TIMELINE OF RISK PERIODS FOLLOWING BMT	Section 5 of 8
Author Information Introduction Risk Factors For Infection Preventing Transmission Of Infection From Bmt Donor To Recipient Timeline Of Risk Periods Following Bmt Prophylaxis And Treatment Outcome Bibliography

A well-recognized and predictable sequence of events occurs in recipients of BMT regarding immunosuppression and immune recovery. Specific immune defects are associated with each of the different stages of transplantation, or risk periods, which put patients at risk of developing different types of infections based on the immune defects for each stage. The sequence of immunosuppression allows for classification of BMT infections into the following 4 distinct stages (Sable, 1994):

• Pretransplantation period

• Preengraftment period (~0-30 d posttransplantation)

• Postengraftment period (~30-100 d posttransplantation)

• Late posttransplantation period (³100 d posttransplantation)

Generally, early infectious complications are considered to be those that occur before day 100, and late infectious complications usually refer to those that occur during stage 4 (ie, ³100 d posttransplantation) (Boulad, 1998; Engels, 1999; Busca, 1999; Kruger, 1999).

Pretransplantation period

Infections during the pretransplantation period are very heterogeneous, as are the conditions necessitating BMT (Sable, 1994). Baseline host status and medication therapy determine risk of infection during this period. Preexisting neutropenia or compromised barrier defenses lead to infections at this stage. Before transplantation, screening is needed to identify potential infectious agents that may put the patient at risk of death following the immunosuppression that precedes the BMT. Most infections that occur during this pretransplantation period are secondary to aerobic gram-negative bacilli (GNB), such as Klebsiella species and Escherichia coli (Sable, 1994). Local infections most commonly involve skin and soft tissue, oral cavity, or urinary tract (60%), whereas sepsis (24%) and pneumonia (10%) occur less commonly (Sable, 1994). As a result of the local nature of most infections during this stage, the associated severity and mortality rate are low (Sable, 1994).

Preengraftment period (~0-30 d posttransplantation)

In both adult and pediatric patients undergoing BMT, engraftment is defined as the point at which the absolute granulocyte count (AGC) is more than 500/mm³ and sustained as well as when the platelet count is more than 20,000 X 10⁶ and sustained with no transfusion required for at least 3 days (CDC, 2000). The preengraftment phase in the patient undergoing allogeneic BMT is generally longer than that of the patient undergoing autologous BMT (van Burik, 2000; CDC, 2000; Leather, 2001). This longer preengraftment phase leads to prolonged exposure of the allogeneic BMT recipient to neutropenia. The prolonged neutropenia increases the time during which the patient undergoing allogeneic BMT is at risk with the immune deficiencies of the preengraftment phase but does not increase the risk for acquiring infection (Ninin, 2001). Empirical antimicrobial therapy should be no different for either group because both are at risk for the same pathogens (Ninin, 2001).

In the preengraftment period, the major risk for acquiring infection is neutropenia and altered barrier defenses resulting from the BMT conditioning regimen (van Burik, 2000; CDC, 2000; Leather, 2001; Sable, 1994). Another factor is the need for vascular access in this group of patients (van Burik, 2000; CDC, 2000; van Burik, 1999). The sources of pathogens for infection during this period are the skin flora, oral flora, and gastrointestinal tract flora (CDC, 2000). The disruption of these normal barrier defenses allows microorganisms that normally colonize these areas to invade, rendering them pathogenic.

Different conditioning regimens exist for the varying indications for BMT. The degree of barrier damage and the profundity and length of neutropenia vary depending on the conditioning used. Total body irradiation, in conjunction with ablative chemotherapy, is mostly used for the hematologic malignancies to achieve full cytoreduction (Boulad, 1998; Sable, 1994). The combination results in a higher incidence of diarrhea, bacteremia, and herpes zoster than in those who receive chemotherapy alone (Sable, 1994).

The predominant infections during the preengraftment phase of transplantation are bacterial; occurring in 15-50% of recipients of BMT (Sable, 1994). The first fever that the BMT recipient acquires posttransplantation is usually caused by a bacterial pathogen; however, isolating the responsible organism or determining the source of infection is unusual (Woo, 2001). Just as in the febrile neutropenic patient, a shift in the etiologic agents of bacteremia has occurred in these patients.

In the 1980s, GNB such as Klebsiella species and Pseudomonas aeruginosa were most common. However, with the increased use of indwelling catheters and increasing use of antibacterial fluoroquinolone prophylaxis during the 1990s, gram-positive organisms have become more frequent and currently are the most common etiologic agents (Leather, 2001; Sable, 1994; Collin, 2001; van Burik, 1999). Staphylococcal infections secondary to the coagulase-negative staphylococci and Staphylococcus aureus are most commonly isolated and are usually the result of line sepsis secondary to an infected central venous catheter (Sable, 1994). Streptococcal infections, especially the Streptococcus viridans group, are becoming more common and are associated with mucositis and use of antibiotic prophylaxis (Leather, 2001; Sable, 1994).

Pulmonary infections usually occur later in the course of the transplantation, but up to 35% of these types of infections may also occur in the preengraftment phase (Sable, 1994). As with pneumonia in the immunocompetent patient, recovery of an organism is rare (<20%) (Sable, 1994). The empiric use of broad-spectrum antibiotic therapy for febrile episodes in the patient undergoing BMT has reduced the incidence of bacterial pneumonias in these patients (Aronchick, 2000). Bacterial pneumonias have an incidence of 12-15% in the first 100 days after BMT and are more commonly observed in patients who have had an allogeneic transplantation (Aronchick, 2000).

Most pulmonary infections occurring in the preengraftment phase are secondary to opportunistic fungal infections (Aspergillus most commonly, with Fusarium, Cryptococcus, Candida, and Mucor observed less commonly) (Aronchick, 2000). Even less commonly observed is typhilitis or neutropenic enterocolitis, which tends to occur with severe neutropenia (Sable, 1994). It is characterized clinically by fever, abdominal pain, nausea, and vomiting. This condition is characterized by bowel wall thickening, especially around the region of the cecum. Cecal masses and pneumatosis of the intestinal wall can be observed on ultrasonographic and CT scanning findings. The etiology of bowel inflammation observed in typhilitis is polymicrobial (Sable, 1994). The gastrointestinal normal flora that usually colonizes the gastrointestinal tract (ie, gram-negative organisms, anaerobes, Candida species) becomes pathogenic in this immunocompromised state. Typhilitis has a reported mortality rate of 50-100% (Sable, 1994).

