155 Hematopoietic Stem Cell Transplantation Patient
Bone marrow transplantation was developed as a treatment for hematologic malignancies in the early 1970s. Since peripheral blood stem cells or umbilical cord blood can be used as sources of donor stem cells, the term bone marrow transplantation has been replaced by the more inclusive hematopoietic stem cell transplantation (HSCT). The use of peripheral blood stem cells provides a shorter duration of neutropenia and more rapid hematopoietic reconstitution, which may reduce some of the infectious and bleeding complications.1 Worldwide in 2006, approximately 50,000 to 60,000 patients received an HSCT. Of these, peripheral blood was the most common source in adults. Approximately 45% of all allogeneic transplants were from unrelated donors. Between 2003 and 2007, 10% of HSCT recipients were older than 60 years. Given that the indications for HSCT are increasing, older patients receiving an HSCT will likely increase as well. The most common indications for HSCT in general are multiple myeloma and lymphoma, while acute myeloid leukemia is the most common reason for allogeneic HSCT.2 HSCT has also been used as a treatment for aplastic anemia and hemoglobinopathies as well as cancers of the breast, ovaries, and testicles.
The immune system fully recovers over a period of several months; rapidity is dependent on the type of transplant (autologous or allogeneic) as well as source of stem cells, with peripheral blood generally being the earliest, and umbilical cord blood being the longest. Other factors that impact on immune reconstitution include age of the recipient, conditioning regimen (myeloablative versus non-myeloablative), graft-versus-host disease (GVHD) status, use of immunosuppressive medications, and donor’s age and gender.3
Immune reconstitution occurs in three rough timeframes. Phase I (preengraftment) occurs between days 0 and 30, and host risk factors for infection and includes prolonged neutropenia and disruption in mucocutaneous barriers due to mucositis or vascular access devices. Phase II (early postengraftment) occurs from days 30 to 100, at which time cell-mediated immunity is impaired. Pathogens including cytomegalovirus (CMV), Pneumocystis jirovecii (formerly Pneumocystis carinii), and Aspergillus spp. are the predominant causes of infection. Phase III (late postengraftment) occurs beyond 100 days and is of particular risk for allogeneic patients with chronic GVHD or alternative donors (matched unrelated, umbilical cord blood, or mismatched related donor) because of impaired function of the reticuloendothelial system as well as cell-mediated and humoral defects. Patients are at risk for infection from encapsulated bacteria, gram-negative bacilli, CMV, varicella-zoster virus (VZV), and Epstein-Barr virus (EBV).4 Over the following year, there is further gradual reconstitution.
Various series have reported rates of intensive care unit (ICU) admission ranging from 5% to as high as 55%, with lower rates in autologous HSCT.5 In one study of umbilical cord blood recipients, 57% required ICU admission, which was most likely to be predicted by the preparative regimen, while a higher number of infused nucleated cells appeared to be protective from ICU transfer.6 Complications of HSCT that require ICU care develop in up to 40% and often involves the lung.7,8 Respiratory manifestations account for up to 58% of ICU admissions of HSCT recipients,5 and almost half of those require mechanical ventilation. Certain pulmonary complications are unique to the HSCT patient, including cumulative lung damage from repeated chemotherapy and radiation, pulmonary infections from immunosuppression, and lung manifestations of the underlying hematologic disease.9 Other reasons for ICU admission include septic shock, hypotension, mucositis, cardiac dysfunction, neurologic complications, bleeding, and hepatic veno-occlusive disease.7,10 Less common primary reasons for ICU admission include seizures, intracranial or gastrointestinal bleeding, or renal failure.5
Risk factors for ICU admission include conditioning with total body irradiation, posttransplant immunosuppression, visceral organ toxicity, and GVHD.11 A number of risk factors for mechanical ventilation per se have been identified, including older age, hematologic disease in relapse at the time of transplantation, and receipt of a mismatched HSCT graft.12 The complications that may result in critical illness are shown in Boxes 155-1 and 155-2. Space does not permit in-depth discussion of all these issues, so this chapter will focus on the pulmonary complications of HSCT and discuss bronchoscopy, hepatic veno-occlusive disease, outcomes, prognosis, and triage.
