ABSTRACT: Blood and marrow transplantation, a curative treatment for a variety of serious diseases, induces a period of sustained immunosuppression predisposing recipients to opportunistic infections. Both for the protection of the individual transplant recipient and as a matter of public health policy, the US Centers for Disease Control and Prevention (CDC) has developed guidelines for the use of vaccination in the prevention of infectious disease following transplantation. This review examines the primary clinical research supporting vaccination policies in this target population. Widely accepted recommendations for transplant recipients based on scientific data are sparse, as few large studies have been conducted in this population. Anecdotal reports, expert advice, summaries, and limited series involving less than 50 patients using surrogate end points form the basis of the scientific literature, with the result being a wide variation in practice. Although based largely on inadequate scientific data, the CDC recommendations offer a pragmatic approach to the prevention of opportunistic disease in hematopoietic transplant recipients and serve as a useful starting point for standardization of practice while defining the direction of future studies in transplant recipients and other immunocompromised hosts.
Blood and marrow stem cell transplantation is a potentially curative treatment for a variety of hematologic malignancies, marrow failure syndromes, immunodeficiency states, and selected solid tumors. This aggressive treatment induces a period of sustained immunosuppression predisposing transplant recipients to opportunistic infections. Strategies for the prevention of these infections include the judicious use of prophylactic antibiotics and both active and passive immunization.[1]
Recently, both the US Centers for Disease Control and Prevention (CDC)[2] and the European Group for Bone Marrow Transplantation[ 3,4] issued recommendations for infectious disease immunization of hematopoietic stem cell transplant recipients. As increasing numbers of transplant recipients survive and return to the community setting, it becomes incumbent upon primary care physicians to ensure appropriate vaccination both for the protection of transplant recipients and as a matter of community public health.
Causes of Altered Immunity Following Transplantation
Transplant recipients become severely immunocompromised following high-dose therapy.[5] The transplant conditioning (chemoradiotherapy) regimen is the major contributor to early immune dysfunction. High-dose therapy causes damage to skin, gastrointestinal mucosa, and respiratory tract linings, permitting direct entry of pathogens. Alterations in protective barrier secretions (including immunoglobulin [Ig]A and saliva) may persist for months after treatment. The conditioning regimen also causes severe myelosuppression and a brief period of absolute neutropenia.
Engraftment of neutrophils, typically within 10 to 30 days after stem cell infusion, restores significant phagocytic function and considerably reduces the risk of bacterial infection. However, long-lasting immune impairment, primarily as a result of the depression of cellular immunity (lymphoid lineage driven), persists for months even in the absence of additional immunosuppressive medications or graft-vs-host reactions. These impairments are characterized by deficiencies in total immunoglobulin levels, IgG subclass concentrations, and in vitro B-cell and T-cell function.[6-8]
The incorporation of highly immunosuppressive medications into the conditioning regimens (permitting nonmyeloablative transplantation)[9] and the expanding role of posttransplant immunotherapy [10] may further affect immune recovery. The use of cytokines (hematopoietic growth factors) may also influence recovery. For example, granulocyte colonystimulating factor (G-CSF, Neupogen) appears to polarize recovering T lymphocytes toward a tolerance phenotype.[11]
Graft Characteristics
The rate of immunologic reconstitution also depends on characteristics of the hematopoietic graft including the stem cell source. Neutrophil recovery occurs most rapidly with peripheral blood stem cells, less rapidly with marrow, and slowest with umbilical cord cells. A more rapid neutrophil recovery after blood stem cell transplant is associated with a decrease in early mortality from infectious causes, compared to bone marrow stem cell sources among recipients of allogeneic transplants.[12] Lymphoid recovery also differs by stem cell source, leading to qualitative differences in immune function. Peripheral blood stem cell transplant recipients achieve faster recovery of total lymphocyte counts, total T cells (CD3), CD8, and CD4 cells, compared to marrow recipients.[13]
Among allogeneic transplant recipients, the use of marrow vs peripheral blood was associated with a 1.7-fold increase in documented infections, which was greatest for fungal infections, intermediate for bacterial infections, and least for viral infections.[14] Among autologous transplant recipients, one study comparing peripheral blood stem cell recovery to bone marrow recovery noted that 47% of blood and 29% of marrow recipients maintained immunity against tetanus.[15] However, a recent comparative study of vaccine responses to influenza, pneumococcal polysaccharide, and tetanus toxoid vaccines found no differences in serologic outcomes among allogeneic sibling marrow, autologous marrow, and autologous blood stem cell transplant recipients, thus supporting a broader vaccination policy.[16]
In addition, there are major differences in immune reconstitution between allogeneic and autologous transplant recipients. Although patients who undergo autologous transplant reconstitute the immune system more rapidly, significant impairment may occur among patients with lymphoid malignancies or recipients of grafts who have undergone ex vivo pharmacologic purging to remove tumor cells or CD34 selection (which reduces T-cell content).[17] Among allogeneic recipients, passive transfer of immune function from the donor may be beneficial but transient, and recipients are at risk of developing immune deregulation caused by disparity between the donor and recipient (commonly known as graft-vs-host disease [GVHD]). Patients who develop chronic GVHD experience significantly delayed lymphoid recovery (lasting for years), which may contribute to an excess of infections and delayed response to vaccinations. Recipients of mismatched or haploidentical allografts and those receiving immature cord blood grafts may experience extreme delays in immune recovery.
Late Infections
Although the conditioning regimen, type of transplant, and underlying disease affect the rate of immune reconstitution, all transplant recipients are at increased risk of late infection. In a study of 818 recipients of autografts and 1,007 recipients of allografts, 6.2% developed a late infection that required hospitalization 3 months or more following the transplant. The most common infectious pathogens were cytomegalovirus (n = 19), pneumococcus (n = 15), pneumocystis (n = 12), aspergillosis (n = 8), and pseudomonas (n = 7).[18] In a series of 244 autologous peripheral blood stem cell transplants, 64 (26%) developed an infection after engraftment. Varicella zoster virus (VZV, n = 36) and pneumonia (n = 16) were most common.
Risk factors for late infections in these autograft recipients included the administration of total-body irradiation (odds ratio [OR]: 2.5), previous use of fludarabine (Fludara, OR: 2.5), and a diagnosis of myeloma (OR: 2.6).[19] In the allogeneic setting, a 1982 series of 98 patients noted that approximately one-third of long-term survivors had three or more infections. Of the 244 infections in this series, 62 were of pulmonary origin (23 bacterial pneumonia, 25 bronchitis, 7 interstitial pneumonia), 49 cutaneous (including 29 VZV), 84 involving the ear, nose, and throat, 17 systemic (including 11 bacterial sepsis), and 15 ophthalmologic.[20]
In a more recent series of 151 allogeneic-related donor recipients, 67% had a late infection, and among 98 unrelated transplant recipients, 81% had a late infection (P = .015). Bacterial infections were most common, causing 52% of events (52% of these were gram-positive). Viruses caused 37%, and fungi were involved in 11%. Sixty-seven percent of the infections occurred between day 50 and 6 months, with 43% occurring between days 50 and 100; 22% occurred between 3 and 6 months, 26% between 6 months and 1 year, and 8% beyond 1 year. Of the 367 late infections, 103 were lifethreatening.[ 21]
