Biology of Blood and Marrow Transplantation 12:949-953 (2006) 䊚 2006 American Society for Blood and Marrow Transplantation 1083-8791/06/1209-0001$32.00/0 doi:10.1016/j.bbmt.2006.05.012
Diffuse Alveolar Hemorrhage: Retrospective Review of Clinical Outcome in Allogeneic Transplant Recipients Treated With Aminocaproic Acid Sam O. Wanko,1 Gloria Broadwater,2 Rodney J. Folz,3 Nelson J. Chao1 1
Department of Medicine, Division of Cellular Therapy/BMT, 2Center for Biostatistics, and 3Division of Pulmonary, Allergy, and Critical Care, Duke University Medical Center, Durham, North Carolina Correspondence and reprint requests: Nelson Chao, MD, Duke University Medical Center, DUMC Box 3961, Durham, NC 27710 (e-mail:
[email protected]). Received March 3, 2006; accepted May 26, 2006
ABSTRACT Diffuse alveolar hemorrhage (DAH) after allogeneic hematopoietic stem cell transplantation (HSCT) is often fatal. Standard therapy with high-dose corticosteroid is not always effective. There is paucity of data in the literature about other potentially useful agents, such as aminocaproic acid (Amicar) in the post-transplantation setting. We retrospectively reviewed our data on 115 consecutive patients who underwent HSCT and had pulmonary complications, with the aim of determining the overall clinical outcome in recipients of allogeneic transplants and in the subgroup of these patients who were treated with concomitant Solu-Medrol and aminocaproic acid. Aminocaproic acid was added at the discretion of the attending physician. We identified 14 allogeneic transplant recipients (median age, 41 years) with 15 episodes of DAH who were treated with Solu-Medrol (250 mg to 1 g intravenously per day). Of these, 8 patients also received concomitant aminocaproic acid at 1000 mg intravenously every 6 hours. Failure to improve was the most common reason for adding aminocaproic acid. The incidence of DAH was 12.2% (10.3% in myeloablative versus 1.9% in nonmyeloablative recipients). The overall 100-day DAH mortality and median transplantation survival were 60% and 99 days, respectively. Among the subset of patients treated with the combination of Solu-Medrol and aminocaproic acid, we observed a 100-day DAH mortality and median transplantation survival of 44% and 167 days, respectively, compared with 83% and 96.5 days in those treated with Solu-Medrol alone. The median time to DAH was 40.5 days, and the median time to death was 53 days in the combined treatment group compared with 29.5 days in those treated with steroid alone. There were no significant differences in coagulation parameters between subsets. Infections (yeast, respiratory syncytial virus, herpes simplex virus, and parainfluenza) were isolated and treated from 6 diagnostic bronchial alveolar lavage samples and were more common in the subgroup treated with Solu-Medrol only. Respiratory failure was the documented cause of death in 89% of patients. There were no clinically significant side effects from aminocaproic acid. Although these historically lower DAH outcomes are intriguing, prospective studies are needed to confirm the role of aminocaproic acid in DAH occurring in the allogeneic transplantation setting. © 2006 American Society for Blood and Marrow Transplantation
KEY WORDS Allogeneic hematopoietic stem cell transplantation Diffuse alveolar hemorrhage
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) has become an important treatment modality for a number of hematologic malignancies and often provides the only curative option. Worldwide, nearly 50 000 allogeneic transplantations were performed for various malignancies in 2004 [1]. Pulmonary compli-
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Aminocaproic acid
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Corticosteroids
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cations occur in 30%-60% of allogeneic transplant recipients and are frequent causes of mortality [2,3]. Diffuse alveolar hemorrhage (DAH) is a recognized pulmonary complication in the allogeneic transplantation setting, although it was first described in autologous bone marrow transplantation [1]. Although the incidence of DAH in autologous and allogeneic trans949
