Transplantation of hematopoietic stem cells (HSCs) from bone marrow or from peripheral or cord blood for cancer, immunodeficiency, or autoimmune disease results in a transient state of complete immunologic incompetence. Immediately after myeloablative chemotherapy and transplantation, both innate immune cells (phagocytes, natural killer cells) and adaptive immune cells (T and B cells) are absent, and the host is extremely susceptible to infection. The reconstitution that follows transplantation has been likened to maturation of the immune system in neonates. The analogy does not entirely predict infections seen in HSC transplant recipients, however, because the stem cells mature in an old host who has several latent infections already. The choice among the current variety of methods for obtaining stem cells is determined by availability and by the need to optimize the chances of cure for an individual recipient. One strategy is autologous HSC transplantation, in which the donor and the recipient are the same. After chemotherapy, stem cells are collected and are purged (ex vivo) of residual neoplastic populations. Allogeneic HSC transplantation has the advantage of providing a graft-versus-tumor effect. In this case, the recipient is matched to varying degrees for human leukocyte antigen (HLA) with a donor who may be related or unrelated. In some individuals, nonmyeloablative therapy (mini-allo transplantation) is used and permits recipient cells to persist for some time after transplantation while preserving the graft-versus-tumor effect and sparing the recipient myeloablative therapy. Cord-blood transplantation is increasingly utilized in adults; two independent cord-blood units are typically required for suitable neutrophil engraftment early after transplantation, even though only one of the units is likely to provide long-term engraftment. In each circumstance, a different balance is struck between the toxicity of conditioning therapy, the need for a maximal graft-versus-target effect, short-term and long-term infectious complications, and the risk of graft-versus-host disease (GVHD; acute versus chronic). The various approaches differ in terms of reconstitution speed, cell lineage, and likelihood of GVHD—all factors that can produce distinct effects on the risk of infection after transplantation (Table 132-2). Despite these caveats, most infections occur in a predictable time frame after transplantation (Table 132-3).
In the first month after HSC transplantation, infectious complications are similar to those in granulocytopenic patients receiving chemotherapy for acute leukemia (Chap. 86). Because of the anticipated 1- to 4-week duration of neutropenia and the high rate of bacterial infection in this population, many centers give prophylactic antibiotics to patients upon initiation of myeloablative therapy. Quinolones decrease the incidence of gram-negative bacteremia among these patients. Bacterial infections are common in the first few days after HSC transplantation. The organisms involved are predominantly those found on the skin, mucosa, or IV catheters (Staphylococcus aureus, coagulase-negative staphylococci, streptococci) or aerobic bacteria that colonize the bowel (Escherichia coli, Klebsiella, Pseudomonas). Bacillus cereus, although rare, has emerged as a pathogen early after transplantation and can cause meningitis, which is unusual in these patients. Chemotherapy, use of broad-spectrum antibiotics, and delayed reconstitution of humoral immunity place HSC transplant patients at risk for diarrhea and colitis caused by Clostridium difficile overgrowth and toxin production.
Beyond the first few days of neutropenia, infections with nosocomial pathogens (e.g., vancomycin-resistant enterococci, Stenotrophomonas maltophilia, Acinetobacter species, and extended-spectrum β-lactamase-producing gram-negative organisms) as well as with filamentous bacteria (e.g., Nocardia species) become more common. Vigilance is indicated, particularly for patients with a history of active or known latent tuberc ulosis, even when they have been appropriately pretreated. Episodes of bacteremia due to encapsulated organisms mark the late posttransplantation period (>6 months after HSC reconstitution); patients who have undergone splenectomy and those with persistent hypogammaglobulinemia are at particular risk.
