Inflammatory Cytokines and the Development of Pulmonary Complications after Allogeneic Hematopoietic Cell Transplantation in Patients with Inherited Metabolic Storage Disorders

Article Outline

• Abstract
• Introduction
• Materials and methods
  • Patients
  • Pre-HCT BAL Fluid Analysis
  • Pulmonary Complications
  • Statistical Analysis
• Results
  • Pulmonary Complications
  • Cytokine Analysis
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Patients with inherited metabolic storage disorders are at a higher risk of developing pulmonary complications after hematopoietic cell transplantation (HCT). This single-center prospective study of 48 consecutive inherited metabolic storage disorder patients was performed to identify risk factors for the development of pulmonary complications after HCT. Before HCT, subjects underwent bronchoalveolar lavage (BAL) for cell count, culture, nitrite levels, and analysis of proinflammatory cytokines and chemokines. The overall incidence of pulmonary complications was 52% (infectious, 23%; noninfectious, 29%) over a period of 4 years. Diffuse alveolar hemorrhage was the most frequent noninfectious complication and occurred in 19% of patients, all of whom had a diagnosis of mucopolysaccharidosis (Hurler and Maroteaux-Lamy syndromes). Levels of interleukin (IL)–1β, IL-6, IL-8, tumor necrosis factor α, macrophage inflammatory protein 1α, and granulocyte colony-stimulating factor in BAL fluid samples obtained before HCT were higher in patients with mucopolysaccharidoses than in patients with leukodystrophies. In addition, levels of IL-1β, IL-6, IL-8, and granulocyte colony-stimulating factor were increased in the BAL fluid of patients who developed noninfectious pulmonary complications compared with those who did not develop pulmonary complications. It is interesting to note that most noninfectious pulmonary complications occurred in patients with mucopolysaccharidoses, especially diffuse alveolar hemorrhage, which occurred exclusively in patients with mucopolysaccharidoses. Higher levels of bronchial proinflammatory cytokines and chemokines may be predictive of the development of subsequent posttransplantation noninfectious complications in patients with mucopolysaccharidoses, especially those with Hurler syndrome. Larger studies will be required to further elucidate etiologic mechanisms and predictive factors.

Key words:  Inherited metabolic storage disorder , Hematopoietic cell transplantation , Bronchoalveolar lavage , Pulmonary complications , Inflammatory cytokines

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Introduction 

Allogeneic hematopoietic cell transplantation (HCT) has been used as effective therapy for some inherited metabolic storage disorders (IMSDs) for the past 2 decades [1]. IMSDs that can be effectively treated by HCT include the mucopolysaccharidoses (MPS), such as Hurler [2, 3, 4] and Maroteaux-Lamy [5] syndromes; leukodystrophies, such as cerebral X-linked adrenoleukodystrophy [6, 7, 8]; metachromatic leukodystrophy [9, 10]; globoid cell leukodystrophy [11]; and glycoprotein metabolism disorders, such as α mannosidosis [12, 13] and mucolipidosis II (I-cell disease) [14].

The success of HCT in treating IMSDs is limited particularly by a high incidence, approaching 33%, of posttransplantation pulmonary complications [15, 16]. At the University of Minnesota, 233 patients with IMSDs have undergone HCT over 21 years. Review of our data revealed a 16% incidence of diffuse alveolar hemorrhage (DAH) in patients with Hurler syndrome [17]. A recent report found a 20% incidence (3 of 15 patients) of DAH in patients with Hurler syndrome [18]. The incidence of DAH in both allogeneic and autologous HCT recipients has been reported to be 5% [19, 20], whereas that of idiopathic pneumonia syndrome (IPS) has been 8%-12% [21, 22], in both adult and pediatric patients.