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plantations are 5%-21% and 2%-17%, respectively [3-11], the mortality rates for allogeneic recipients can be up to 100% [2-7,10-12]. In their review of 48 patients, Afessa and colleagues [2] reported a mortality rate of 28% in the autologous group compared with 70% in allogeneic transplant recipients (P ⫽ .0040). In this series, mortality was higher (70%) for DAH that occurred 30 days after transplantation compared with DAH that occurred in the first 30 days. The risk factors and pathogenesis for DAH are not well characterized but are believed to be multifactorial. Age ⬎40 years, intensity of preparative regime, presence of proinflammatory cells and cytokines, thrombocytopenia, infections, late engraftment, and graft-versus-host disease are some of the risk factors often cited [3,5,13,14] The usual management approach for suspected DAH involves bronchoscopy for diagnosis, low- to high-dose corticosteroids, and mechanical ventilation for acute respiratory failure. Despite the widespread use of corticosteroids in DAH, its mechanism of action, efficacy, and optimal dose have not been defined in a prospective fashion. Anecdotal evidence suggests that clinical responses to corticosteroids in this setting occur within 48 hours after therapy. In part, because of the lack of uniformity in dose selection and duration of treatment, response to corticosteroid is often transient, resulting in rebleeding, progressive respiratory failure, and death, even when high doses are used [7,10]. Aminocaproic acid (Amicar, Wyeth-Ayerst, PA) is an antifibrinolytic agent that has been used to achieve hemostasis in various settings, such as dental extractions, after biopsies, cardiac surgery, and solid organ transplantation [15-19]. However, there is paucity of data in the literature about its clinical use or efficacy in DAH that occurs after HSCT.
METHODS Patients and Study Design
Electronic medical, bronchoscopic, and pharmacy records of 115 consecutive patients with hematologic malignancies who had pulmonary complications after HSCT at Duke University Medical Center (Durham, NC) between August 1999 and January 2005 were reviewed with the aim of identifying allogeneic transplant recipients with DAH, their overall clinical outcome, and the outcome in the subsets of these patients who were treated with aminocaproic acid in combination with standard corticosteroids. Fourteen patients with 15 episodes of DAH (Table 1) were identified and analyzed descriptively as a group and based on the type of DAH therapy they received. High-dose SoluMedrol (Pfizer, NY) is the standard therapy for DAH used by our transplant group, whereas aminocaproic acid was added at the discretion of the attending physicians.
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Table 1. Patient Characteristics Total number of patients Age, median (range) Gender Male Female Episodes of DAH Time of DAH diagnosis (days), median (range) Solu-Medrol treatment per episode Aminocaproic acid treatment per episode Number of days on aminocaproic acid, median (range) Indication for aminocaproic acid No improvement on Solu-Medrol Concurrent with Solu-Medrol Diagnosis AML ALL NHL CLL MDS-AML Breast cancer Type of transplant Ablative Non-myeloablative ICU admission Without intubation With intubation
14 41 (20-54) 11 3 15 40.5 (11-177) 15/15 9/15
17 (1-49) 8/9 1/9 6 3 2 1 1 1 12 2 1 3
AML indicates acute myeloblastic leukemia; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; CLL, chronic lymphoblastic leukemia; MDS-AML, myelodysplastic syndrome; ICU, intensive care unit.
Diagnosis and Treatment of DAH
Table 2 lists the bronchoscopic characteristics for all patients. DAH was diagnosed when patients’ symptoms and/or abnormal radiographs, including computed tomograms, led to bronchoscopic evaluation, in which progressively bloodier return was observed with each aliquot of bronchial alveolar lavage (BAL). All bronchoscopies were performed by a single pulmonologist (RJF), which enhanced consistency in diagnosis and therapeutic recommendation. The usual dose and schedule of Solu-Medrol was 250 mg every 6 hours tapered by 50% every 3 days, and aminocaproic acid was administered at a dose of 1000 mg intravenously every 6 hours. Statistical Analysis
The study group of 14 patients (with 15 episodes of DAH) was analyzed descriptively. The 100-day DAH mortality was defined as death in the first 100 days after the diagnosis of DAH. The time to death represents the period from DAH diagnosis to death. Transplantation survival represents the duration from stem cell infusion (day 0) to patients’ censure. KaplanMeier estimates were used to calculate median transplantation survival days.
