Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation

Please note: An erratum has been published for this article. To view the erratum, please click here.

Abbreviations Used in This Publication

The following CDC staff members prepared this report:

Clare A. Dykewicz, M.D., M.P.H.
Harold W. Jaffe, M.D., Director
Division of AIDS, STD, and TB Laboratory Research
National Center for Infectious Diseases

Jonathan E. Kaplan, M.D.
Division of AIDS, STD, and TB Laboratory Research
National Center for Infectious Diseases
Division of HIV/AIDS Prevention --- Surveillance and Epidemiology
National Center for HIV, STD, and TB Prevention

in collaboration with the Guidelines Working Group Members from CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation

Clare A. Dykewicz, M.D., M.P.H., Chair
Harold W. Jaffe, M.D.
Thomas J. Spira, M.D.
Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D.
Hospital Infections Program
National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D.
Division of AIDS, STD, and TB Laboratory Research
National Center for Infectious Diseases
Division of HIV/AIDS Prevention --- Surveillance and Epidemiology
National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D.
Division of HIV/AIDS Prevention---Surveillance and Epidemiology
National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A.
Beth Hibbs, R.N., M.P.H.
Epidemiology and Surveillance Division
National Immunization Program, CDC

Raleigh A. Bowden, M.D.
Keith Sullivan, M.D.
Fred Hutchinson Cancer Research Center
Seattle, Washington 

David Emanuel, M.B.Ch.B.
Indiana University
Indianapolis, Indiana

David L. Longworth, M.D.
Cleveland Clinic Foundation
Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S.
International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry
Milwaukee, Wisconsin

Robert H. Rubin, M.D.
Massachusetts General Hospital
Boston, Massachusetts
and
Massachusetts Institute of Technology
Cambridge, Massachusetts

Kent A. Sepkowitz, M.D.
Memorial-Sloan Kettering Cancer Center
New York, New York

John R. Wingard, M.D.
University of Florida
Gainesville, Florida

Additional Contributors

John F. Modlin, M.D.
Dartmouth Medical School
Hanover, New Hampshire

Donna M. Ambrosino, M.D.
Dana-Farber Cancer Institute
Boston, Massachusetts

Norman W. Baylor, Ph.D.
Food and Drug Administration
Rockville, Maryland

Albert D. Donnenberg, Ph.D.
University of Pittsburgh
Pittsburgh, Pennsylvania 

Pierce Gardner, M.D.
State University of New York at Stony Brook
Stony Brook, New York

Roger H. Giller, M.D.
University of Colorado
Denver, Colorado

Neal A. Halsey, M.D.
Johns Hopkins University
Baltimore, Maryland

Chinh T. Le, M.D.
Kaiser-Permanente Medical Center
Santa Rosa, California

Deborah C. Molrine, M.D.
Dana-Farber Cancer Institute
Boston, Massachusetts

Keith M. Sullivan, M.D.
Fred Hutchinson Cancer Research Center
Seattle, Washington

Summary

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

INTRODUCTION

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

Using These Guidelines

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

BACKGROUND

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

Immune System Recovery After HSCT

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm³ and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)₂, IgG₄, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

Opportunistic Pathogens After HSCT

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

• Phase I, preengraftment. During the first month posttransplant, HSCT recipients have two critical risk factors for infection --- prolonged neutropenia and breaks in the mucocutaneous barrier resulting from the HSCT preparative regimens and frequent vascular access required for patient care. Consequently, oral, gastro-intestinal, and skin flora are sources of infection. Prevalent pathogens include Candida species, and as neutropenia continues, Aspergillus species. Additionally, herpes simplex virus (HSV) reactivation can occur during this phase. During preengraftment, the risks for infection are the same for autologous or allogeneic patients, and OIs can appear as febrile neutropenia. Although a recipient's first fever during preengraftment is probably caused by a bacterial pathogen, rarely is an organism or site of infection identified. Instead, such infections are usually treated preemptively or empirically (48) until the neutropenia resolves (49). Growth factors can be administered during phase I to decrease neutropenia duration and complications (e.g., febrile neutropenia) (50).
• Phase II, postengraftment. Phase II is dominated by impaired cell-mediated immunity for allogeneic or autologous recipients. Scope and impact of this defect for allogeneic recipients are determined by the extent of GVHD and its immunosuppressive therapy. After engraftment, the herpes viruses, particularly CMV, are critical pathogens. At 30--100 days after HSCT, CMV causes pneumonia, hepatitis, and colitis and potentiates superinfection with opportunistic pathogens, particularly among patients with active GVHD. Other dominant pathogens during this phase include Pneumocystis carinii and Aspergillus species.
• Phase III, late phase. During phase III, autologous recipients usually have more rapid recovery of immune system function and, therefore, a lower risk for OIs than do allogeneic recipients. Because of cell-mediated and humoral immunity defects and impaired reticuloendothelial system function, allogeneic patients with chronic GVHD and recipients of alternate donor allogeneic transplants are at risk for certain infections during this phase. Alternate donors include matched unrelated, UCB, or mismatched family-related donors. These patients are at risk for infections that include CMV, varicella-zoster virus (VZV), EBV-related posttransplant lymphoproliferative disease, community-acquired respiratory viruses (CRV), and infections with encapsulated bacteria (e.g., Ha. influenzae and Stre. pneumoniae). Risk for these infections is approximately proportional to the severity of the patient's GVHD during phases II and III. Patients receiving mismatched allogeneic transplants have a higher attack rate and severity of GVHD and, therefore, a higher risk for OIs during phases II and III than do patients receiving matched allogeneic HSCTs. In contrast, patients undergoing autologous transplantation are primarily at risk for infection during phase I.

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

BACTERIAL INFECTIONS

General Recommendations

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Recommendations Regarding Stre. pneumoniae

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Recommendations Regarding Streptococci viridans

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Recommendations Regarding Ha. influenzae type b

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

VIRAL INFECTIONS

Recommendations Regarding Cytomegalovirus

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 10⁶ leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Recommendations Regarding EBV

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Recommendations Regarding HSV

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

Other Recommendations

HSV prophylaxis lasting >30 days after HSCT might be considered for persons with frequent recurrent HSV (CIII) (Appendix). Acyclovir can be used during phase I for administration to HSV-seropositive autologous recipients who are likely to experience substantial mucositis from the conditioning regimen (CIII). Antiviral prophylaxis doses should be modified for use among children (Appendix), but no published data were found regarding valacyclovir safety and efficacy among children.

Recommendations Regarding VZV

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-VZV IgG antibodies (AIII). However, these tests are not 100% reliable, particularly among severely immunosuppressed patients. Researchers recommend that a past history of varicella accompanied by a positive titer is more likely to indicate the presence of immunity to VZV than a low positive titer alone. All HSCT candidates and recipients, particularly those who are VZV-seronegative, should be informed of the potential seriousness of VZV disease among immunocompromised persons and advised of strategies to decrease their risk for VZV exposure (116--122) (AII).

