Pulmonary Complications of Hematopoietic Stem Cell Transplantation

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Chapter 77 Pulmonary Complications of Hematopoietic Stem Cell Transplantation

Rodrigo Cavallazzi, Rodney J. Folz

Hematopoietic stem cell transplantation (HSCT) refers to the transplantation of stem cells from bone marrow, growth factor–stimulated peripheral blood, and umbilical blood for the treatment of malignant and nonmalignant hematologic, autoimmune, and genetic diseases. Transplant recipients are at risk of serious complications as a result of pretransplant cytoreductive conditioning regimens, immunologic sequelae from engraftment of allogeneic lymphoid cells (which mediate graft-versus-host responses), the patient’s immunosuppressed status, and infections secondary to immunosuppression. Autopsy studies show that pulmonary complications are responsible for more than 70% of deaths in HSCT recipients.

Overview of Hematopoietic stem cell transplantation

Types

Hematopoietic stem cell transplantation is classified as autologous, allogeneic, or syngeneic. In autologous HSCT, patients receive their own hematopoietic stem cells. In allogeneic HSCT, patients receive hematopoietic stem cells from a nonidentical sibling or unrelated matched donor. In syngeneic HSCT, patients receive hematopoietic stem cells from a genetically identical twin. The source of the donor hematopoietic stem cells can be bone marrow, peripheral blood, or umbilical cord blood. Because autologous and syngeneic transplants involve stem cells that are immunologically identical to the recipient, reactions between graft and host are avoided. In allogeneic transplants, mismatch between donor and recipient human leukocyte antigens (HLAs) mediate graft-versus-host disease (GVHD), which may lead to allograft rejection.

Factors that determine the type of transplant to be performed include the nature and stage of the underlying disease, the availability of a suitable donor, and the medical condition of the recipient. The advantages of allogeneic transplantation over autologous transplantation include a higher likelihood that the stem cell product is free of tumor contamination and graft-versus-host activity.

Indications

A survey from several countries found that the most common indications for HSCT are lymphoproliferative disorders (55%), leukemias (34%), solid tumors (6%), and nonmalignant disorders (5%). The lymphoproliferative disorders included plasma cell disorder, Hodgkin disease, and non-Hodgkin lymphoma. Autologous HSCT was slightly more common than allogeneic HSCT. For allogeneic HSCT, the most frequent malignant disease was acute myeloid leukemia (33%) and the most common nonmalignant disease, bone marrow failure syndrome (6%). For autologous HSCT, the most frequent indication was for a plasma cell disorder (41%); the most common nonmalignant indications included bone marrow failure, hemoglobinopathies, immune deficiencies, inherited diseases of metabolism, and autoimmune disorders.

Conditioning Regimens

Before undergoing HSCT, patients receive a conditioning regimen with the goals of reducing the tumor burden (with malignancy), ablating the bone marrow, and suppressing the recipient’s immune system, thereby allowing engraftment of stem cells. The three regimen types are myeloablative conditioning, reduced-intensity conditioning, and nonmyeloablative conditioning. This classification is based on the duration of cytopenia and the requirement for stem cell support. Myeloablative conditioning causes irreversible cytopenia, for which stem cell support is always necessary, whereas nonmyeloablative conditioning causes minimal cytopenia, for which stem cell support may not be needed. Reduced-intensity conditioning causes cytopenia of variable duration, and stem cell support should be given.

Conventional myeloablative conditioning regimens include cyclophosphamide and total-body irradiation (TBI) or busulfan. The more recent nonmyeloablative or reduced-intensity conditioning regimens have used fludarabine and reduced-dose alkylating agents or TBI. Although these less intensive regimens do not provide a strong cytoreductive effect, they allow engraftment of the donor stem cells with a subsequent potentially beneficial graft-versus-malignancy effect. The nonmyeloablative or reduced-intensity conditioning regimens are associated with reduced transplant-associated morbidity and lower incidence of pulmonary complications after transplantation.

Prophylaxis after allogeneic transplant to prevent GVHD usually involves methotrexate, cyclosporin, corticosteroids, or in vitro T cell depletion of the graft before infusion.

Posttransplant Pulmonary Complications

Pulmonary complications after HSCT are common, with an incidence of 40% to 60% and with up to one third of recipients requiring intensive care after transplantation. Respiratory failure is the most common cause of critical illness, and pneumonia is the leading infectious cause of death after HSCT (Figure 77-1). Pulmonary complications can occur early or late in the posttransplant course, can have infectious and noninfectious etiologies, and can present with assorted radiographic findings. The pulmonary complications of HSCT also vary depending on the indication for, type of, and preparative regimen preceding HSCT.