Atypical bacterial infections may also occur in the preengraftment phase of BMT. Mycobacterium infections, although commonly observed in patients with impaired CMI (eg, HIV), have not been observed with a high incidence in patients undergoing BMT (Leather, 2001; van Burik, 1999). This low incidence of mycobacterial infection is speculated to be because most transplantations are performed in developed countries where mycobacterial infections are less common (Leather, 2001). In patients undergoing BMT in countries that have an increased incidence of mycobacterial infections, an increased incidence of infection would be expected (Hughes, 2000). A high index of suspicion should be maintained for mycobacterial infection in the high-risk patient (eg, ethnic origin, prior tuberculosis exposure, positive purified protein derivative [PPD] test result) with fever of unknown origin (Leather, 2001).

Another rarely described opportunistic microorganism in recipients of BMT is Nocardia species. These atypical bacteria are gram-positive aerobic actinomycetes that are found in soil and decaying organic matter (Leather, 2001). A published review of 27 cases of Nocardia infection in recipients of BMT revealed isolation of the bacteria from blood, brain abscess, sputum, bronchoalveolar lavage (BAL) washings, open lung biopsy specimens, and skin (eg, catheter exit sites and from abscesses) (Leather, 2001; van Burik, 1997). Most commonly, Nocardia infection was associated with a pulmonary illness with nodules with or without pulmonary infiltrates; 56% of patients had documented abnormal findings on chest radiographs (Leather, 2001; van Burik, 1997).

The treatment and prevention of bacterial infection is discussed later in this article (see Bacterial infections. A consequence of the use of broad-spectrum antibiotics in this group of patients is the eradication or significant alteration of the normal colonizing gastrointestinal flora. The shift away from the normal colonizing flora has led to the development of Clostridium difficile–associated disease at a higher frequency in this population (van Burik, 1999).

The next most common infection in the preengraftment phase of BMT is that which occurs secondary to fungal infections. Invasive fungal infections are one of the leading causes of infectious mortality after allogeneic BMT (Leather, 2001; Baddley, 2001; Dictar, 2000; Ribaud and Chastang, 1999). The incidence of invasive fungal infections has been reported to be 10-20% of the patient population with BMT (Hovi, 2000). These patients typically have had prolonged neutropenia, have been on broad-spectrum antibiotic therapy, have a central venous line, have possibly been exposed to corticosteroids, and possibly are on parenteral nutrition; all of these are significant risk factors for the development of fungemia (Sable, 1994).

The risk of developing fungal infection is directly proportional to the duration of neutropenia and is particularly increased after approximately 5-7 days of neutropenia (Leather, 2001). Fungal infections are generally caused by 2 pathogens (which account for >80% of fungal episodes): Candida species, which are endogenous fungi found in the gastrointestinal tract, and Aspergillus species, which are ubiquitous exogenous molds usually acquired from the environment (Sable, 1994; van Burik, 1999; Dictar, 2000; Hovi, 2000).

Candida infections are present in approximately 11% of patients undergoing BMT (Sable, 1994). Candida albicans are still the most prevalent candidal species isolated from the BMT population; however, cases of nonalbicans candidemia now account for 50% of candidal infections (Sable, 1994; Wingard, 1999). Candida glabrata, Candida krusei, and more azole-resistant C albicans are probably being observed secondary to increased antifungal prophylaxis with fluconazole (Leather, 2001; Sable, 1994; van Burik, 1999; Wingard, 1999).

The next most common fungal infections are with Aspergillus species; infections with these exogenous fungi/molds appear to have increased during the past decade. Aspergillus infections are present in 4-20% of BMT recipients (Sable, 1994). These fungi are ubiquitous in the environment, but increased amounts are found around areas of recent construction within hospitals. Aspergillus is acquired through inhalation of spores into the respiratory tract into the lungs or into the sinus tracts. The most common clinical syndromes associated with Aspergillus are pulmonary and sinus disease. However, in immunocompromised patients, this mold can invade into the circulation and disseminate widely. Numerous other fungi have been reported as causing infection in the BMT patient, including Pseudallescheria boydii and Scopulariopsis, Fusarium, Trichosporon, Rhodotorula, Alternaria, Acremonium, Pityrosporum, Bipolaris, Curvularia, and Penicillium species (Sable, 1994).

The virus most commonly documented during the preengraftment phase is HSV, and the usual mechanism of appearance is reactivation of prior latent infection (Sable, 1994). A large proportion (80%) of patients who were seropositive for HSV before the transplantation develop clinical disease if prophylaxis is not provided (Leather, 2001; van Burik, 1999). The most common clinical presentation in this phase is gingivostomatitis (85%) (Sable, 1994). Pneumonia and HSV-2 genital ulcers or extragenital vesicles (eg, perianal) also occasionally occur. Human herpesvirus 6 (HHV-6) infection may also be a cause of undiagnosed fevers during the preengraftment period. VZV infections, although less common during this phase, may also reactivate.

Postengraftment period (~30-100 d posttransplantation)

The postengraftment period is heralded by the resolution of the severe neutropenia that is present before engraftment and continues to day 100 after BMT. The barrier defenses that were compromised in the prior phase secondary to induction chemotherapy and radiotherapy have also begun to heal at this phase. The major determinants of immunosuppression in this period are related to impairment of CMI and humoral immunity, as well as diminished phagocyte function (Sable, 1994). Other important causes of impaired immunity include acute GVHD and the use of immunosuppressive agents as part of the management of GVHD episodes in allogeneic transplantation (Sable, 1994). GVHD prevents recovery of immune function and damages epithelial cells in multiple organ systems, leading to further breakdown of barrier defenses.

Bacterial infections become less frequent during the postengraftment period except in patients with continued central venous line access. These patients are at continued risk for central line infections secondary to staphylococcal bacteria and less common pathogens (Leather, 2001).

The most important pathogens during the postengraftment phase of the BMT are the herpes viruses, especially CMV. CMV remains latent in peripheral blood leukocytes and reactivates in seropositive patients or manifests as a primary infection in patients who were seronegative before transplantation but received stem cells from a seropositive donor. The latter group of patients constitutes the greatest concern. Active CMV infections may be asymptomatic, but symptomatic CMV infections manifest as pneumonia, hepatitis, and colitis, with a high associated mortality rate. Of patients with BMT who acquire CMV infection, 15-20% die (Sable, 1994). CMV pneumonia is associated with a case-fatality rate of 80-90% (Sable, 1994).

CMV disease as a result of infection occurs more commonly in allogeneic BMT (compared to autologous) with associated risk factors that include recipient seropositivity, histocompatibility differences (between donor and recipient), T-cell depletion of the donated stem cells, graft source unrelated donor, older age, intense GVHD prophylaxis, and intensity of cytoreductive conditioning regimens (Leather, 2001). Approaches to the prophylaxis versus early empiric therapy of CMV disease are varied and are discussed later in this article (see Viral infections). Remember that the risk for acquiring CMV in patients who are seronegative comes not only from the bone marrow donor, but also from transfusion of blood products and from close sexual contact in adolescents.