Although the pathophysiology of DAH is not well understood, IPS has been studied by many investigators in murine models of bone marrow transplantation. DAH that occurs as a complication of autoimmune diseases has been thought to be secondary to small vessel vasculitis [23]. Shankar et al. [24] described DAH as an early complication of HCT when the cytokine milieu in the lung parenchyma is antifibrotic. Proinflammatory cytokines including interleukin (IL)–6, tumor necrosis factor (TNF)–α, and interferon γ have been found to play a critical role in the development of IPS in murine models of HCT. In addition to cytokines, chemokine levels such as monocyte chemotactic protein (MCP, or CCL2), macrophage inflammatory protein (MIP)–1α (or CCL3), and RANTES (regulated upon activation normal T cells expressed and secreted, or CCL5) have been found to be increased in the lungs of mice that developed IPS in an allogeneic HCT system [25, 26]. Moreover, early after HCT, nitric oxide (NO), superoxide, and their derived reactive species have been shown to play important roles in inflammatory and oxidant responses that lead to IPS-related injury and death, probably via activation of proinflammatory cytokines such as TNF-α and interferon γ [27, 28]. Compared with serum, bronchoalveolar lavage (BAL) allows direct sampling of the alveolar space. It is a useful diagnostic tool in evaluating HCT-related pulmonary complications [29]. In a recent study, increased levels of TNF-α and reduced levels of IL-18 in BAL fluid were found in patients with pulmonary complications after HCT [30].

Thus, the immune system—in particular, a complex interaction between proinflammatory cytokines and chemokines—seems to play a critical role in the development of pulmonary complications after HCT. It is unclear whether the cytokine response is exaggerated in patients with IMSDs, especially those with MPS (Hurler and Maroteaux-Lamy), to account for their increased risk of pulmonary complications, particularly DAH. We hypothesized that increased levels of proinflammatory cytokines and NO production within the lung before HCT would be correlated with the development of significant pulmonary complications after HCT. This article describes a prospective study that analyzed BAL fluid before HCT to determine whether cytokine abnormalities were more likely to be present in patients who developed pulmonary complications after HCT.

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Materials and methods 

Patients 

Between August 1999 and March 2003, 48 consecutive patients with IMSDs were enrolled in this prospective study. The study protocol was approved by the Human Subjects Committee at the University of Minnesota, and informed consent was obtained from the subject or a parent or legal guardian. Twenty-three patients had a diagnosis of MPS (ie, Hurler or Maroteaux-Lamy syndrome), and the remaining 25 had primary genetic diseases other than MPS, including X-linked adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, I-cell disease, and α-mannosidosis. Patient characteristics are shown in Table 1.

Table 1. Patient Characteristics

Characteristics	MPS I (n = 21)	MPS VI (n = 2)	Mann (n = 1)	ALD (n = 16)	MLD (n = 6)	GLD (n = 1)	I-Cell (n = 1)
Median age at HCT, y (range)	1.5 (0.8-2.8)	6.2 (4.6-7.8)	4.1	9.3 (4.0-16)	8.1 (4.0-40)	3.0	1.2
Sex
Male	12	1	0	16	3	1	1
Female	9	1	1	0	3	0	0
Stem cell source
Unrelated bone marrow	10	1	0	7	1	0	1
Unrelated cord blood	6	1	1	5	5	1	0
Related bone marrow	5	0	0	4	0	0	0
HLA match
6/6	12	1	0	10	1	0	1
5/6	7	1	0	3	3	1	0
4/6	2	0	1	3	2	0	0
Conditioning regimen
Bu/Cy	18	2	1	2	5	0	1
Cy/TBI	0	0	0	14	1	1	0
Other	3	0	0	0	0	0	0
GVHD prophylaxis
CSA + prednisone	4	1	1	8	5	1	1
T-cell depletion	12	1	0	8	1	0	0
CSA + other	5	0	0	0	0	0	0

MPS I indicates Hurler syndrome; MPS VI, Maroteaux-Lamy syndrome; Mann, Mannosidosis; ALD, adrenoleukodystrophy; GLD, globoid cell leukodystrophy; MLD, metachromatic leukodystrophy; I-Cell, mucolipidosis type II; Bu/Cy, busulfan/cyclophosphamide; Cy/TBI, cyclophosphamide/total body irradiation; other, busulfan, fludarabine, total body irradiation; CSA, cyclosporin A.

