Stem cell transplantation (SCT) is the only known curative treatment for many patients with life-threatening hematologic and solid tumor malignancies. Likewise, solid organ transplantation (SOT) provides life-saving treatment for many patients with end-stage organ disease. Approximately 20,000 SCT and 28,000 SOT procedures are performed each year in the United States. These patients are at constant risk for opportunistic infections, drug-related pulmonary toxicities, and malignancies due to their chronic state of immune suppression. The aim of this chapter is to review the infectious and noninfectious pulmonary complications of stem cell and solid organ transplantation with a focus on the diagnostic and therapeutic challenges presented by these patients.
Despite effective prophylaxis strategies, infections in the lower respiratory tract remain a common life-threatening complication. The risk of infection is primarily determined by epidemiologic exposures of the donor and recipient and “the net state of immune suppression.” The spectrum of microorganisms responsible for posttransplantation infections is similar among SCT and SOT recipients, and the infections follow a fairly characteristic pattern. Figures 91-1 and 91-2 show timelines for the pulmonary complications, both infectious and noninfectious, following SCT and SOT, respectively.
The first phase of infection risk is considered the first month after transplant. For SCT recipients, infectious risks in the first month are due to neutropenia and immune suppression related to the development of acute graft-versus-host disease (GVHD) and its treatment. Conventional nosocomial infections with gram-positive and gram-negative bacteria, as well herpes simplex virus (HSV) and Candida species, predominate. For SOT recipients, during the first month posttransplantation, infectious risks are predominantly related to surgery and intensive care, along with the initiation of immunosuppressive therapy.
The second phase of infection risk extends from 1 to 6 months during the period of maximum immunosuppression prescribed to treat GVHD in SCT patients or to avoid acute allograft rejection in SOT recipients. This interval is characterized by the emergence of opportunistic pathogens. The third phase of infection risk is after 6 months when immunosuppressive therapy can be decreased in the majority of patients. Infections during this phase are predominantly due to community-acquired organisms and, to a lesser extent, opportunistic pathogens.
Previously common pathogens such as Pneumocystis jirovecii (PCP) and cytomegalovirus (CMV) are now less common due to routine use of antimicrobial prophylaxis. However, prophylactic antimicrobials and nosocomial exposures have contributed to the emergence of antimicrobial-resistant pathogens such as Stenotrophomonas species, mucormycosis, and ganciclovir-resistant CMV. In addition, improved microbiologic diagnostic techniques have allowed the recognition of previously undiagnosed infections.
The lung is the leading site of infection in lung and heart transplant recipients and is the second most common site in liver transplant recipients. In a retrospective, multicenter study of 236 lung transplant recipients, pneumonia was reported in 25.8% of recipients. The microbiologic etiology was established in 57 (67%) of the cases. Of the microbiologically proven cases, 82.7% were bacterial, 14% were fungal, and 10.3% were due to viruses.
Given the broad spectrum of pathogens that cause pneumonia in transplant recipients and the potential for complications from empiric antibiotics, it is important to identify the causative organisms whenever possible. Bronchoscopy is the procedure of choice in most transplant recipients. The diagnostic yield of bronchoscopy in SCT recipients is reported to range from 42% to 65% and is highest when performed before the initiation of antimicrobials and within 24 hours of presentation. Likewise, in SOT recipients, the diagnostic yield of bronchoscopy ranges from 30% to 72% and is highest when performed for pulmonary opacities within the first 6 months of transplantation. The recommended laboratory evaluation of bronchoscopic specimens for specific pathogens in the lower respiratory tract of transplant recipients is listed in eTable 91-1 .
Bacterial pneumonia after transplantation can be either nosocomial or community acquired with each mode having a characteristic time of onset, causative organisms, and outcome. Bacterial pneumonia develops in 21% to 38% of lung transplant, 5% to 34% of liver transplant, 11% to 19% of heart transplant, and 4% to 7% of renal transplant recipients. The most frequently documented bacterial pathogens in lower respiratory tract infections (LRTI) after SOT are gram-negative organisms, including Pseudomonas ( eFig. 91-1 ), Klebsiella, Escherichia, Legionella, Acinetobacter, and Stenotrophomonas, as well as gram-positive bacteria such as Staphylococcus, Corynebacterium, and Enterococcus. Anaerobic infections are rare.
Although the precise incidence of bacterial pneumonia after SCT is difficult to ascertain due to the frequent use of empiric broad-spectrum antibiotics in the early posttransplant period, bacterial pneumonia has been reported in 7% to 11% of allogeneic and 5% to 15% of autologous SCT recipients. The most common bacterial pathogens include Escherichia, Pseudomonas, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae . Late-onset bacterial pneumonia, defined as beyond day 100 posttransplant, is frequently due to K. pneumoniae, Pseudomonas, S. pneumoniae , and Staphylococcus species.
The prevalence of active tuberculosis following SCT has been estimated to be 0.23% to 0.79%, whereas the prevalence ranges 0.5% to 15% for SOT recipients depending on the prevalence of tuberculosis in the general population. The median time to tuberculosis onset is 9 months (range, 0.5 to 13 months), although the disease can arise as late as 2 years after transplantation. First-line antituberculosis therapy in transplant recipients generally includes isoniazid, pyrazinamide, and ethambutol. Rifampin is generally avoided due to its ability to induce cytochrome P450 isoenzymes resulting in decreased serum concentrations of several immunosuppressants, including cyclosporine, tacrolimus, sirolimus, everolimus, and mycophenolate mofetil, which could result in allograft rejection. Interactions between common antimicrobial agents and immunosuppressants used in transplantation patients are listed in eTable 91-2 .