Beyond the first week after transplantation, fungal infections become increasingly common, particularly among patients who have received broad-spectrum antibiotics. As in most granulocytopenic patients, Candida infections are most commonly seen in this setting. However, with increased use of prophylactic fluconazole, infections with resistant fungi—in particular, Aspergillus and other molds (Fusarium, Scedosporium, Penicillium)—have become more common, prompting some centers to replace fluconazole with agents such as micafungin, voriconazole, and even posaconazole. The role of antifungal prophylaxis with these different agents, in contrast to empirical treatment for suspected (based on positive β-d-glucan assay or galactomannan antigen test) or documented infection, remains controversial (Chap. 86). In patients with GVHD who require prolonged or indefinite courses of glucocorticoids and other immunosuppressive agents [e.g., cyclosporine, tacrolimus (FK 506, Prograf), mycophenolate mofetil (Cellcept), rapamycin (sirolimus, Rapamune), antithymocyte globulin, or anti-CD52 antibody (alemtuzumab, Campath, an antilymphocyte and antimonocyte monoclonal antibody)], there is a high risk of fungal infection (usually with Candida or Aspergillus), even after engraftment and resolution of neutropenia. These patients are also at high risk for reactivation of latent fungal infection (histoplasmosis, coccidioidomycosis, or blastomycosis) in areas where endemic fungi reside and after involvement in activities such as gardening or caving. Prolonged use of central venous catheters for parenteral nutrition (lipids) increases the risk of fungemia with Malassezia. Some centers administer prophylactic antifungal agents to these patients. Because of the high and prolonged risk of Pneumocystisjiroveci pneumonia (especially among patients being treated for hematologicmalignancies), most patients receive maintenance prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) starting 1 month after engraftment and continuing for at least 1 year.
The regimen just described for the fungal pathogen Pneumocystis may also protect patients seropositive for the parasite T. gondii, which can cause pneumonia, visceral disease (occasionally), and central nervous system (CNS) lesions (more commonly). The advantages of maintaining HSC transplant recipients on daily TMP-SMX for 1 year after transplantation include some protection against Listeria monocytogenes and nocardial disease as well as late infections with Streptococcus pneumoniae and Haemophilus influenzae, which stem from the inability of the immature immune system to respond to polysaccharide antigens.
With increasing international travel, parasitic diseases typically restricted to particular environmental niches may pose a risk of reactivation in certain patients after HSC transplantation. Thus, in recipients with an appropriate history who were not screened and/or treated before transplantation or in patients with recent exposures, evaluation for infection with Strongyloides, Leishmania, or various parasitic causes of diarrheal illness (Giardia, Cryptosporidium, microsporidia) may be warranted.
HSC transplant recipients are susceptible to infection with a variety of viruses, including primary and reactivation syndromes caused by most human herpesviruses (Table 132-4) and acute infections caused by viruses that circulate in the community.
Table 132-4 Herpesvirus Syndromes of Transplant Recipients |Favorite Table|Download (.pdf)
Table 132-4 Herpesvirus Syndromes of Transplant Recipients
|Herpes simplex virus type 1|
Pneumonia (only in HSC transplant recipients)
|Herpes simplex virus type 2|
|Varicella-zoster virus||Zoster (can disseminate)|
Associated with graft rejection
Fever and malaise
Bone marrow failure
B cell lymphoproliferative disease/lymphoma
Oral hairy leukoplakia (rare)
|Human herpesvirus type 6|
Delayed monocyte/platelet engraftment
|Human herpesvirus type 7||Undefined|
|Kaposi's sarcoma–associated virus|
Primary effusion lymphoma (rare)
Multicentric Castleman's disease (rare)
Marrow aplasia (rare)
Within the first 2 weeks after transplantation, most patients who are seropositive for HSV-1 excrete the virus from the oropharynx. The ability to isolate HSV declines with time. Administration of prophylactic acyclovir (or valacyclovir) to seropositive HSC transplant recipients has been shown to reduce mucositis and prevent HSV pneumonia (a rare condition reported almost exclusively in allogeneic HSC transplant recipients). Both esophagitis (usually due to HSV-1) and anogenital disease (commonly caused by HSV-2) may be prevented with acyclovir prophylaxis. For further discussion, see Chap. 179.