Box 155-1
Complications of Hematopoietic Stem Cell Transplantation That May Lead To Intensive Care
Box 155-2
Timeline of Complications After Hematopoietic Stem Cell Transplantation
Pulmonary Infections
Pulmonary complications can occur in up to 50% of patients undergoing HSCT13; they are more frequent in recipients of allogeneic or matched unrelated transplants than in those receiving autologous transplants. Pneumonia that develops during the first 100 days after HSCT is usually caused by gram-negative enteric bacilli (see Box 155-1). As the immune system recovers and the patient spends less time in the hospital, this pattern changes, and gram-positive organisms become more common. CMV infection used to be a major cause of pulmonary morbidity and mortality in the HSCT population. The introduction of CMV antigen surveillance and the use of preemptive treatment with ganciclovir have reduced the incidence of CMV pneumonitis to less than 10%.14 The incidence of P. jirovecii pneumonia in the HSCT population has also been reduced to about 2% with effective use of antibiotic prophylaxis.15
Despite these advances, prevention and treatment of invasive fungal infection remains a serious problem in this population. Invasive pulmonary aspergillosis remains the leading cause of infectious death in recipients of allogeneic or matched unrelated transplants,16 despite the development of newer antifungal agents such as caspofungin and voriconazole.17,18 The role of combination antifungal therapy remains unclear, owing to the lack of a well-controlled prospective trial. However, expert consensus recognizes the role of this strategy as salvage therapy in which case agents of different classes should be used.19
Additionally, the recently described human metapneumovirus has been reported to cause mild to severe respiratory disease in HSCT recipients. Infections can occur as early as at the time of transplantation up to 4 years later and most commonly occurs in the late winter or early spring months.20,21 The immunocompromised HSCT population is also vulnerable to outbreaks of pneumonia from Legionella pneumophila22 and respiratory syncytial virus.
Noninfectious Pulmonary Disease
Acute adverse reactions can occur during stem cell infusions and range from benign symptoms such as nausea, vomiting, asymptomatic hypotension, and arrhythmias to more serious complications such as cerebrovascular ischemia, malignant cardiac arrhythmias, acute renal failure, and sudden death.23–27 The causes and mechanisms are unclear, but recipient age, dimethylsulfoxide (DMSO) concentration, and content of non-mononuclear cells in the stem cell mixture, as well as histamine and other byproducts of cell lysis, have been implicated.27,28 Infusion of DMSO-washed stem cells under cardiac monitoring or in the ICU is occasionally advocated for high-risk patients. However, the administration of antihistaminic agents and close observation in the ICU does not mitigate the risks of significant adverse reactions, because the pathophysiology is likely multifactorial. Treatment is often supportive.
Respiratory failure that develops within days after transplantation may be caused by cardiogenic pulmonary edema. There is usually a brisk response to aggressive treatment, and intubation and mechanical ventilation can sometimes be avoided. Pulmonary edema causing respiratory failure in the HSCT recipient is a positive predictor of survival in those requiring mechanical ventilation.29 The large volumes of intravenous (IV) fluids and blood products used during HSCT can increase the circulating blood volume. Additionally, cyclophosphamide is commonly used in the preparative regimen and may cause acute cardiac toxicity.30 Findings that suggest cardiogenic pulmonary edema include diffuse pulmonary infiltrates, a rapid response to diuretics, and reduced left ventricular ejection fraction on echocardiogram. The risk/benefit ratio of hemodynamic monitoring with a pulmonary artery catheter in this setting is not clear. These subjects often have a significant bleeding diathesis in addition to leukopenia, increasing the risk of hemorrhage and infection with catheter use.