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Diffuse Alveolar Hemorrhage
Table 2. Bronchoscopic Characteristics Number of episodes Indication for bronchoscopy per episode Hypoxia/dyspnea Abnormal radiograph Hemoptysis Median number of lobes lavaged Preprocedure platelets count (ⴛ103), median (range) Median (PT/INR/PTT) All patients Steroid-treated patients Steroids and aminocaproic acid Progressive blood return on BAL per episode BAL RBC count, median (range) WBC count, median (range) Infectious agents isolated per episode Yeast HSV Yeast, parainfluenza, RSV Parainfluenza, RSV
15 13 15 3 2 40 (12-99) 14.2/1.2/29.7 13.8/1.2/29.9 15.4/1.2/28.0 15 12,069 (50-143,750) 40 (10-5650) 6 3 1 1 1
PT indicates prothrombin time; INR, international normalized ratio; PTT, partial thromboplastin time; RBC, red blood cell; WBC, white blood cell; HSV, herpes simplex virus; RSV, respiratory syncytial virus.
RESULTS Patients’ characteristics are listed in Table 1. Fifteen episodes of DAH occurred in 14 allogeneic transplant recipients (11 men and 3 women). The incidence of DAH was 12.2% (14 of 115), with 10.3% (12 of 115) in myeloablative compared with 1.9% (2 of 115) in nonmyeloablative transplant recipients. Median age was 41 years (range, 20-54 years) and time to DAH after transplantation was 40.5 days (range, 11-177 days). Overall 100-day DAH mortality and median transplantation survival were 60% and 99 days, respectively. In the subset of patients treated with concomitant Solu-Medrol and aminocaproic acid, the 100-day DAH mortality and median transplantation survival were 44% and 167 days, respectively, compared with 83% and 96.5 days in those treated with Solu-Medrol alone. Median times to death were 53 and 29.5 days in the combined treatment and steroidonly groups, respectively. Respiratory failure was the documented cause of death in 89% of patients (8 of 9) and specific cause was not listed for 1 patient, although DAH was the terminal event. Median coagulation parameters (Table 2) were near the normal range and were similar across subsets. Two patients (1 treated with SoluMedrol and the other with combined therapy) were on low-dose heparin (100 U · kg⫺1 · d⫺1) at the time of their DAH diagnosis. Infectious agents (yeast, respiratory syncytial virus, herpes simplex virus, and parainfluenza) were isolated from 6 diagnostic BAL samples and were more common in the Solu-Medrol-only subgroup. There were no major, clinically apparent side effects from the addition of aminocaproic acid, although 1 patient had recurrent DAH in this group. Dyspnea and
abnormal radiograph were the most common reasons for bronchoscopy. Poor clinical improvement after 48 hours of Solu-Medrol therapy was the primary reason for initiating aminocaproic acid.
DISCUSSION In this study of allogeneic transplant recipients with DAH, the overall mortality of 60% is similar to the historically reported mortality of ⬎70% from other series [2,5,7]. However, in the subset of patients treated with concomitant aminocaproic acid and SoluMedrol, we observed differences in 100-day DAH mortality and overall survival of 44% and 167 days, respectively, compared with 83% and 96.5 days in those treated with Solu-Medrol alone. Although intriguing, we cannot confidently attribute these findings to the solitary effects of aminocaproic acid without further prospective examination. Nonetheless, to our knowledge, this is the first reported series on the use of aminocaproic acid for DAH occurring in the allogeneic hematopoietic transplantation setting. To be sure, this study provokes several important clinical questions that are addressed in subsequent paragraphs, which include controversy about the criteria for DAH diagnosis, the clinical significance of diagnostic BAL isolated infectious agents, the efficacy, and dose of corticosteroids, the toxicity of using aminocaproic acid, and the role of other potentially confounding factors seen in the period immediately after allogeneic transplantation. DAH remains a syndrome without standardized clinical, radiographic, or laboratory markers for diagnosis. Although we used patients’ symptoms, abnormal radiographic findings, and progressive bloody BAL on bronchoscopy as the basis for DAH diagnosis, other investigators have advocated stricter diagnostic criteria similar to those reported in autopsy series. The latter are difficult to duplicate and use in clinical practice without compromising patient care. For instance, the diagnostic criteria used by Agusti et al [13] in their autopsy review of DAH in allogeneic bone marrow transplant recipients required the presence of blood in ⱖ30% of the evaluated lung tissue and the absence of infection or other pathologic changes that could account for DAH. Such a criterion may not be feasible in living patients, even when overt hemoptysis is the initial presenting symptom. Thus, abnormal radiographs and patients’ symptoms remain the initial surrogate evidence of DAH. Similarly, progressive bloodier return of BAL on bronchoscopy, which has often been held as a higher criterion for DAH diagnosis, also has its limitations. Of the patients with confirmed DAH in the autopsy series by Agusti and colleagues [13] who had undergone bronchoscopic examination within 1 week of death, 50% had normal BAL fluid, and 54% of those without DAH had