Reactivation of VZV manifests as herpes zoster and may occur within the first month but more commonly occurs several months after transplantation. Reactivation rates are ∼40% for allogeneic HSC transplant recipients and 25% for autologous recipients. Localized zoster can spread rapidly in an immunosuppressed patient. Fortunately, disseminated disease can usually be controlled with high doses of acyclovir. Because of frequent dissemination among patients with skin lesions, acyclovir is given prophylactically in some centers to prevent severe disease. Low doses of acyclovir (400 mg orally, three times daily) appear to be effective in preventing reactivation of VZV. However, acyclovir can also suppress the development of VZV-specific immunity. Thus, its administration for only 6 months after transplantation does not prevent zoster from occurring when treatment is stopped. Administration of low doses of acyclovir for an entire year after transplantation is effective and may eliminate most cases of posttransplantation zoster. For further discussion, see Chap. 180.
The onset of CMV disease (interstitial pneumonia, bone marrow suppression, graft failure, hepatitis/colitis) usually begins 30–90 days after HSC transplantation, when the granulocyte count is adequate but immunologic reconstitution has not occurred. CMV disease rarely develops earlier than 14 days after transplantation and may become evident as late as 4 months after the procedure. It is of greatest concern in the second month after transplantation, particularly in allogeneic HSC transplant recipients. In cases in which the donor marrow is depleted of T cells (to prevent GVHD or eliminate a T cell tumor), the disease may be manifested earlier. The use of alemtuzumab to prevent GVHD in nonmyeloablative transplantation has been associated with an increase in CMV disease. Patients who receive ganciclovir for prophylaxis, preemptive treatment, or treatment (see below) may develop recurrent CMV infection even later than 4 months after transplantation, as treatment appears to delay the development of the normal immune response to CMV infection. Although CMV disease may present as isolated fever, granulocytopenia, thrombocytopenia, or gastrointestinal disease, the foremost cause of death from CMV infection in the setting of HSC transplantation is pneumonia.
With the standard use of CMV-negative or filtered blood products, primary CMV infection should be a major risk in allogeneic transplantation only when the donor is CMV-seropositive and the recipient is CMV-seronegative. Reactivation disease or superinfection with another strain from the donor is also common in CMV-positive recipients, and most seropositive patients who undergo HSC transplantation excrete CMV, with or without clinical findings. Serious CMV disease is much more common among allogeneic than autologous recipients and is often associated with GVHD. In addition to pneumonia and marrow suppression (and, less often, graft failure), manifestations of CMV disease in HSC transplant recipients include fever with or without arthralgias, myalgias, hepatitis, and esophagitis. CMV ulcerations occur in both the lower and the upper gastrointestinal tract, and it may be difficult to distinguish diarrhea due to GVHD from that due to CMV infection. The finding of CMV in the liver of a patient with GVHD does not necessarily mean that CMV is responsible for hepatic enzyme abnormalities. It is interesting that the ocular and neurologic manifestations of CMV infections, which are common in patients with AIDS, are uncommon in patients who develop disease after transplantation.
Management of CMV disease in HSC transplant recipients includes strategies directed at prophylaxis, preemptive therapy (suppression of silent replication), and treatment of disease. Prophylaxis results in a lower incidence of disease at the cost of treating many patients who otherwise would not require therapy. Because of the high fatality rate associated with CMV pneumonia in these patients and the difficulty of early diagnosis of CMV infection, prophylactic IV ganciclovir (or oral valganciclovir) has been used in some centers and has been shown to abort CMV disease during the period of maximal vulnerability (from engraftment to day 120 after transplantation). Ganciclovir also prevents HSV reactivation and reduces the risk of VZV reactivation; thus acyclovir prophylaxis should be discontinued when ganciclovir is administered. The foremost problem with the administration of ganciclovir relates to adverse effects, which include dose-related bone marrow suppression (thrombocytopenia, leukopenia, anemia, and pancytopenia). Because the frequency of CMV pneumonia is lower among autologous HSC transplant recipients (2–7%) than among allogeneic HSC transplant recipients (10–40%), prophylaxis in the former group will not become the rule until a less toxic oral antiviral agent becomes available.