Patients with allogeneic transplantation and GVHD who have been given subsequent therapy with high-dose corticosteroids also are at risk for Aspergillus infection (late-onset aspergillosis) and Candida infections (Leather, 2001). GVHD and its treatment also place the patient at increased risk of viral infection with CMV and VZV (Leather, 2001).

With diminished CMI and humoral immunity, other viral infections also occur in the postengraftment period of transplantation. Adenovirus can lead to significant morbidity and mortality in the recipient of a BMT (Hale, 1999; Howard, 1999; Baldwin, 2000; La Rosa, 2001). In the immunocompromised patient, adenoviral infections result in systemic illness of increased severity and longer duration (Hale, 1999). Adenovirus can cause hepatitis (with or without hepatic necrosis), pancreatitis, colitis, hemorrhagic cystitis, pneumonia, nephritis, and disseminated disease (Hale, 1999). Case reports of adenoviral meningoencephalitis have been documented (Davis, 1988). Adenoviral infection has been reported to occur in 4.9-20.9% of patients undergoing BMT (Howard, 1999).

The mortality rate in immunocompromised patients with adenoviral infection is high (18-60%) and is dependent on patient age, type of BMT, and adenovirus subtype (Hale, 1999; Howard, 1999). Higher mortality rates were observed in patients with disseminated adenoviral disease (61%) and adenoviral pneumonia (73%) (La Rosa, 2001).

Community-acquired respiratory viruses, such as respiratory syncytial virus (RSV), influenzae, parainfluenzae, and the picornaviruses can be found in the postengraftment phase, leading to respiratory disease. In immunocompromised individuals, respiratory viruses are associated with a high mortality rate and often have a prolonged course, progress to pneumonia, and are nosocomially acquired (Leather, 2001; van Burik, 1999; Lujan-Zilbermann, 2001).

Respiratory virus infections were found to be a common problem (11%) in a pediatric population with BMT and were associated with substantial morbidity (28% developed pneumonia, ~5% had complications with croup) and mortality (9.4%) (Zilbermann, 2001). Parainfluenzae type 3 was found to be the most common pathogen. Risk factors for the acquisition of respiratory viral infections are the type of BMT (higher risk with allogeneic BMT than with autologous BMT) and the degree of GVHD present (Zilbermann, 2001). Enteroviral infections have also been described to occur in the postengraftment period of transplantation.

Recent studies have focused on another virus in the herpes group, HHV-6 (Zerr, 2001; Cone, 1999; Zerr, 2002). This virus in is generally asymptomatic in immunocompetent patients, but it may cause a self-limited febrile illness that is associated with roseola rash, otitis media, and other clinical presentations. In individuals with BMT, HHV-6 mostly leads to asymptomatic seroconversion, but it can be associated with prolonged febrile illnesses and central nervous system syndromes, such as encephalitis (Zerr, 2001; Cone, 1999). Asymptomatic reactivation appears to occur commonly throughout the post-BMT period (Zerr, 2001; Cone, 1999).

Parasitic infections also tend to occur during this period. Pneumocystis carinii (PCP) was a major opportunistic infection leading to significant morbidity and mortality in patients. However, with the use of trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis, PCP is now infrequently observed except in patients who are not compliant with prophylaxis or are taking inferior prophylaxis (Sable, 1994). Toxoplasmosis has also been described in a small number of patients during this phase of transplantation.

Late posttransplantation period (>100 d posttransplantation)

The late posttransplantation period is heralded by the recovery of CMI and humoral immunity. This phase begins at day 100 and continues until the BMT recipient stops all immunosuppressive medication for GVHD, which is approximately 18-36 months posttransplantation (van Burik, 1999). Infection is unusual in this period if chronic GVHD is not present.

The presence of chronic GVHD often requires continued immunosuppression of the recipient during this posttransplantation phase. Chronic GVHD and its treatment lead to ongoing cellular and humoral immunity defects in the patient. Barrier protection of the skin, mucous membranes, and gastrointestinal tract are compromised with chronic GVHD. Infection in this phase is generally localized to the skin, the upper respiratory tract, and the lungs (van Burik, 1999). Viral infections, especially secondary to VZV, are responsible for more than 40% of infections during this phase, bacteria are responsible for approximately 33%, and fungi cause approximately 20% (Sable, 1994).

VZV infections are most likely to occur in patients with BMT during the late posttransplantation period and are usually secondary to reactivation. The median time for occurrence of VZV is 5 months after transplantation (Sable, 1994). Eighty-five percent of patients develop herpes zoster, whereas approximately 15% develop chicken pox (Sable, 1994). Patients who develop chicken pox have an increased risk of systemic dissemination (eg, leading to pneumonia), but it can also occur with zoster. Chronic GVHD leads to functional asplenia in these patients and, therefore, to increased susceptibility to encapsulated pathogens (eg, Streptococcus pneumoniae, Neisseria meningitidis) (Sable, 1994). Systemic fungemia is not commonly observed at this stage, but oropharyngeal candidiasis and Aspergillus infections may occur.

	PROPHYLAXIS AND TREATMENT	Section 6 of 8
Author Information Introduction Risk Factors For Infection Preventing Transmission Of Infection From Bmt Donor To Recipient Timeline Of Risk Periods Following Bmt Prophylaxis And Treatment Outcome Bibliography

The Centers for Disease Control and Prevention (CDC) produced a report in its Morbidity and Mortality Weekly Report (RR-10) that provides guidelines for preventing opportunistic infections in patients undergoing BMT (CDC, 2000). These guidelines are a good resource guide for reviewing the variety of techniques available for preventing these infections in the BMT recipient.

Before examining antimicrobial prophylaxis techniques for specific infections, review the basics of infection prevention and control. Hospitals that perform BMTs should have appropriate designed facilities that have rooms with more than 12 air exchanges per hour and point-of-use high-efficiency particulate air (HEPA) filtration (CDC, 2000). The HEPA filters should be able to remove particles at least 0.3 mm in diameter (CDC, 2000). Laminar airflow rooms, in which air moves in one direction, have been shown to protect patients from Aspergillus infections during outbreaks (Barnes, 1989; Sherertz, 1987). Rooms should have positive air pressure compared to the hallway unless it is housing a patient who has active disease with a pathogen that has airborne transmission; in this case, a negative pressure room is recommended.

Policies and procedures should be in the hospital infection control manual to address issues of construction and renovation, cleaning, and isolation and barrier precautions. Hand washing should be strongly emphasized to prevent nosocomial transmission of infection. Most researchers recommend that plants and dried or fresh flowers should not be allowed in rooms, although exposure has not been conclusively proven to cause fungal infections. Health care workers should follow a policy with regard to their immunizations and vaccinations. Visitor policies should also be strictly adhered to, particularly for children with potentially infectious conditions (eg, varicella). Oral and skin care should be stressed to patients throughout the BMT process. All patients undergoing BMT should receive a dental evaluation before the initiation of the conditioning phase of transplantation. Patients with mucositis during conditioning or posttransplantation should maintain a regimen of proper oral care with rinses (CDC, 2000).

