Infections After Bone Marrow Transplantation

Updated: Apr 07, 2015
  • Author: Rupesh Chawla, MD, MSc, FRCPC; Chief Editor: Stuart M Greenstein, MD  more...
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Overview

Overview

Patients undergoing bone marrow transplantation (BMT) are at risk for granulocytopenia, impairment of barrier defenses, and impairment of cell-mediated immunity (CMI) and humoral immunity. This impairment leads to an immunocompromised state, allowing microorganisms to cause infection more easily, even those with limited pathogenicity. Patients undergoing BMT experience a sequential suppression of host defenses, allowing for various infectious processes at different phases of the transplantation process.

The term BMT is currently used to refer to the processes of bone marrow transplantation and peripheral blood stem cell transplantation. [1, 2] The procedure involves the harvesting of hematopoietic stem cells from a donor (from peripheral blood or bone marrow) and then infusing these stem cells into the recipient who has had chemotherapy with or without irradiation, which generally has destroyed the cells in the recipient's bone marrow. [3] Peripheral blood cells that are harvested require treatment with hematopoietic colony-stimulating factors (eg, granulocyte colony-stimulating factor [GCSF]) before infusing them into the recipient. [3] Because peripheral blood is much easier to access than bone marrow, this is increasingly becoming the standard method of harvesting stem cells. [3, 4]

BMT is currently used for patients with hematologic malignancies (eg, leukemia, lymphoma, multiple myeloma), solid tumors (eg, sarcomas, neuroblastoma, breast cancer, testicular cancer), and nonmalignant conditions (eg, aplastic anemia, autoimmune disorders, myelodysplastic syndrome, immunodeficiency syndromes, congenital disorders of metabolism). [1, 2, 3, 4, 5] For some of these conditions, BMT is now standard therapy; for others, it is used as a rescue when standard therapy is unsuccessful. [6, 7, 8]

BMTs are classified as either autologous or allogeneic, based on the source of the hematopoietic stem cells.

In allogeneic transplantations, the stem cells are harvested from a donor who is other than the recipient of the BMT. Allogeneic transplants are used for patients with severe aplastic anemia, chronic myelogenous leukemia (CML), and acute myelogenous leukemia (AML). [3, 7, 8, 9] Donors for these transplants may be related or unrelated; however, transplants from human leukocyte antigen (HLA)–matched sibling are associated with a lower risk of graft versus host disease (GVHD), and the recipient’s immune system tends to recover faster following transplantation. [2, 3, 10]

The donor graft may be depleted of T lymphocytes, which are the main effectors of GVHD; however, with these new techniques, higher rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)–associated posttransplantation lymphoproliferative disease have been noted. [3, 11]

Autologous transplantations involve stem cells that are harvested from the recipient patient. Syngeneic transplants refer to stem cells from an HLA-matched identical twin. Autologous transplantations are performed in patients with bone marrow that is healthy and has no disease. These types of transplantations are most frequently used to treat Hodgkin lymphoma, non-Hodgkin lymphoma, and breast cancer. [3, 12] Patients with autologous transplantations tend to have more rapid recovery of their immune system than patients with allogeneic transplantations. [13] GVHD does not occur in patients undergoing autologous or syngeneic transplantation. [1, 2, 3]

Placental or umbilical cord blood obtained immediately after birth has been used to harvest stem cells for transplantation, [2, 3] primarily for use in allogeneic transplantations in children. [3] Whether parents should create their own stem cell donor for the purpose of treating another of their children is currently an issue of ethical debate.

Infection and GVHD remain the major source of morbidity and mortality in patients who undergo BMT. [5, 13, 14, 15, 16, 17, 18] According to the National Marrow Donor Program, of 462 patients in the United States who underwent an unrelated allogeneic BMT between December 1987 and November 1990, 66% had died by 1991, with infection as the most common primary and secondary cause of death (37% of 307 patients). [3, 19] This article is focused on the common infections in patients who have undergone BMT, the risk factors for these infections, and the approaches to their prevention and treatment.