Preemptive treatment of CMV—that is, initiation of therapy with drugs only after CMV is detected in blood, typically by a nucleic acid amplification test—is used at most centers. The preemptive approach has supplanted prophylactic therapy, or treatment of all seropositive (recipient and/or donor) HSC transplants with an antiviral agent (typically ganciclovir), because of toxic drug side effects (e.g., neutropenia and bone marrow suppression). Quantitative viral load assays, which are not dependent on circulating leukocytes, have supplanted older antigen-based assays for CMV. A positive test (or increasing viral load) prompts the initiation of preemptive therapy with ganciclovir. Preemptive approaches that target patients who have polymerase chain reaction (PCR) evidence of CMV can still lead to unnecessary treatment of many individuals with drugs that have adverse effects on the basis of a laboratory test that is not highly predictive of disease; however, invasive disease, particularly in the form of pulmonary infection, is difficult to treat and is associated with high mortality rates. When prophylaxis or preemptive therapy is stopped, late manifestations of CMV replication may occur, although by then the HSC transplant patient is often equipped with improved graft function and is better able to combat disease.
CMV pneumonia in HSC transplant recipients (unlike that in other clinical settings) is often treated with both IV immunoglobulin (IVIg) and ganciclovir. In patients who cannot tolerate ganciclovir, foscarnet is a useful alternative, although it may produce nephrotoxicity and electrolyte imbalance. When neither ganciclovir nor foscarnet is clinically tolerated, cidofovir can be used; however, its efficacy is less well established, and its side effects include nephrotoxicity. Case reports have suggested that the immunosuppressive agent leflunomide may be active in this setting, but controlled studies are lacking. Transfusion of CMV-specific T cells from the donor has decreased viral load in a small series of patients; this result suggests that immunotherapy may play a role in the treatment of this disease in the future.
For further discussion, see Chap. 182.
Human Herpesviruses 6 and 7
Human herpesvirus type 6 (HHV-6), the cause of roseola in children, is a ubiquitous herpesvirus that reactivates (as determined by quantitative plasma PCR) in ∼50% of HSC transplant recipients 2–4 weeks after transplantation. Reactivation is more common among patients requiring glucocorticoids for GVHD and among those receiving second transplants. Reactivation of HHV-6, primarily type B, may be associated with delayed monocyte and platelet engraftment. Limbic encephalitis developing after transplantation has been associated with HHV-6 in cerebrospinal fluid (CSF). The causality of the association is not well defined: in several cases, plasma viremia was detected long before the onset of encephalitis. Nevertheless, most patients with encephalitis had very high viral loads in plasma at the time of CNS illness, and viral antigen has been detected in hippocampal astrocytes. HHV-6 DNA is sometimes found in lung samples after transplantation. However, its role in pneumonitis is unclear, as co-pathogens are frequently present. While HHV-6 is susceptible to foscarnet or cidofovir (and possibly to ganciclovir) in vitro, the efficacy of antiviral treatment has not been well studied. Little is known about the related herpesvirus HHV-7 or its role in posttransplantation infection. For further discussion, see Chap. 182.
Primary EBV infection can be fatal to HSC transplant recipients; EBV reactivation can cause EBV–B cell lymphoproliferative disease (EBV-LPD), which may also be fatal to patients taking immunosuppressive drugs. Latent EBV infection of B cells leads to several interesting phenomena in HSC transplant recipients. The marrow ablation that occurs as part of the HSC transplantation procedure may sometimes eliminate latent EBV from the host. Infection can then be reacquired immediately after transplantation by transfer of infected donor B cells. Rarely, transplantation from a seronegative donor may result in cure. The recipient is then at risk for a second primary infection.