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Figure 77-1 Types and location of pulmonary complications after hematopoietic stem cell transplantation (bronchiolitis obliterans organizing pneumonia now called cryptogenic organizing pneumonia).

Cellular interactions between graft and host cells are essentially eliminated with autologous transplantation, obviating the need for immunosuppression to prevent or treat GVHD. As such, autologous transplantation is associated with lower incidence of infection, particularly viral pneumonias or cytomegalovirus (CMV) pneumonitis, invasive fungal disease, and other opportunistic infections (e.g., toxoplasmosis), as well as late airflow obstruction defects.

Risk Factors for Pulmonary Disease

Relapse status at transplant and donor-recipient HLA mismatching or nonidentity are risk factors for pulmonary complications and mortality after HSCT (Box 77-1). Active phase of malignancy, age over 21 years, and receipt of HLA-nonidentical donor marrow are risk factors for respiratory failure after HSCT.

Box 77-1

Risk Factors for Pulmonary Complications After Hematopoietic Stem Cell Transplantation (HSCT)

Donor-recipient human leukocyte antigen mismatch

Relapse status

Active phase of malignancy

Age over 21 years

Pretransplant pulmonary function abnormalities

Reduced diffusion capacity

Increased alveolar-arterial oxygen gradient

Restrictive lung disease

FEV1 <80% predicted

Elevated pretransplant cytokine levels (TGF-β, TGF-α, GM-CSF)

Allogeneic transplantation

Graft-versus-host disease and type of GVHD prophylaxis

Renal disease

Abnormalities in pretransplant pulmonary function tests (PFTs) may be predictive of subsequent risk of pulmonary complications and mortality. Reduced diffusing capacity and increased alveolar-arterial oxygen gradient are independent risk factors for interstitial pneumonitis and also independently associated with increased early mortality after HSCT.

Patients with elevated levels of transforming growth factor beta (TGF-β) in plasma, TGF-α in bronchoalveolar lavage (BAL) fluid, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in BAL fluid seem to be at increased risk for pulmonary complications. One study showed that elevated pretransplant TGF-β levels in patients with breast cancer undergoing autologous HSCT were associated with increased posttransplant risk of pulmonary toxicity and hepatic venoocclusive disease.

Recipients of allogeneic transplantation have more infection complications than recipients of autografts, not only because of chronic immunosuppression, but also because GVHD itself causes an immunodeficient state by affecting the mucosal surfaces, the reticuloendothelial system, and bone marrow. These factors predispose allogeneic recipients to fatal viral pneumonias, multidrug-resistant bacteria, and invasive fungi. Similarly, bronchiolitis obliterans is almost exclusively seen after allogeneic HSCT.

Genetics and Pulmonary Complications

Some patients may be genetically predisposed to develop toxicity from the HSCT-related treatments. Indeed, recent studies suggest that certain genetic polymorphisms appear to play a role in the pathogenesis of diverse post-HSCT pulmonary complications. For example, having a polymorphism in the gene for angiotensin-converting enzyme (ACE) increases the likelihood of developing noninfectious pulmonary dysfunction after allogeneic HSCT. Polymorphisms in genes that code for proteins involved in stress-induced oxidant and antioxidant balance may be associated with acute lung injury after HSCT. In some patients, genetic polymorphisms may also be the basis for an increased susceptibility to infection after HSCT. For example, polymorphisms in the mannose-binding lectin gene in both the donor and the recipient are associated with increased risk of major infection.

Although still not routinely used in clinical practice, genetic screening may lead to a more refined prediction of risk for pulmonary complications in future patients undergoing HSCT.

Time Course

Specific pulmonary complications associated with HSCT tend to occur in a relatively well-defined timeline. The timing and intensity of cytoreductive therapies and the resulting pattern of immune reconstitution influence the duration of these intervals.

Preengraftment

The preengraftment phase (0-30 days after transplant) is characterized by prolonged neutropenia and breaks in the mucocutaneous barriers. Accordingly, infectious complications are expected and primarily caused by bacterial and fungal infections. However, most pulmonary complications during this phase are noninfectious and related to regimen-related toxicities.