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Risk Factors for Infection

Certain risk factors place patients undergoing bone marrow transplantation (BMT) at increased risk for infections. Host factors, type of transplant (allogeneic vs autologous, peripheral blood vs bone marrow), immunosuppressive regimen, and graft reactions are the major categories of risk factors to consider. [20] The baseline medical status of the BMT recipient can lead to an increased predilection to infection. Underlying medical state, previous immune status, prior colonization, prior latent infections, and medications all determine the recipient's baseline medical status. [20] Patients with malignant conditions probably have a higher risk of infection than patients with nonmalignant conditions because of the immunosuppression associated with the malignancy.

Immune status is critical to infection risk. For example, determining preexisting immunity to and/or evidence of prior infection with the herpes group of viruses pretransplantation is important for assessing the patient's need for prophylaxis. [3, 4, 20] The risk of reactivation of these viruses is high in the immunocompromised state acquired during the BMT process. [3, 4, 5, 20, 21] Previous colonization with organisms such as Candida species is a risk factor in developing systemic candidemia when mucosal barriers are compromised. [4, 21] Latent infections, such as tuberculosis, can reactivate during immunosuppression. Medications, such as corticosteroids, that can cause further immunosuppression in the patient undergoing BMT can increase the risk of infection. [20]

Compared with patients undergoing autologous transplantation, patients undergoing allogeneic transplantation are at a greater risk of infection because of a longer time to achieve engraftment (prolonged neutropenia) and the added risk of graft versus host disease (GVHD). [4, 13]

The use of peripheral blood stem cells compared to stem cells from the bone marrow has led to faster hematopoietic cell reconstitution with a reduced potential for recurrence of initial disease. [22, 23] Peripheral blood contains more progenitor cells and lymphocytes, which may help engraftment and provide antileukemic effects but may result in a greater risk of developing GVHD. [23] The risk for acute GVHD has not been shown to differ, but chronic GVHD may be more common. [22, 23]

Immunosuppressive regimens vary according to the condition being treated. The conditioning regimen received is more intense in certain conditions (marrow ablative), such as with hematologic malignancies, than in immunodeficiency syndromes, which do not require cytoreduction to be as potent. [1] GVHD is a condition in which the stem cell graft attacks the host tissue. Multiple organs are involved, and barrier defenses are broken down. [1] Immune deficiency caused by defective humoral and cell-mediated immunity and functional asplenia is also associated with GVHD. [1]

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Preventing Transmission of Infection From Bone Marrow Donor To Recipient

All prospective bone marrow transplantation (BMT) donors should be thoroughly evaluated with a complete history (including exposure history), physical examination, and serologic testing. [3] The initial donor screen and physical examination should be performed 8 weeks or less before the planned transplantation. [3] Serologic testing should be conducted 30 days or less before the BMT. [3] Some experts suggest that serologic testing be repeated within 7 days before transplantation. [3] All donors should be in good general health; any acute or chronic illness in the donor must be investigated to determine the etiology. [3, 24]

The following should be obtained in the medical history of the prospective BMT donor to evaluate eligibility as a donor: [3]

  • History of vaccination during the 4 weeks before donation: The donation should be deferred for 4 weeks after the donor receives any live-attenuated vaccine.
  • Travel history: Determine whether the donor has resided in or traveled to countries in which endemic disease that can be transmitted by BMT could have been acquired, eg, malaria.
  • History of denial of plasma or blood donation
  • History of viral hepatitis
  • History of receiving a blood product transfusion, solid organ transplantation, or transplantation of tissue in the past 12 months
  • History of risk factors for classic Creutzfeldt-Jacob disease (CJD)
  • Past medical history that reveals high risk for acquisition of a blood-borne pathogen

Patients at high risk for acquisition of a blood-borne pathogen include the following:

  • Men who have had or are having sex with other men
  • Intravenous drug abusers
  • Persons with hemophilia or other clotting disorders who have received human-derived clotting factor concentrates
  • Inmates of correctional centers
  • Individuals receiving treatment for any sexually transmitted disease in the past 12 months
  • Persons who have engaged in sex in exchange for money or drugs during the preceding 5 years
  • Persons who have been exposed through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane during the preceding 12 months to any person known or suspected to have blood infected with HIV, hepatitis B, or hepatitis C

Serologic testing in donors should include the following: [3, 20]

  • HIV-1 antigen
  • Antibodies to HIV-1 and HIV-2
  • Antibodies to human T-cell lymphotrophic virus type 1 (HTLV-I) and human T-cell lymphotrophic virus type 2 (HTLV-II)
  • Hepatitis B surface antigen
  • Hepatitis B core antibody
  • Antibody to hepatitis C
  • Antibody to CMV
  • Syphilis serology