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bloody BAL fluid. Thus, descriptive bloodier return on BAL, which is not highly specific for DAH, should be viewed in association with other suggestive clinical evidence of DAH. Therefore, DAH remains a clinical diagnosis, guided mostly by high index of suspicion. In its purest form, DAH occurs in the absence of any confounding infectious agents. However, infectious agents are often isolated from diagnostic BAL and lead to confusion about their causative role in DAH. This is especially true when other evidence of clinical infection, such as fever, productive cough, leukocytosis, parallel isolation of similar infectious agent from other body samples, or purulent bronchoscopic samples, are absent. It is known that infectious agents can be isolated from diagnostic BAL in patients without clinically apparent infections, whereas those with infectious pneumonia often have negative BAL [3,5,14]. Although infections are believed to cause DAH, there are no prospective studies that have investigated whether infectious agent isolated from BAL are directly responsible for DAH or whether treating all such infections reduces or eliminates the high mortality rates associated with DAH. In this review, yeast, respiratory syncytial virus, herpes simplex virus, and parainfluenza were the most common infections identified in 6 diagnostic BAL samples and occurred more commonly in patients treated with only Solu-Medrol. Like most centers, our group is aggressive and proactive when treating pharmacologically treatable infections isolated from diagnostic BAL, even when their clinical relevance is uncertain. Even so, the issue of infectious DAH and the effect treatment will remain unsettled in the absence of good preclinical and prospective clinical studies. The latter will, among other things, entail repeating bronchoscopies to confirm eradication of infectious agents to truly assess the correlation between eradication of BAL-isolated infection and DAH mortality [8,14,20]. For 89% of patients in this study, respiratory failure was the contributing cause of death and 1 patient did not have documented cause of death, although DAH was the terminal event. The mechanisms of action of corticosteroids in DAH is unknown but may include modulation of proinflammatory conditions induced by lung alveolar endothelial swelling, thrombotic microangiopathy, inflammatory cells and cytokines, and graft-versus-host disease [21-27]. In contrast, aminocaproic acid is a known antifibrinolytic agent with proved efficacy in various spontaneous or procedure-related bleeding conditions [15-18,28-31]. However, the nature of the balance between profibrinolytic and antifibrinolytic factors in the allogeneic transplantation setting has not been well characterized, leading us to only speculate that this balance is probably weighted toward profibrinolysis. The reported efficacy of corticosteroid for DAH in the literature is mixed. The rapidity of clinical response after therapy is also unknown, although anecdotal evidence suggests that responses in
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DAH usually occur within 48 hours. In allogeneic bone marrow transplant recipients treated with corticosteroids, Lewis and colleagues [7] reported a transient response rate of 67% and a mortality rate of 74%, leading the investigators to conclude that highdose corticosteroids have limited efficacy for DAH. Although high-dose therapy usually entails SoluMedrol, given at 1 g/day, lower doses have been studied. Metcalf et al [8] assessed the efficacy and dosing of methylprednisolone in 3 patient groups: those treated with supportive care (no treatment) versus low dose (ⱕ30 mg daily) versus high dose (ⱖ30 mg daily). The investigators found significantly improved overall survival (P ⫽ .0005) in the high-dose group compared with the other 2 groups. The prehospital discharge mortality was 91% for the supportive and low-dose corticosteroids groups compared with 67% in the high-dose group. There were no survival differences between the low-dose and supportive arms of the study. Thus, although methylprednisolone doses ⬎30 mg daily are commonly used, prospective