EBV-LPD can develop in the recipient's B cells (if any survive marrow ablation) but is more likely to be a consequence of outgrowth of infected donor cells. Both lytic replication and latent replication of EBV are more likely during immunosuppression (e.g., they are associated with GVHD and the use of antibodies to T cells). Although less likely in autologous transplantation, reactivation can occur in T cell–depleted autologous recipients (e.g., patients being given antibodies to T cells for the treatment of a T cell lymphoma with marrow depletion). EBV-LPD, which can become apparent as early as 1–3 months after engraftment, can cause high fevers and cervical adenopathy resembling the symptoms of infectious mononucleosis but more commonly presents as an extranodal mass. The incidence of EBV-LPD among allogeneic HSC transplant recipients is 0.6–1%, which contrasts with figures of ∼5% for renal transplant recipients and up to 20% for cardiac transplant patients. In all cases, EBV-LPD is more likely to occur with high-dose, prolonged immunosuppression, especially that caused by the use of antibodies to T cells, glucocorticoids, and calcineurin inhibitors (e.g., cyclosporine, tacrolimus). Ganciclovir, administered to preempt CMV disease, may reduce EBV lytic replication and thereby diminish the pool of B cells that can become newly infected and give rise to LPD. Increasing evidence indicates that replacement of calcineurin inhibitors with m-Tor inhibitors (e.g., rapamycin) exerts an antiproliferative effect on EBV-infected B cells that decreases the likelihood of developing LPD or unrelated proliferative disorders associated with transplant-related immunosuppression.
PCR can be used to monitor EBV production after HSC transplantation. High or increasing viral loads predict an enhanced likelihood of developing EBV-LPD and should prompt rapid reduction of immunosuppression and search for nodal or extra nodal disease. If reduction of immunosuppression does not have the desired effect, administration of a monoclonal antibody to CD20 (rituximab or others) for the treatment of B cell lymphomas that express this surface protein has elicited dramatic responses and currently constitutes first-line therapy for CD20-positive EBV-LPD. However, long-term suppression of new antibody responses accompanies therapy, and recurrences are not infrequent. Additional B cell–directed antibodies, including anti-CD22, are under study. The role of antiviral drugs is uncertain because no available agents have been documented to have activity against the different forms of latent EBV infection. Diminishing lytic replication and virion production in these patients would theoretically produce a statistical decrease in the frequency of latent disease by decreasing the number of virions available to cause additional infection. In case reports and small animal studies, ganciclovir and/or high-dose zidovudine (AZT), together with other agents, has been used to eradicate EBV-LPD and CNS lymphomas, another EBV-associated complication of transplantation. Both interferon and retinoic acid have been employed in the treatment of EBV-LPD, as has IVIg, but no large prospective studies have assessed the efficacy of any of these agents. Several additional drugs are undergoing preclinical evaluation. Standard chemotherapeutic regimens are used if disease persists after reduction of immunosuppressive agents and administration of antibodies. EBV-specific T cells generated from the donor have been used experimentally to prevent and to treat EBV-LPD in allogeneic recipients, and efforts are under way to increase the activity and specificity of ex vivo–generated T cells. For further discussion, see Chap. 181.
Human Herpesvirus 8 (Kshv)
The EBV-related gammaherpesvirus KSHV, which is causally associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, has rarely resulted in disease in HSC transplant recipients, although some cases of virus-associated marrow aplasia have been reported in the peritransplantation period. The relatively low seroprevalence of KSHV in the population and the limited duration of profound T cell suppression after HSC transplantation provide a plausible explanation for the currently low incidence of KSHV disease compared with that in recipients of solid organ transplants and patients with HIV infection. For further discussion, see Chap. 182.