|Immunosuppressant||Antimicrobial Agent||Effect on Immunosuppressant||Reference|
|Ketoconazole||↑ Concentrations, 3×|
|Itraconazole||↑ Concentrations, 2×|
|Voriconazole||↑ Concentrations, 1.7×|
|Posaconazole||↑ Concentrations, 2×|
|Voriconazole||↑ Concentrations, 3×|
|Posaconazole||↑ Concentrations, 4.5×|
|Sirolimus||Erythromycin||↑ Concentrations, 5×|
|Voriconazole||↑ Concentrations, 11×|
|Everolimus||Erythromycin||↓ Clearance, ≈20%|
|Voriconazole||↑ Concentrations, 7.5×|
|Posaconazole||↑ Concentrations, 3.8×|
|Mycophenolate mofetil||Amoxicillin-clavulanate||↓ Concentrations|
SCT and SOT recipients are vulnerable to two categories of viral infections: opportunistic viruses, especially herpesviruses, and community-acquired respiratory viruses. Opportunistic viruses responsible for pulmonary disease posttransplantation include CMV, HSV, varicella zoster virus (VZV), and Epstein-Barr virus (EBV). In the era of early detection and prophylactic or preemptive treatment, the incidence of CMV pneumonia is 4% to 32% for lung ( eFigs. 91-2 and 91-3 ), 0% to 9.2% for liver, 0.8% to 6.6% for heart, and less than 1% for kidney ( eFig. 91-4 ) transplant recipients. The incidence rate of CMV pneumonia after SCT ( eFig. 91-5 ) is 2% to 6%. CMV infection traditionally develops within the first 3 months after SCT and SOT; however, the use of antiviral prophylaxis has delayed its onset until after prophylaxis has been discontinued.
Current guidelines for diagnosis and management of CMV in SCT and SOT recipients support the use of either detection of pp65 antigen via immunoassay or quantitative polymerase chain reaction (PCR) for the recognition of CMV infection in serum or bronchoalveolar lavage (BAL). There are two accepted strategies for the prevention of CMV disease in transplant recipients: (1) universal prophylaxis in which antivirals are administered to all posttransplantation patients at risk and (2) preemptive therapy in which at-risk patients are monitored for viral replication and antivirals are initiated at a predetermined level of virus replication. Intravenous (IV) ganciclovir is recommended for the treatment of severe CMV disease, whereas oral valganciclovir is an alternative in less severe cases.
HSV disease develops in 35% to 68% of transplant recipients not receiving prophylaxis. HSV most commonly reactivates during the first month posttransplantation. For this reason, it is recommended that all HSV-seropositive transplant recipients receive at least 4 weeks of antiviral prophylaxis after transplantation, usually with acyclovir. The clinical picture of HSV pneumonitis in posttransplant patients ranges from dyspnea with normal radiographic findings to failure to wean and acute respiratory distress syndrome (ARDS). Direct fluorescent antibody testing or real time PCR assay of BAL or other samples provides a rapid diagnosis. HSV pneumonia should be treated with IV acyclovir, 10 mg/kg every 8 hours, and, if the HSV disease is life-threatening, a reduction in immunosuppression should be considered. Foscarnet is recommended for the treatment of acyclovir-resistant HSV, although this is an infrequent problem in transplant patients.
VZV has been reported as a rare and usually late cause of pneumonia in transplant recipients typically presenting with a vesicular rash that precedes respiratory symptoms. IV acyclovir 10 mg/kg IV every 8 hours is the treatment of choice.
Community-acquired respiratory viruses (CARVs) are a common cause of infection after SCT and SOT. CARVs include respiratory syncytial virus (RSV), influenza, metapneumovirus (MPV) and parainfluenza serotypes 1 and 2, which have their peak primarily in the winter months, and parainfluenza serotype 3 and adenovirus, which are present year round. Risk factors for progression of upper respiratory tract CARV infection to pneumonia in SCT recipients include infection early after transplantation, allogeneic SCT, myeloablative conditioning, GVHD, and lymphopenia. Risk factors for progression to pneumonia in SOT recipients have not been as well defined; however, the most-immunosuppressed recipients appear to be at greatest risk of severe disease and poor outcome. CARV infections in transplantation recipients are often characterized by prolonged viral shedding and can be complicated by coinfection with other viral, bacterial, or fungal pathogens. In addition to the direct effects, CARV infections can have indirect effects that include an increased risk of acute and chronic rejection such as bronchiolitis obliterans after lung transplantation and concurrent allograft rejection in non-lung SOT recipients.
Respiratory Syncytial Virus
The incidence of RSV infection after SCT is 1% to 12% with 17% to 70% of infections involving the lower respiratory tract. Mortality rates range from 7% to 33% in the setting of pneumonia. The incidence of RSV in lung transplant recipients is 5% to 12% with a 10% to 15% mortality rate, while the incidence in liver transplant recipients is 4%. RSV disease can range from a mild upper respiratory tract infection to life-threatening pneumonia. The most sensitive method for diagnosing RSV infection in symptomatic patients is by reverse transcriptase (RT)-PCR assay of nasal wash or BAL. Ribavirin (orally or IV ± inhaled ribavirin) is approved for treatment of RSV pneumonitis in SCT recipients and may be combined with IV immunoglobulin or IV palivizumab, a humanized monoclonal antibody against RSV used for prophylaxis. Although there is no controlled study of ribavirin therapy in SOT recipients, inhaled ribavirin is commonly prescribed for RSV infection in heart and lung transplant recipients.
