Volume 12, Issue 10 , Pages 1038-1046, October 2006
Diffuse Alveolar Hemorrhage and Infection-Associated Alveolar Hemorrhage following Hematopoietic Stem Cell Transplantation: Related and High-Risk Clinical Syndromes
Article Outline
Abstract
Diffuse alveolar hemorrhage (DAH) is a noninfectious pulmonary complication of hematopoietic stem cell transplantation (HSCT) with unclear pathogenesis and treatment. We reviewed prospectively collected data on 1919 consecutive transplants performed between 1995 and 2004 and compared patients with DAH and infection-associated alveolar hemorrhage (IAH) who presented with similar symptoms of hypoxemia, pulmonary infiltrates, and progressively bloody alveolar lavage but also had microorganisms isolated from blood, bronchoalveolar lavage, or tracheal aspirate within 1 week of alveolar hemorrhage. Overall, 116 patients had alveolar hemorrhage (45 with DAH, 71 with IAH). Older age, allogeneic donor source, myeloablative conditioning regimen, and acute severe graft-versus-host disease (GVHD) were independently predictive of an increased risk of post-HSCT alveolar hemorrhage. The DAH and IAH groups were comparable except for a higher proportion of patients receiving umbilical cord blood as a donor source and total-body irradiation–containing conditioning in the IAH group. The probability of 60-day survival from onset of hemorrhage was 16% (95% CI, 6%–26%) for the DAH and 32% (95% CI, 21%–43%) for the IAH group (P = .08). All except 20 patients were treated with a standard regimen of high-dose corticosteroids. Patients who received corticosteroids had 60-day survival of 26% (95% CI, 18%–34%), compared with 25% (95% CI, 6%–44%) for those who did not (P = .28). The pathogenesis of alveolar hemorrhage after HSCT is multifactorial, and we propose that IAH and DAH in HSCT recipients are related clinical syndromes with similar clinical presentation, risks, and associated high mortality.
Key Words: Hematopoietic stem cell transplantation, Complications, Alveolar hemorrhage, Diffuse alveolar hemorrhage, Infection-associated alveolar hemorrhage
Introduction
Alveolar hemorrhage, a clinical syndrome characterized by the acute onset of alveolar infiltrates and hypoxemia, is diagnosed by the presence of progressively bloodier alveolar lavage on bronchoscopy [1, 2]. Alveolar hemorrhage occurring in hematopoietic stem cell transplantation (HSCT) recipients in the absence of an identifiable infection is called diffuse alveolar hemorrhage (DAH). The reported incidence of DAH after HSCT ranges from 1% to 5% in autologous graft recipients and from 3% to 7% in allogeneic graft recipients [3, 4, 5]. The majority of patients with DAH develop severe respiratory failure, with mortality rates of 70% or higher [3, 4, 5, 6, 7].
DAH originates from the pulmonary microvasculature and is postulated to be a response to alveolar injury; however, the exact etiology of DAH in HSCT remains unknown. Vascular damage and inflammation from chemotherapy and radiation therapy used in the conditioning regimen, and immune-mediated events, including graft-versus-host disease (GVHD), have been implicated in its pathogenesis [3, 5, 8, 9]. Although pulmonary and systemic infections cause alveolar damage through similar mechanisms [10], infection-associated alveolar hemorrhage (IAH) has traditionally been excluded from analyses of DAH. Autopsy studies have shown that pulmonary infections are frequently underdiagnosed in HSCT recipients [11, 12, 13], and hence patients with alveolar hemorrhage and underlying undetected infections can be misclassified as having DAH. We hypothesized that alveolar hemorrhage after HSCT is multifactorial in origin and that both infectious and noninfectious etiologies play important roles in its pathogenesis. Consequently, we compared the clinical courses and outcomes of DAH and IAH.
Risk factors for developing alveolar hemorrhage have not been studied; the literature focuses largely on the incidence and outcomes of alveolar hemorrhage after HSCT. Therefore, we also conducted a risk factor analysis to define factors associated with the development of alveolar hemorrhage in HSCT recipients.
Materials and methods
Patients
Prospectively collected data from the University of Minnesota Bone Marrow Transplant Biostatistics Database was reviewed for pulmonary complications in 1919 patients who underwent HSCT between January 1995 and December 2004. One or more pulmonary complications occurred in 1122 patients undergoing HSCT over this 10-year period; pulmonary hemorrhage as was identified in 229 of these patients. Database information for the 229 patients was supplemented by a review of medical records.