Diffuse alveolar hemorrhage (DAH) occurs in 1% to 5% of autologous and 3% to 7% of allogeneic HSCT recipients.31 Injury to the pulmonary endothelial lining from high-dose chemotherapy and radiation, as well as various infections, play a role in the pathogenesis. Although infection can lead to alveolar hemorrhage, the term DAH in HSCT recipients should be solely used for noninfectious alveolar hemorrhage.32 Old age, severe oral mucositis, acute GVHD, intensive pretransplantation chemotherapy, total body irradiation, and allogeneic stem cells are important risks factors.31,33 Symptoms such as cough, dyspnea, and fevers are frequent, whereas hemoptysis is rare.32 Anemia and pulmonary infiltrates on chest radiographs are usually present. Diagnostic criteria include diffuse multilobar infiltrates, high PaO2/FIO2 ratio or widened alveolar-arterial gradient, absence of any identifiable infection, and progressively bloodier return on bronchoalveolar lavage (BAL), while cytology confirms hemosiderin-laden macrophages.32 Treatment is challenging, with cohort studies reporting variable success rates with high-dose steroids.34 In the past decade, reports of intrapulmonary and IV human recombinant activated factor VIIa and IV aminocaproic acid have resulted in apparent control of active bleeding, but such success did not translate into improved outcomes.35–37 Mortality rates of 30% to 90% have been reported, particularly when DAH is associated with respiratory failure requiring mechanical ventilation or multiorgan failure.38,39 Relapse is occasional and portends a higher mortality rate.34
The term idiopathic pneumonia syndrome (IPS) refers to a diffuse interstitial pneumonia with evidence of widespread alveolar injury and absence of lower respiratory tract infection in an HSCT patient.40 Additional features include abnormal pulmonary physiology and multilobar infiltrates on chest radiography or chest computed tomography (CT). The incidence of IPS is about 7%, and it occurs at a median time of 21 days after HSCT.41 Although there is no difference in incidence between autologous and allogeneic HSCT recipients, significant risk factors have been identified in allogeneic transplantation and include an underlying diagnosis other than leukemia, grade 4 acute GVHD, and CMV-seropositive donor status.41 Other potential risk factors include exposure to pretransplantation radiation, busulfan, and cyclophosphamide.42–44 These data suggest that IPS may be caused by cumulative damage to the lung from chemotherapy, radiation, and GVHD. Almost 70% require mechanical ventilation for respiratory failure. The hospital mortality rate is above 70%, and respiratory failure leading to death occurs in 62% of patients with IPS.41 It is important to differentiate IPS from the other syndromes outlined in this section that may also manifest with bilateral pulmonary infiltrates.41 Treatment is mainly supportive, and even with aggressive care, the prognosis remains poor.41,45 Limited data have suggested high clinical response rates and improved short-term survival with a combination of etanercept and corticosteroids.46
The peri-engraftment respiratory distress syndrome (PERDS) is a well-recognized noninfectious complication of HSCT and occurs between 5 days before and 5 days after the onset of neutrophil production. Symptomatology includes rash, fevers, dyspnea, and occasional weight gain associated with severe hypoxemia and bilateral pulmonary infiltrates.47,48 Endothelial cell damage and cytokine production are the proposed mechanisms of this syndrome. Other possibilities such as acute GVHD, infectious pneumonitis, IPS, and DAH must be ruled out. The diagnosis relies on a high index of suspicion, particularly when the workup for infectious etiologies is negative. Bronchoscopy and BAL are often necessary to rule out DAH and other infectious and noninfectious pulmonary complications. Steroids and supportive care often result in rapid recovery. PERDS has been identified as a marker of increased posttransplantation mortality.48
Bronchoscopy
Several observational and prospective studies have established the safety and diagnostic utility of flexible fiberoptic bronchoscopy in the evaluation of the HSCT recipients who developed focal or diffuse pulmonary infiltrates associated with respiratory insufficiency/failure.49–51 The diagnostic yield of bronchoscopy and BAL ranges from 63% in earlier studies to about 42% to 47% in more recent studies. Indeed, recipients of HSCT tend to be on prophylactic antimicrobials; when they develop apparent sepsis syndrome and/or pulmonary infiltrates, initiation of an empirical antimicrobial regimen is rather prompt. Such strategies may explain the perceived reduction in the diagnostic yield of bronchoscopy. Although bronchoscopy can lead to radical modification in treatment in up to two-thirds of HSCT recipients, it has no impact on survival.52–54 The addition of transbronchial biopsy provides specific information in less than 10% of cases.55 Allogeneic HSCT recipients are three times more likely to undergo bronchoscopy than autologous patients because of greater need for immunosuppression and GVHD prophylaxis/treatment and higher risk of infectious pulmonary complications.52 Diffuse alveolar hemorrhage and pulmonary infections are the most frequent diagnoses obtained by bronchoscopy, followed by IPS, bronchiolitis obliterans with or without organizing pneumonia, and radiation-induced lung injury.54,56
Bronchoscopy can be associated with significant complications such as acute respiratory failure, pneumothoraces, epistaxis, pulmonary bleeding, and even sudden death.50 The use of noninvasive positive pressure ventilation (NIPPV) delivered by face mask and by laryngeal mask airway (LMA) may partially mitigate these risks. Bronchoscopy with BAL via facemask, helmet, or LMA appears to be a safe alternative to intubation in immunocompromised patients.57–59 HSCT recipients who require mechanical ventilation are also at risk of hemodynamic instability and worsening hypoxemia/ARDS when they received sedative and narcotic agents during BAL.