The incidence of influenza infection after SCT is 1% to 4%. Mortality rates are 15% to 28% in the setting of influenza pneumonia. The incidence of influenza in lung transplant recipients is 3% to 14% with progression to lower tract infection in up to 5% of patients. Influenza infection is diagnosed in nasal wash, nasopharyngeal swabs, or BAL by rapid antigen detection or RT-PCR methods. Susceptible influenza A strains are treated with the antiviral agents amantadine and rimantadine, and both influenza A and B strains can be treated with zanamivir and oseltamivir. Because oseltamivir-resistant strains of influenza A have been found in transplant patients who continue to shed virus during therapy, these infections may need to be treated with investigational drugs currently in development. Prolonged shedding of influenza virus during treatment of transplant patients also mandates close attention to infection control procedures to prevent spread to staff and other patients.
Parainfluenza and Metapneumovirus
Parainfluenza (PIV), usually serotype 3, is reported to infect 0.2% to 18% of SCT recipients, with lower respiratory tract involvement in 12% to 50% of cases. The incidence of parainfluenza infection in lung transplant recipients is 2% to 17%. MPV is reported to infect 3% to 7% of SCT recipients ( eFig. 91-6 ) with 27% to 41% of cases involving the lower respiratory tract and has an associated mortality of 33% to 40% for those with pneumonia. The incidence of MPV infection in lung transplant recipients is 4% to 6%. Isolated cases of MPV have also been reported following liver and kidney transplantation. MPV infection appears to increase acute allograft rejection. Infection by PIV or MPV is diagnosed by RT-PCR of nasopharyngeal swab, nasal wash, or BAL. Treatment is supportive care; however, IV or inhaled ribavirin and/or IV immunoglobulin has been used to treat lower respiratory tract disease despite the absence of controlled trials.
On the basis of the Transplant-Associated Infection Surveillance Network (TRANSNET), the 1-year incidence of invasive fungal infections (IFIs) in SOT recipients, in the order of decreasing frequency, is small bowel transplants (11.6%), lung (8.6%), liver (4.7%), heart (4.0%), pancreas (3.4%), and kidney (1.3%). The most common pathogens are invasive candidiasis (53%), invasive aspergillosis (IA) (19%) ( eFigs. 91-7 and 91-8 ), Cryptococcus (8%), non- Aspergillus molds (8%) ( eFig. 91-9 ), endemic fungi (5%), and Zygomycetes (2%). The mortality associated with candidal infections in SOT recipients ranges from 5% to 77% with the highest mortality seen in liver transplant recipients. The mortality rate for IA is related to the type of transplant and ranges from 20% for lung transplants to 66.7% for heart and kidney transplants. Risk factors for IFI in SOT recipients include environmental exposures, the use of high-dose steroids, antilymphocyte therapy, and viral infections, particularly CMV infection. Lung transplant patients are at particular risk for fungal infections in the anastomotic site.
The incidence of IA infection after SCT ( eFig. 91-10 , also see Figs. 38-4 and 38-7 ) ranges from 0.08% to 23% depending on the stem cell source and conditioning regimen. Mortality at 3 months from the time of IA diagnosis ranges from 54% of autologous recipients to 85% for unrelated donor recipients and does not differ for those with early-versus late-onset infections.
Aspergillus infection can present in posttransplantation patients as airway colonization, tracheobronchitis, pulmonary aspergillosis, sinusitis, or disseminated disease. Symptoms of invasive pulmonary aspergillosis include dyspnea, fever, productive cough, chest pain, and hemoptysis; however, up to 41% of transplant recipients may have no respiratory symptoms. After recovery from neutropenia, 64% of allogeneic SCT recipients with invasive filamentous fungal infection presented with dyspnea, but only 32% were febrile.
Diagnostic strategies vary. Culture remains the gold standard for the diagnosis of Candida infections. Similarly, the gold standard for the diagnosis of IA is biopsy with culture in the setting of compatible clinical and radiographic features, although alternative approaches include serologic and molecular testing. For SCT recipients, the serum galactomannan assay has a sensitivity and specificity of 82% and 86%, respectively, for the diagnosis of IA ; in contrast, for SOT recipients, the serum galactomannan assay is of uncertain utility, with a sensitivity and specificity of 22% and 84%, respectively. Compared with serum, BAL appears to have higher specificity; galactomannan testing of BAL has a sensitivity of 60% to 82% and a specificity of 95%. PCR-based methods for the detection of Aspergillus are not yet standardized for clinical use, although published studies indicate that BAL analysis using quantitative RT-PCR has a sensitivity of 67% to 77% and specificity of 90% to 100%.
Treatment of IFI in transplant recipients should be based on the isolated pathogen, hospital-specific susceptibility patterns, and the patient’s clinical condition. Gabardi and colleagues have reviewed potential pathogen-specific treatment options. In general, a two-pronged approach is advised: (1) reduction of the level of immunosuppression to the extent possible and (2) use of an appropriate antifungal agent. It is important to recognize that all clinically relevant azole antimicrobials inhibit cytochrome P450 isoenzyme activity to varying degrees, resulting in increased serum concentrations of cyclosporine, tacrolimus, sirolimus, and everolimus that could lead to neurotoxicity and/or nephrotoxicity (see eTable 91-2 ). Voriconazole is the agent of choice for the treatment of IA based on its superior efficacy and survival benefit in comparison with amphotericin. However, voriconazole is contraindicated in patients receiving sirolimus. Liposomal amphotericin B is an alternative in patients who are azole intolerant. Echinocandins (caspofungin, micafungin, anidulafungin) are also an option for the treatment of AI and have low potential for drug interactions, although they may lower tacrolimus levels. Surgical resection for invasive pulmonary aspergillosis is a reasonable option in neutropenic patients. Inhaled liposomal amphotericin B can be used for the treatment of Aspergillus tracheobronchitis. Current data support the use of antifungal prophylaxis with either azole antifungal agents or liposomal amphotericin B for SOT recipients. This topic is discussed further in Chapter 38 .