Although researchers report that the majority of VZV disease after HSCT is caused by reactivation of endogenous VZV, HSCT candidates and recipients who are VZV-seronegative, or VZV-seropositive and immunocompromised, should avoid exposure to persons with active VZV infections (123) (AII). HCWs, family members, household contacts, and visitors who are healthy and do not have a reported history of varicella infection or who are VZV-seronegative should receive VZV vaccination before being allowed to visit or have direct contact with an HSCT recipient (AIII). Ideally, VZV-susceptible family members, household contacts, and potential visitors of immunocompromised HSCT recipients should be vaccinated as soon as the decision is made to perform HSCT. The vaccination dose or doses should be completed >4 weeks before the conditioning regimen begins or >6 weeks (42 days) before the HSCT is performed (BIII).

HSCT recipients and candidates undergoing conditioning therapy should avoid contact with any VZV vaccine recipient who experiences a rash after vaccination (BIII). When this rash occurs, it usually appears 14--21 days after VZV vaccination (median: 22 days; range: 5--35 days) (personal communication from Robert G. Sharrar, M.D., Merck & Co., Inc.). However, to date, no serious disease has been reported among immuno-compromised patients from transmission of VZV vaccine virus, and the VZV vaccine strain is susceptible to acyclovir.

All HSCT recipients with VZV disease should be placed under airborne and contact precautions (62) (AII) to prevent transmission to other HSCT recipients. Contact precautions should be continued until all skin lesions are crusted. Airborne precautions should be instituted 10 days after exposure to VZV and continued until 21 days after last exposure or 28 days postexposure if the patient received varicella-zoster immunoglobulin (VZIG)**** (62) (AI) because a person infected with VZV can be infectious before the rash appears.

Preventing Disease

VZIG. VZV-seronegative HSCT recipients should be administered VZIG as soon as possible but ideally within 96 hours after close or household contact with a person having either chickenpox or shingles if the HSCT recipient is not immunocompetent (i.e., allogeneic patient <24 months after HSCT, >24 months after HSCT and on immunosuppressive therapy, or having chronic GVHD) (AII). Researchers report VZIG administration for VZV exposure as described for HSCT recipients who were VZV-seropositive before HSCT (CIII).

Because of the high morbidity of VZV-associated disease among severely immunocompromised HSCT recipients and until further data are published, HSCT physicians should administer VZIG to all VZV-seronegative HSCT recipients or candidates undergoing conditioning therapy who are exposed to a VZV vaccinee having a varicella-like rash (BIII). Researchers also report VZIG administration for this situation for VZV-seropositive HSCT recipients and candidates undergoing conditioning therapy (CIII). These recommendations are made because the vaccinee might be unknowingly incubating wild-type varicella, particularly during the first 14 days after varicella vaccination, and because vaccine-strain VZV has been rarely transmitted by VZV vaccinees with vesicular rashes postvaccination (121).

If VZV-seronegative HSCT recipients or candidates undergoing conditioning therapy are closely exposed to varicella >3 weeks after receiving VZIG, they should be administered another dose of VZIG (120) (BIII). Researchers also recommend VZIG administration for this condition for VZV-seropositive HSCT recipients and candidates undergoing conditioning therapy (CIII).

Antiviral Drugs. Any HSCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash (particularly after exposure to a person with wild-type varicella or shingles) should receive preemptive intravenous acyclovir until >2 days after all lesions have crusted (BIII) (Appendix). Any HSCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash after exposure to a VZV vaccinee with a rash should be administered intravenous acyclovir preemptively to prevent severe, disseminated VZV disease (BII). Acyclovir should be administered until 2 days after all lesions have crusted.

Long-term acyclovir prophylaxis to prevent recurrent VZV infection (e.g., during the first 6 months after HSCT) is not routinely recommended (124--126) (DIII); however, this therapy could be considered for use among HSCT recipients with severe, long-term immunodeficiency (CIII). When acyclovir resistance occurs among patients, HSCT physicians should use foscarnet for preemptive treatment of VZV disease (127) (BIII). Researchers report valacyclovir use for preventing HSV among HSCT recipients (CIII). However, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data regarding HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among HSCT recipients. Physicians wishing to use valacyclovir among HSCT recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix). No data were found demonstrating safety and efficacy of preemptive treatment of famciclovir against herpes zoster among HSCT recipients. Consequently, no recommendation for its use can be made.

Live-Attenuated VZV Vaccine. VZV vaccine use is contraindicated among HSCT recipients <24 months after HSCT (128) (EIII). Use of VZV vaccine among HSCT recipients is restricted to research protocols for recipients >24 months after HSCT who are presumed immunocompetent. Further research is needed to determine the safety, immunogenicity, and efficacy of VZV vaccine among HSCT recipients.

Other Recommendations

An inactivated VZV vaccine has been used investigationally among HSCT recipients (129); however, more studies are needed before a recommendation regarding its use can be made. Recommendations for VZV prevention are the same for allogeneic or autologous recipients. Recommendations for preventing VZV disease among pediatric or adult HSCT recipients are the same, except that appropriate dose adjustments for VZIG should be made for pediatric HSCT recipients (AIII) (Appendix).

Recommendations Regarding CRV Infections: Influenza, Respiratory Syncytial Virus, Parainfluenza Virus, and Adenovirus

Preventing Exposure

Preventing CRV exposure is critical in preventing CRV disease (130,131). To prevent nosocomial CRV transmission, HSCT recipients and their HCWs should always follow HSCT infection control guidelines (AIII). To minimize the risk for CRV transmission, HCWs and visitors with upper respiratory infection (URI) symptoms should be restricted from contact with HSCT recipients and HSCT candidates undergoing conditioning therapy (AIII). At a minimum, active clinical surveillance for CRV disease should be conducted on all hospitalized HSCT recipients and candidates undergoing conditioning therapy; this clinical surveillance should include daily screening for signs and symptoms of CRV (e.g., URI or lower respiratory infection [LRI]) (AIII). Viral cultures of asymptomatic HSCT candidates are unlikely to be useful. HSCT recipients with URI or LRI symptoms should be placed under contact precautions to avoid transmitting infection to other HSCT candi dates and recipients, HCWs, and visitors until the etiology of illness is identified (62) (BIII). Optimal isolation precautions should be modified as needed after the etiology is identified (AIII). HSCT recipients and candidates, their family members and visitors, and all HCWs should be informed regarding CRV infection control measures and the potential severity of CRV infections among HSCT recipients (130--140) (BIII). Physicians have routinely conducted culture-based CRV surveillance among HSCT recipients; however, the cost effectiveness of this approach has not been evaluated.