Strategies of safe living posttransplantation after discharge home are also important to discuss with BMT recipients. This should include discussion on how to avoid infectious exposures from the environment, safe sex practices, pet safety, food and water safety, travel safety, and the need for ongoing vaccination posttransplantation (CDC, 2000).

Bacterial infections

The use of prophylactic antibiotic therapy in BMT is controversial (CDC, 2000). During the preengraftment period, fluoroquinolones have been used to decrease the incidence of gram-negative bacteremia in patients, and beta-lactams and macrolides have been used to reduce the incidence of gram-positive bacteremia in patients (Leather, 2001; Dummer, 2000). Studies show that fluoroquinolones have been effective in the reduction of cases of gram-negative bacteremia (Engels, 1999; Cruciani, 1996). However, no studies have shown an improved survival rate with the use of any of the prophylactic antibiotic regimens (Cruciani, 1996; Murphy and Brown, 1997; Engels, 1998).

The major concern with the use of prophylactic antibiotics is the development of resistant organisms. Reports of fluoroquinolone resistance in coagulase-negative staphylococci and in E coli have emerged (Murphy and Brown, 1997; Cometta, 1994). Streptococcal species are showing increased resistance to penicillin, ciprofloxacin, and imipenem (Collin, 2001). Pseudomonas species have also been found to be more resistant to agents such as ceftazidime (Collin, 2001). Another concern with the use of prophylactic antimicrobial therapy is the increase in Clostridium difficile as a pathogen in these patients.

In the late posttransplantation period, because of the increased infection rate related to encapsulated organisms, some centers suggest the use of penicillin prophylaxis and vaccination with the 23-valent polysaccharide Streptococcus pneumoniae vaccine (CDC, 2000). However, the role of this vaccine in infants and younger children is absent or limited. The role of the newer conjugate pneumococcal vaccines in younger children with BMT remains to be elucidated.

The use of hematopoietic colony-stimulating factors, such as GCSF, has been shown to reduce the period of neutropenia; however, the incidence of bacteremia and outcome has not been influenced (Sable, 1994; Vose, 1995; Spitzer, 1994). Granulocyte transfusion does not appear to be beneficial, even in the presence of profound neutropenia (van Burik, 1999).

The treatment of bacterial infections in the preengraftment phase is usually empiric, with broad-spectrum antibiotic therapy with the onset of any fever. Treatment is tailored with the isolation of organisms but remains suitably broad spectrum for continued coverage of all other pathogens that are likely in patients with neutropenic risk. Treatment with empiric antibiotics usually continues until neutrophil count recovery occurs. Generally, empiric coverage consists of one or more antipseudomonal agents, either alone or in combination with an antistaphylococcal antibiotic. Common choices include antipseudomonal penicillins (eg, piperacillin, ticarcillin) in combination with an aminoglycoside (eg, gentamicin, tobramycin), ceftazidime alone or in combination with vancomycin, piperacillin-tazobactam, or meropenem. Consideration of the local antimicrobial resistance patterns of the institution is essential when choosing the specific antimicrobial agents.

Fungal infections

Factors that increase invasive fungal infection risk following BMT include the following:

• Neutropenia

• Central venous lines

• Broad-spectrum antibiotics (empiric antibiotic therapy)

• Immunosuppressive agents (eg, corticosteroids)

• Total parenteral nutrition

• Severe mucositis

Viral infections

Reactivation of HSV infection can occur any time following transplantation. The use of prophylactic acyclovir has been shown to be very effective at reducing the amount of HSV reactivation from 80% to less than 5% among BMT recipients who are HSV seropositive (van Burik, 1999). Acyclovir (250 mg/m²/dose IV q8h or 125 mg/m²/dose IV q6h) should be started when initiating the conditioning regimen, and it should continue until mucositis has markedly improved or disappeared and with engraftment (CDC, 2000).

Acyclovir (5-10 mg/kg IV q8h for 7-14 d) is also the treatment of choice if HSV infection does occur (American Academy of Pediatrics, Antiviral drugs for non-human immunodeficiency virus infections, 2000). When patients do not respond to acyclovir, foscarnet (80-120 mg/kg/d IV divided q8-12h) is used until infection resolves (American Academy of Pediatrics, Antiviral drugs for non-human immunodeficiency virus infections, 2000). If foscarnet is unsuccessful, therapy with cidofovir (limited data exist, check most recent protocol for dose) should be attempted.

CMV was the leading cause of morbidity and mortality in patients after BMT. The advent of ganciclovir for prophylaxis in these patients has profoundly decreased severe CMV disease. The highest risk for disease is in BMT recipients who are CMV negative and who received transplantation from a donor who is CMV positive. The group at next highest risk is BMT recipients who are CMV positive, and the lowest risk is in BMT recipients who are CMV negative receiving transplantation from a donor who is CMV negative. Minimal risk exists if a CMV negative recipient receives filtered leukocytes and irradiated filtered blood products for all transfusions.

Two approaches currently exist when treating patients at risk for CMV disease (ie, CMV-negative recipient and CMV-positive donor or CMV-positive recipient) (CDC, 2000; Leather, 2001). One approach is to administer prophylaxis to every patient at risk for CMV disease with ganciclovir. Administer ganciclovir by loading with 5 mg/kg IV q12h for 1 wk; then, administer 5 mg/kg IV qd for 5 d per week from time of engraftment to 100 d after BMT (CDC, 2000). The prophylactic therapy approach has been shown to be very effective in patients who are CMV seropositive (29% reactivation in placebo arm versus 0% in ganciclovir arm, P <0.001) (Goodrich, 1991).

The disadvantage of prophylaxis is that all patients are treated, leading to unnecessary therapy, and ganciclovir has the adverse effect of myelosuppression and is associated with an increased risk of fungal infections. The other approach is to perform active surveillance to evaluate for evidence of CMV in the body by antigenemia assays (pp65) or by polymerase chain reaction (PCR) (CDC, 2000).

Weekly surveillance is performed in patients who are CMV seropositive or in those who are CMV seronegative and receiving BMT from donors who are CMV seropositive. Once CMV is detected (>5 cells per slide or >2 consecutively positive PCR test results), early preemptive therapy with ganciclovir is initiated as indicated above and continued for several weeks after negative CMV test results. Load with 5 mg/kg IV q12h for 1-2 wk; then, administer 5 mg/kg IV qd 5 d per week until day 100 after BMT or for a minimum of 3 wk, whichever is longer. This is continued for several weeks after negative CMV test results (CDC, 2000). Oral ganciclovir is not currently recommended.