Mucormycosis has emerged as an important IFI and accounts for 8% and 2% of IFIs in SCT (see eFig. 38-8 , eFig. 38-9 , eFig. 38-10 , eFig. 38-11 , eFig. 38-12 ) and SOT (see eFig. 91-9 ) recipients, respectively, most often as a late complication (>3 months after transplantation) with pulmonary involvement in more than half of cases. The overall mortality rates among SOT recipients are 38% to 48%, while in SCT recipients mortality is at least 75%. First-line therapy is liposomal amphotericin B for at least 6 to 8 weeks and extensive early surgical debridement. A combination of liposomal amphotericin and an echinocandin may be considered in cases that are refractory to first-line therapy.
Pneumocystis jirovecii (previously Pneumocystis carinii ) remains a potentially life-threatening infection after SCT and SOT, developing in 5% to 15% of recipients in the absence of prophylaxis and having an attributable mortality of 18%. The risk of infection is greatest during the first 6 months after transplantation and decreases significantly after 1 year in all patients except lung transplant recipients. The clinical presentation can include progressive dyspnea, cough, fever, and hypoxemia. Chest radiographs typically show bilateral abnormalities that can include perihilar, interstitial or alveolar opacities, nodules, cystic lesions, or pneumothorax. The diagnosis of PCP is confirmed by the morphologic identification of the Pneumocystis organisms in induced sputum, BAL fluid, or tissue. First-line therapy for PCP is high-dose trimethoprim-sulfamethoxazole combined with corticosteroids. Trimethoprim induces cytochrome P450 activity and can lead to decreased serum concentrations of cyclosporine. Most transplantation centers use low-dose TMP/SMX for PCP prophylaxis, which is discontinued at 1 year for all groups except lung transplant recipients for whom it is continued indefinitely.
Endemic fungal infections (EFIs) such as blastomycosis (see eFig. 37-15 ) or histoplasmosis develop in less than 1% of SCT and SOT recipients. The median time from transplant to onset of EFI is 10.5 months (range 2 to 192 months), although 20% of cases are diagnosed 5 or more years after transplantation. The lungs are the most common site of infection, reported in up to 83% of EFI cases; however, the disease can disseminate in more than half of SOT recipients. In posttransplant patients, disease with blastomycosis or histoplasmosis has an attributable mortality of 25% to 36% and 0% to 11%, respectively. The incidence of posttransplant coccidioidomycosis in the era of targeted prophylaxis is less than 3%; however, the rates of dissemination and mortality are high at 30% and 29%, respectively. Coccidioides serology is of uncertain utility in posttransplant recipients due to its low sensitivity.
Although transplantation recipients are clearly at increased risk for infection, these patients can also experience noninfectious pulmonary complications. These noninfectious complications can be attributed to pulmonary toxicities of chemoradiation therapy used in preparative regimens or associated with immunosuppressive medications, postoperative surgical complications, alloreactive lung injury due to allograft rejection or GVHD or as a result of malignancies impacting the lung (see Figs. 91-1 and 91-2 ). eTable 91-3 describes the most common complications in the immediate postoperative period.
|Transplantation||Noninfectious Postoperative Complications|
Individual components of some chemotherapy regimens used in SCT are associated with pulmonary toxicity. Carmustine (or bischloroethylnitrosourea, BCNU), used as a single agent or in combination before autologous SCT for solid tumor and hematologic malignancies, is associated with acute-onset pneumonitis with an incidence of 4% to 59%. Prior mediastinal radiation therapy, BCNU dose greater than 1000 mg, and age younger than 54 were independent risk factors for developing pneumonitis after autologous SCT for lymphoma. The mechanism of BCNU-associated pulmonary toxicity has not been entirely elucidated but is thought to include oxidative stress, glutathione dysfunction, and immune-mediated lung injury.
Cyclophosphamide is another agent used in combination with total body radiation or other chemotherapy agents in preparative regimens for autologous and allogeneic SCT, which is associated with pulmonary toxicity thought to be related to increased reactive oxygen species generation and depletion of glutathione stores. Pulmonary toxicity associated with other chemotherapeutic agents and radiation are discussed elsewhere in this text.
Postoperative respiratory failure has been well described in the transplantation literature as an early cause of mortality. After liver transplantation, the incidence of postoperative respiratory failure is reported to be 4% to 42%. In a single-center, retrospective study of 212 liver transplant recipients, the causes of postoperative respiratory failure were pneumonia (56%), pulmonary edema (17%), acute lung injury (ALI)/ARDS (17%), and neurologic dysfunction (8%). In the immediate posttransplantation period, the most common risk factors for noncardiogenic pulmonary edema include reperfusion syndrome, transfusion-related acute lung injury (TRALI), sepsis, pneumonia, gastric aspiration, and acute allograft rejection. After kidney and cardiac transplantation, perioperative respiratory failure is less common. In a single-center retrospective study, perioperative respiratory failure was identified in 4% of 178 kidney transplant recipients. Similarly, heart transplantation has a low risk of respiratory failure. In a retrospective single-center study by Lenner and associates, 4% of 157 cardiac transplant recipients developed respiratory failure posttransplantation with 71% of episodes in the first 6 months.
After lung transplantation, respiratory failure in the early postoperative period is most commonly the result of infections or primary graft dysfunction (PGD). PGD, a form of acute lung injury arising within 72 hours of lung transplantation, is a severe form of ischemia/reperfusion injury ( Fig. 91-3 ). The incidence is 10% to 30% of all lung transplant recipients. Treatment is primarily supportive care including low-stretch ventilation strategies and avoidance of excessive fluid administration. (A more detailed discussion of PGD is presented in Chapter 106 ).