Influenza vaccination of family members and close or household contacts is strongly recommended during each influenza season (i.e., October--May) starting the season before HSCT and continuing >24 months after HSCT (141) (AI) to prevent influenza exposure among the recipients or candidates. All family members and close or household contacts of HSCT recipients who remain immunocompromised >24 months after HSCT should continue to be vaccinated annually as long as the HSCT recipient's immuno-compromise persists (141) (AI). Seasonal influenza vaccination is strongly recommended for all HCWs of HSCT recipients (142,143) (AI).

If HCWs, family members, or other close contacts of HSCT recipients receive influenza vaccination during an influenza A outbreak, they should receive amantadine or rimantadine chemoprophylaxis for 2 weeks after influenza vaccination (BI) while the vaccinee experiences an immunologic response to the vaccine. Such a strategy is likely to prevent transmission of influenza A to HCWs and other close contacts of HSCT recipients, which could prevent influenza A transmission to HSCT recipients themselves. However, if a nosocomial outbreak occurs with an influenza A strain that is not contained in the available influenza vaccine, all healthy family members, close and household contacts, and HCWs of HSCT recipients and candidates should be administered influenza A chemoprophylaxis with amantadine or rimantadine until the end of the outbreak (141) (BIII).

In 1999, two neuroaminidase inhibitors (zanamivir and oseltamivir) were approved for treatment of influenza, but are not currently approved for prophylaxis. To date, experience is limited regarding use of zanamivir or oseltamivir in the treatment or prophylaxis of influenza among HSCT settings. However, HCWs, family members, or other close contacts can be offered a neuroaminidase inhibitor (e.g., zanamivir or oseltamivir) using the same strategies outlined previously, if a) rimantadine or amantadine cannot be tolerated, b) the outbreak strain of influenza A is amantadine or rimantadine-resistant, or c) the outbreak strain is influenza B (144--147) (BI). Zanamivir can be administered to persons aged >12 years, and oseltamivir can be administered to persons aged >18 years. Patients with influenza should be placed under droplet and standard precautions (AIII) to prevent transmission of influenza to HSCT recipients. HCWs with influenza should be excused from patient care until they are no longer infectious (AIII).

Preventing Disease

HSCT physicians should determine the etiology of a URI in an HSCT recipient or candidate undergoing conditioning therapy, if possible, because respiratory syncytial virus (RSV), influenza, parainfluenza, and adenovirus URIs can progress to more serious LRI, and certain CRVs can be treated (BIII). Appropriate diagnostic samples include nasopharyngeal washes, swabs or aspirates, throat swabs, and bronchoalveolar lavage (BAL) fluid. HSCT candidates with URI symptoms at the time conditioning therapy is scheduled to start should postpone their conditioning regimen until the URIs resolve, if possible, because certain URIs might progress to LRI during immunosuppression (131,133,137,138) (BIII).

Recommendations Regarding Influenza. Life-long seasonal influenza vaccination is recommended for all HSCT candidates and recipients, beginning during the influenza season before HSCT and resuming >6 months after HSCT (142) (BIII). Influenza vaccinations administered to HSCT recipients <6 months after HSCT are unlikely to be beneficial and are not recommended (142) (DII). HSCT recipients <6 months after HSCT should receive chemoprophylaxis with amantadine or rimantadine during community or nosocomial influenza A outbreaks (BIII). These drugs are not effective against influenza B. Additionally, antiviral-resistant strains of influenza can emerge during treatment with amantadine or rimantadine and transmission of resistant strains can occur (148,149). During such outbreaks, HSCT recipients 6--24 months after HSCT, or >24 months after HSCT and still substantially immunocompromised (i.e., receiving immunosuppressive therapy, have had a relapse of their underlying disease, or have GVHD) and who have not yet received a current influenza vaccination, should be vaccinated against influenza immediately (BIII). Additionally, to allow sufficient time for the patient to experience an immunologic response to influenza vaccine, chemoprophylaxis with amantadine or rimantadine can be used for these HSCT recipients for 2 weeks after vaccination during a nosocomial or community influenza A outbreak (CIII). Influenza A chemoprophylaxis with amantadine or rimantadine has been recommended for all influenza A-exposed HSCT recipients <24 months after HSCT or >24 months after HSCT and substantially immunocompromised regardless of vaccination history, because of their likely suboptimal immunologic response to influenza vaccine (142,143). However, no recommendation regarding such chemoprophylaxis can be made because of lack of data.

To prevent severe disease, early preemptive therapy with amantadine or rimantadine has been reported for HSCT recipients with unexplained acute URI or LRI symptoms during a community or nosocomial outbreak of influenza A (141). However, the effectiveness in preventing influenza-related complications and the safety of this strategy have not been evaluated among HSCT recipients. Therefore, data are insufficient to make a recommendation.

Neuroaminidase inhibitors (zanimivir and oseltamivir), intravenous and aerosol ribavirin, and combination drug therapy (e.g., rimantadine or amantadine with ribavirin or interferon) (143,150--153) have been proposed for investigational, preemptive treatment to prevent severe influenza disease among HSCT recipients. However, because of lack of data, no recommendation for use of these strategies among HSCT recipients can be made.

Recommendations Regarding RSV. Respiratory secretions of any hospitalized HSCT candidate or recipient who experiences signs or symptoms of CRV infection should be tested promptly by viral culture and rapid diagnostic tests for RSV (BIII). If two diagnostic samples taken >2 days apart do not identify a respiratory pathogen despite persistence of respiratory symptoms, BAL and further testing are advised (BIII). This testing is critical because of the high morbidity and case fatality of RSV disease among HSCT recipients (154,155). HSCT recipients, particularly those who are preengraftment and at highest risk for severe RSV pneumonia, should have their illness diagnosed early (i.e., during RSV URI), and their illness should be treated aggressively to prevent fatal RSV disease (BIII).

Although a definitive, uniformly effective preemptive therapy for RSV infection among HSCT recipients has not been identified, certain strategies have been proposed, including use of aerosolized ribavirin (155,156), RSV antibodies (i.e., passive immunization with high RSV-titered IVIG or RSV immunoglobulin) in combination with aerosolized ribavirin (137,157), and RSV monoclonal antibody (158). Clinical trials are currently underway to evaluate the efficacy of these strategies. No recommendation regarding the optimal method for RSV prevention and preemptive therapy can be made because of limited data. Further, current data do not support use of intravenous ribavirin for preemptive therapy for RSV pneumonia among HSCT recipients (60) (DIII), and no commercially licensed vaccines against RSV are currently available.

Recommendations Regarding Parainfluenza Virus and Adenovirus. Immuno-prophylaxis, chemoprophylaxis, and preemptive treatment for parainfluenza virus and adenovirus infections among HSCT recipients have been proposed (159,160). However, no recommendation can be made in these guidelines because of insufficient data. No commercially licensed vaccines against parainfluenza or adenovirus are currently available.

Other Disease Prevention Recommendations

The recommendations for preventing CRV infections and their recurrence are the same for allogeneic or autologous recipients. Generally, these recommendations apply to children or adults (161--164), but with appropriate adjustments in antiviral drug and influenza vaccine doses for children (Appendix).