Sepsis
HSCT recipients have a number of risk factors for infection and septic shock, including immunosuppression, mucositis from preparative regimens, and the use of long-term indwelling catheters for vascular access. There is a temporal pattern to some of the infections, as shown in Box 155-2. Some of the more common organisms isolated are gram-positive cocci, gram-negative enteric bacilli, Candida spp., and Aspergillus spp. Infection with CMV and herpesviruses also occurs. Impaired host defenses in the HSCT patient may prevent localization of infection, and as a result, septic shock may develop. Septic shock is the admitting diagnosis in about 18% of HSCT patients transferred to the ICU, and the diagnosis of septic shock is made in about 60% of all HSCT patients receiving ICU care.60,61 HSCT patients with septic shock require vasopressor support in most cases and may progress to multisystem organ failure. The prognosis of septic shock in the HSCT patient is poor, and the 30-day mortality rate after ICU admission exceeded 80% in one recent study.60 The need for more than 4 hours of vasopressor support has been shown to increase mortality among mechanically ventilated HSCT patients.10 Empirical antibiotics and antifungal agents, along with blood products, form an important part of the management of critical illness in the HSCT patient. To date, there has been no randomized controlled trial evaluating the efficacy and safety of recombinant human activated protein C in the treatment of sepsis in the HSCT population.62
Hepatic Veno-Occlusive Disease
Veno-occlusive disease (VOD) is the most common cause of liver failure in HSCT patients and has also been referred to as sinusoidal obstruction syndrome (SOS), because sinusoidal obstruction is prominent on pathology. The mean incidence is 13.7% (0%-62.5%) in all HSCT recipients and has increased over time.63 The diagnosis should be suspected if jaundice, painful hepatomegaly, ascites, fluid retention, and weight gain develop within the first 4 weeks after HSCT, although it can occur later.64 As the liver fails, encephalopathy, coagulopathy, bleeding, fluid retention, and renal failure may develop and result in critical illness. The spectrum of disease ranges from mild reversible disease to a severe syndrome associated with multiorgan failure (MOF). The overall mortality in severe VOD is 84.3%, which increases to almost 100% at 100 days after HSCT and is most commonly due to MOF.63,65,66 A number of risk factors have been identified, including receipt of an allogeneic transplant, abnormal liver function tests before transplantation, high-dose chemotherapy, and previous abdominal radiation.66
Right upper quadrant ultrasonography with color Doppler typically shows hepatomegaly, ascites, and reversal of blood flow through the hepatic vein. Liver biopsy, although uncommonly performed, should be considered if the differential diagnosis includes acute GVHD or drug toxicity and may change therapeutic plans. Treatment of VOD is mainly supportive, with careful fluid balance, preservation of renal function, and judicious diuresis for management of ascites. Thrombolytic agents and heparin have been used but have a success rate of less than 30% with a high risk of bleeding.67 Defibrotide is an oligonucleotide with local antithrombotic, antiischemic and antiinflammatory effects. In a dose-finding trial, defibrotide was shown to be effective in 46% of patients with severe VOD, achieving clinical remission and 42% alive at 100 days after HSCT.64
Supportive Care
Advances have been made in regard to overall HSCT care as well as ICU management, and recent trials that have shown improved outcomes in critically ill patients are generally applicable to HSCT patients. Strategies such as NIPPV, low tidal volumes for ALI/ARDS, early goal-directed therapy, and glycemic control should be utilized when appropriate.11
NIPPV has been shown to be effective in immunocompromised patients with hypoxemic respiratory failure. In a small prospective randomized study of 52 neutropenic patients with hypoxemia and pulmonary infiltrates, the use of intermittent NIPPV was associated with a lower intubation rate, fewer serious complications, and improved ICU and hospital survival, compared with spontaneous breathing and supplemental oxygen alone.68 Only 17 (33%) of the subjects enrolled in this study had undergone HSCT. Sources of bias included patient selection and the inability to blind the study. NIPPV may be useful in the HSCT population, but mucositis and severe GVHD of the oropharynx are complications that may interfere with NIPPV. In general, it is important to not delay intubation if the patient does not improve with NIPPV.