Pre-HCT BAL Fluid Analysis 

Patients underwent fiberoptic bronchoscopy and BAL before HCT, and these were performed during other necessary pre-HCT procedures that required general anesthesia (eg, placement of a central venous catheter). The bronchoscope was advanced into the endotracheal tube and directed to either the lingula or the right middle lobe. The bronchoscope was wedged into a segmental or subsegmental airway, and 3 sequential aliquots of 1 mL/kg sterile, preservative-free normal saline were instilled and immediately withdrawn by gentle suction. Typically, 33% to 50% of the total amount of fluid instilled was recovered. BAL fluid was analyzed for cell count, differential, microbiology, total protein, cytokine levels, and nitrite levels. Microbiologic studies included bacterial, mycobacterial, fungal, and viral cultures. Cell count with differential and cultures were performed by using conventional techniques in the clinical laboratory. Nitrite in BAL fluid was measured according to the Greiss method after conversion of nitrate to nitrite with the reduced nicotinamide adenine dinucleotide–dependent enzyme nitrate reductase (Calbiochem, La Jolla, CA). BAL fluid total protein was determined by the bicinchoninic acid (Sigma, St. Louis, MO) method with bovine serum albumin as the standard. BAL samples were centrifuged to remove cells and debris, and the fluid was stored at −80°C until cytokine or chemokine analysis. MCP-1 (CCL2) and MIP-1α (CCL3) were determined by using commercial enzyme-linked immunosorbent assay methods (R&D Systems, Minneapolis, MN). BAL fluid was also assayed by the Luminex method (Austin, TX) by using human-specific bead sets (R&D Systems) that included IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α. For the cytokine analyses, all specimens were assayed in duplicate, and results were averaged.

Pulmonary Complications 

Pulmonary complications were categorized depending on the clinical, radiographic, and bronchoscopic findings. Patients whose BAL or lung biopsy results were positive for specific pathogens and who had radiographic findings suggestive of infection were considered to have developed an infectious pulmonary complication. Patients whose BAL or lung biopsy results were negative for specific pathogens and who had abnormal radiographic findings consistent with IPS or DAH were considered to have developed a noninfectious pulmonary complication. Patients were monitored weekly for the development of infectious and noninfectious pulmonary complications through day 100 after transplantation, and then monitoring continued at days 180 and 270 and 1 year. The method of monitoring was chosen according to the standard institutional practice, which included investigating any febrile episode lasting more than 72 hours without an identifiable source by obtaining computed tomographic scans of chest and investigating further by bronchoscopy or lung biopsy in case of positive radiographic findings. All patients in the infectious complications group had clinical and/or radiologic evidence of pulmonary involvement, and a specific infectious organism was identified. All pulmonary events were reviewed by study investigators (S.K. and K.S.B) and classified as either infectious or noninfectious on the basis of all clinical, radiologic, and laboratory data available. Within the noninfectious group, DAH was defined as active pulmonary hemorrhage, as evidenced by bloody return of the lavage fluid obtained during bronchoscopic evaluation or the presence of blood in the lower airway upon endotracheal intubation, an absence of pulmonary infections, a requirement for ventilatory support, and a chest radiograph showing a diffuse alveolar pattern. IPS was defined as diffuse lung injury occurring after HCT for which an infectious etiology was not identified [21]. The diagnosis of pulmonary cytolytic thrombi was made on the basis of pulmonary nodules with confirmed histology on lung biopsy specimens [31]. Similarly, the diagnosis of posttransplantation lymphoproliferative disease with pulmonary involvement was made by open lung biopsy. Pulmonary hypertension was diagnosed in 1 patient by chest imaging and echocardiographic findings and ultimately confirmed histologically. The cause of death was defined as the primary event that led to death in the absence of other underlying contributing factors.

Statistical Analysis 

To account for variations in the volume of BAL fluid collected during the bronchoscopy for each subject, all cytokine and chemokine levels were standardized according to the total protein content of each sample and analyzed as picograms per gram of total protein. Two-sample t tests were used to compare differences between the means of any 2 of the 3 pulmonary complication groups. Two-sample t tests were also used to compare differences in mean cytokine values between children with MPS who developed a pulmonary complication and those with MPS who did not develop any pulmonary complication, between all children with MPS and those with leukodystrophy, and between children with MPS who had a pulmonary complication and children with leukodystrophy who had a pulmonary complication. All statistical analyses were performed with SAS version 8.02 (SAS Institute, Cary, NC).