For pediatric HSCT recipients and candidates aged >6 months, annual seasonal influenza vaccination is recommended HSCT (BIII). Children aged <9 years who are receiving influenza vaccination for the first time require two doses administered >1 months apart (AI). Healthy children who receive influenza vaccination for the first time might not generate protective antibodies until 2 weeks after receipt of the second dose of influenza vaccine. Therefore, during an influenza A outbreak, pediatric recipients aged <9 years, >6 months after HSCT, and receiving their first influenza vaccination, should be administered >6 weeks of influenza A chemoprophylaxis after the first dose of influenza vaccine (141) (BIII) (Appendix). Amantadine and rimantadine are not FDA-approved for children aged <1 year (141,161) (DIII).

To prevent RSV disease, researchers report substituting RSV-IVIG for IVIG during RSV season (i.e., November--April) for pediatric recipients (i.e., children aged <18 years) who receive routine IVIG therapy (164) (i.e., those with hypogammaglobulinemia) (CIII) (Appendix). Other researchers report that pediatric recipients with RSV can be considered for preemptive therapy (e.g., during URI or early LRI) with aerosolized ribavirin (CIII), although this therapy remains controversial (164) (Appendix). Droplet and contact precautions for the duration of illness are required for pediatric recipients for the duration of adenovirus (62) (AIII).

FUNGAL INFECTIONS

General Recommendations

Preventing Exposure

Limited data were found that demonstrate to what extent preventing fungal exposures is effective in preventing infection and disease. However, HSCT recipients and candidates undergoing conditioning therapy have been advised to avoid contact with certain areas and substances, including foods, that might increase a patient's risk for fungal exposures (CII). Specific precautions have included avoiding areas of high dust exposure (e.g., excavation sites, areas of building construction or renovation, chicken coops, and caves), occupations involving soil, and foods that contain molds (e.g., blue cheese).

Preventing Disease

Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (165); however, no data were found that indicate which growth factors effectively reduce the attack rate of invasive fungal disease. Therefore, no recommendation for use of growth factors solely for prophylaxis against invasive fungal disease can be made.

Topical antifungal drugs, which are applied to the skin or mucosa (e.g., nystatin or clotrimazole), might reduce fungal colonization in the area of application. However, these agents have not been proven to prevent generation of locally invasive or disseminated yeast infections (e.g., candidiasis) or mold infections (e.g., aspergillosis) and are not recommended for their prophylaxis (DII). Performing fungal surveillance cultures is not indicated for asymptomatic HSCT recipients (166,167) (DII), but cultures should be obtained from symptomatic HSCT recipients (BIII).

Recommendations Regarding Yeast Infections

Preventing Exposure

Invasive candidiasis is usually caused by dissemination of endogenous Candida species that have colonized a patient's gastrointestinal tract (168). Consequently, methods of preventing exogenous yeast exposure usually do not prevent invasive yeast infections after HSCT. However, because Candida species can be carried on the hands, HCWs and others in contact with HSCT recipients should follow appropriate hand-washing practices to safeguard patients from exposure (AIII).

Preventing Disease

Allogeneic recipients should be administered fluconazole prophylaxis to prevent invasive disease with fluconazole-susceptible Candida species during neutropenia, particularly among centers where Can. albicans is the predominant cause of invasive fungal disease preengraftment (AI) (Appendix). Because candidiasis occurs during phase I (169), fluconazole (400 mg/day by mouth or intravenously) should be administered (169,170) from the day of HSCT until engraftment (AII). However, fluconazole is not effective against certain Candida species, including Can. krusei (171) and Can. glabrata and is, therefore, not recommended for their prevention (DI). Further studies are needed to determine the optimal duration of fluconazole prophylaxis. Preliminary studies have reported that low-dose fluconazole prophylaxis (100--200 mg/day by mouth) among neutropenic patients has variable efficacy in preventing candidiasis (172). Therefore, this therapy is not recommended for HSCT recipients (DII). Oral, nonabsorbable antifungal drugs, including oral amphotericin B (500 mg suspension every 6 hours), nystatin, and clotrimazole troches, might reduce superficial colonization and control local mucosal candidiasis, but have not been demonstrated to reduce invasive candidiasis (CIII).

Other Recommendations

HSCT candidates with candidemia or invasive candidiasis can safely receive transplants (173) if a) their infection was diagnosed early and treated immediately and aggressively with amphotericin B or alternatively with appropriate doses of fluconazole if the organism is susceptible; and b) evidence of disease control is reported (e.g., by serial computed tomography scans) before the transplant (BIII). Such patients should continue receiving therapeutic doses of an appropriate antifungal drug throughout phase I (BII) and until a careful review of clinical, laboratory, and serial computed tomography scans verifies resolution of candidiasis (BII).

Because autologous recipients generally have an overall lower risk for invasive fungal infection than allogeneic recipients, certain autologous recipients do not require routine antiyeast prophylaxis (DIII). However, researchers recommend administering antiyeast prophylaxis to a subpopulation of autologous recipients with underlying hematologic malignancies (e.g., lymphoma or leukemia) and who have or will have prolonged neutropenia and mucosal damage from intense conditioning regimens or graft manipulation, or have received fludarabine or 2-CDA recently (BIII). Recommendations regarding preventing invasive yeast infections among pediatric or adult HSCT recipients are the same, except that appropriate dose adjustments for prophylactic drugs should be made for pediatric recipients (Appendix).

Recommendations Regarding Mold Infections

Preventing Exposure

Nosocomial mold infections among HSCT recipients result primarily from respiratory exposure to and direct contact with fungal spores (174). Ongoing hospital construction and renovation have been associated with an increased risk for nosocomial mold infection, particularly aspergillosis, among severely immunocompromised patients (175--177). Therefore, whenever possible, HSCT recipients who remain immunocompromised should avoid hospital construction or renovation areas (AIII). When constructing new HSCT centers or renovating old ones, hospital planners should ensure that rooms for HSCT patients have an adequate capacity to minimize fungal spore counts through use of

• high-efficiency (>90%) particulate air (HEPA) filtration (140,178,179) (BIII);
• directed room airflow (i.e., positive air pressure in patient rooms in relation to corridor air pressure) so that air from patient rooms flows into the corridor (180) (BIII);
• correctly sealed rooms, including correctly sealed windows and electrical outlets (140) (BIII);
• high rates of room air exchange (i.e., >12 air changes/hour) (140,178) (BIII); and
• barriers between patient care and renovation or construction areas (e.g., sealed plastic) that prevent dust from entering patient care areas and that are
• impermeable to Aspergillus species (175,179) (BIII).