As a result of the conditioning regimen, pancytopenia is expected, and neutropenia is a major factor for the development of infectious complications in the early posttransplant phase. Even with the use of prophylactic antibiotics and colony stimulating factors (CSF), infection due bacteria or fungi are common in this population. Granulocyte-CSF (G-CSF) can enhance granulocyte function by increasing production of superoxide radicals, phagocytosis, and cytotoxicity. Granulocyte transfusions have been used in neutropenic septic patients, but a Cochrane review concluded that the available evidence could neither refute nor support this practice. A possible survival benefit was suggested with doses of greater than 1 × 1010 granulocytes, but further investigation is required.69
Outcomes, Prognostication, and Triage
Initial studies on outcomes of HSCT patients generally reported an overall poor outcome for those requiring ICU care. An early report on mechanical ventilation use in HSCT found that only 3% survived 6 months beyond ICU admission12; however, more recent data found that up to 10% were alive at 6 months. Overall hospital survival has also improved to 20% to 32.5% for those requiring mechanical ventilation70–72 and 95% for those who did not need it.72 However, the overall hospital and 30-day mortality for critically ill HSCT recipients remains high at 74%.5 Patients who require more than 4 hours of vasopressor support and have two other organ failures (e.g., serum bilirubin >4 mg/dL and serum creatinine >2 mg/dL), have a mortality rate of almost 100%.10,60,61,70 There are conflicting data on any association between ICU outcome and the timing of ICU admission after transplantation.10,29,60 Data demonstrating a survival benefit to early posttransplantation admission have not been reproducible. The need for endotracheal intubation to manage respiratory failure and the need for more than 15 days of mechanical ventilation have been associated with a survival rate of less than 5%.7,10,29,73,74
Attributed mortality in allogeneic HSCT is most commonly due to disease relapse, followed by infection, GVHD, and organ toxicity.2 Prognostic factors that influence outcomes of critically ill HSCT patients include age, coexisting comorbidities, and functional status. Severity of illness as measured by ICU scoring systems have generally underestimated actual mortality rates even if they account for immunosuppression, hematologic malignancy, or metastatic neoplasm.5,7,61 Additionally, the models do not take into account unique features such as GVHD or prior chemotherapy, and none have been evaluated specifically in predicting mortality of HSCT recipients. The utility of the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system in the HSCT population is unclear, but there is evidence that a score higher than 45 is associated with poor survival.7,61 One study has suggested that APACHE III scores better predict ICU mortality.60
A pragmatic approach to deciding when to admit an HSCT patient to the ICU would employ providing full supportive care during the engraftment process, especially for those patients with isolated or limited organ failure.71 An ongoing need for mechanical ventilation, vasopressors, and multiple organ support generally portends a poor prognosis, particularly if hepatic failure, renal failure, or active GVHD is present.71,75 Such conditions would warrant a reassessment of goals after a defined period of supportive treatment.11,76
Patients who consent to receive an HSCT are hopeful and are making a commitment to proceed with a complex procedure that has inherent risks. Prior to developing critical illness, a great deal of effort is made in preparation, evaluation, and donor search. Intensivists are not part of the discussion that occurs during this period and therefore cannot offer their perspective until a patient is admitted to the ICU. Once the need for ICU care becomes evident, there has been a deep investment in that patient’s care as well as desire to control the underlying problem that required transplantation. Nevertheless, the critical care team should work closely with the transplant team to ensure that uniform and clear communication occurs with the patient and families. As such, both teams must be able to agree to specific endpoints during the patient’s critical illness. One study looking at a 72-hour interval of ICU care found that continued presence of respiratory failure as well as degree (PaO2/FIO2 <250), BUN over 40 mg/dL, and urinary output of less than 150 mL for any 8-hour period portended a worse prognosis. When combined with clinical judgment, these parameters could help guide discussions about goals of care.76 Additionally, the presence of respiratory failure requiring mechanical ventilation with combined hepatic and renal dysfunction was highly predictive of death.75 HSCT recipients with acute lung injury requiring mechanical ventilation who had a prolonged need for vasopressors or sustained hepatic and renal failure had a mortality rate of almost 100%.10 By reevaluating the ICU course with objective data and clinical judgment, discussions of end-of-life care should be jointly reviewed with the family.
The Future
The field of stem cell transplantation is evolving. The development of reduced-intensity (nonmyeloablative) conditioning regimens rely on a graft-versus-tumor effect to control residual disease, rather than high-dose chemotherapy and its attendant toxicity. As a result, transplantation in older patients with more comorbid illnesses can be feasible.77 Other strategies for the future include focused therapies to reduce the incidence of GVHD such as cytokine blockade or modified T cells, more specific HLA typing, increased use of umbilical cord blood, or possibly embryonic stem cells.78–81 Additionally, indications for transplantation may expand to nononcologic conditions such as sickle cell disease and hemoglobinopathies or inborn errors of metabolism.