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Results 

Pulmonary Complications 

The overall incidence of pulmonary complications in this study of 48 patients with IMSD was 52% (25/48) over a period of 4 years: this included 11 (23%) infectious and 14 (29%) noninfectious complications. Data regarding the various complications are presented in Table 2. Infectious pulmonary complications occurred in 6 MPS and 5 non-MPS patients. These included pneumonias caused by cytomegalovirus, respiratory syncytial virus, adenovirus, herpes simplex 1, parainfluenza, Pseudomonas aeruginosa, α-hemolytic Streptococcus species, and Candida albicans. Overall, 14 patients developed noninfectious complications, and 12 of these had an underlying diagnosis of MPS (10 Hurler syndrome and 2 Maroteaux-Lamy syndrome), whereas 2 had non-MPS diagnoses (1 adrenoleukodystrophy and 1 I-cell disease). The most frequent noninfectious complication was DAH (9 patients; 19%), IPS (4 patients; 8%), pulmonary cytolytic thrombi, and posttransplantation lymphoproliferative disease with primary pulmonary involvement. The combined incidence of DAH and IPS, the 2 major noninfectious complications, was 27% (13/48). Although the other noninfectious complications were equally distributed in the study population, DAH occurred exclusively in patients with MPS (Hurler syndrome, n = 7; Maroteaux-Lamy, syndrome, n = 2).

Table 2. Post-HCT Pulmonary Complications

Pulmonary Complication	MPS (n = 23)	Non-MPS (n = 25)
Infectious (n = 11)⁎	6	5
Viral	4	2
Bacterial	2	0
Fungal	0	4
Median time after HCT, d (range)	101 (7-189)	75 (12-138)
Noninfectious (n = 14)†	12	2
Diffuse alveolar hemorrhage	9	0
Idiopathic pneumonia syndrome	2	2
Pulmonary cytolytic thrombi	1	0
PTLD	1	0
Median time after HCT, d (range)	62 (7-194)	150 (13-300)

MPS indicates mucopolysaccharidoses; PTLD, posttransplantation lymphoproliferative disease.

Patient outcomes are shown in Table 3. The overall mortality in this study sample of 48 IMSD patients was 42% (20/48), with 25% (5/20) deaths secondary to pulmonary complications. Four of the 5 deaths from pulmonary causes were in children with MPS, as opposed to only 1 with a non-MPS diagnosis. Overall, 36% of deaths in patients with MPS were from pulmonary causes.

Table 3. Patient Outcomes

Outcome	MPS (n = 23)	Non-MPS (n = 25)
Alive	12 (52%)	16 (64%)
Pulmonary causes of death	5	2
DAH	2	0
PTLD with pulmonary involvement	2	0
Pulmonary hypertension	0	1
Respiratory failure	1	1
Nonpulmonary causes of death	6	7
Sudden cardiac event	1	0
GVHD	1	0
Infection	3	3
Hemolytic anemia	1	1
Disease progression	0	2
HUS/TTP	0	1

DAH indicates diffuse alveolar hemorrhage; PTLD, Epstein-Barr virus posttransplantation lymphoproliferative disease; GVHD, graft-versus-host disease; HUS/TTP, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; MPS, mucopolysaccharidoses.

BAL fluid obtained immediately before transplantation was analyzed for infectious organisms. Five patients who were clinically asymptomatic had BAL fluid cultures positive for Pseudomonas aeruginosa (n = 2), Streptococcus pneumoniae (n = 1), α-hemolytic Streptococcus species (n = 1), and Branhamella catarrhalis (n = 1). These patients were treated with appropriate antibiotics before HCT. None of these patients developed an infectious pulmonary complication after HCT. No pretransplantation viral or fungal cultures from BAL fluid were positive.

BAL fluid was analyzed for protein and nitrite levels. These levels were not different in patients who developed pulmonary complications compared with patients who had no complications.