Other (Nonherpes) Viruses
The diagnosis of pneumonia in HSC transplant recipients poses special problems. Because patients have undergone treatment with multiple chemotherapeutic agents and sometimes irradiation, their differential diagnosis should include—in addition to bacterial and fungal pneumonia—CMV pneumonitis, pneumonia of other viral etiologies, parasitic pneumonia, diffuse alveolar hemorrhage, and chemical- or radiation-associated pneumonitis. Since fungi and viruses [e.g., influenza A and B viruses, respiratory syncytial virus (RSV), parainfluenza virus (types 1–4), adenovirus, enterovirus, bocavirus, human metapneumovirus, coronavirus, and rhinovirus (increasingly detected by multiplex PCR)] can also cause pneumonia in this setting, it is important to diagnose CMV specifically (see “Cytomegalovirus,” above). M. tuberculosis has been an uncommon cause of pneumonia among HSC transplant recipients in Western countries (accounting for <0.1–0.2% of cases) but is common in Hong Kong (5.5%) and in countries where the prevalence of tuberculosis is high. The recipient's exposure history is clearly critical in an assessment of posttransplantation infections.
Both RSV and parainfluenza viruses, particularly type 3, can cause severe or even fatal pneumonia in HSC transplant recipients. Infections with both of these agents sometimes occur as disastrous nosocomial epidemics. Therapy with palivizumab or ribavirin for RSV infection remains controversial. Influenza also occurs in HSC transplant recipients and generally mirrors the presence of infection in the community. Progression to pneumonia is more common when infection occurs early after transplantation and when the recipient is lymphopenic. Several drugs are available for the treatment of influenza. Amantadine and rimantadine have limited effects, primarily reducing symptoms and shortening the duration of illness caused by sensitive strains of influenza A virus. The neuraminidase inhibitors oseltamivir (oral) and zanamivir (aerosolized) are active against both influenza A virus and influenza B virus and are a reasonable treatment option. Parenteral forms of neuraminidase inhibitors such as peramivir (intravenous) are undergoing clinical trials. Peramivir is currently available through the Centers for Disease Control and Prevention (CDC) for the treatment of severe H1N1 influenza. An important preventive measure is immunization of household members, hospital staff members, and other frequent contacts. Adenoviruses can be isolated from HSC transplant recipients at rates varying from 5% to ≤18%. Like CMV infection, adenovirus infection usually occurs in the first to third month after transplantation and is often asymptomatic, although pneumonia, hemorrhagic cystitis/nephritis, severe gastroenteritis with hemorrhage, and fatal disseminated infection have been reported. A role for cidofovir therapy has been suggested, but the efficacy of this agent is unproven in adenovirus infection.
Although diverse respiratory viruses can sometimes cause severe pneumonia and respiratory failure in HSC transplant recipients, mild or even asymptomatic infection may be more common. For example, rhinoviruses and coronaviruses are frequent co-pathogens in HSC transplant recipients; however, whether they independently contribute to significant pulmonary infection is not known. At present, the overall contribution to the burden of lower respiratory tract disease in HSC transplant recipients for the secondary group of viral respiratory pathogens listed above is unknown.
Infections with parvovirus B19 (presenting as anemia or occasionally as pancytopenia) and disseminated enteroviruses (sometimes fatal) can occur. Parvovirus B19 infection can be treated with IVIg (Chap. 184). Intranasal pleconaril, a capsid-binding agent, is being studied for the treatment of enterovirus (and rhinovirus) infection.
Rotaviruses are a common cause of gastroenteritis in HSC transplant recipients. The polyomavirus BK virus is found at high titers in the urine of patients who are profoundly immunosuppressed. BK viruria may be associated with hemorrhagic cystitis in these patients. Compared with the incidence among patients with impaired T cell function due to HIV infection, progressive multifocal leukoencephalopathy caused by the related JC virus is relatively rare among HSC transplant recipients (Chap. 381). When transmitted by mosquitoes or by blood transfusion, West Nile virus can cause encephalitis and death after HSC transplantation.