Early Postengraftment

The early postengraftment period spans days 30 to 100 after transplant and is characterized by persistent impairment in cellular and humoral immunity, in part determined by exogenous immunosuppression, GVHD, deficiency of immunoglobulins, and a loss of protective alveolar macrophages. During this period, neutropenia usually resolves, decreasing the risk of bacterial and fungal infections. The epidemiology of infectious etiologies thus changes to involve predominantly viral infections, especially CMV. With the routine use of antivirals, however, the incidence of posttransplant CMV pneumonia has decreased substantially. Noninfectious etiologies during this time include engraftment syndrome and delayed pulmonary toxicity syndrome.

Late Postengraftment

The late postengraftment period begins at day 100 after transplant. During this time, immune recovery and function are variable and depend on the type of HSCT. Autologous recipients recover more rapidly than allogeneic recipients. T cell responses to alloantigens return to normal, but immunoglobulin levels frequently remain depressed. Viral pathogens cause infections because of poor lymphocyte function, whereas inadequate cellular immunity results in bacterial and fungal pathogens. Noninfectious etiologies are primarily responsible for the pulmonary complications seen during this time, including chronic GVHD, drug-related pulmonary toxicity, bronchiolitis obliterans, restrictive or fibrotic lung disease, and cryptogenic organizing pneumonia (formerly BOOP).

Infectious Complications

The overall risk of pulmonary infection in patients receiving HSCT depends on multiple risk factors, including chemotherapy and radiation-induced neutropenia, lung injury induced by the conditioning regimen, rejection in the form of GVHD, local disruption of host defenses, and intensity of pathogen exposure. In addition, HSCT recipients need to develop a functional immune system from donor-derived cells. Although the production of red blood cells, platelets, and granulocytes occurs soon after HSCT, production of lymphocytes, especially T cells, is considerably delayed. In the first 2 years after transplant, serious infections occur in 50% of otherwise uncomplicated transplants from histocompatible sibling donors and in 80% to 90% of matched unrelated donors or histocompatible recipients with GVHD.

Supportive care in the posttransplant period has changed the microbiology of pneumonia. Prophylactic administration of trimethoprim-sulfamethoxazole (TMP-SMX), antivirals, antifungals, and fluoroquinolones has decreased the incidence of Pneumocystis jirovecii, CMV, herpes simplex, and Candida albicans infections (Box 77-2). Resistant gram-negative and gram-positive bacteria, viruses, and other fungi remain important pathogens.

Box 77-2

Prevention Strategies for Post-HSCT Opportunistic Infectious

Infections

Pneumocystis jirovecii (formerly P. carinii)

Cytomegalovirus (CMV)

Herpe simplex virus (HSV)

Candida spp.

Aspergillus spp.

Toxoplasma

Prophylaxis

Acyclovir

Ganciclovir

Fluconazole

Posaconazole

Trimethoprim-sulfamethoxazole (TMP-SMX)

HSCT, hematopoietic stem cell transplantation.

Bacterial Infections

Bacterial pneumonia is a major cause of morbidity and mortality in patients receiving HSCT. The first month after transplant is notable for pneumonias caused by usual pathogens. Bacterial pneumonia is frequently caused by Staphylococcus and Streptococcus spp. (24% and 13%, respectively, in one series) and gram-negative organisms, including Pseudomonas, Klebsiella, Escherichia, Stenotrophomonas, Legionella, Acinetobacter, Serratia, Proteus, Enterobacter, and Citrobacter spp. Other organisms include Enterococcus and rare anaerobes such as Bacteroides and Fusobacterium spp. Community pathogens emerge after the immediate posttransplant period. Haemophilus influenzae is the most common isolate, followed by Streptococcus pneumoniae and Legionella spp.

Fungal Infections

Fungal disease should be considered in patients with persistent focal radiographic abnormalities that do not respond to empirical antibiotic therapy and in those with nodular opacities on chest imaging, prolonged neutropenia, corticosteroid use, or a history of prior fungal infections.

Invasive aspergillosis is the leading cause of infectious death in HSCT patients, with a mortality of 70% to 90% in allogeneic recipients, despite treatment. The incidence of invasive aspergillosis in allogeneic recipients is 10% to 15%, with a bimodal distribution of cases. During the early preengraftment period that is characterized by profound neutropenia, both allogeneic and autologous recipients are at increased risk for invasive aspergillosis. Allogeneic patients experience a second period of vulnerability, however, during the postengraftment phase, coincident with the development of chronic GVHD, because of the need for augmented immunosuppression. The vulnerability to invasive aspergillosis is higher during the second period than during neutropenia.

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