For SCT patients, a spectrum of noninfectious pulmonary complications can develop in the early posttransplantation period that falls under the category of the idiopathic pneumonia syndrome (IPS). IPS is broadly defined as widespread alveolar injury seen after SCT in the absence of active lower respiratory tract infection, cardiac dysfunction, acute renal failure, or iatrogenic fluid overload ( eFig. 91-11 ). IPS encompasses a spectrum of clinical presentations thought to result from a variety of lung insults including toxic effects of the SCT conditioning regimen, immunologic cell-mediated injury, inflammatory cytokines, and occult pulmonary infections.
The cumulative incidence of IPS after allogeneic SCT ranges from 2.2% following nonmyeloablative conditioning to 8.4% following conventional, full-intensity radiation containing preparative regimens. The median time of onset after allogeneic SCT is 19 days (range, 4 to 106 days) with mortality rates ranging from 60% to 80% overall to greater than 95% for patients requiring mechanical ventilation. Although IPS also develops after autologous SCT, the incidence is lower, the median time to onset is generally later (63 days; range 7 to 336 days), the response to corticosteroids is usually prompt and the prognosis is favorable compared with IPS in allogeneic SCT recipients. Risk factors for IPS after allogeneic SCT include full-intensity conditioning with total body irradiation, acute GVHD, older recipient age, and an underlying diagnosis of acute leukemia or myelodysplastic syndrome. Risk factors for IPS following autologous SCT include older patient age, severe oral mucositis, conditioning regimens using total body irradiation or BCNU, chest irradiation within 2 weeks before transplant, female gender, and an underlying diagnosis of solid tumor.
Current standard treatment strategies of IPS include broad-spectrum antibiotics and IV corticosteroids and supportive care with lung protective mechanical ventilation and venovenous ultrafiltration for those with respiratory failure. Response to corticosteroids (≤2 mg/kg/day) has shown mixed efficacy in allogeneic SCT recipients, which likely reflects the diversity of underlying causes responsible for the lung insult. Compared with lower doses, higher doses of corticosteroid therapy (>2 mg/kg/day) have not been shown to improve outcome but are associated with increased complications including fungal infection. Prophylaxis against filamentous fungal infection with voriconazole or micafungin is recommended during treatment with corticosteroids (≥0.5 mg/kg/day) because fungal pneumonia was identified in 16% (4/25) of IPS patients at the time of autopsy in a single-center study.
Preclinical and clinical studies suggest that neutralization of tumor necrosis factor (TNF)-α may be a useful therapeutic strategy for IPS. In a single-center study, etanercept (0.4 mg/kg administered subcutaneously twice weekly for 4 weeks) in conjunction with systemic corticosteroids and empiric antibiotics was associated with significant clinical improvement in 66% (10/15) of IPS patients. In a multicenter, Phase II single-arm, open-label study by Yanik and colleagues in pediatric SCT recipients, treatment with etanercept (0.4 mg/kg/dose twice weekly for 8 doses) plus corticosteroids (2 mg/kg/day) resulted in a complete response in 71% (20 of 28) of patients and was associated with a high overall survival compared with historical controls.
As a clinical spectrum, IPS encompasses several descriptive forms of lung dysfunction. One such subset is termed diffuse alveolar hemorrhage (DAH), also called acute pulmonary hemorrhage ( Fig. 91-4 and ) or hemorrhagic alveolitis. DAH generally develops in the immediate posttransplant period and is characterized by progressive dyspnea, cough, and hypoxemia with or without fever. The cumulative incidence of DAH is 5% to 12% of SCT patients with a median time of onset of 19 days (range, 5 to 34 days) in allogeneic recipients and 12 days (range, 0 to 40 days) in autologous patients. The diagnosis of DAH is based on progressively bloodier return of BAL fluid (see Fig. 67-3 ). Treatment of DAH consists of aggressive platelet support to maintain a platelet count greater than or equal to 100,000 and high-dose systemic corticosteroids (2 mg/kg/day to 1 g/m 2 /day). The addition of aminocaproic acid or recombinant factor VII may further improve outcomes. Despite these interventions, the mortality from DAH ranges from 60% to 100% with death usually due to multiorgan failure within 3 weeks of diagnosis.
Peri-engraftment respiratory distress syndrome (PERDS) is another clinical subset of IPS. PERDS by definition develops within 5 days of engraftment and accounts for 33% of IPS cases after allogeneic SCT ( eFig. 91-12 and ). Although the clinical presentation of PERDS after SCT is similar to other subsets of IPS, lung dysfunction is more responsive to corticosteroids and the prognosis is better.
Delayed pulmonary toxicity syndrome (DPTS) also falls within the spectrum of IPS. The incidence of DPTS is 29% to 64% in autologous SCT recipients ( eFig. 91-13 ) receiving chemotherapy with regimens containing BCNU, cyclophosphamide, and cisplatin. The median time of onset is 45 days (range, 21 to 149 days), and treatment with corticosteroids (1 mg/kg/day) results in resolution in up to 92% of cases.
Venous Thromboembolic Disease
Venous thromboembolism (VTE) is an under-recognized complication of SOT, especially in lung transplant recipients. In an autopsy series, pulmonary embolism was diagnosed in 34 (27%) of 126 lung and heart-lung transplant recipients. By comparison, pulmonary embolism is diagnosed in 5% to 7% of lung transplant recipients antemortem, suggesting underdiagnosis of this complication. In renal transplant patients, the incidence of VTE ranges from 0.6% to 25% and is associated with advanced renal insufficiency, acute CMV infection, and cyclosporine use, whereas in liver transplant patients, the incidence of pulmonary embolism was 1% overall. In a cohort of 159 heart recipients from a single center, only 2 patients developed VTE.
