoietic stem cell transplantation: can we effectively predict outcomes? Chest 1999;116:1012–1018.[Abstract/Free Full Text]
348. Khassawneh BY, White P Jr, Anaissie EJ, Barlogie B, Hiller FC. Outcome from mechanical ventilation after autologous peripheral blood stem cell transplantation. Chest 2002;121:185–188.[Abstract/Free Full Text]
349. Hilbert G, Gruson D, Vargas F, Valentino R, Gbikpi-Benissan G, Dupon M, Reiffers J, Cardinaud JP. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med 2001;344:481–487.[Abstract/Free Full Text]
350. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998;338:1813–1821.[Free Full Text]
351. Guinan EC, Boussiotis VA, Neuberg D, Brennan LL, Hirano N, Nadler LM, Gribben JG. Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med 1999;340:1704–1714.[Abstract/Free Full Text]

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				O.S. Zmeili and A.O. Soubani Pulmonary aspergillosis: a clinical update QJM, June 1, 2007; 100(6): 317 - 334. [Abstract] [Full Text] [PDF]

				M. N. Ballinger, D. M. Aronoff, T. R. McMillan, K. R. Cooke, K. Olkiewicz, G. B. Toews, M. Peters-Golden, and B. B. Moore Critical Role of Prostaglandin E2 Overproduction in Impaired Pulmonary Host Response following Bone Marrow Transplantation J. Immunol., October 15, 2006; 177(8): 5499 - 5508. [Abstract] [Full Text] [PDF]

				T. Franquet, S. Rodriguez, R. Martino, A. Gimenez, T. Salinas, and A. Hidalgo Thin-Section CT Findings in Hematopoietic Stem Cell Transplantation Recipients with Respiratory Virus Pneumonia Am. J. Roentgenol., October 1, 2006; 187(4): 1085 - 1090. [Abstract] [Full Text] [PDF]

				M. D. Duncan and D. S. Wilkes Transplant-related Immunosuppression: A Review of Immunosuppression and Pulmonary Infections Proceedings of the ATS, December 1, 2005; 2(5): 449 - 455. [Abstract] [Full Text] [PDF]

				J. F. Aduen, W. C. Hellinger, D. J. Kramer, W. H. Stapelfeldt, H. Bonatti, J. E. Crook, J. L. Steers, and C. D. Burger Spectrum of Pneumonia in the Current Era of Liver Transplantation and Its Effect on Survival Mayo Clin. Proc., October 1, 2005; 80(10): 1303 - 1306. [Abstract] [PDF]

				S. Sharma, H. F. Nadrous, S. G. Peters, A. Tefferi, M. R. Litzow, M.-C. Aubry, and B. Afessa Pulmonary Complications in Adult Blood and Marrow Transplant Recipients: Autopsy Findings Chest, September 1, 2005; 128(3): 1385 - 1392. [Abstract] [Full Text] [PDF]

				D. L. Escuissato, E. L. Gasparetto, E. Marchiori, G. de Melo Rocha, C. Inoue, R. Pasquini, and N. L. Muller Pulmonary Infections After Bone Marrow Transplantation: High-Resolution CT Findings in 111 Patients Am. J. Roentgenol., September 1, 2005; 185(3): 608 - 615. [Abstract] [Full Text] [PDF]

				J. J. Fullmer, L. L. Fan, M. K. Dishop, C. Rodgers, and R. Krance Successful Treatment of Bronchiolitis Obliterans in a Bone Marrow Transplant Patient With Tumor Necrosis Factor-{alpha} Blockade Pediatrics, September 1, 2005; 116(3): 767 - 770. [Abstract] [Full Text] [PDF]

				T. D. Bradley, Y. E. Miller, F. J. Martinez, D. C. Angus, W. MacNee, and E. Abraham Interstitial Lung Disease, Lung Cancer, Lung Transplantation, Pulmonary Vascular Disorders, and Sleep-disordered Breathing in AJRCCM in 2004 Am. J. Respir. Crit. Care Med., April 1, 2005; 171(7): 675 - 685. [Full Text] [PDF]

				D. D. Benoit, E. A. Hoste, P. O. Depuydt, F. C. Offner, N. H. Lameire, K. H. Vandewoude, A. W. Dhondt, L. A. Noens, and J. M. Decruyenaere Outcome in critically ill medical patients treated with renal replacement therapy for acute renal failure: comparison between patients with and those without haematological malignancies Nephrol. Dial. Transplant., March 1, 2005; 20(3): 552 - 558. [Abstract] [Full Text] [PDF]

				T. Franquet, N. L. Muller, K. S. Lee, A. Gimenez, and J. D. Flint High-Resolution CT and Pathologic Findings of Noninfectious Pulmonary Complications After Hematopoietic Stem Cell Transplantation Am. J. Roentgenol., February 1, 2005; 184(2): 629 - 637. [Full Text] [PDF]

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