Alveolar hemorrhage was diagnosed by strict clinical criteria, which included acute onset of hypoxemia with presence of diffuse pulmonary infiltrates on a chest X-ray or computed tomography scan and the presence of progressively bloodier return on bronchoalveolar lavage (BAL). In the absence of any identifiable infection within 1 week of diagnosis of alveolar hemorrhage, the diagnosis of DAH was made. Patients who presented with similar hypoxemia, pulmonary infiltratesm and progressively bloodier BAL but also had microorganisms (excluding Aspergillus spp) isolated from blood, BAL, or tracheal aspirate within 1 week of alveolar hemorrhage were classified as having IAH.
Of the 229 patients with suspected pulmonary hemorrhage, 116 met the study criteria for alveolar hemorrhage. The 113 excluded cases consisted of 57 patients diagnosed only by clinical or radiologic findings without concurrent BAL, 31 patients with diagnosis made on autopsy without antemortem BAL, and 6 patients with invasive aspergillosis. Also, among the patients who underwent bronchoscopy, 16 were excluded because the BAL findings did not meet our study definition of alveolar hemorrhage, and another 3 were excluded because the BAL was negative and the diagnosis was made by transbronchial lung biopsy only.
Study Methods
BAL was performed in all patients during fiberoptic bronchoscopy. Aliquots of saline were successively instilled and aspirated and then visually examined to detect the presence of alveolar hemorrhage. BAL fluid for all patients was submitted for cytological and microbiological examination. Cytological evaluation included specimen review using potassium hydroxide, Giemsa, and Papanicolaou stains. Appropriate microbiological and cytological examinations for bacteria, fungi, mycobacteria, Pneumocystis carinii, and viruses were also performed for all patients. In some intubated patients, in addition to BAL, tracheal aspirates for microbiological examination were also obtained within 1 week of diagnosis of alveolar hemorrhage. These specimens were submitted for similar cytological and microbiological examinations as for BAL fluid. Blood was also routinely sent for bacterial and fungal cultures.
Treatment of Alveolar Hemorrhage
Supportive measures for the management of alveolar hemorrhage included correction of platelet and coagulation abnormalities, careful maintenance of fluid and electrolyte balance, and aggressive ventilatory and oxygen support. All patients received prophylactic and empiric antimicrobial agents as clinically indicated; patients with IAH also received appropriate antibiotics to treat the underlying infection. Corticosteroids, if administered, consisted of a standard regimen of high-dose methylprednisolone, 500 mg twice a day for 3 days, followed by 250 mg twice a day for 3 days, 125 mg twice a day for 3 days, 60 mg twice a day for 3 days, and then 60 mg once a day tapered off over a 2-month period.
Study Definitions and Statistical Analysis
The time of neutrophil engraftment was defined as the first of 3 consecutive days with an absolute neutrophil count ≥ 0.5 × 109/L. The period within 5 days of neutrophil engraftment was defined as the periengraftment period. For this study, onset of hemorrhage within 30 days of HSCT was classified as early alveolar hemorrhage, whereas that occurring after 30 days was classified as late alveolar hemorrhage. A second hemorrhage occurring in the same patient more than 30 days after the initial episode was classified as recurrent alveolar hemorrhage; hemorrhage recurring within 30 days was considered part of the initial episode.
For risk factor analysis, the source cohort included all 1919 patients who received HSCT at the University of Minnesota between 1995 and 2004. However, patients who were listed as having “pulmonary hemorrhage” in the database but did not meet our study definition of alveolar hemorrhage (n = 113) were excluded. The following exposures were investigated for association with risk of developing alveolar hemorrhage after HSCT using Cox regression analysis [14] in the remaining 1806 patients: age at transplantation, sex, donor source (autologous vs allogeneic), intensity of conditioning regimen (myeloablative vs reduced intensity), use of total-body irradiation (TBI) or busulfan in the conditioning regimen, and history of severe (grade 3 or 4) acute GVHD (time-dependent analysis). Risk factor analysis using this model was also performed separately for DAH and IAH.