Individuals who have a positive screening medical history result should be excluded from donating. [3] Positive serologic results of any of the above tests (especially HIV and hepatitis C) can also be a reason for denying a person eligibility for transplant donation. [3] Anyone who refuses serologic testing should also be refused donor status. [3, 20]

Similarly, for the transplant recipient, screening must include a complete history, physical examination, and serologic testing. This helps to establish the presence of chronic viral infections (herpes group) and to assess susceptibility for reactivation of pathogens that appear during BMT. [20] The serology serves as a baseline by which future events can be compared.

Before transplantation, the recipient should be screened for CMV, EBV, herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), hepatitis B, hepatitis C, HIV, tuberculin skin test, and stool for ova and parasites. (For laboratories in which focused testing is performed, a full parasitology screen should be requested. [20] ) Before harvesting, autologous BMT recipients should also undergo serologic testing, including for the herpes group of viruses, hepatitis viruses, and HIV. [20]

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Timeline of Risk Periods Following Bone Marrow Transplantation

A well-recognized and predictable sequence of events occurs in recipients of bone marrow transplantation (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. The sequence of immunosuppression allows for classification of BMT infections into the following 4 distinct stages: [5]

  • Pretransplantation period
  • Preengraftment period (approximately 0-30 d posttransplantation)
  • Postengraftment period (approximately 30-100 d posttransplantation)
  • Late posttransplantation period (≥100 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, ≥100 d posttransplantation). [1, 13, 17, 18]

Pretransplantation period

Infections during the pretransplantation period are very heterogeneous, as are the conditions necessitating BMT. [5] 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, such as Klebsiella species and Escherichia coli. [5] Local infections most commonly involve skin and soft tissue, the oral cavity, or urinary tract (60%), whereas sepsis (24%) and pneumonia (10%) occur less commonly. [5] As a result of the local nature of most infections during this stage, the associated severity and mortality rates are low. [5]

Preengraftment period (approximately 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/µL 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. [3] The preengraftment phase in the patient undergoing allogeneic BMT is generally longer than that in the patient undergoing autologous BMT. [2, 3, 4]

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 during the preengraftment phase but does not increase the risk for acquiring infection. [14] Empirical antimicrobial therapy should be no different for either group because both are at risk for the same pathogens. [14]

In the preengraftment period, the major risk for acquiring infection is neutropenia and altered barrier defenses resulting from the BMT conditioning regimen. [2, 3, 4, 5] Another factor is the need for vascular access in this group of patients. [2, 3, 21] The sources of pathogens for infection during this period are the patient's skin flora, oral flora, and GI tract flora. [3] The disruption of the normal barrier defenses allows microorganisms that normally colonize these areas to invade, rendering them pathogenic.

Different conditioning regimens exist depending on the indication 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. [1, 5] The combination results in a higher incidence of diarrhea, bacteremia, and herpes zoster than in those who receive chemotherapy alone. [5]

The predominant infections during the preengraftment phase of transplantation are bacterial, occurring in 15%-50% of recipients of BMT. [5] The first fever that develops in the BMT recipient posttransplantation is usually caused by a bacterial pathogen; however, isolating the responsible organism or determining the source of infection is unusual. [16] Just as in the febrile neutropenic patient, a shift in the etiologic agents of bacteremia has occurred in these patients.

In the 1980s, gram-negative bacilli 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 since the 1990s, gram-positive organisms have become more frequent and currently are the most common etiologic agents. [4, 5, 15, 21] Staphylococcal infections secondary to coagulase-negative staphylococci and Staphylococcus aureus are most common and are usually the result of an infected central venous catheter. [5] Streptococcal infections, especially the Streptococcus viridans group, are becoming more common and are associated with mucositis and the use of antibiotic prophylaxis. [4, 5]

Pulmonary infections usually occur later in the course of the transplant, but up to 35% of these types of infections occur in the preengraftment phase. As with pneumonia in the immunocompetent patient, recovery of an organism is rare (< 20%). [5] 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. [25] Bacterial pneumonias have an incidence of 12%-15% in the first 100 days after BMT and are more commonly observed in patients who have undergone allogeneic transplantation. [25] 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). [25]