Preventing Disease

No regimen has been reported to be clearly effective or superior in preventing aspergillosis, and therefore, no recommendation can be made. Further studies are needed to determine the optimal strategy for aspergillosis prevention. Moderate-dose (0.5 mg/kg/day) amphotericin B (181--184), low-dose (0.1--0.25 mg/kg/day) amphotericin B (185--187), intranasal amphotericin B spray (188), lipid formulations of amphotericin B (182,189), and aerosolized amphotericin B (190) have been administered for aspergillosis prophylaxis, but data are limited regarding the safety and efficacy of these formulations among HSCT recipients. Additionally, itraconazole capsules are not recommended for fungal prophylaxis among HSCT recipients (191) (DII) for three reasons. First, itraconazole capsules are poorly absorbed gastrointestinally, particularly among patients who are fasting (192) or receiving cytotoxic agents (193). Second, persons taking itraconazole capsules do not achieve steady-state serum levels for 2 weeks (188,194), and when achieved, these levels are lower than the average Aspergillus species minimum inhibitory concentration (MIC) among HSCT recipients (195). Third, itraconazole has adverse interactions with other drugs (e.g., antiepileptics, rifampin, oral hypoglycemics, protease inhibitors, vinca alkaloids, cyclosporine, methylprednisolone, and warfarin-like anticoagulants) (196). Trials assessing the efficacy of the recently licensed cyclodextrin oral solution and intravenous formulations of itraconazole in preventing invasive fungal disease among HSCT recipients are in progress; however, no recommendations regarding its use for Aspergillus species infection prophylaxis can be made. For HSCT recipients whose respiratory specimens are culture positive for Aspergillus species, acute invasive aspergillosis should be diagnosed presumptively (197) and treated preemptively and aggressively (e.g., with intravenous amphotericin) (AIII).

The risk for aspergillosis recurrence has been high among allogeneic recipients with preexisting invasive aspergillosis. Previously, allogeneic HSCTs were avoided among persons with uncontrolled, proven aspergillosis. However, HSCT center personnel have recently reported successful allogeneic or autologous HSCT among a limited number of persons who have had successfully treated, prior invasive pulmonary aspergillosis (198--200). Because of limited data, no recommendations regarding strategies for preventing aspergillosis recurrence can be made.

PROTOZOAL AND HELMINTHIC INFECTIONS

Recommendations Regarding PCP

Preventing Exposure

Although a possible cause of PCP is reactivation of latent infection among immunocompromised persons, cases of person-to-person transmission of PCP have been reported (201--206). Generally, standard precautions should be used for patients with PCP (62) (BIII), but researchers have reported patients with PCP being isolated (201,204) and contact precautions being used if evidence existed of person-to-person transmission in the institution (CIII). This subject remains controversial, and until further data are published, HSCT recipients should avoid exposure to persons with PCP (62) (CIII).

Preventing Disease and Disease Recurrence

Physicians should prescribe PCP prophylaxis for allogeneic recipients throughout all periods of immunocompromise (207) after engraftment. Prophylaxis should be administered from engraftment until 6 months after HSCT (AII) for all patients, and >6 months after HSCT for the duration of immunosuppression for those who a) are receiving immunosuppressive therapy (e.g. prednisone or cyclosporine) (AI), or b) have chronic GVHD (BII). However, PCP prophylaxis can be initiated before engraftment if engraftment is delayed (CIII). Researchers report an additional 1- to 2-week course of PCP prophylaxis before HSCT (i.e., day --14 to day --2) (CIII).

Preferred PCP prophylaxis is TMP-SMZ (AII); however, if TMP-SMZ is administered before engraftment, the associated myelosuppression could delay engraftment, and patients might experience sensitivity to the drug. Every effort should be made to keep such patients on the drug, including assessment of desensitization therapy, although data regarding this technique among HSCT recipients are limited. For patients who cannot tolerate TMP-SMZ, physicians can choose to use alternative PCP prophylaxis regimens (e.g., dapsone) (208) (BIII). Use of aerosolized pentamidine (209) is associated with the lowest PCP prevention rates and should only be used if other agents cannot be tolerated. Atovaquone is a possible alternative drug for PCP prophylaxis among dapsone-intolerant persons with HIV infection (210); however, no recommendation regarding use of atovaquone among HSCT recipients can be made because of lack of data. Although data are limited, concomitant use of leucovorin (folinic acid) and TMP-SMZ is not recommended (211,212) (DIII). A patient's history of PCP should not be regarded as a contraindication to HSCT (213) (DIII).

Recurrent PCP among HSCT recipients is rare; however, patients with continued immunosuppression should remain on PCP prophylaxis until their immunosuppression is resolved (AI). The regimen recommended for preventing toxoplasmosis recurrence among HSCT recipients (i.e., TMP-SMZ) will also prevent PCP recurrence.

Other Recommendations

PCP prophylaxis should be considered for autologous recipients who have underlying hematologic malignancies (i.e., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-CDA (207,214) (BIII). PCP prophylaxis should be administered >6 months after HSCT if substantial immunosuppression or immunosuppressive therapy (e.g., steroids) persists (CIII). Use of PCP prophylaxis among other autologous recipients is controversial (CIII). Generally, indications for PCP prophylaxis are the same among children or adults, but pediatric doses should be used (Appendix).

Recommendations Regarding Toxoplasma gondii

Preventing Exposure

All HSCT recipients should be provided information regarding strategies to reduce their risk for Toxoplasma species exposure. Researchers report that potential donors for allogeneic HSCT be tested for To. gondii antibodies (215,216) by using FDA-licensed or -approved screening tests that include IgG antibody testing because To. gondii has been reported to be transmitted by leukocyte transfusion (217) and HSCT (218,219) (CIII).

Preventing Disease and Disease Recurrence

Because most toxoplasmosis among HSCT recipients is caused by disease reactivation, researchers report that candidates for allogeneic HSCT can be tested for IgG antibody to determine whether they are at risk for disease reactivation after HSCT (215,216,218) (CIII). However, the value of such testing is controversial because a limited number of patients who were seronegative for To. gondii pretransplant experienced the infection posttransplant (220). If testing is performed, only FDA-licensed or -approved screening tests should be used.

Researchers recommend toxoplasmosis prophylaxis for seropositive allogeneic recipients with active GVHD or a prior history of toxoplasmic chorioretinitis (221,222), but data demonstrating efficacy are limited (CIII). The optimal prophylactic regimen for toxoplasmosis among HSCT recipients has not been determined, but a proposed drug is TMP-SMZ (BII), although allogeneic recipients have experienced break-through clinical disease despite TMP-SMZ prophylaxis (218). For patients who are TMP-SMZ--intolerant, a combination of clindamycin, pyramethamine, and leucovorin can be substituted for To. gondii prophylaxis (Appendix). After therapy for toxoplasmosis, HSCT recipients should continue receiving suppressive doses of TMP-SMZ or an alternate regimen for the duration of their immunosuppression (BIII) (Appendix).

Other Recommendations

Recipients of autologous transplants are at negligible risk for toxoplasmosis reactivation (218). No prophylaxis or screening for toxoplasmosis infection is recommended for such patients (DIII). Indications for toxoplasmosis prophylaxis are the same among children or adults, but pediatric doses should be used among children (Appendix).