Among the smaller combined group with DAH or IAH, Cox regression analysis was also performed to identify factors influencing survival beyond 60 days of the onset of alveolar hemorrhage. The following potential prognostic variables were considered in the forward-stepwise regression model: age at HSCT, sex, presence of infection, donor source, intensity of conditioning regimen, use of TBI, use of busulfan, time to hemorrhage from HSCT, time between hemorrhage and engraftment, absolute neutrophil count at the time of hemorrhage, presence of acute GVHD (time-dependent analysis), and corticosteroid use.
The cumulative incidence of alveolar hemorrhage was calculated by treating deaths from other causes as competing risks [15]. Comparison of patient characteristics was done using the χ2 test or Fisher’s exact test for categorical variables and Wilcoxon’s rank-sum test for continuous variables [16]. The probability of overall survival at 60 days from the onset of DAH was calculated using the Kaplan-Meier method [17], with 95% confidence intervals (CIs) derived from the standard errors; survival curves were compared using the log-rank test. All P values reported are 2-sided, and a P values < .05 were considered statistically significant. Data analysis was performed using SAS software, version 8.0 (SAS Institute, Cary, NC). The analysis was performed in December 2005.
Results
Patient Characteristics
Table 1 details patient and transplant characteristics for the 116 cases of alveolar hemorrhage. The median age at onset of alveolar hemorrhage was 40 years (range, 0.6–71 years). Most of the patients (89%) received an allogeneic HSCT. The indications for HSCT included acute myeloid leukemia (n = 29), chronic myeloid leukemia (n = 23), non-Hodgkin’s lymphoma (n = 16), myelodysplastic and myeloproliferative disorders (n = 12), acute lymphocytic leukemia (n = 9), Hodgkin’s lymphoma (n = 8), Fanconi’s anemia (n = 7), chronic lymphocytic leukemia (n = 2), multiple myeloma (n = 1) and other metabolic disorders (n = 9). The median time to onset of alveolar hemorrhage from HSCT was 28 days (range, 3 days–26 months); 55 (47%) patients had late-onset alveolar hemorrhage. Severe hemorrhage requiring intubation and ventilatory support occurred in 85% of the patients.
Table 1. Patient and Transplant Characteristics (All Patients and DAH vs IAH)
| Characteristics | All Patients (n = 116) (%) | DAH (n = 45) (%) | IAH (n = 71) (%) | P⁎ |
|---|---|---|---|---|
| Age | ||||
 Median (years) | 40 | 37 | 41 | .51 |
| Range (years) | 0.6–71 | 0.6–71 | 0.6–63 | |
| Sex | ||||
| Male | 70(60) | 25(56) | 45(63) | .40 |
| Female | 46(40) | 20(44) | 26(37) | |
| Time to hemorrhage from HSCT | ||||
| Median (days) | 28 | 21 | 31 | .22 |
| Range (days) | 3–785 | 5–785 | 3–450 | |
| Type of HSCT | ||||
| Autologous | 13(11) | 7(16) | 6(8) | .04 |
| MSD | 49(42) | 18(40) | 31(44) | |
| MUD | 28(24) | 15(33) | 13(18) | |
| UCB | 26(23) | 5(11) | 21(30) | |
| Stem cell source | ||||
| BM | 48(41) | 20(44) | 28(39) | .06 |
| PBSC | 42(36) | 20(44) | 22(31) | |
| UCB | 26(23) | 5(11) | 21(30) | |
| Conditioning regimen | ||||
| Busulfan | 17(15) | 9(20) | 8(11) | .19 |
| No busulfan | 99(85) | 36(80) | 63(89) | |
| Conditioning regimen | ||||
| TBI | 98(84) | 34(76) | 64(90) | .04 |
| No TBI | 18(16) | 11(24) | 7(10) | |
| Conditioning regimen | ||||
| Myeloablative | 98(84) | 39(87) | 59(83) | .61 |
| RIC | 18(16) | 6(13) | 12(17) | |
| Acute GVHD | ||||
| Yes | 47(41) | 14(31) | 33(46) | .10 |
| No | 69(59) | 31(69) | 38(54) | |
| Absolute neutrophil count at time of hemorrhage (× 109/L) | ||||
| Median | 1.7 | 1.6 | 1.7 | .50 |
