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Acute noninfectious lung injury after transplant continues to pose problems
Inflammatory mediators such as TNFα and lipopolysaccharide, along with donor-derived Th1 effector cells, directly contribute to lung injury.
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Over the past three decades, allogeneic stem cell transplants (SCTs) have emerged as an important treatment for a number of malignant and nonmalignant disorders. Unfortunately, several complications, including graft-versus-host disease (GVHD) and pulmonary dysfunction, limit the utility of this form of therapy.
Infectious and noninfectious lung complications occur in 25% to 55% of SCT recipients and account for up to 50% of transplant-related mortality. In about half of affected patients, no infectious organisms are identified in the lungs. Within this context, two major types of noninfectious pulmonary injury have been recognized: acute idiopathic pneumonia syndrome (IPS) and subacute lung injury (obstructive airway disease or bronchiolitis obliterans [BrOb] and restrictive lung disease).
Idiopathic pneumonia syndrome
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IPS refers to a diffuse, noninfectious lung injury occurring in the acute setting, typically within the first 100 days post transplant. In 1993, a panel convened by the NIH proposed a broad working definition of IPS to include widespread alveolar injury in the absence of active lower respiratory tract infection following SCT (Clark et al. Am Rev Respir Dis. 1993;147).
The NIH panel was careful to stress that it considered this definition to be that of a clinical syndrome with variable histopathologic correlates and several potential etiologies. Diagnostic criteria of IPS include signs and symptoms of pneumonia, non-lobar radiographic infiltrates (Figure 1), abnormal pulmonary function and the absence of infectious organisms in the lower respiratory tract. A variety of histopathologic findings are associated with IPS, with acute interstitial pneumonitis most commonly noted.
The time of onset for IPS ranges from 14 to 90 days after the infusion of donor hematopoietic cells. Survival after onset is poor, with mortality rates of 50% to 70% reported. Potential etiologies for IPS include direct toxic effects of SCT conditioning regimens, occult pulmonary infections and inflammatory cytokines that have been implicated in other forms of pulmonary injury. Additionally, immunologic factors may be important, since IPS is more frequent with allogeneic, compared with autologous SCT and in patients with acute GVHD.
An investigator’s experience
A retrospective review of 651 allogeneic transplants, including 304 unrelated donor transplants, performed at the University of Michigan Medical Center in Ann Arbor from 1996 to 2002 noted a 9% incidence of IPS by day 100 post transplant. IPS was more common in recipients of unrelated donor grafts (14.1%) vs. recipients of related donor grafts (4.6%). Donor-recipient human leukocyte antigen mismatch was also associated with higher incidences of IPS in both unrelated and related donor transplants.
Age, gender, underlying disease and pre-transplant preparative regimen did not predict for IPS in this series. The median time to onset of IPS was 15 days post transplant: the mean, 22 days. Acute GVHD was present at diagnosis in 70% of IPS cases. Affected patients were treated with high-dose corticosteroids and broad-spectrum antimicrobial therapy. Survival rates at 28 and 56 days post onset of IPS were 33% and 26%, respectively. Survival was not affected by donor source or underlying disease. The median time to death following the onset of IPS was 14 days.
Pathophysiology
The association between IPS and GVHD suggests a mechanistic relationship. The pathophysiology of GVHD is complex and is now known to involve donor T-cell responses to host antigens, inflammatory cytokines and endotoxin.
Endotoxin or lipopolysaccharide (LPS) is a component of endogenous bowel flora and is a potent enhancer of inflammatory cytokine release. Translocation of LPS across a gut mucosa damaged early in the post-transplant period by the effects of conditioning and GVHD has been demonstrated after both experimental and clinical SCT.
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| Figure 1. Chest radiograph of patient with idiopathic pneumonia syndrome |
When LPS reaches the systemic circulation, it induces the release of inflammatory cytokines from monocytes and macrophages that have been “primed” or made more sensitive to LPS through the effects of interferon γ (IFNγ) produced by donor lymphocytes. These cytokines, along with cellular effectors, contribute to GVHD target organ damage and dysfunction.
During recent years, several lines of investigation have added to our understanding of how inflammatory cytokines contribute to complications of allogeneic SCT. In particular, tumor necrosis factor α (TNFα) is an established effector of both clinical and experimental GVHD. The clinical importance of TNFα was initially suggested by studies demonstrating elevated levels of TNFα in the serum of patients with acute GVHD. Patients with higher serum TNF levels during the conditioning regimen had a 90% incidence of grade-2 to -4 acute GVHD. Their mortality was above 70%, compared with 20% mortality in patients without acute GVHD (Holler, et al. Transplant Proc.1993;25).