SCT patients are at increased risk of developing VTE. In a retrospective study of 1514 SCT recipients, the incidence of symptomatic VTE within the first 180 days posttransplantation was 4.6% including a 0.7% incidence of non–catheter-associated lower extremity DVT and 0.6% incidence of pulmonary embolism. This result is comparable with a smaller, retrospective study of 589 SCT patients. The median time after SCT admission to the development of non–catheter-associated lower extremity DVT was 63 days and for pulmonary embolism, 66 days. Independent risk factors for the development of VTE were prior VTE and GVHD. Importantly, thrombocytopenia was only partially protective against the development of VTE. The safety and efficacy of thromboprophylaxis in SCT patients remains uncertain, and anticoagulant therapy for documented VTE should be accompanied by platelet transfusions to maintain a platelet count of 50 × 10 9 /L or greater to reduce the risk of bleeding complications.
Diaphragmatic dysfunction can develop due to injury to the phrenic nerve, perhaps from hypothermia or mechanical damage during surgery. The incidence of diaphragmatic dysfunction after heart or heart-lung transplantation has been reported from 12% to 43% and after lung transplantation from 7% to 30%. The reported incidence of diaphragmatic paralysis among liver transplant recipients ranges from 38% to 44% and is attributed to right phrenic nerve crush injury at the time of suprahepatic vena cava clamping. Diaphragmatic dysfunction has been associated with a significantly increased number of ventilator days and ICU length of stay for liver, heart-lung, and lung-only transplant recipients compared with recipients without phrenic nerve damage.
Drug-Induced Pulmonary Toxicity
A spectrum of drug-induced lung diseases has been reported after transplantation in association with immunosuppressive therapies. Implicated immunosuppressive agents and their patterns of pulmonary toxicity are listed in eTable 91-4 .
Monoclonal antibodies used as induction immunosuppressive therapy after SOT are infrequently associated with pulmonary toxicity. Infusion of muromanab-CD3 (OKT3) can produce a cytokine release syndrome thought to be from a transient activation of T cells before they undergo cell lysis. The clinical manifestations of this syndrome are fever, chills, headache, dyspnea, myalgia, and hypotension and can result in pulmonary edema and intra-allograft thrombosis. Basiliximab is linked to severe noncardiogenic pulmonary edema within 48 hours of infusion. Alemtuzumab is associated with DAH. The off-label use of rituximab, as part of the induction immunosuppressive regimen for renal transplantation, has also been reported to result in a cytokine release syndrome, with ARDS and DAH developing within hours of administration. Additional patterns of rituximab-induced lung injury include interstitial pneumonitis and cryptogenic organizing pneumonia, which can develop within weeks of administration and in most cases completely resolve after discontinuation of therapy with or without corticosteroids.
IV and oral cyclosporine given after liver, kidney, and bone marrow transplantation has been reported to cause a noncardiogenic pulmonary edema and ARDS that resolves when the medication is discontinued. The reaction is postulated to be idiosyncratic.
The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, bind to rapamycin-FK–binding protein-12 to inhibit T and B lymphocyte proliferation for induction and long-term maintenance of immunosuppression. Pulmonary toxicity has been reported in up to 11% of SOT recipients receiving sirolimus. Pulmonary toxicity developed within 6 months of the initiation of sirolimus therapy in 47% of cases and within 12 months in 65% of recipients. The clinical presentation includes cough (96%), fatigue (83%), fever (67%), dyspnea (33%), and hemoptysis (8%). Physical examination is notable for hypoxemia (50%) and inspiratory crackles (50%). Radiographic findings on CT scan include patchy bilateral asymmetrical peripheral consolidations (organizing pneumonia-like pattern) (79%), reticular and ground-glass opacities (17%), and lobar consolidation (4%). BAL is reported to show lymphocytic or eosinophilic alveolitis in up to 92% of cases. The predominant histologic patterns are organizing pneumonia, pulmonary hemorrhage, diffuse alveolar damage, and, in a minority of cases, pulmonary alveolar proteinosis. Drug discontinuation with or without corticosteroids (1 mg/kg/day) is the mainstay of treatment, with complete resolution of symptoms within 2 to 4 months. Less severe cases can be managed by a reduction in the sirolimus dose with close monitoring of serum levels; however, relapses have been reported with this approach. Sirolimus is also thought to be a potent antifibroproliferative agent and has been associated with severe wound healing complications leading to a high rate of bronchial anastomosis dehiscence after lung transplantation. As a consequence, sirolimus administration is not started until 3 months after transplantation or after bronchial wound healing is complete.
Everolimus, a derivative of sirolimus, is associated with pulmonary toxicity in 3.3% of heart transplant recipients with clinical, radiographic, and histologic features similar to those reported with sirolimus.
Obliterative Bronchiolitis and Cryptogenic Organizing Pneumonia
In allogenic SCT recipients, late-onset noninfectious pulmonary complications have been reported in 13% to 26%. Obliterative bronchiolitis, also called bronchiolitis obliterans syndrome (BOS), and cryptogenic organizing pneumonia (COP), formerly called bronchiolitis obliterans organizing pneumonia (BOOP), are two late-onset noninfectious pulmonary complications of allogeneic SCT strongly associated with GVHD. The clinical hallmark of BOS is the development of new-onset, fixed airflow obstruction that is pathologically characterized by progressive circumferential fibrosis of the terminal bronchioles.
Historically, the incidence of BOS after SCT has ranged from 2% to 26%, depending on the definition of airflow obstruction used in the study. In an attempt to standardize the definition of BOS after SCT for clinical and research purposes, the National Institutes of Health Chronic GVHD consensus project published in 2005 diagnostic criteria, which define BOS by five characteristics: (1) forced expiratory volume in 1 second (FEV 1 ) less than 75% predicted; (2) FEV 1 / forced vital capacity (FVC) ratio less than 0.7; (3) evidence of air trapping, small airway thickening, or bronchiectasis on high-resolution computed tomography ( eFig. 91-14 ) or residual volume (RV) greater than 120% predicted or pathologic confirmation of constrictive bronchiolitis; (4) absence of respiratory tract infection; and (5) clinical manifestation of chronic GVHD in at least one other organ. Using the consensus diagnostic criteria in a single-center, retrospective study of 1145 allogeneic SCT recipients, Au and colleagues reported the overall prevalence of BOS to be 5.5% among all transplanted patients and 14% among patients with chronic GVHD. In this study, the median time from transplant to diagnosis of BOS was 439 days (range, 274 to 1690 days). BOS conferred a 1.6-fold increased risk for death after diagnosis. Multivariate analysis of this same cohort of SCT recipients identified chronic GVHD and lower IgG levels (<350 ng/dL) as independent risk factors for the development of BOS.