| Range | <0.1–39.1 | <0.1–39.1 | <0.1–29.9 | |
| Time to engraftment | ||||
| Median (days) | 17 | 15 | 18 | .09 |
| Range (days) | 6–94 | 6–29 | 7–94 | |
| Time between hemorrhage and engraftment† | ||||
| Pre-engraftment | 25(21) | 9(20) | 16(22) | .70 |
| Periengraftment | 31(27) | 14(31) | 17(24) | |
| Postengraftment | 60(52) | 22(49) | 38(54) | |
| Use of corticosteroids | ||||
| Yes | 96(83) | 41(91) | 55(78) | .06 |
| No | 20(17) | 4(9) | 16(22) | |
| Need for intubation and ventilatory support | ||||
| Yes | 99(85) | 41(91) | 58(82) | .16 |
| No | 17(15) | 4(9) | 13(18) |
⁎P value for comparison between DAH and IAH. |
†Pre-engraftment, hemorrhage more than 5 days before engraftment; periengraftment, hemorrhage within 5 days of engraftment; postengraftment, hemorrhage more than 5 days after engraftment. |
Alveolar Hemorrhage: Incidence
A total of 114 cases of alveolar hemorrhage occurred in the 1919 patients who underwent transplantation between 1995 and 2004. (Two patients who underwent transplantation in 2004 but developed hemorrhage in 2005 were excluded from the incidence analysis.) Overall, the cumulative incidence of alveolar hemorrhage at 180 days after HSCT was 5% (95% CI, 4%–6%). The 180-day cumulative incidence was 2% (95% CI, 1%–3%) for DAH and 4% (95% CI, 3%–5%) for IAH (Figure 1A). According to donor source, the 180-day cumulative incidence of alveolar hemorrhage was 2% (95% CI, 1%–3%) for autologous donor, 8% (95% CI, 6%–10%) for matched sibling donor, 6% (95% CI, 4%–8%) for matched unrelated donor, and 7% (95% CI, 5%–9%) for unrelated umbilical cord blood HSCT (P < .01 for all pairwise comparisons between autologous and each allogeneic donor source) (Figure 1B).
Figure 1.
Cumulative incidence of alveolar hemorrhage according to (A) type of hemorrhage (DAH vs IAH) and (B) donor source (autologous [Auto] vs matched sibling donor [MSD] vs matched unrelated donor [MUD] vs unrelated umbilical cord blood [UCB]).
Alveolar Hemorrhage: DAH versus IAH
A total of 45 patients met the strict study definition of DAH, and 71 patients were diagnosed with IAH. The 2 groups were comparable except for a higher proportion of patients receiving unrelated umbilical cord blood transplant (30% vs 11%; P = .04) and TBI-containing conditioning regimens (90% vs 76%; P = .04) in the IAH cohort (Table 1). There was no significant difference in time to hemorrhage from HSCT, time to neutrophil engraftment, time between hemorrhage and neutrophil engraftment, absolute neutrophil count at the onset of hemorrhage, and rate of acute GVHD between the 2 groups.
Microorganisms were isolated from BAL or tracheal aspirate only in 50 patients, from blood only in 12 patients, and from both respiratory and blood specimens in 9 patients; 10 patients had polymicrobial infection. A total of 67 microorganisms were identified in 59 patients with positive BAL or tracheal aspirate, including coagulase-negative Staphylococcus spp. (n = 18), Enterococcus spp. (n = 12), cytomegalovirus (n = 8), Candida albicans (n = 6), Candida glabrata (n = 4), Pseudomonas aeruginosa (n = 4), Staphylococcus aureus (n = 4), respiratory syncytial virus (n = 3), Enterobacter cloacae (n = 2), Streptococcus viridans (n = 2), adenovirus (n = 1), Hemophilus influenzae (n = 1), Saccharomyces cerevisiae (n = 1), and Pneumocystis carinii (n = 1). Among the 21 patients with positive blood cultures, 22 organisms were isolated, including coagulase-negative Staphylococcus spp. (n = 9), Enterococcus spp. (n = 4), Pseudomonas aeruginosa (n = 4), Candida krusei (n = 1), Corynebacterium spp. (n = 1), Escherichia coli (n = 1), Staphylococcus aureus (n = 1), and Streptococcus viridans (n = 1).