Even less commonly observed is typhlitis or neutropenic enterocolitis, which tends to occur with severe neutropenia. [5] 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 scan findings. The etiology of the bowel inflammation observed in typhlitis is polymicrobial. [5] The GI flora that usually colonizes the GI tract (ie, gram-negative organisms, anaerobes, Candida species) becomes pathogenic in the immunocompromised state. Typhlitis has a reported mortality rate of 50%-100%. [5]

Other unusual 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 often been observed in patients undergoing BMT. [4, 21] This low incidence of mycobacterial infection is speculated to be because most transplantations are performed in developed countries where mycobacterial infections are less common. [4] In patients undergoing BMT in countries that have an increased incidence of mycobacterial infections, an increased incidence of infection would be expected. [26] A high index of suspicion should be maintained for mycobacterial infection in the high-risk patient (eg, national origin, prior tuberculosis exposure, positive purified protein derivative [PPD] test result) with fever of unknown origin. [4, 27]

Another rarely described opportunistic microorganism in recipients of BMT is Nocardia. These atypical bacteria are gram-positive aerobic actinomycetes that are found in soil and decaying organic matter. [4] A published review of 27 cases of nocardiosis 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). [4, 28] Most commonly, Nocardia infection was associated with a pulmonary illness with nodules with or without pulmonary infiltrates; 56% of the patients had documented abnormal findings on chest radiographs. [4, 28]

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 GI 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. [21]

The next most common infection in the preengraftment phase of BMT is fungal. Invasive fungal infections are one of the leading causes of infectious mortality after allogeneic BMT. [4, 29, 30, 31] The incidence of invasive fungal infections has been reported to be 10%-20%. [32] 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 are possibly on parenteral nutrition; all of these are significant risk factors for the development of fungemia. [5]

The risk of developing fungal infection is directly proportional to the duration of neutropenia and is particularly increased after approximately 5-7 days. [4] Fungal infections are generally caused by two specific pathogens (which account for >80% of fungal episodes): Candida species, which are endogenous fungi found in the GI tract, and Aspergillus species, which are ubiquitous exogenous molds, usually acquired from the environment. [5, 21, 30, 32]

Candida infections occur in approximately 11% of patients undergoing BMT. [5] Candida albicans is still the most prevalent candidal species isolated from the BMT population; however, cases of nonalbicans candidemia now account for 50% of candidal infections. [5, 33] Candida glabrata, Candida krusei, and more azole-resistant C albicans are probably being observed secondary to increased antifungal prophylaxis with fluconazole. [4, 5, 21, 33]

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 occur in 4%-20% of BMT recipients. [5] 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 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.

In the past, fluconazole has been used to reduce the number of Candida infections. Unfortunately, fluconazole has no activity against Aspergillus. Therefore, centers have started using newer agents such as the triazoles (voriconazole), especially in patients at high risk of Aspergillus infection. [34]

With the use of voriconazole, pathogens of the class Zygomycetes have emerged in more BMT centers. [35, 36] Zygomycosis (mucormycosis) has been found at incidence rates of up to 8% in autopsied leukemia patients and 2% in allogeneic BMT patients. [35, 36] This infection is acquired by inhalation, ingestion, or trauma and has a mortality of up to 80% in transplant recipients. [35] Numerous other fungi have been reported to cause infection in the BMT patient, including Pseudallescheria boydii and Scopulariopsis, Fusarium, Trichosporon, Rhodotorula, Alternaria, Acremonium, Pityrosporum, Bipolaris, Curvularia, and Penicillium species. [5]

The virus most commonly documented during the preengraftment phase is HSV, and the usual mechanism of appearance is reactivation of prior latent infection. [5] A large proportion (80%) of patients who were seropositive for HSV before the transplantation develop clinical disease if prophylaxis is not provided. [4, 21] The most common clinical presentation in this phase is gingivostomatitis (85%). [5] 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 (approximately 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 begun to heal at this phase. The major determinants of immunosuppression in this period include impairment of CMI and humoral immunity, as well as diminished phagocyte function. [5, 37]

Other important causes of impaired immunity include acute graft versus host disease (GVHD) and the use of immunosuppressive agents as part of the management of GVHD episodes in allogeneic transplantation. [5] 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. [4]

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 who have undergone BMT who acquire CMV infection, 15%-20% die. [5] CMV pneumonia is associated with a case-fatality rate of 80%-90%. [5]

CMV disease due to 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. [4] To prevent development of CMV disease, both prophylaxis and early empiric therapy of CMV viremia have been used at BMT centers and is discussed below (see Viral infections). 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 in the postengraftment phase of transplant.