Recommendations Regarding Strongyloides stercoralis

Preventing Exposure

Allogeneic recipients should avoid contact with outhouses and cutaneous exposure to soil or other surfaces that might be contaminated with human feces (223) (AIII). Allogeneic recipients who work in settings (e.g., hospitals or institutions) where they could be exposed to fecal matter should wear gloves when working with patients or in areas with potential fecal contamination (AIII).

Preventing Disease and Disease Recurrence

Travel and residence histories should be obtained for all patients before HSCT to determine any exposures to high-risk areas (e.g., such moist temperate areas as the tropics, subtropics, or the southeastern United States and Europe) (223) (BIII). HSCT candidates who have unexplained peripheral eosinophilia or who have resided in or traveled to areas endemic for strongyloidiasis, even during the distant past, should be screened for asymptomatic strongyloidiasis before HSCT (BIII). Serologic testing with an enzyme-linked immunosorbent assay is the preferred screening method and has a sensitivity and specificity of >90% (223,224) (BIII). FDA-licensed or -approved screening tests should be used. Although stool examinations for strongyloidiasis are specific, the sensitivity obtained from >3 stool examinations is 60%--70%; the sensitivity obtained from concentrated stool exams is, at best, 80% (223). A total of >3 stool examinations should be performed if serologic tests are unavailable or if strongyloidiasis is clinically suspected in a seronegative patient (BIII).

HSCT candidates whose screening tests before HSCT are positive for Strongyloides species, and those with an unexplained eosinophilia and a travel or residence history indicative of exposure to Strongyloides stercoralis should be empirically treated before transplantation (225,226), preferably with ivermectin (BIII), even if seronegative or stool-negative (Appendix).

To prevent recurrence among HSCT candidates with parasitologically confirmed strongyloidiasis, cure after therapy should be verified with >3 consecutive negative stool examinations before proceeding with HSCT (AIII). Data are insufficient to recommend a drug prophylaxis regimen after HSCT to prevent recurrence of strongyloidiasis. HSCT recipients who had strongyloidiasis before or after HSCT should be monitored carefully for signs and symptoms of recurrent infection for 6 months after treatment (BIII).

Other Recommendations

Hyperinfection strongyloidiasis has not been reported after autologous HSCT; however, the same screening precautions should be used among autologous recipients (BIII). Indications for empiric treatment for strongyloidiasis before HSCT are the same among children or adults except for children weighing <15 kg, for whom the preferred drug is thiabendazole (BIII) (Appendix).

Recommendations Regarding Trypanosoma cruzi

Preventing Exposure

HSCT physicians should be aware that Trypanosoma cruzi, the etiologic agent of Chagas' disease, can be transmitted congenitally, through blood transfusion (227), and possibly through HSCT. Additionally, treatment for persons infected with Tr. cruzi is not always effective, even during the acute stage of infection (227). Therefore, potential donors who were born, received a blood transfusion, or ever lived for >6 months in a Chagas' disease endemic area (e.g., parts of South and Central America and Mexico) should be screened serologically for anti-Tr. cruzi serum IgG antibody (228) (BIII). Persons who lived <6 months in a Chagas'-endemic area but who had high-risk living conditions (e.g., having had extensive exposure to the Chagas' disease vector --- the reduviid bug --- or having lived in dwellings with mud walls, unmilled logs and sticks, or a thatched roof) should also be screened for evidence of Tr. cruzi infection (BIII). Because Chagas' disease can be transmitted congenitally, researchers report that any person with extensive multigenerational maternal family histories of cardiac disease (e.g., cardiomegaly and arrhythmias) should be screened serologically for serum IgG anti-Tr. cruzi antibodies (227) (CIII). To decrease the risk for misdiagnosis by false-positive or false-negative serologic tests, Tr. cruzi screening should consist of >2 conventional serologic tests (e.g., enzyme immunoassay, indirect hemagglutination, indirect fluorescent antibody) or >1 conventional serologic tests, followed by a confirmatory serologic test (e.g., radioimmunoprecipitation assay) (229) (BIII). Persons with active Chagas' disease should not serve as HSCT donors (DIII). Researchers also recommend deferral of HSCT donation for a past history of Chagas' disease (CIII).

Preventing Disease

HSCT candidates who are at risk for being infected with Tr. cruzi should be screened for serum IgG anti-Tr. cruzi antibody (228) (BIII). Tr. cruzi seropositivity is not a contraindication to HSCT (228,230). However, if an acute illness occurs in a Tr. cruzi-seropositive HSCT recipient, particularly during neutropenia, Tr. cruzi reactivation should be included in the differential diagnosis (230) (BIII). Researchers have proposed use of beznidazole or nifurtimox for preemptive therapy or prophylaxis of recurrent Tr. cruzi among seropositive HSCT recipients (230,231), but insufficient data were found to make a recommendation.*****

Other Recommendations

Recommendations are the same for autologous or allogeneic recipients. However, recurrence of Chagas' disease is probably less likely to occur among autologous recipients because of the shorter duration of immunosuppression. Recommendations are the same among children or adults.

HOSPITAL INFECTION CONTROL

Room Ventilation

HSCT center personnel should follow published guidelines for hospital room design and ventilation (140,180) (BIII). HSCT centers should also prevent birds from gaining access to hospital air-intake ducts (140,174) (AII). All allogeneic recipients should be placed in rooms with >12 air exchanges/hour (232,233) and point-of-use HEPA filters that are capable of removing particles >0.3 µm in diameter (140,178,180,233) (AIII). Correct filtration is critical in HSCT centers with ongoing construction and renovation (179). When portable HEPA filters are used as adjuncts to the primary ventilation system, they must be placed centrally in patient rooms so that space is available around all surfaces to allow free air circulation (BIII). The need for environmental HEPA filtration for autologous recipients has not been established. However, HEPA-filtered rooms should be evaluated for autologous recipients if they experience prolonged neutropenia, a substantial risk factor for nosocomial aspergillosis (CIII).

A laminar air flow (LAF) room contains filtered air that moves in parallel, unidirectional flow --- the air enters the room from one wall and exits the room on the opposite wall (232). Although LAF has been demonstrated to protect patients from infection during aspergillosis outbreaks related to hospital construction (234,235), the value of routine LAF room use for all HSCT recipients is doubtful because substantial overall survival benefit has not been reported (236). During 1983, LAF rooms were preferred for allogeneic recipients with aplastic anemia and HLA-identical sibling donors because use of regular rooms was associated with a mortality rate that was approximately four times higher than for those recipients treated in LAF rooms (237). However, the survival of aplastic anemia HSCT recipients during the late 1990s exceeds that reported during the early 1980s, and no studies have been done to determine whether HSCT recipients with aplastic anemia still have an improved survival rate when treated in an LAF room. Therefore, HSCT centers need not construct LAF rooms for each HSCT recipient. Use of LAF rooms, if available, is optional (CII).