Key Points
Afessa B, Tefferi A, Litzow MR, et al. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002;166:641-645.
Patel NR, Lee PS, Kim JH, et al. The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients. Chest. 2005;127:1388-1396.
Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344:481-487.
Rubenfeld GD, Crawford SW. Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: a case for evidence-based guidelines. Ann Intern Med. 1996;125:625-633.
Capizzi SA, Kumar S, Huneke NE, et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:1299-1303.
1 Cutler C, Giri S, Jeyapalan S, et al. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol. 2001;19:3685-3691.
2 Pasquini M, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: Part I CIBMTR summary slides, 2009. CIBMTR Newsletter [serial online]. 2009;1(15):7-11. 2009 http://www.cibmtr.org/ReferenceCenter/Newsletters/PDF/Newsletter_Aug2009.pdf Accessed May 27, 2010
3 Laffan A, Biedrzycki B. Immune reconstitution: the foundation for safe living after an allogeneic hematopoietic stem cell transplantation. Clin J Oncol Nurs. 2006;10:787-794.
4 Dykewicz CA. summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis. 2001;33:139-144.
5 Afessa B, Azoulay E. Critical care of the hematopoietic stem cell transplant recipient. Crit Care Clin. 2010;26:133-150.
6 Naeem N, Eyzaguirre A, Kern JA, et al. Outcome of adult umbilical cord blood transplant patients admitted to a medical intensive care unit. Bone Marrow Transplant. 2006;38:733-738.
7 Afessa B, Tefferi A, Hoagland HC, et al. Outcome of recipients of bone marrow transplants who require intensive-care unit support. Mayo Clin Proc. 1992;67:117-122.
8 Horak DA, Forman SJ. Critical care of the hematopoietic stem cell patient. Crit Care Clin. 2001;17:671-695.
9 Bojko T, Notterman DA. Reversal of fortune? Respiratory failure after bone marrow transplantation. Crit Care Med. 1999;27:1061-1062.
10 Rubenfeld GD, Crawford SW. Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: a case for evidence-based guidelines. Ann Intern Med. 1996;125:625-633.
11 McArdle JR. Critical care outcomes in the hematologic transplant recipient. Clin Chest Med. 2009;30:155-167. ix-x
12 Crawford SW, Petersen FB. Long-term survival from respiratory failure after marrow transplantation for malignancy. Am Rev Respir Dis. 1992;145:510-514.
13 Soubani AO, Miller KB, Hassoun PM. Pulmonary complications of bone marrow transplantation. Chest. 1996;109:1066-1077.
14 Atkinson K, Nivison-Smith I, Dodds A, et al. A comparison of the pattern of interstitial pneumonitis following allogeneic bone marrow transplantation before and after the introduction of prophylactic ganciclovir therapy in 1989. Bone Marrow Transplant. 1998;21:691-695.
15 Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Transplant. 1992;10:267-272.
16 Wald A, Leisenring W, van Burik JA, et al. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis. 1997;175:1459-1466.
17 Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415.
18 Steinbach WJ, Stevens DA, Denning DW. Combination and sequential antifungal therapy for invasive aspergillosis: review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001. Clin Infect Dis. 2003;37(Suppl 3):S188-S224.
19 Rogers TR, Frost S. Newer antifungal agents for invasive fungal infections in patients with haematological malignancy. Br J Haematol. 2009;144:629-641.
20 Kamboj M, Gerbin M, Huang CK, et al. Clinical characterization of human metapneumovirus infection among patients with cancer. J Infect. 2008;57:464-471.
21 Oliveira R, Machado A, Tateno A, et al. Frequency of human metapneumovirus infection in hematopoietic SCT recipients during 3 consecutive years. Bone Marrow Transplant. 2008;42:265-269.
22 Oren I, Zuckerman T, Avivi I, et al. Nosocomial outbreak of Legionella pneumophila serogroup 3 pneumonia in a new bone marrow transplant unit: evaluation, treatment and control. Bone Marrow Transplant. 2002;30:175-179.
23 Stroncek DF, Fautsch SK, Lasky LC, et al. Adverse reactions in patients transfused with cryopreserved marrow. Transfusion. 1991;31:521-526.
24 Davis JM, Rowley SD, Braine HG, et al. Clinical toxicity of cryopreserved bone marrow graft infusion. Blood. 1990;75:781-786.
25 Hoyt R, Szer J, Grigg A. Neurological events associated with the infusion of cryopreserved bone marrow and/or peripheral blood progenitor cells. Bone Marrow Transplant. 2000;25:1285-1287.