CMV infection rates in autologous BMTs are as high as with allogeneic BMTs, but much less CMV disease occurs; therefore, patients with autologous BMT are not administered prophylactic therapy and do not follow preemptive therapy strategies (CDC, 2000). However, patients with autologous BMT do need ongoing screening and early therapy if evidence of CMV reactivation is identified. Foscarnet (60 mg/kg IV q12h for 7 d, followed by 90-120 mg/kg/d IV until day 100 after BMT) and cidofovir have been used in patients with apparent resistant CMV disease (Gilbert, 2001).

CMV-specific immunoglobulin (CMVIG) has been used in addition to ganciclovir in recipients of allogeneic BMT who are CMV seronegative. Randomized controlled trials (RCT) that examined CMV prophylaxis with CMVIG have shown conflicting evidence. Meta-analysis of the literature has been completed (Wittes, 1996; Messori, 1994). The meta-analysis by Messori reviewed 5 RCT and found benefit in using CMVIG in CMV-seronegative recipients of allogeneic BMT. Benefit was shown with regard to CMV infection (pooled OR 0.444, 95% CI:0.237-0.832) and CMV disease (pooled OR 0.445, 95% CI:0.223-0.887). The RCT included CMV pneumonitis, but not exclusively. The 5 studies were of similar size: 62 (30 treatment arm, 32 controls), 37 (17 treatment arm, 20 controls), 97 (45 treatment arm, 52 controls), 63 (32 treatment arm, 31 controls), and 120 (60 treatment arm, 60 controls). The patients in these RCT were at high risk of CMV disease because of allogeneic transplant and initial CMV-seronegative status.

A second meta-analysis, by Wittes in 1996, described a very heterogenous group of patients. Patients with BMT as well as solid organ transplants were included in the meta-analysis. RCT, prospective controlled trials, and retrospective controlled trials were included, totaling 23 studies. The studies included 295 BMT and 321 solid organ transplant patients. Twelve papers were randomized, with one blinded. CMV infection and CMV disease/pneumonia were examined as separate outcomes. CMVIG prophylaxis was statistically significant when all studies were examined (pooled OR 0.56, 95% CI: 0.41, 0.77) and also when only randomized studies were considered (pooled OR 0.56, 95% CI: 0.37, 0.84).

BMT patients were not considered separately from solid organ transplant patients. Prevention of severe CMV-related disease or CMV-related pneumonia was also statistically significant with all studies considered (pooled OR 0.59, 95% CI: 0.40, 0.86) and with only the randomized studies (pooled OR 0.47, 95% CI: 0.29, 0.76). Again, BMT patients were not considered separately from solid organ transplant patients in the statistical analysis. The paper by Wittes included all published literature on CMV immunoglobulin use in transplant patients, but the sizes of the studies were not presented except as an aggregate.

Varicella infections can occur in the late posttransplantation period. Although prophylaxis is not recommended in this period, prevention should be attempted following exposure with the administration of varicella zoster immunoglobulin (VZIG). VZIG, at a dose of 125 units (1.25 mL) per 10 kg, should be attempted in patients before 24 months post BMT and in those more than 24 months after BMT who are on immunosuppressive therapy or have chronic GVHD (CDC, 2000). VZIG should ideally be administered within 48-96 hours after exposure to a person with chicken pox or shingles. Patients with BMT who develop varicella should be treated for 7-10 days with intravenous acyclovir (10 mg/kg IV q8h for children <1 y or 1500 mg/m²/d divided q8h for children >1 y) (American Academy of Pediatrics, Antiviral drugs for non-human immunodeficiency virus infections, 2000).

Treatment for the respiratory viruses and adenovirus in the patient with BMT is not currently standardized. Adenoviral infections, including hemorrhagic cystitis, gastroenteritis, and pneumonitis, have been managed with some degree of success with ribavirin therapy, as documented by case reports (Jurado and Chacon, 1998; Kapelushnik, 1995; Liles, 1993; Cassano, 1991; Jurado, 1995). However, studies have also shown that treatment with ribavirin appears to make no difference in infections secondary to adenovirus (Chakrabarti, 1999; Mann, 1998; Hromas, 1994; La Rosa, 2001; Bordigoni, 2001). Cidofovir has been shown to have some activity against adenovirus in vitro and has been used with some success at a dose of 5 mg/kg once weekly for 3 weeks and then every 2 weeks in treating patients with adenoviral cystitis, gastroenteritis, and disseminated infection (Bordigoni, 2001; Ribaud and Scieux, 1999; Legrand, 2001; Hoffman, 2001).

The respiratory viruses (eg, RSV, influenzae, parainfluenzae, rhinovirus) do not have a standard treatment protocol either. Ribavirin treatment has been attempted (15-20 mg/kg/d divided q8h or the inhalation form) (Sparrelid, 1997). The success of ribavirin in treating these infections has been inconsistent (Sparrelid, 1997; Bowden, 1997; Lewinsohn, 1996; Nichols, 2001; Adams, 2001).

In 2 recent studies, the addition of RSV immune globulin therapy (palivizumab at 15 mg/kg IM monthly) to traditional ribavirin therapy has shown promise in preventing the progression of RSV upper respiratory infection to lower respiratory disease and also in the treatment of RSV pneumonia (DeVincenzo, 2000; Boeckh, 2001).

Rimantadine or amantadine can be used for prophylaxis or early preemptive therapy for influenzae A infections. Rimantadine is administered at 5 mg/kg/d PO qd or divided bid, not to exceed 150 mg, for children aged 1-9 years and at 5 mg/kg/d PO divided bid, not to exceed 100 mg bid, for children older than 10 years. Amantadine is administered at 5 mg/kg PO qd, not to exceed 150 mg/d, for children aged 1-9 years and at 100 mg PO bid for children older than 10 years (CDC, 2000). Amantadine and rimantadine are not recommended by the CDC for the 2005-2006 influenza season because of resistance. Laboratory testing by the CDC on the predominant strain of influenza (H3N2) currently circulating in the United States shows that it is resistant to these drugs.

Parasitic infections

Prophylaxis against PCP should begin with engraftment and continue until 6 months after the transplantation (CDC, 2000). Continued prophylaxis (>6 mo) is required in patients with chronic GVHD or patients receiving immunosuppressive therapy (eg, prednisone) (CDC, 2000). Prophylaxis can be started earlier if engraftment is delayed. Some centers also provide prophylaxis for 1-2 weeks before performing the BMT (14-20 d before transplantation) (CDC, 2000).

A combination product that includes TMP-SMZ is the agent of choice in the prevention of PCP at a dose of 150 mg TMP/750 mg SMX/m²/d PO divided bid and administered 3 d/wk (CDC, 2000). The major adverse effect is bone marrow suppression; therefore, if it is used before engraftment, it can delay engraftment. Other agents that have been proven effective include dapsone (2 mg/kg/d PO, not to exceed 100 mg/d), atovaquone, and aerosolized pentamidine (recommended dose for children <5 y is 9 mg/kg/dose qmo; recommended dose for children >5 y is 300 mg qmo) (CDC, 2000).

