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stem cells or umbilical cord blood can be used as sources of donor stem cells, the term bone marrow transplantation has been replaced by the more inclusive hematopoietic stem cell transplantation (HSCT).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
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