Cytokine Analysis 

Complete cytokine data were available for 35 of 48 patients in the study. This was due to logistic problems in obtaining the samples given that bronchoscopy was performed only when patients were scheduled to undergo an elective procedure in the operating room, to prevent unnecessary sedation or anesthesia risks associated with a bronchoscopy performed only for research. In 12 patients, BAL specimens could not be obtained for the this reason, and 1 patient was not included in the analysis because his follow-up period was <100 days at the time of analysis. Five of the 35 patients developed infectious complications, 8 had noninfectious complications, and the remaining 22 had no complications. Levels of various cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α, IL-10, and granulocyte colony-stimulating factor (G-CSF), and chemokines, including MCP-1 and MIP-1α, were compared and are shown in Table 4. Patients who developed noninfectious pulmonary complications that were either IPS or DAH were compared with those who had no pulmonary complications. Patients with IPS or DAH were found to have higher concentrations of IL-1β (P = .03), IL-6 (P = .04), IL-8 (P = .04), and G-CSF (P = .003) when compared with patients who had no pulmonary complications after HCT. There was no difference in the cytokine levels between patients who developed infectious pulmonary complications and those who had none (data not shown).

Table 4. Comparisons of Mean Cytokine and Chemokine Concentrations in BAL fluid between Patients with Noninfectious Pulmonary Complications (DAH or IPS) and Those with No Pulmonary Complications

VEGF indicates vascular endothelial growth factor.

Because DAH was seen exclusively in patients with MPS, concentrations of cytokines and chemokines in their pretransplantation BAL fluid were compared in this group of patients with those who had leukodystrophies (Table 5). Patients with MPS had significantly higher concentrations of IL-1β (P = .03), IL-6 (P = .01), IL-8 (P = .02), TNF-α (P = .03), G-CSF (P = .005), and MIP-1α (P = .06). However, when patients with MPS who developed pulmonary complications were compared with MPS patients who did not develop pulmonary complications, no significant differences were found in the levels of various cytokines and chemokines tested (Table 6).

Table 5. Comparison of Mean Cytokine/Chemokine Levels in MPS versus Non-MPS Group

Means are presented as picograms per gram of total protein.

Table 6. Comparisons of Mean Cytokine and Chemokine Concentrations in BAL Fluid between MPS Patients with and without Pulmonary Complications

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Discussion 

The pathogenesis of pulmonary complications in patients undergoing HCT is unclear. Various studies, both in mice and humans, suggest that the local proinflammatory cytokine cascade generated by the alveolar macrophages, as well as donor-derived cytokines such as TNF-α, play a key role in the development of these noninfectious complications after HCT. These cytokines are secreted as a result of interactions of host alveolar macrophages in the lung tissue and donor-derived T cells present locally in the lung [32]. In addition, endothelial cell apoptosis, which occurs in IPS, is associated with increased levels of TNF-α in the BAL fluid of mice, and neutralization of TNF-α was found to prevent endothelial injury and significantly reduced the severity of lung disease in these animals [33]. Neutralization of TNF-α has been shown to decrease lung injury after experimental allogeneic HCT in other murine models of IPS as well [34, 35]. Shukla et al. [28] have shown that mice that are TNF receptor 1 deficient exhibit decreased IPS injury, which was also associated with decreased levels of NO. In addition, 3 patients with IPS who were treated with anti–TNF-α antibody showed clinical improvement in their lung disease [36]. Serum levels of proinflammatory cytokines such as IL-6, IL-8, and TNF-α are increased early after HCT in patients with major transplant-related complications, including IPS [37]. Conversely, high levels of IL-10 have been associated with fewer HCT-related complications and early deaths, thus suggesting that IL-10 may play a protective role [38].

In another recent study, production of IL-1β, IL-6, IL-8, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by the alveolar macrophages in the BAL fluids of patients undergoing HCT, both before HCT and during the period of pancytopenia after HCT, was analyzed. This study found higher levels of TNF-α, GM-CSF, and IL-6 in patients who developed pulmonary complications after HCT as opposed to those who did not. GM-CSF, in particular, was believed to play an important role in maintaining the proinflammatory environment after HCT, as evidenced by its higher levels during the pancytopenic period as well [39].