SCT recipients with a genetic polymorphism associated with high (TNFα) production are reported to have enhanced early mortality and an increased incidence of severe acute GVHD. (TNFα)appears critical for the development of early gastrointestinal injury from acute GVHD. Its role in GVHD mediated damage to other target organs is less well defined (Hattori et al. Blood. 1997;90).
Although the lung is historically not recognized as a classic target organ of GVHD, the clinical association between IPS and GVHD and the demonstration of pathologic lung changes in rodents with acute GVHD make this possibility intriguing. Pertinent to this hypothesis, elevations of TNFα are reported in the serum of patients who develop IPS and in the lungs of animals with GVHD. Furthermore, evidence for cytokine activation and LPS amplification, previously recognized in the bronchoalveolar compartment during adult respiratory distress syndrome were recently demonstrated in patients with IPS after allogeneic SCT.
Clark and colleagues found increased vascular permeability and bronchoalveolar lavage (BAL) fluid containing interleukin-1 (IL-1), IL-12, IL-6 and TNFα and components of the LPS amplification system (LPB and CD14) in patients with IPS2. The investigators concluded that pro-inflammatory cytokine activation contributed to the pathogenesis of IPS and suggested patients with this complication may be at increased risk for LPS-mediated lung injury.
During the last several years, my associate, Ken Cooke, studied murine models of allogeneic SCT to investigate mechanisms of IPS. A causal role for TNFα in the development of IPS was found using TNFα knock out (TNF α-/-) mice as SCT donors. Using an established parent (P) → F1 system (B6 → B6D2F1), we found that allogeneic SCT using TNFα -/- donors resulted in significantly less lung injury as measured by lung pathology and BAL cellularity compared to SCT using wild type donors (Figure 2). Lung histology in the wild type controls resembled the microscopic features of patients with IPS (Sloane et al. J Clin Pathol. 1983;36). Neutralization of TNFα, using a TNF binding agent (rhTNFR;Fc), administered 4 to 8 weeks post transplant significantly reduced GVHD mortality and reduced the progression of lung injury in a separate series of murine experiments (Cooke et al. Transplantation. 2000;70).
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Current treatment regimens for IPS include supportive care measures in conjunction with broad-spectrum antimicrobial agents with or without IV corticosteroids (Table). Although anecdotal reports of responses to standard therapy are available, such responses are limited and the mortality of patients diagnosed with IPS remains unacceptably high. Advances in supportive care including the early institution of continuous venovenous hemofiltration may help to improve survival in some patients. Prospective studies addressing the treatment of IPS, including the specific use of steroids, are lacking in the literature, and no agent or combination of agents has been proven superior.
Role of TNFα
In light of the poor response rate to standard treatment, the lack of prospective treatment trials and preclinical and clinical data that suggest a potential role for TNFα in the development of noninfectious lung injury after SCT, etanercept (Enbrel, Amgen) was administered to three consecutive pediatric patients at the University of Michigan SCT program who met criteria for IPS (Yanik et al. Biol Blood Marrow Transplant. 2202;8). In all three patients, BAL fluid was negative for infection, and pulmonary edema from fluid overload or cardiogenic factors was also ruled out prior to the administration of etanercept.
Each patient received empiric broad-spectrum antimicrobial therapy and methylprednisolone (2 mg/kg/day) prior to and during etanercept therapy. The administration of etanercept was well tolerated, and, with standard immunosuppressive therapy, it was associated with significant clearing of radiographic infiltrates and improvements in pulmonary function within the first week of therapy.
A pilot study testing the safety and feasibility of using etanercept to treat patients with IPS that was subsequently completed at the University of Michigan and the Dana-Farber Cancer Institute and the Brigham and Woman’s Hospital, both in Boston. Fifteen patients (median 18 yrs, 1 - 60 yrs), each meeting the diagnostic criteria for IPS, were enrolled over a 30-month period. Seven of the 15 patients required mechanical ventilation at the time of study entry. Etanercept was administered at 0.4 mg/kg through subcutaneous injection, twice weekly for a maximum of eight doses. Therapy was well tolerated overall. Ten of 15 patients had a complete response and were able to completely withdraw from supplemental oxygen support within 28 days of initiation of etanercept therapy. Survival at day 28 and day 56 (from the first etanercept dose) was 73% and 60%, respectively. Based upon these encouraging results, a phase-2 pediatric study and a phase-3 adult trial are now being developed.
For more information:
- Gregory Yanik, MD, is an associate professor of pediatric hematology/oncology at the University of Michigan in Ann Arbor.