studies have yet to determine the optimal doses of corticosteroids for DAH. Our group commonly uses high-dose SoluMedrol at 250 mg intravenously every 6 hours, with a taper of 50% every 3 days. The known side effects of aminocaproic acid are numerous and range from serious events, such as thrombosis, seizures, strokes, and dysrhythmias, to common side effects, such as headaches, cytopenias, hypertension, nausea, bleeding, and myopathy. In this study, none of these major side effects was reported during the course of aminocaproic acid therapy. However, 1 patient had recurrence of DAH, which could not be directly attributable to this agent. As is usually the case after allogeneic transplantation, nausea, cytopenias, hypertension, and headaches were common but did not worsen with initiation of aminocaproic acid. There was no significant abnormal coagulation disparity between subsets (Table 2). The major limitations of this study include its small sample and retrospective nature, which did not allow for a more rigorous control of other complex clinical factors that may have contributed to poor outcome in the period immediately after allogeneic transplantation. Therefore, we make conclusions from our observations cautiously until prospectively confirmed. Even so, the importance of our result primarily relates to difficult practical patient care issues after allogeneic transplantation, where clinical decisions such as failure to add a potentially useful agent such as aminocaproic acid in patients clinically unresponsive to corticosteroids or rapidly deteriorating might lead to avoidable adverse consequences. In summary, DAH remains a clinical diagnosis that requires a high index of suspicion to identify, especially in the complex clinical setting of allogeneic HSCT. The significance of infectious agents often
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isolated from diagnostic BAL remains unclear, although these are treated routinely. Despite widespread use of high-dose corticosteroids for DAH, mortality remains high, making the search for alternative or adjunct therapies necessary. In this small study, we have documented the interesting observation that addition of aminocaproic acid to SoluMedrol may improve DAH mortality and survival beyond what had been historically reported in other series. Additional studies are needed to prospectively determine the coagulation milieu, the optimal dose of Solu-Medrol, and the contribution of aminocaproic acid to these clinical results. REFERENCES 1. CIBMTR: Progress Report for January-December 2004. http://www.ibmtr.org/pdf/AnnualReport.pdf 2005:10. 2. Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002;166:1364-1368. 3. Roychowdhury M, Pambuccian SE, Aslan DL, et al. Pulmonary complications after bone marrow transplantation: an autopsy study from a large transplantation center. Arch Pathol Lab Med. 2005;129:366-371. 4. Chao NJ, Duncan SR, Long GD, Horning SJ, Blume KG. Corticosteroid therapy for diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Ann Intern Med. 1991;114:145-146. 5. Cordonnier C, Bernaudin JF, Bierling P, Huet Y, Vernant JP. Pulmonary complications occurring after allogeneic bone marrow transplantation. A study of 130 consecutive transplanted patients. Cancer. 1986;58:1047-1054. 6. Jules-Elysee K, Stover DE, Yahalom J, White DA, Gulati SC. Pulmonary complications in lymphoma patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev Respir Dis. 1992;146:485-491. 7. Lewis ID, DeFor T, Weisdorf DJ. Increasing incidence of diffuse alveolar hemorrhage following allogeneic bone marrow transplantation: cryptic etiology and uncertain therapy. Bone Marrow Transplant. 2000;26:539-543. 8. Metcalf JP, Rennard SI, Reed EC, et al. Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. University of Nebraska Medical Center Bone Marrow Transplant Group. Am J Med. 1994;96:327-334. 9. Nevo S, Swan V, Enger C, et al. Acute bleeding after bone marrow transplantation (BMT)—incidence and effect on survival. A quantitative analysis in 1,402 patients. Blood. 1998;91:1469-1477. 10. Raptis A, Mavroudis D, Suffredini A, et al. High-dose corticosteroid therapy for diffuse alveolar hemorrhage in allogeneic bone marrow stem cell transplant recipients. Bone Marrow Transplant. 1999;24:879-883. 11. Robbins RA, Linder J, Stahl MG, et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med. 1989;87:511-518. 12. Soubani AO, Miller KB, Hassoun PM. Pulmonary complications of bone marrow transplantation. Chest. 1996;109:1066-1077. 13. Agusti C, Ramirez J, Picado C, et al. Diffuse alveolar hemorrhage in allogeneic bone marrow transplantation. A postmortem study. Am J Respir Crit Care Med. 1995;151:1006-1010.
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