26 Lopez-Jimenez J, Cervero C, Munoz A, et al. Cardiovascular toxicities related to the infusion of cryopreserved grafts: results of a controlled study. Bone Marrow Transplant. 1994;13:789-793.
27 Alessandrino P, Bernasconi P, Caldera D, et al. Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases. Bone Marrow Transplant. 1999;23:533-537.
28 Milone G, Mercurio S, Strano A, et al. Adverse events after infusions of cryopreserved hematopoietic stem cells depend on non-mononuclear cells in the infused suspension and patient age. Cytotherapy. 2007;9:348-355.
29 Huaringa AJ, Leyva FJ, Giralt SA, et al. Outcome of bone marrow transplantation patients requiring mechanical ventilation. Crit Care Med. 2000;28:1014-1017.
30 Brockstein BE, Smiley C, Al-Sadir J, et al. Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors. Bone Marrow Transplant. 2000;25:885-894.
31 Majhail NS, Parks K, Defor TE, et al. Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes. Biol Blood Marrow Transplant. 2006;12:1038-1046.
32 Afessa B, Tefferi A, Litzow MR, et al. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002;166:641-645.
33 Wanko SO, Broadwater G, Folz RJ, et al. Diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid. Biol Blood Marrow Transplant. 2006;12:949-953.
34 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.
35 Estella A, Jareno A, Perez-Bello Fontaina L. Intrapulmonary administration of recombinant activated factor VII in diffuse alveolar haemorrhage: a report of two case stories. Cases J. 2008;1:150.
36 Pastores SM, Papadopoulos E, Voigt L, et al. Diffuse alveolar hemorrhage after allogeneic hematopoietic stem-cell transplantation: treatment with recombinant factor VIIa. Chest. 2003;124:2400-2403.
37 Hicks K, Peng D, Gajewski JL. Treatment of diffuse alveolar hemorrhage after allogeneic bone marrow transplant with recombinant factor VIIa. Bone Marrow Transplant. 2002;30:975-978.
38 Afessa B, Tefferi A, Litzow MR, et al. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002;166:1364-1368.
39 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.
40 Clark JG, Hansen JA, Hertz MI, et al. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis. 1993;147:1601-1606.
41 Kantrow SP, Hackman RC, Boeckh M, et al. Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation. 1997;63:1079-1086.
42 Haddad IY, Panoskaltsis-Mortari A, Ingbar DH, et al. High levels of peroxynitrite are generated in the lungs of irradiated mice given cyclophosphamide and allogeneic T cells. A potential mechanism of injury after marrow transplantation. Am J Respir Cell Mol Biol. 1999;20:1125-1135.
43 Bilgrami SF, Metersky ML, McNally D, et al. Idiopathic pneumonia syndrome following myeloablative chemotherapy and autologous transplantation. Ann Pharmacother. 2001;35:196-201.
44 Shankar G, Scott Bryson J, Darrell Jennings C, et al. Idiopathic pneumonia syndrome after allogeneic bone marrow transplantation in mice. Role of pretransplant radiation conditioning. Am J Respir Cell Mol Biol. 1999;20:1116-1124.
45 Crawford SW, Hackman RC. Clinical course of idiopathic pneumonia after bone marrow transplantation. Am Rev Respir Dis. 1993;147:1393-1400.
46 Yanik GA, Ho VT, Levine JE, et al. The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood. 2008;112:3073-3081.
47 Capizzi SA, Kumar S, Huneke NE, et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:1299-1303.
48 Gorak E, Geller N, Srinivasan R, et al. Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival. Biol Blood Marrow Transplant. 2005;11:542-550.
49 Milburn HJ, Prentice HG, du Bois RM. Role of bronchoalveolar lavage in the evaluation of interstitial pneumonitis in recipients of bone marrow transplants. Thorax. 1987;42:766-772.
50 White P, Bonacum JT, Miller CB. Utility of fiberoptic bronchoscopy in bone marrow transplant patients. Bone Marrow Transplant. 1997;20:681-687.
51 Huaringa AJ, Leyva FJ, Signes-Costa J, et al. Bronchoalveolar lavage in the diagnosis of pulmonary complications of bone marrow transplant patients. Bone Marrow Transplant. 2000;25:975-979.
52 Dunagan DP, Baker AM, Hurd DD, et al. Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest. 1997;111:135-141.
53 Feinstein MB, Mokhtari M, Ferreiro R, et al. Fiberoptic bronchoscopy in allogeneic bone marrow transplantation: findings in the era of serum cytomegalovirus antigen surveillance. Chest. 2001;120:1094-1100.