When agents other than TMP-SMZ are used for prophylaxis, a high index of suspicion for PCP should exist in patients with respiratory signs and symptoms. The treatment of choice in the patient with PCP is high-dose TMP-SMZ (15-20 mg/kg/d based on TMP component). Second-line agents include intravenous pentamidine, intravenous trimetrexate plus oral folinic acid, oral trimethoprim plus oral dapsone, oral atovaquone, or oral primaquine plus clindamycin (American Academy of Pediatrics, Drugs for parasitic infections, 2000).

Toxoplasmosis prophylaxis should be provided for allogeneic BMT recipients who are seropositive and have active GVHD or have a history of previous chorioretinitis secondary to toxoplasma. The recommended agent for prophylaxis is TMP-SMZ (150 mg TMP/750 mg SMZ/m²/d PO divided q12h 3 d/wk), although it is not optimal because clinical failures have occurred (CDC, 2000).

Vaccinations

Reimmunizations are required for most autologous and allogeneic BMT recipients because they lose immunity to the common childhood illnesses. Immunization should occur in the first to second year posttransplantation (van Burik, 1999). All nonlive vaccines should be administered, and boosters for diphtheria and tetanus toxoid should continue every 10 years (van Burik, 2000; CDC, 2000; van Burik, 1999). Patients should receive lifelong seasonal influenzae vaccinations (CDC, 2000). Live virus vaccines, such as measles, mumps, and rubella (MMR), should not be administered until at least 2 years following transplantation, and the patient should no longer have active GVHD and should not be on immunosuppressive therapy (van Burik, 2000; CDC, 2000). Varicella vaccine is currently contraindicated in BMT recipients (CDC, 2000).

	OUTCOME	Section 7 of 8
Author Information Introduction Risk Factors For Infection Preventing Transmission Of Infection From Bmt Donor To Recipient Timeline Of Risk Periods Following Bmt Prophylaxis And Treatment Outcome Bibliography

In 1993, approximately 15,000 autologous and allogeneic BMTs were carried out worldwide; in 1998, approximately 20,000 BMTs were performed in North America alone, with approximately 20% of them occurring in children (Boulad, 1998; CDC, 2000; Sable, 1994). Long-term survival is now a reality for 50-70% of pediatric patients with chronic leukemias, with disease-free survival rates as high as 80-90% in patients with aplastic anemia (Boulad, 1998).

Infection remains a major source of mortality in recipients of BMT, despite recent advances in supportive care, growth factors, more potent antimicrobials, prophylaxis strategies, and new diagnostic techniques. Prevention of infection in these patients remains the optimal method of decreasing morbidity and mortality. Once infections occur in the recipient of a BMT, the mortality rate is high. Pathogens that are benign in an immunocompetent host can lead to significant mortality in these patients.

Aspergillus, which is generally benign in the immunocompetent host, has a mortality rate of close to 100% in recipients of BMT (Baddley, 2001). Adenovirus, which generally causes a mild self-limited illness in the immunocompetent host, can lead to a mortality rate of 18-60% (Hale, 1999). Appropriate management of infectious diseases in this population involves understanding of transplantation techniques, clinical syndromes, stages of immunosuppression, natural history of certain infections, immune system reconstitution, early empiric therapy, and different antimicrobial agents.

Patients who have survived in the long term generally have good health, stressing the importance of prevention and management of infectious diseases. In a survey of 798 patients who had a BMT before 1985 and had survived more than 5 years, 93% of them were in good health and 89% had returned to work or school full time (CDC, 2000; Duell, 1997).

	BIBLIOGRAPHY	Section 8 of 8
Author Information Introduction Risk Factors For Infection Preventing Transmission Of Infection From Bmt Donor To Recipient Timeline Of Risk Periods Following Bmt Prophylaxis And Treatment Outcome Bibliography