Hospital rooms should have directed airflow so that air intake occurs at one side of the room and air exhaust occurs at the opposite side (140) (BIII). Each hospital room should also be well-sealed (e.g, around windows and electrical outlets) (140) (BIII). To provide consistent positive pressure in the recipient's room, HSCT centers should maintain consistent pressure differentials between the patient's room and the hallway or anteroom at >2.5 Pa (i.e., 0.01 inches by water gauge) (232,233) (BIII). Generally, hospital rooms for HSCT recipients should have positive room air pressure when compared with any adjoining hallways, toilets, and anterooms, if present.

Anterooms should have positive air pressure compared with hallways (180). An exception is the HSCT recipient with an active disease that has airborne transmission (e.g., pulmonary or laryngeal Mycobacteria tuberculosis [TB] or measles). These HSCT patients should be placed in negative isolation rooms (62) (BIII), and a room with an anteroom is recommended for such patients (180) (BIII).

Whenever possible, HSCT centers should have self-closing doors to maintain constant pressure differentials among the HSCT recipients' room and anterooms, if available, and hallways (233) (BIII). To enable the nursing staff to observe the HSCT recipient even when the doors are closed, windows can be installed in either the door or the wall of the HSCT recipient's room (233) (CIII).

HSCT centers should provide backup emergency power and redundant air-handling and pressurization systems to maintain a constant number of air exchanges and room pressurization in the center when the central ventilation system is shut off for maintenance and repair (238) (BIII). Additionally, infection control personnel should work with maintenance personnel to develop protocols to protect HSCT centers at all times from bursts of mold spores that might occur when air-handling systems are restarted after routine maintenance shut-downs (BIII).

Construction, Renovation, and Building Cleaning

Construction and Renovation

Hospital construction and renovation have been associated with an increased risk for nosocomial fungal infection, particularly aspergillosis, among severely immuno-compromised patients (175,176). Therefore, persons responsible for HSCT center construction or renovation should consult published recommendations regarding environmental controls during construction (239,240) (AIII).

Whenever possible, HSCT recipients, HCWs, and visitors should avoid construction or renovation areas (240) (AIII). Also, equipment and supplies used by HSCT recipients or their HCWs should not be exposed to construction or renovation areas (240). When planning for construction or renovation, the HSCT center should include plans for intensified aspergillosis-control measures (AIII). Construction and renovation infection control planning committees should include engineers, architects, housekeeping staff, infection control personnel, the director of the HSCT center, the administration, and safety officers (241) (BIII).

When constructing new HSCT centers, planners should ensure that patient rooms will have adequate capacity to minimize fungal spore counts by following room ventilation recommendations. During outdoor construction and demolition, the intake air should be sealed (BIII), if possible; if not, filters should be checked frequently. Additionally, to protect HSCT patient care areas during fire drills and emergencies, weather stripping should be placed around stairwell doors, or alternatively, the stairwell air should be filtered to the level of safety of the adjacent hospital air (BIII). False ceilings should be avoided whenever possible (174) (BII). If use of false ceilings cannot be avoided, the area above false ceilings should be vacuumed routinely to minimize dust and, therefore, fungal exposure to patients (174) (BIII).

During hospital construction or renovation, hospitals should construct rigid, dust-proof barriers with airtight seals (242) between patient care and construction or renovation areas to prevent dust from entering patient care areas; these barriers (i.e., sealed drywall) should be impermeable to Aspergillus species (140,175,176,179,240) (BIII). If impervious barriers cannot be created around the construction or renovation area, patients should be moved from the area until renovation or construction is complete and the area has been cleaned appropriately (176) (BIII). HSCT centers should direct pedestrian traffic occurring near construction or renovation areas away from patient care areas to limit the opening and closing of doors or other barriers that might cause dust dispersion, entry of contaminated air, or tracking of dust into patient areas (140), particularly those in the HSCT center (176) (BIII). If possible, specific corridors, entrances, and exits should be dedicated to construction use only (240). An elevator to which patients do not have access also should be dedicated to construction use only (240). Construction workers, whose clothing might be contaminated with Aspergillus species spores, should use the construction elevator and avoid contact with patients, patient care areas, other elevators, and nonconstruction areas (BIII).

Hospital construction or renovation areas should have negative air pressure relative to that in adjacent patient care areas, if no contraindications exist for such pressure differential (140,176,179,240,242) (BIII). Ideally, air from the construction or renovation areas should be exhausted to the outside of the hospital (176) (BIII) or if recirculated, it should be HEPA-filtered first (BIII).

Researchers have proposed that HSCT recipients wear the N95 respirator to prevent mold exposure during transportation near hospital construction or renovation areas (CIII) because the N95 respirators are regarded as effective against any aerosol. However, to be maximally effective, N95 respirators must be fit-tested and all users must be trained. With correct personnel fit-testing and training, N95 respirators reliably reduce aerosol exposure by 90%. Without fit-testing and training, aerosol exposure would be reduced but not necessarily by 90% (243). For patients who cannot use or tolerate an N95 respirator, researchers have proposed using the powered air purifying respirator (244,245), which can be used by patients in wheelchairs. Limitations of the powered air purifying respirator include its cost and that it is not appropriate for young children and infants. General limitations of using respirators are that no commercially available respi rator, including N95, has been tested specifically for its efficacy in reducing exposure to Aspergillus species in hospital construction or renovation areas, and no studies have been done that assess the usefulness and acceptability of using respirators among HSCT recipients. Standard surgical masks provide negligible protection against mold spores and are not recommended for this indication (DIII).

Newly constructed or renovated areas should be cleaned before patients are allowed to enter them (140,176) (AIII). Decontamination of fungal-contaminated areas that cannot be extracted and replaced should be done using copper-8-quinolate (179) (BIII). Also, areas above false ceilings located under or adjacent to construction areas should be vacuumed (174) (BIII). Additionally, the ventilation, direction of airflow, and room pressurization should be tested and correctly adjusted before patients are allowed to enter (BIII).

Cleaning

HSCT centers should be cleaned >1 times/day with special attention to dust control (BIII). Exhaust vents, window sills, and all horizontal surfaces should be cleaned with cloths and mop heads that have been premoistened with an FDA- or Environmental Protection Agency (EPA)-registered hospital disinfectant (BIII). Thorough cleaning during and after any construction activity, including minor renovation projects, is critical (BIII).

HSCT center personnel should prohibit exposures of patients to such activities as vacuuming or other floor or carpet vacuuming that could cause aerosolization of fungal spores (e.g., Aspergillus species) (140) (AIII). Accordingly, doors to patient rooms should be closed when vacuuming HSCT center corridors. All vacuum cleaners used in the HSCT center should be fitted with HEPA filters. An FDA- or EPA-registered disinfectant (246,247) should be used daily for environmental disinfection and when wet vacuuming is performed in the HSCT center (BIII). If an HSCT center provides care for infants, phenolic disinfectants can be used to clean the floors only if the compound is diluted according to the product label; but phenolic compounds should not be used to clean basinets or incubators (246) (DIII).