The onset of BOS is usually insidious, with nonproductive cough (60% to 100%), dyspnea (50% to 70%), and wheezing (40%). Although histologic evaluation of lung tissue is considered the gold standard for the diagnosis of bronchiolitis obliterans, the utility of transbronchial biopsies is limited by low sensitivity (≈20% to 50%) attributed to the heterogeneity of the lesions and small biopsy size. In general, more invasive procedures such as open-lung biopsy or video-assisted thorascopic (VATS) procedures are reserved for unusual presentations. In most instances, the diagnosis of BOS is based on the presence of persistent expiratory airflow obstruction on spirometry in the absence of other causes such as asthma, tobacco-related emphysema, or lower respiratory tract infection. Although the etiology of BOS remains uncertain, the suspected cause is immune-mediated injury of lung epithelium due to allorecognition of lung antigens.
There are no prospective studies of the treatment of airflow obstruction after SCT. Given the presumed alloimmune pathogenesis of BOS, immunosuppressive therapy remains the foundation of treatment. The historic clinical approach to BOS treatment has been with high-dose systemic corticosteroids for extended periods of time such as 12 to 24 months. However, given the limited response to treatment and substantial morbidities associated with high-dose systemic corticosteroid therapy, adjunctive approaches have been tried, including the use of inhaled corticosteroids, azithromycin, and montelukast, a leukotriene inhibitor, which have shown some efficacy in small clinical trials of BOS after SCT. Other emerging therapies for BOS include extracorporeal photophoresis, TNF-α blockade with infliximab, imatinib, and statins. Despite aggressive treatment, BOS after SCT has a poor prognosis with an overall survival rate of 44% at 2 years and 13% at 5 years.
After lung transplantation, the BOS that develops has similar clinical manifestations and histologic characteristics as the BOS of allogeneic SCT recipients. However, BOS is much more common after lung transplantation, developing in 50% of lung transplant recipients at 5.6 years posttransplantation (see Fig. 106-5 ). A detailed discussion on obliterative bronchiolitis syndrome after lung transplantation is available in Chapter 106 .
After SCT, COP is an infrequent, late-onset noninfectious complication. In a single-center, retrospective case-control study, Freudenberger and colleagues identified 49 cases (0.9%) of biopsy-proven COP among 5340 allogeneic patients. In a smaller, retrospective study COP was diagnosed in 12 (2%) of 603 allogeneic SCT recipients. The median time to diagnosis following SCT is reported to be 108 days (range 5 to 2819 days). Patients commonly present with fever (61%), dyspnea (45%), and nonproductive cough (43%) with a median symptom duration of 13 days (range 3 to 65 days). Pipavath and associates reported the imaging features of biopsy-proven COP in a cohort of 16 allogeneic SCT recipients. The CT findings included ground-glass opacities (94%), consolidation (50%) ( Fig. 91-5 ), and linear opacities (50%) with an upper lobe predominance (63%). The pulmonary physiologic changes associated with a diagnosis of COP were predominantly new restrictive (43%) and diffusing capacity abnormalities (64%) and, to a lesser extent, a new obstructive pattern (11%).
Bronchoscopy and BAL are recommended to rule out lower respiratory tract infection and to establish the diagnosis of COP. BAL is characterized by lymphocytosis (>20% lymphocytes) with a decreased CD4/CD8 ratio. Unlike bronchiolitis obliterans, COP can usually be diagnosed by bronchoscopic biopsy, although VATS may be required in cases presenting with atypical features. The histologic characteristics included (1) patchy filling of respiratory bronchioles, alveolar ducts, and peribronchiolar sacs with polypoid masses of granulation tissue; (2) widening of alveolar septa and infiltration by mononuclear cells; and (3) accumulation of foamy macrophages within alveoli (see Figs. 63-34 and 63-35 ). There is an association between acute and chronic GVHD and subsequent development of COP. Patients with COP were more likely to have acute GVHD involving the skin and chronic GVHD involving the gut and oral cavity, suggesting that the pathogenesis is, at least in part, related to alloreactive lung injury.
Corticosteroid therapy is the standard treatment for COP after SCT, although doses and duration have been empirically derived. Historically, prednisone doses of 0.75 to 1.5 mg/kg/day were prescribed with a progressive decrease for a total duration of 24 weeks. However, in order to limit the risk of iatrogenic complications, current recommendations are to start with prednisone at 0.75 mg/kg/day for 4 weeks and taper over a total of 12 weeks, possibly in conjunction with use of a macrolide. The prognosis of COP in SCT recipients is generally favorable with resolution in 57%, stable disease in 21%, and progressive COP in 22% despite corticosteroids with 16% of patients dying from respiratory failure. Up to 75% of patients relapse during the corticosteroid taper or after stopping treatment and typically respond to reinitiation or increased dosing of corticosteroid therapy.