• Abruzzo GK, Gill CJ, Flattery AM, et al: Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice. Antimicrob Agents Chemother 2000 Sep; 44(9): 2310-8[Medline].
• Adams RH: Preemptive treatment of pediatric bone marrow transplant patients with asymptomatic respiratory syncytial virus infection with aerosolized ribavirin. Biol Blood Marrow Transplant 2001; 7 Suppl: 16S-18S[Medline].
• American Academy of Pediatrics: Aspergillosis In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. American Academy of Pediatrics; 2000:178-9.
• American Academy of Pediatrics: Antiviral drugs for non-human immunodeficiency virus infections. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. American Academy of Pediatrics; 2000:676-7.
• American Academy of Pediatrics: Drugs for parasitic infections. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. American Academy of Pediatrics; 2000:693-725.
• Appelbaum FR: The use of bone marrow and peripheral blood stem cell transplantation in the treatment of cancer. CA Cancer J Clin 1996 May-Jun; 46(3): 142-64[Medline].
• Arikan S, Lozano-Chiu M, Paetznick V, Rex JH: In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrob Agents Chemother 2001 Jan; 45(1): 327-30[Medline].
• Arikan S, Lozano-Chiu M, Paetznick V, Rex JH: In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob Agents Chemother 2002 Jan; 46(1): 245-7[Medline].
• Aronchick JM: Pulmonary infections in cancer and bone marrow transplant patients. Semin Roentgenol 2000 Apr; 35(2): 140-51[Medline].
• Baddley JW, Stroud TP, Salzman D, Pappas PG: Invasive mold infections in allogeneic bone marrow transplant recipients. Clin Infect Dis 2001 May 1; 32(9): 1319-24[Medline].
• Baldwin A, Kingman H, Darville M, et al: Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplant 2000 Dec; 26(12): 1333-8[Medline].
• Barnes RA, Rogers TR: Control of an outbreak of nosocomial aspergillosis by laminar air-flow isolation. J Hosp Infect 1989 Aug; 14(2): 89-94[Medline].
• Boeckh M, Berrey MM, Bowden RA, et al: Phase 1 evaluation of the respiratory syncytial virus-specific monoclonal antibody palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis 2001 Aug 1; 184(3): 350-4[Medline].
• Bordigoni P, Carret AS, Venard V, et al: Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2001 May 1; 32(9): 1290-7[Medline].
• Boulad F, Sands S, Sklar C: Late complications after bone marrow transplantation in children and adolescents. Curr Probl Pediatr 1998 Oct; 28(9): 273-97[Medline].
• Bowden RA: Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med 1997 Mar 17; 102(3A): 27-30; discussion 42-3[Medline].
• Bowden RA: Fungal infections after hematopoietic cell transplantation. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc; 1998:550-559.
• Busca A, Saroglia EM, Giacchino M, et al: Analysis of early infectious complications in pediatric patients undergoing bone marrow transplantation. Support Care Cancer 1999 Jul; 7(4): 253-9[Medline].
• Cassano WF: Intravenous ribavirin therapy for adenovirus cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 1991 Mar; 7(3): 247-8[Medline].
• CDC: Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 2000 Oct; 49(RR-10): 1-125, CE1-7[Medline].
• Chakrabarti S, Collingham KE, Fegan CD, Milligan DW: Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: failure of intravenous ribavirin therapy. Bone Marrow Transplant 1999 Jun; 23(11): 1209-11[Medline].
• Collin BA, Leather HL, Wingard JR, Ramphal R: Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients. Clin Infect Dis 2001 Oct 1; 33(7): 947-53[Medline].
• Cometta A, Calandra T, Bille J, Glauser MP: Escherichia coli resistant to fluoroquinolones in patients with cancer and neutropenia. N Engl J Med 1994 Apr 28; 330(17): 1240-1[Medline].
• Cone RW, Huang ML, Corey L, et al: Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations. J Infect Dis 1999 Feb; 179(2): 311-8[Medline].
• Cruciani M, Rampazzo R, Malena M, et al: Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996 Oct; 23(4): 795-805[Medline].
• Davis D, Henslee PJ, Markesbery WR: Fatal adenovirus meningoencephalitis in a bone marrow transplant patient. Ann Neurol 1988 Apr; 23(4): 385-9[Medline].
• Denning DW, del Favero A, Gluckman E: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: clinical efficacy in acute invasive aspergillosis. Program and Abstracts of the 35th Interscience Conference on Antimicrobial Agent. 1995; 126.
• DeVincenzo JP, Hirsch RL, Fuentes RJ, Top FH Jr: Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation - a compassionate use experience. Bone Marrow Transplant 2000 Jan; 25(2): 161-5[Medline].
• Dictar MO, Maiolo E, Alexander B, et al: Mycoses in the transplanted patient. Med Mycol 2000; 38 Suppl 1: 251-8[Medline].
• Duell T, van Lint MT, Ljungman P, et al: Health and functional status of long-term survivors of bone marrow transplantation. EBMT Working Party on Late Effects and EULEP Study Group on Late Effects. European Group for Blood and Marrow Transplantation. Ann Intern Med 1997 Feb 1; 126(3): 184-92[Medline].
• Dummer JS, Ho M: Risk factors and approaches to infections in transplant recipients. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000:3126-36.
• Edwards JE Jr, Bodey GP, Bowden RA, et al: International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections. Clin Infect Dis 1997 Jul; 25(1): 43-59[Medline].
• Engels EA, Ellis CA, Supran SE, et al: Early infection in bone marrow transplantation: quantitative study of clinical factors that affect risk. Clin Infect Dis 1999 Feb; 28(2): 256-66[Medline].
• Engels EA, Lau J, Barza M: Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol 1998 Mar; 16(3): 1179-87[Medline].
• Espinel-Ingroff A, Boyle K, Sheehan DJ: In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: review of the literature. Mycopathologia 2001; 150(3): 101-15[Medline].
• Ferrara JL, Deeg HJ: Graft-versus-host disease. N Engl J Med 1991 Mar 7; 324(10): 667-74[Medline].
• Gilbert DN, Moellering Jr RC, Sande MA: Antiviral therapy (non-HIV). In: Sanford Guide to Antimicrobial Therapy 2001. 31st ed. Hyde Park, Vt: Antimicrobial Therapy Inc; 2001:98-107.
• Goodman JL, Winston DJ, Greenfield RA, et al: A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992 Mar 26; 326(13): 845-51[Medline].
• Goodrich JM, Mori M, Gleaves CA, et al: Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med 1991 Dec 5; 325(23): 1601-7[Medline].
• Hale GA, Heslop HE, Krance RA, et al: Adenovirus infection after pediatric bone marrow transplantation. Bone Marrow Transplant 1999 Feb; 23(3): 277-82[Medline].
• Hoffman HL, Ernst EJ, Klepser ME: Novel triazole antifungal agents. Expert Opin Investig Drugs 2000 Mar; 9(3): 593-605[Medline].
• Hoffman JA, Shah AJ, Ross LA, Kapoor N: Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001; 7(7): 388-94[Medline].
• Hovi L, Saarinen-Pihkala UM, Vettenranta K, Saxen H: Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years. Bone Marrow Transplant 2000 Nov; 26(9): 999-1004[Medline].
• Howard DS, Phillips II GL, Reece DE, et al: Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 1999 Dec; 29(6): 1494-501[Medline].
• Hromas R, Clark C, Blanke C, et al: Failure of ribavirin to clear adenovirus infections in T cell-depleted allogeneic bone marrow transplantation. Bone Marrow Transplant 1994 Oct; 14(4): 663-4[Medline].
• Hughes WT: Mycobacterial infections in bone marrow transplant recipients. Biol Blood Marrow Transplant 2000; 6(4): 359-60[Medline].
• Jezequel SG, Clark M, Evans K: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: Disposition in animals. Program and Abstracts of the 35th Interscience Conference on Antimicrobial Agent. 1995; 126.