54 Campbell JH, Blessing N, Burnett AK, et al. Investigation and management of pulmonary infiltrates following bone marrow transplantation: an eight year review. Thorax. 1993;48:1248-1251.
55 Patel NR, Lee PS, Kim JH, et al. The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients. Chest. 2005;127:1388-1396.
56 Glazer M, Breuer R, Berkman N, et al. Use of fiberoptic bronchoscopy in bone marrow transplant recipients. Acta Haematol. 1998;99:22-26.
57 Antonelli M, Conti G, Riccioni L, et al. Noninvasive positive-pressure ventilation via face mask during bronchoscopy with BAL in high-risk hypoxemic patients. Chest. 1996;110:724-728.
58 Antonelli M, Pennisi MA, Conti G, et al. Fiberoptic bronchoscopy during noninvasive positive pressure ventilation delivered by helmet. Intensive Care Med. 2003;29:126-129.
59 Hilbert G, Gruson D, Vargas F, et al. Bronchoscopy with bronchoalveolar lavage via the laryngeal mask airway in high-risk hypoxemic immunosuppressed patients. Crit Care Med. 2001;29:249-255.
60 Afessa B, Tefferi A, Dunn WF, et al. Intensive care unit support and Acute Physiology and Chronic Health Evaluation III performance in hematopoietic stem cell transplant recipients. Crit Care Med. 2003;31:1715-1721.
61 Jackson SR, Tweeddale MG, Barnett MJ, et al. Admission of bone marrow transplant recipients to the intensive care unit: outcome, survival and prognostic factors. Bone Marrow Transplant. 1998;21:697-704.
62 Pastores SM, Papadopoulos E, van den Brink M, et al. Septic shock and multiple organ failure after hematopoietic stem cell transplantation: treatment with recombinant human activated protein C. Bone Marrow Transplant. 2002;30:131-134.
63 Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16:157-168.
64 Richardson PG, Soiffer RJ, Antin JH, et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multi-organ failure post stem cell transplantation: a multi-center, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010.
65 McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267.
66 Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood. 1998;92:3599-3604.
67 Bearman SI, Lee JL, Baron AE, et al. Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood. 1997;89:1501-1506.
68 Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344:481-487.
69 Stanworth SJ, Massey E, Hyde C, et al. Granulocyte transfusions for treating infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev 2005:CD005339.
70 Khassawneh BY, White PJr, Anaissie EJ, et al. Outcome from mechanical ventilation after autologous peripheral blood stem cell transplantation. Chest. 2002;121:185-188.
71 Pene F, Aubron C, Azoulay E, et al. Outcome of critically ill allogeneic hematopoietic stem-cell transplantation recipients: a reappraisal of indications for organ failure supports. J Clin Oncol. 2006;24:643-649.
72 Soubani AO, Kseibi E, Bander JJ, et al. Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest. 2004;126:1604-1611.
73 Paz HL, Crilley P, Weinar M, et al. Outcome of patients requiring medical ICU admission following bone marrow transplantation. Chest. 1993;104:527-531.
74 Denardo SJ, Oye RK, Bellamy PE. Efficacy of intensive care for bone marrow transplant patients with respiratory failure. Crit Care Med. 1989;17:4-6.
75 Bach PB, Schrag D, Nierman DM, et al. Identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation. Blood. 2001;98:3234-3240.
76 Groeger JS, Glassman J, Nierman DM, et al. Probability of mortality of critically ill cancer patients at 72 h of intensive care unit (ICU) management. Support Care Cancer. 2003;11:686-695.
77 Popplewell LL, Forman SJ. Is there an upper age limit for bone marrow transplantation? Bone Marrow Transplant. 2002;29:277-284.
78 Jacobsohn DA, Vogelsang GB. Anti-cytokine therapy for the treatment of graft-versus-host disease. Curr Pharm Des. 2004;10:1195-1205.
79 Cutler C, Antin JH. Novel drugs for the prevention and treatment of acute GVHD. Curr Pharm Des. 2008;14:1962-1973.
80 Hoffmann P, Edinger M. CD4+CD25+ regulatory T cells and graft-versus-host disease. Semin Hematol. 2006;43:62-69.
81 Burt RK, Verda L, Kim DA, et al. Embryonic stem cells as an alternate marrow donor source: engraftment without graft-versus-host disease. J Exp Med. 2004;199:895-904.