Survival at 60 days from the onset of hemorrhage was 16% (95% CI, 6%–26%) for the DAH group and 32% (95% CI, 21%–43%) for the IAH group (P = .08) (Figure 2A). Within the IAH group, patients with respiratory infections had a 60-day survival of 34% (95% CI, 22%–46%) compared to 25% (95% CI, 0–53%) in those with positive blood cultures only (P = .20). The 60-day survival did not differ significantly among patients with bacterial infections (33%; 95% CI, 20%–46%), patients with fungal infections (38%; (95% CI, 4%–72%), and patients with viral infections (36%; 95% CI, 8%–64%) (P = .87). Three patients with polymicrobial infections due to a combination of bacteria, fungi, and viruses were excluded from this analysis.
Figure 2.
Survival at 60 days from the onset of alveolar hemorrhage. (A) DAH versus IAH. (B) Early-onset (≤ 30 days) versus late-onset (> 30 days) hemorrhage. (C) Time between hemorrhage and engraftment (hemorrhage > 5 days before engraftment (pre-engraftment) versus within 5 days of engraftment (periengraftment) versus > 5 days after engraftment (postengraftment). (D) Use of high-dose corticosteroids.
Survival and Prognostic Factors
Overall, 86 patients (74%) died within 60 days and 92 patients (79%) died within 180 days from the onset of alveolar hemorrhage; the median time from onset of hemorrhage to death was 15 days (range, 1–166 days). The probability of overall survival at 60 days from the onset of alveolar hemorrhage for the whole cohort was 26% (95% CI, 18%–34%) (Figure 3).
Figure 3.
Overall survival from the onset of alveolar hemorrhage (all patients).
Of the 24 patients surviving beyond 180 days of alveolar hemorrhage, 13 are still alive with a median follow-up of 50 months (range, 12–100 months). The causes of death in the remaining 11 patients were relapse of primary disease (n = 6), chronic GVHD (n = 3), and infection (n = 2). None of these 24 patients experienced any long-term major pulmonary sequelae. Results of pulmonary function tests done pretransplantation and beyond 6 months after alveolar hemorrhage were available for comparison in 7 patients. The mean (± standard deviation) drop in forced expiratory volume in 1 second was 1% ± 13% (P = .25), that of forced vital capacity was 6% ± 23% (P = .45), and that of diffusing capacity of the lung for CO2 was 32% ± 22% (P = .11).
Univariate analysis found that early-onset alveolar hemorrhage and hemorrhage occurring in the periengraftment period were associated with a favorable outcome (Table 2). Patients with early-onset alveolar hemorrhage had 60-day survival of 34% (95% CI, 22%–46%), compared with 16% (95% CI, 6%–26%) for patients with late-onset hemorrhage (P = .02) (Figure 2B). The 60-day survival for patients with hemorrhage occurring in the periengraftment period was 48% (95% CI, 31%–65%), compared with 24% (95% CI, 7%–41%) for those with onset before 5 days of engraftment and 15% (95% CI, 6%–24%) for those with onset after 5 days of engraftment (P < .01) (Figure 2C). Time between hemorrhage and engraftment was the only factor independently predictive of overall survival in Cox regression analysis; onset of alveolar hemorrhage in the periengraftment period correlated with a better 60-day survival (relative risk, 0.5; 95% CI, 0.3–0.8; P < .01).