Additionally, chemokines such as RANTES have been found to play a contributory role in lung injury of IPS. Increased levels of RANTES were found to coincide with increased expression of CCR1 and CCR5, the receptors for RANTES, and the use of RANTES-deficient donor T cells resulted in a significant reduction in lung injury, thereby demonstrating an important role of this chemokine in the pathophysiology of IPS. Similarly, interactions between CXCR3, a chemokine receptor, with its ligands have been shown to significantly contribute to donor T-cell recruitment to the lung after allo-HCT, and blockade of this interaction has been shown to reduce the severity of IPS in a murine bone marrow transplantation model [40].

Donor-derived TNF-α is also critical to the development of IPS, as was recently shown by Hildebrandt et al. [41]. These investigators demonstrated that allogeneic bone marrow transplantation from TNF-α^−/− donors significantly reduced the production of key chemokines, including RANTES, monokine induced by interferon γ, MIP-1α, and MCP-1. Thus, proinflammatory cytokines and chemokines play an important role in the pathogenesis of IPS.

The pathogenesis of DAH, conversely, is not known. After HCT, patients with IMSD, especially those with Hurler syndrome, have a higher risk of developing DAH. Although there has been no large series reported in the literature, small series and case reports have described post-HCT pulmonary complications such as DAH and IPS in patients with Hurler syndrome [17, 18, 20, 42].

This single-center study is the first to prospectively evaluate the risk of pulmonary complications in patients with IMSDs after HCT, as well as to begin to investigate the underlying pathogenesis in this high-risk group. Our study confirms a high risk of developing DAH and IPS after HCT in this group of patients. Although IPS was seen in patients with MPS as well as non-MPS, DAH was seen exclusively in patients with MPS in our series. DAH developed early after HCT and was found to be severe and frequently life-threatening; it typically necessitated prolonged ventilatory support. In the general HCT population, DAH is a relatively uncommon complication after HCT, with an incidence of approximately 5% [19, 20]. Various risk factors that have been associated with DAH include the pretransplantation conditioning regimen, autologous transplantation, thoracic radiation, and an older age at HCT [43].

In this study, high local concentrations of proinflammatory cytokines, including IL-1β, IL-6, IL-8, and G-CSF, were found in patients who subsequently developed noninfectious pulmonary complications compared with those who did not develop any pulmonary complications after HCT. No significant differences were found with regard to cytokine levels in the group that developed infectious pulmonary complications. Most noninfectious pulmonary complications developed in patients with MPS, including those with Hurler and Maroteaux-Lamy syndromes. It is interesting to note that significantly higher concentrations of several proinflammatory cytokines were found in the MPS group compared with the non-MPS group. However, within the MPS patients themselves, those who developed pulmonary complications after HCT did not have significant differences in the concentrations of these cytokines and chemokines. This finding suggests that other factors, in addition to these cytokines and/or other cytokines that were not evaluated in our study, may promote the development of noninfectious pulmonary complications. Other factors that may be important, such as conditioning regimen, HLA disparity, and stem cell source, could not be analyzed because of small numbers of patients within the different groups. In addition, our study did not include analysis of donor TNF-α levels, which in some very recent animal experiments have been found to play an important role in initiating pulmonary chemokine response and, ultimately, lung injury, as seen in IPS [41]. Understanding the pathophysiology of pulmonary complications in patients with IMSDs has clinical implications in terms of treatment options or even preventive strategies based on their cytokine and chemokine profiles. Corticosteroids have been traditionally used for the treatment of DAH, but whether their use would be beneficial in preventing the development of DAH by suppressing the inflammatory response in patients with Hurler syndrome is not clear.

In conclusion, patients with IMSDs are at a high risk of developing pulmonary complications after HCT. Of the IMSD patients, patients with MPS, including Hurler and Maroteaux-Lamy syndromes, are at a significantly higher risk of developing DAH after HCT than patients with other metabolic disorders. Patients with MPS have higher concentrations of proinflammatory cytokines in the BAL fluid before HCT, which could be related to the deposition of glycosaminoglycans in the lung tissue, and this, in combination with other factors, may predispose them to the development of noninfectious pulmonary complications, particularly DAH, in the early period after HCT. Further studies of larger numbers of MPS patients and, potentially, other cytokines or chemokines will be necessary to further investigate this observation.[31]

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Acknowledgments 

Supported by the Children’s Cancer Research Fund and the Vikings Children’s Research Fund.

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