Pulmonary veno-occlusive disease (PVOD) is a rare, late-onset complication after SCT that presents with the insidious onset of fatigue and exertional dyspnea within 3 to 4 months after transplant. The physical examination typically shows hypoxemia and resting tachycardia consistent with pulmonary hypertension. Right heart catheterization demonstrates elevated pulmonary artery pressures with normal pulmonary capillary wedge pressure, and angiography is used to exclude pulmonary emboli as the etiology for the pulmonary hypertension. The diagnosis of PVOD is strongly supported by the triad of pulmonary artery hypertension, radiographic evidence of pulmonary edema, and normal pulmonary artery occlusion pressures; however, lung biopsy confirms the diagnosis by the presence of extensive and diffuse intimal proliferation and fibrosis of pulmonary venules. Treatment consists of high-dose corticosteroids (methylprednisolone 2 mg/kg/day) with anecdotal success, but the overall prognosis of PVOD after SCT remains poor.
Pulmonary cytolytic thrombus (PCT) is another noninfectious pulmonary complication that involves the pulmonary vasculature, seen exclusively in allogeneic SCT recipients and almost always in children. The incidence of PCT has been reported to range from 1.2% to 4% with a median onset at 3 months (range 1.3 to 11.3 months) after transplant. The clinical manifestations include fever, cough, and respiratory distress, and CT findings range from small, peripheral nodules to diffuse opacities. Diagnosis requires lung biopsy that is characterized by vascular occlusions in distal pulmonary vessels, entrapment of leukocytes, endothelial disruption, and infarction of adjacent tissue. In a single-center, retrospective study, grades II to IV acute and chronic GVHD were independent risk factors for developing PCT. Treatment for PCT consists of systemic corticosteroids (prednisone 1 to 2 mg/kg/day) until pulmonary symptoms resolve (typically within 2 weeks) followed by a steroid taper over 2 to 4 weeks. The strong association with acute and chronic GVHD, as well as the response to corticosteroid therapy, suggest that PCT is an alloreactive lung injury. The prognosis with PCT is favorable, and there have been no reported deaths attributable to this entity.
Pulmonary Metastatic Calcifications
Pulmonary metastatic calcification is a well-known complication of chronic renal failure and a rare complication in renal transplant recipients. The lesions are typically nodular opacities of 2 to 12 mm in diameter that may be unilateral or diffuse with a predilection for the upper lobes ( eFig. 91-15 ). Patients can be asymptomatic, although progression of the lesions may lead to dyspnea along with a restrictive pattern and diffusing capacity abnormality on pulmonary function testing. The clinical significance of pulmonary metastatic calcification is distinguishing this entity from pulmonary infections or malignancy in the transplant recipient.
Organ transplantation is associated with an increased risk of developing malignancies. Risk factors for malignancy include prolonged use of immunosuppressive therapy, infection with oncogenic viruses, progressive aging of transplant recipients, longer survival after transplantation and, less commonly, malignant cells transmitted in the donor tissue. Transplant-related malignancies affecting the lung include non-Hodgkin lymphoma, bronchogenic carcinoma, posttransplantation lymphoproliferative disorder, and Kaposi sarcoma (KS). In a large, population-based, registry linkage study of 175,732 SOT recipients, the incidence of non-Hodgkin lymphoma was 7.54-fold higher in transplant recipients compared with the general population. Likewise, the incidence of lung cancer was increased 6.13-fold in lung, 2.67-fold in heart, 1.95-fold in liver, and 1.46-fold in kidney transplant recipients compared with the general population. For further discussion of lung cancer in lung transplant recipients, see Chapter 106 .
Posttransplantation lymphoproliferative disorder (PTLD) is an infrequent but serious complication composed of a heterogeneous group of altered B-cell monoclonal and polyclonal proliferation disorders that can develop in association with immunosuppressive therapy. After SOT, the incidence of PTLD in adults varies among studies but is generally higher in lung (4.2% to 10.0%), heart-lung (2.2% to 5.8%) and heart (1% to 6.3%) compared with liver (1% to 2.8%) and kidney (1% to 2.3%) ( eFig. 91-16 ) recipients. The incidence appears to have a bimodal distribution after lung transplantation with 25% to 47% of cases developing within the first 12 months of transplantation. Risk factors for the development of PTLD after SOT include age at the time of transplantation, degree of immunosuppression, use of OKT3 or antilymphocyte globulin, number of episodes of acute rejection, seronegativity to EBV before transplantation (especially with an EBV-seropositive donor) and CMV or hepatitis C infection.
After allogeneic SCT, PTLD is a rare but serious complication as well ( eFig. 91-17 ). In a multicenter study of 18,014 allogeneic SCT recipients, the overall incidence of PTLD was 1% with 82% of cases diagnosed within the first year posttransplantation. For early-onset PTLD after SCT, risk factors included unrelated or HLA mismatched related donor stem cell source, T-cell depletion of the donor marrow, and use of antithymocyte globulin or anti-CD3 monoclonal antibody for prophylaxis or treatment of acute GVHD. For late-onset PTLD, the only risk factor identified was chronic extensive GVHD. The incidence of PTLD increased to 8% for patients with two risk factors and to 22% for those with three or more risk factors. Pulmonary involvement with PTLD after allogeneic SCT has been reported in 18% of cases. Overall long-term survival was lower for SCT recipients (35%) compared with SOT recipients (55%) and was the worst for patients transplanted for hematologic malignancies. Additional information on PTLD is presented in Chapter 106 .
KS is a soft tissue malignancy associated with immunosuppression in SOT recipients. In a large population-based study, among 234,127 recipients, the incidence of KS was 8.8 per 100,000 person-years with the median time from transplantation to KS of 1.5 years. Risk factors for the development of KS posttransplantation in the United States included male gender, older recipient age, Hispanic ethnicity, non-U.S. citizenship, and number of mismatches at the HLA-B locus. KS develops primarily in transplant recipients with preexisting human herpesvirus-8 infection. Twenty percent of KS cases after organ transplantation have visceral involvement including the lungs.