Table 2. Univariate Analysis of Factors Influencing Survival at 60 Days from the Onset of Alveolar Hemorrhage
| Percent 60-day Survival (95% CI) | |||
|---|---|---|---|
| Factor | All Patients (n = 116) | DAH (n = 45) | IAH (n = 71) |
| Overall | 26(18–34) | 16(6–26) | 32(21–43) |
| Age at HSCT | |||
| ≤45 years | 24(14–34) | 17(3–21) | 28(15–41) |
| >45 years | 30(17–43) | 13(0–29) | 39(21–57) |
| Donor type | |||
| Autologous | 23(0–46) | 0 | 50(10–90) |
| Allogeneic | 26(18–34) | 18(6–30) | 31(20–42) |
| Donor source | |||
| Autologous | 23(0–46) | 0 | 50(10–90) |
| Matched related donor | 28(16–40) | 22(3–41) | 32(16–48) |
| Matched unrelated donor | 21(6–36) | 20(0–40) | 23(0–46) |
| Umbilical cord blood | 28(10–46) | 0 | 33(13–53) |
| Time to hemorrhage from HSCT | |||
| Early onset (≤30 days) | 34(22–46)⁎ | 18(4–32) | 46(29–63)⁎ |
| Late onset(>30 days) | 16(6–26)⁎ | 12(0–27) | 20(7–33)⁎ |
| Time between hemorrhage and engraftment‡ | |||
| <5 days | 24(7–41)† | 0⁎ | 38(14–62)⁎ |
| ±5 days | 48(31–65)† | 36(11–61)⁎ | 59(36–82)⁎ |
| >5 days | 15(6–24)† | 9(0–21)⁎ | 18(6–30)⁎ |
| Conditioning regimen§ | |||
| Myeloablative | 26(17–35) | 22(8–36) | 28(16–40) |
| Reduced-intensity | 28(7–49) | 0 | 42(14–70) |
| Steroids | |||
| Received | 26(18–34) | 15(4–26) | 35(22–48) |
| Not received | 25(6–46) | 25(0–67) | 25(4–46) |
⁎P < .05 for within-group comparison. |
†P < .01 for within-group comparison. |
‡<5 days, hemorrhage occurring pre-engraftment; ±5 days, hemorrhage occurring periengraftment; >5 days, hemorrhage occurring postengraftment. |
§Allogeneic HSCT only (n = 103). |
Risk Factors for Development of Alveolar Hemorrhage
The results of Cox regression analysis for variables associated with increased risk of alveolar hemorrhage after HSCT are given in Table 3. Older age, allogeneic donor source, myeloablative conditioning regimen, and severe acute GVHD were independently associated with increased incidence of post-HSCT alveolar hemorrhage.
Table 3. Multivariate Analysis of Factors Associated with an Increased Risk of Alveolar Hemorrhage, DAH and IAH Following HSCT
| Variable | All Patients | DAH | IAH |
|---|---|---|---|
| Age (per decade) | 1.4 (1.2–1.6) | 1.2 (1.1–1.6) | 1.5 (1.3–1.7) |
| p<0.01 | p<0.01 | p<0.01 | |
| Donor type | |||
| Allogeneic | 1.0 | 1.0 | 1.0 |
| Autologous | 0.2 (0.1–0.3) | 0.2 (0.1–0.6) | 0.1 (0.04–0.3) |
| p<0.01 | p<0.01 | p<0.01 | |
| Conditioning regimen1 | |||
| Myeloablative | 1.0 | 1.0 | 1.0 |
| Reduced-intensity | 0.5 (0.3–0.9) | 0.6 (0.2–1.5) | 0.5 (0.2–1.0) |
| p=0.03 | p=0.24 | p=0.05 | |
| Severe acute GVHD1 | |||
| Absent | 1.0 | 1.0 | 1.0 |
| Present | 2.5 (1.3–4.8) | 1.9 (0.6–6.6) | 2.9 (1.4–6.1) |
| p<0.01 | p=0.29 | p<0.01 |
1Allogenic HSCT only. |
Efficacy of Corticosteroids
Overall, 96 (83%) patients were treated with a standardized regimen of intravenous high-dose methylprednisolone. A higher proportion of patients received this regimen in the DAH group than in the IAH group (91% vs 71%; P = .06). The 60-day survival from the onset of alveolar hemorrhage was 26% (95% CI, 18%–34%) for patients who received high-dose methylprednisolone, compared with 25% (95% CI, 6%–44%) for those who did not (P = .28) (Figure 2D). Furthermore, use of high-dose methylprednisolone was not associated with a significant difference in the 60-day survival in the DAH, IAH, and early-onset hemorrhage subgroups.
Discussion
Pulmonary complications are among the most common causes of morbidity and mortality in HSCT recipients. Alveolar hemorrhage is a posttransplantation pulmonary complication associated with a particularly fulminant clinical course and high mortality.