Water leaks should be cleaned up and repaired as soon as possible but within 72 hours to prevent mold proliferation in floor and wall coverings, ceiling tiles, and cabinetry in and around all HSCT patients care areas (BIII). If cleanup and repair are delayed >72 hours after the water leak, the involved materials should be assumed to contain fungi and handled accordingly. Use of a moisture meter to detect water penetration of walls should be used whenever possible to guide decision-making (238) (BIII). For example, if the wall does not have <20% moisture content >72 hours after water penetration, it should be removed (BIII). Design and selection of furnishings should focus on creating and maintaining a dust-free environment. Flooring and finishes (i.e., wall coverings, window shades, and countertops) used in HSCT centers should be scrubbable, nonporous, easily disinfected, and they should collect minimal dust (BIII).

Isolation and Barrier Precautions

HSCT center personnel should follow published guidelines for hospital isolation practices, including CDC guidelines for preventing nosocomial infections (62,140,248) (AIII). However, the efficacy of specific isolation and barrier precautions in preventing noso-comial infections among HSCT recipients has not been evaluated.

HSCT recipients should be placed in private (i.e., single-patient) rooms (BIII). If contact with body fluids is anticipated, standard precautions should be followed (AIII). These precautions include hand washing and wearing appropriate gloves, surgical masks or eye and face protection, and gowns during procedures and activities that are likely to generate splashes or sprays of blood, body fluids, secretions or excretions, or cause soiling of clothing (62). When indicated, HSCT recipients should also be placed on airborne, droplet, or contact precautions in addition to standard precautions (62) (AIII). Careful observation of isolation precautions is critical in preventing transmission of infectious agents among HSCT recipients, HCWs, visitors, and other HSCT recipients. Physicians are cautioned that HSCT recipients might have a prolonged or episodic excretion of organisms (e.g., CMV).

Researchers have proposed that HSCT recipients wear surgical mask and gloves when exiting their hospital rooms before engraftment (CIII). All HSCT recipients who are immunocompromised (phases I--III of immune system recovery) and candidates undergoing conditioning therapy should minimize the time spent in crowded areas of the hospital (e.g., waiting areas and elevators) (BIII) to minimize potential exposure to persons with CRV infections.

Hand Hygiene

Hand washing is the single-most critical and effective procedure for preventing nosocomial infection (62). All persons, but particularly HCWs, should wash their hands before entering and after leaving the rooms of HSCT recipients and candidates undergoing conditioning therapy (62,249) or before and after any direct contact with patients regardless of whether they were soiled from the patient, environment, or objects (AI). HSCT recipients should be encouraged to practice safe hand hygiene (e.g., washing hands before eating, after using the toilet, and before and after touching a wound) (BIII). Hand washing should be done with an antimicrobial soap and water (AIII); alternatively, use of hygienic hand rubs is another acceptable means of maintaining hand hygiene (250,251). If gloves are worn, HCWs should put them on in the patient's room after hand washing and then discard them in the same patient's room before washing hands again after exiting the room. When worn, gloves should always be changed between patients or when soiled before touching a clean area (e.g., change gloves after touching the perineum and before going to a "clean" area) (AIII). Appropriate gloves should be used by all persons when handling potentially contaminated biological materials (AII). Items worn on the hands and fingers (e.g., rings or artificial nails [248,252]) and adhesive bandage strips, can create a nidus for pathogenic organisms that is difficult to clean. Thus, HCWs should avoid wearing such items whenever possible (BII).

Equipment

All HSCT center personnel should sterilize or disinfect and maintain equipment and devices using only EPA-registered compounds as directed by established guidelines (140,180,246,247,253--256) (AIII). HSCT center personnel should monitor opened and unopened wound-dressing supplies (e.g., adhesive bandages [257,258] and surgical and elastic adhesive tape [259]) to detect mold contamination and prevent subsequent cutaneous transmission to patients (BII).

Monitoring should consist of discarding all bandages and wound dressings that are out of date, have damaged packaging, or are visually contaminated by construction debris or moisture (BIII). When arm boards are used to provide support for intravenous lines, only sterile dressing materials should be used (260), and arm boards should be changed frequently (e.g., daily) (BIII). Additionally, unsterile tongue depressors inserted into a piece of foam tubing should not be used as splints for intravenous and arterial catheter sites because these have been associated with an outbreak of fatal invasive nosocomial Rhizopus microsporus among preterm (i.e., very low-birth--weight) infants (261) (DII). HSCT centers should not install carpeting in hallways outside (DII) or in patient rooms (DIII) because contaminated carpeting has been associated with outbreaks of aspergillosis among HSCT recipients (262,263).

Plants, Play Areas, and Toys

Although to date, exposure to plants and flowers has not been conclusively reported to cause fungal infections among HSCT recipients, most researchers strongly recommend that plants and dried or fresh flowers should not be allowed in the rooms of hospitalized HSCT candidates undergoing conditioning therapy and HSCT recipients (phases I--III of immune system recovery) because Aspergillus species have been isolated from the soil of potted ornamental plants (e.g., cacti), the surface of dried flower arrangements, and fresh flowers (140,174,178,264) (BIII).

Play areas for pediatric HSCT recipients and candidates undergoing conditioning therapy should be cleaned and disinfected >1 times/week and as needed (BIII). Only toys, games, and videos that can be kept clean and disinfected should be allowed in the HSCT center (BIII). HSCT centers should follow published recommendations for washing and disinfecting toys (265) (BIII). All HSCT center toys, games, and videos should be routinely and thoroughly washed or wiped down when brought into the HSCT center and thereafter >1 times/week and as needed by using a nontoxic FDA- or EPA-registered disinfectant (246,247,265) followed by a water rinse (BIII). Cloth or plush toys should be washed in a hot cycle of a washing machine or dry-cleaned >1 times/week and as needed (BIII). Alternatively, machine washing in a cold cycle is acceptable if laundry chemicals for cold water washing are used in proper concentration (265). Hard plastic toys should be scrubbed with warm soapy water using a brush to clean crevices, rinsed in clean water, immersed in a mild bleach solution, which should be made fresh daily, for 10--20 minutes, rinsed again, and allowed to air dry (246). Alternatively, hard plastic toys can be washed in a dishwasher or hot cycle of a washing machine (BIII). Broviac dolls****** should be disassembled upon completion of play and washed with a nontoxic FDA- or EPA-registered disinfectant (246,247), rinsed with tap water, and allowed to air dry before other children are allowed to play with them (BIII). Toys that cannot be washed, disinfected, or dry-cleaned after use should be avoided (BIII). Infants, toddlers, and children who put toys in their mouths should not share toys (265) (DIII). For children in isolation, researchers recommend the following:

• Disposable play items should be offered whenever possible (BIII).
• Before returning a washable toy used in an isolation room to the