• Jurado Chacon M, Hernandez Mohedo F, Navarro Mari JM, et al: Adenovirus pneumonitis successfully treated with intravenous ribavirin. Haematologica 1998 Dec; 83(12): 1128-9[Medline].
• Jurado M, Navarro JM, Hernandez J, et al: Adenovirus-associated haemorrhagic cystitis after bone marrow transplantation successfully treated with intravenous ribavirin. Bone Marrow Transplant 1995 Apr; 15(4): 651-2[Medline].
• Kapelushnik J, Or R, Delukina M, et al: Intravenous ribavirin therapy for adenovirus gastroenteritis after bone marrow transplantation. J Pediatr Gastroenterol Nutr 1995 Jul; 21(1): 110-2[Medline].
• Kappe R: Antifungal activity of the new azole UK-109, 496 (voriconazole). Mycoses 1999; 42 Suppl 2: 83-6[Medline].
• Keating GM, Jarvis B: Caspofungin. Drugs 2001; 61(8): 1121-9; discussion 1130-1[Medline].
• Kernan NA, Bartsch G, Ash RC, et al: Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 1993 Mar 4; 328(9): 593-602[Medline].
• Kirkpatrick WR, McAtee RK, Fothergill AW, et al: Efficacy of voriconazole in a guinea pig model of disseminated invasive aspergillosis. Antimicrob Agents Chemother 2000 Oct; 44(10): 2865-8[Medline].
• Kruger W, Russmann B, Kroger N, et al: Early infections in patients undergoing bone marrow or blood stem cell transplantation--a 7 year single centre investigation of 409 cases. Bone Marrow Transplant 1999 Mar; 23(6): 589-97[Medline].
• La Rosa AM, Champlin RE, Mirza N, et al: Adenovirus infections in adult recipients of blood and marrow transplants. Clin Infect Dis 2001 Mar 15; 32(6): 871-6[Medline].
• Leather HL, Wingard JR: Infections following hematopoietic stem cell transplantation. Infect Dis Clin North Am 2001 Jun; 15(2): 483-520[Medline].
• Legrand F, Berrebi D, Houhou N, et al: Early diagnosis of adenovirus infection and treatment with cidofovir after bone marrow transplantation in children. Bone Marrow Transplant 2001 Mar; 27(6): 621-6[Medline].
• Lewinsohn DM, Bowden RA, Mattson D, Crawford SW: Phase I study of intravenous ribavirin treatment of respiratory syncytial virus pneumonia after marrow transplantation. Antimicrob Agents Chemother 1996 Nov; 40(11): 2555-7[Medline].
• Liles WC, Cushing H, Holt S, et al: Severe adenoviral nephritis following bone marrow transplantation: successful treatment with intravenous ribavirin. Bone Marrow Transplant 1993 Oct; 12(4): 409-12[Medline].
• Lujan-Zilbermann J, Benaim E, Tong X, et al: Respiratory virus infections in pediatric hematopoietic stem cell transplantation. Clin Infect Dis 2001 Oct 1; 33(7): 962-8[Medline].
• Mann D, Moreb J, Smith S, Gian V: Failure of intravenous ribavirin in the treatment of invasive adenovirus infection following allogeneic bone marrow transplantation: a case report. J Infect 1998 Mar; 36(2): 227-8[Medline].
• Marmont AM, Horowitz MM, Gale RP, et al: T-cell depletion of HLA-identical transplants in leukemia. Blood 1991 Oct 15; 78(8): 2120-30[Medline].
• Martin MV, Yates J, Hitchcock CA, et al: Comparison of voriconazole (UK-109,496) and itraconazole in prevention and treatment of Aspergillus fumigatus endocarditis in guinea pigs. Antimicrob Agents Chemother 1997 Jan; 41(1): 13-6[Medline].
• Messori A, Rampazzo R, Scroccaro G, Martini N: Efficacy of hyperimmune anti-cytomegalovirus immunoglobulins for the prevention of cytomegalovirus infection in recipients of allogeneic bone marrow transplantation: a meta-analysis. Bone Marrow Transplant 1994 Feb; 13(2): 163-7[Medline].
• Murphy M, Brown AE, Sepkowitz KA, et al: Fluoroquinolone prophylaxis for the prevention of bacterial infections in patients with cancer--is it justified? Clin Infect Dis 1997 Aug; 25(2): 346-8[Medline].
• Murphy M, Bernard EM, Ishimaru T, Armstrong D: Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother 1997 Mar; 41(3): 696-8[Medline].
• National Marrow Donor Program: Standards: effective September 1, 1999. 17th ed. National Marrow Donor Program; 1999:1-35.
• Nichols WG, Gooley T, Boeckh M: Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience. Biol Blood Marrow Transplant 2001; 7 Suppl: 11S-15S[Medline].
• Ninin E, Milpied N, Moreau P, et al: Longitudinal study of bacterial, viral, and fungal infections in adult recipients of bone marrow transplants. Clin Infect Dis 2001 Jul 1; 33(1): 41-7[Medline].
• Peterson PK, McGlave P, Ramsay NK, et al: A prospective study of infectious diseases following bone marrow transplantation: emergence of Aspergillus and Cytomegalovirus as the major causes of mortality. Infect Control 1983 Mar-Apr; 4(2): 81-9[Medline].
• Pfaller MA, Yu WL: Antifungal susceptibility testing. New technology and clinical applications. Infect Dis Clin North Am 2001 Dec; 15(4): 1227-61[Medline].
• Pfaller MA, Messer SA, Mills K, et al: Evaluation of Etest method for determining caspofungin (MK-0991) susceptibilities of 726 clinical isolates of Candida species. J Clin Microbiol 2001 Dec; 39(12): 4387-9[Medline].
• Ribaud P, Chastang C, Latge JP, et al: Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis 1999 Feb; 28(2): 322-30[Medline].
• Ribaud P, Scieux C, Freymuth F, et al: Successful treatment of adenovirus disease with intravenous cidofovir in an unrelated stem-cell transplant recipient. Clin Infect Dis 1999 Mar; 28(3): 690-1[Medline].
• Rotstein C, Bow EJ, Laverdiere M, et al: Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group. Clin Infect Dis 1999 Feb; 28(2): 331-40[Medline].
• Rowlings PA: 1996 summary slides show current use and outcome of blood and marrow transplantation. Autologous Blood & Marrow Transplant Registry-North America. ABMTR Newsletter 1996; 3: 6-12.
• Sable CA, Donowitz GR: Infections in bone marrow transplant recipients. Clin Infect Dis 1994 Mar; 18(3): 273-81; quiz 282-4[Medline].
• Schwartz S, Milatovic D, Thiel E: Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia. Br J Haematol 1997 Jun; 97(3): 663-5[Medline].
• Sherertz RJ, Belani A, Kramer BS, et al: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 1987 Oct; 83(4): 709-18[Medline].
• Slavin MA, Osborne B, Adams R, et al: Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation--a prospective, randomized, double-blind study. J Infect Dis 1995 Jun; 171(6): 1545-52[Medline].
• Sparrelid E, Ljungman P, Ekelof-Andstrom E, et al: Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections. Bone Marrow Transplant 1997 May; 19(9): 905-8[Medline].
• Spitzer G, Adkins DR, Spencer V, et al: Randomized study of growth factors post-peripheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit. J Clin Oncol 1994 Apr; 12(4): 661-70[Medline].
• Storb R, Longton G, Anasetti C, et al: Changing trends in marrow transplantation for aplastic anemia. Bone Marrow Transplant 1992; 10 Suppl 1: 45-52[Medline].
• Thomas ED, Clift RA, Fefer A, et al: Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986 Feb; 104(2): 155-63[Medline].
• van Burik J, Weisdorf D: Infections in recipients of blood and marrow transplantation. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000: 3136-47.
• van Burik JA, Hackman RC, Nadeem SQ, et al: Nocardiosis after bone marrow transplantation: a retrospective study. Clin Infect Dis 1997 Jun; 24(6): 1154-60[Medline].
• van Burik JH, Weisdorf DJ: Hematopoietic Stem Cell Therapy Infections In Recipients Of Blood And Marrow Transplantation. Hematology/Oncology Clinics of North America 1999; 13: 1065-89.
• Vose JM, Armitage JO: Clinical applications of hematopoietic growth factors. J Clin Oncol 1995 Apr; 13(4): 1023-35[Medline].
• Wingard JR: Fungal infections after bone marrow transplant. Biol Blood Marrow Transplant 1999; 5(2): 55-68[Medline].
• Wittes JT, Kelly A, Plante KM: Meta-analysis of CMVIG studies for the prevention and treatment of CMV infection in transpl