The etiopathogenesis of alveolar hemorrhage in the post-HSCT setting remains largely unknown; the current paradigm is based on DAH observed in the nontransplantation setting. The prototypical disorders for nontransplantation DAH are the systemic vasculitides and collagen vascular diseases, where alveolar injury and capillaritis due to various immune-mediated mechanisms leads to damage to the alveolar microcirculation [18]. However, alveolar hemorrhage in the posttransplantation setting is multifactorial in origin. Besides similar immune-mediated injury, other putative mechanisms of small-vessel damage after HSCT include vasculopathy due to high-dose chemotherapy, radiation therapy, or GVHD [3, 5, 9]; thrombotic microangiopathy [19]; effect of inflammatory mediators [3, 20]; and alterations in cardiopulmonary hemodynamics in the peritransplantation period. Infections frequently occur in the posttransplantation period and are potentially significant contributors to the pathogenesis of this syndrome. Current techniques of BAL may miss certain infections; autopsy studies have shown high rates of occult pulmonary infections in HSCT recipients [11, 12, 13]. Emerging pathogens, such as human herpesvirus-6 (HHV-6), which are not regularly sought in the BAL fluid, might also contribute to its development. The contemporary literature on alveolar hemorrhage after HSCT has focused primarily on DAH and has excluded patients with underlying infections. We found no differences between the clinical syndromes of DAH and IAH with respect to presentation, response to corticosteroids, and overall outcome. We suggest that clinically distinguishing DAH and IAH in HSCT recipients is difficult. The approach to posttransplantation alveolar hemorrhage needs to reflect this entity’s diverse and complex pathogenesis.
Coagulase-negative Staphylococcus spp. was the most commonly isolated organism in the IAH group. Establishing the pathogenicity of this less virulent organism in HSCT recipients can be a challenge; however, we used strict criteria for diagnosing infections, and it is unlikely that this organism’s isolation from BAL fluid represented mere contamination. Furthermore, even colonization of the deep bronchial airways and alveolar epithelium by such microbes could play a role in the development of this syndrome. We speculate that microorganisms could potentiate alveolar injury caused by chemotherapy, radiation therapy, and GVHD. In addition, they could independently cause local inflammation and increase alveolar permeability. The heterogeneity of microorganisms recovered in the IAH group, particularly from pulmonary specimens, points to the difficulty in attributing posttransplantation alveolar hemorrhage to infection or DAH. These observations again highlight the overlap between DAH and IAH.
Factors independently predictive of increased incidence of alveolar hemorrhage after HSCT were older age, allogeneic donor source, use of myeloablative conditioning, and presence of severe acute GVHD. Each of these risk factors has the potential to either cause lung injury or make the lungs more susceptible to other insults. In addition, infections (particularly respiratory infections) may be important contributing factors to the risk of posttransplantation alveolar hemorrhage.
In our study, patients with early-onset alveolar hemorrhage, particularly hemorrhage in the periengraftment period, had better survival. In a retrospective study of 48 patients, Afessa et al [21] also found an association between early-onset DAH and lower mortality. The reason for this observation is unclear; however, it can be speculated that the more favorable outcome in this cohort of patients might be related to the transient nature of periengraftment “cytokine storm” occurring due to release of inflammatory mediators from recovering neutrophils, compared with other mechanisms of alveolar hemorrhage in which alveolar injury tends to be more sustained.
Because inflammation is thought to play a role in the pathogenesis of post-HSCT DAH, high-dose corticosteroids have been widely used for its treatment. However, their use originates from a few case reports and small retrospective series [6, 22, 23], and there are no well-designed clinical trials investigating their role in this disorder. The use of high-dose corticosteroids has not altered the poor outcome associated with this syndrome, and mortality rates remain unchanged at 70%–100% [4, 6, 7, 24, 25]. The overall mortality rate at 60 days from the onset of hemorrhage was 74% in our study and was unaffected by the use of corticosteroids, for both DAH and IAH. However, although all of the patients in our cohort received a standard regimen of high-dose corticosteroids, the overall benefit of this therapy needs to be interpreted cautiously in view of the retrospective nature of our analysis.
There remains an urgent need for newer agents to treat posttransplantation alveolar hemorrhage. There are case reports describing the use of recombinant factor VIIa for the management of post-HSCT DAH [26, 27, 28]; however, limited and mostly anecdotal experience suggest that it should be used cautiously. A better understanding of the pathogenetic mechanisms of transplantation-associated alveolar hemorrhage could lead to development of more effective therapies. Because cytokine release during engraftment and the presence of airway inflammation are postulated mechanisms for this syndrome, management with cytokine antagonists (eg, anti–tumor necrosis factor, interleukin-1) and anti-inflammatory agents may merit formal study.
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PII: S1083-8791(06)00408-3
doi:10.1016/j.bbmt.2006.06.002
© 2006 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 12, Issue 10 , Pages 1038-1046, October 2006