Patients with GVHD who have undergone allogeneic transplantation and who have been given subsequent therapy with high-dose corticosteroids are at risk for Aspergillus infection (late-onset aspergillosis) and Candida infections. [4] GVHD and its treatment also place the patient at increased risk of viral infection with CMV and VZV. [4]

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. [38, 39, 40, 41] In the immunocompromised patient, adenoviral infections result in systemic illness of increased severity and longer duration than in patients with normal immune systems. [38] Adenovirus can cause hepatitis (with or without hepatic necrosis), pancreatitis, colitis, hemorrhagic cystitis, pneumonia, nephritis, and disseminated disease. [38] Case reports of adenoviral meningoencephalitis have been documented. [42] Adenoviral infection has been reported to occur in 4.9%-20.9% of patients undergoing BMT. [39]

The mortality rate in immunocompromised patients with adenoviral infection is high (18-60%) and depends on patient age, type of BMT, and adenovirus subtype. [38, 39] Higher mortality rates were observed in patients with disseminated adenoviral disease (61%) and adenoviral pneumonia (73%). [41]

Community-acquired respiratory viruses, such as respiratory syncytial virus (RSV), influenza, parainfluenza, and the picornaviruses can be found in the postengraftment phase, leading to respiratory disease. In immunocompromised individuals, respiratory viruses are nosocomially acquired and are associated with a high mortality rate and often have a prolonged course and progress to pneumonia. [4, 21, 43] Human metapneumovirus is increasingly being recognized as a significant etiologic agent in patients with lower respiratory tract disease, with an associated mortality rate of up to 50%. [44]

Respiratory virus infections were found to be a common problem (11%) in a pediatric population who underwent BMT and were associated with substantial morbidity (28% developed pneumonia, approximately 5% had complications with croup) and mortality (9.4%). [43] Parainfluenza type 3 was found to be the most common. Risk factors for the acquisition of respiratory viral infections depend on the type of BMT (higher risk with allogeneic BMT than with autologous BMT) and the degree of GVHD present. [43] Enteroviral infections have also been reported to occur in the postengraftment period of transplantation.

Recent studies have focused on another virus in the herpes group, HHV-6. [45, 46, 47] This infection 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 who have undergone BMT, HHV-6 mostly leads to asymptomatic seroconversion, but it can be associated with prolonged febrile illnesses and CNS syndromes, such as encephalitis. [45, 46] HHV-6 has also been linked to interstitial pneumonitis, early and late graft failure, and bone marrow suppression. [48, 49] Asymptomatic reactivation appears to occur commonly throughout the post-BMT period. [45, 46] HHV-7, another beta-herpesvirus (related to CMV), has been associated with febrile illness. [49]

Hemorrhagic cystitis is a well known complication of BMT and is known to be caused by two viruses: adenovirus (as previously discussed) and BK virus (a polyoma virus). BK virus is an emerging pathogen in the BMT population. The DNA of BK virus can be revealed by polymerase chain reaction (PCR). Some studies have reported that hemorrhagic cystitis may be more likely to be associated with BK virus than adenovirus. [50] There is no established therapy for BK virus, but cidofovir has in vitro activity against polyoma viruses and has been used with success in case reports. [51]

Parasitic infections also tend to occur during this period. Pneumocystis jiroveci pneumonia (PCP) was a major opportunistic infection leading to significant morbidity and mortality. However, with the use of trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis, PCP is now uncommon except in patients who are not compliant with prophylaxis or are taking inferior prophylaxis. [5] 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. [21] In the absence of chronic GVHD, infection is unusual in this period.

Chronic GVHD often requires continued immunosuppression during this posttransplantation phase. Chronic GVHD and its treatment lead to ongoing cellular and humoral immunity defects. Barrier protection of the skin, mucous membranes, and GI tract are compromised by chronic GVHD. Infection in this phase is generally localized to the skin, the upper respiratory tract, and the lungs. [21] 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%. [5]

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

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Prophylaxis and Treatment

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 bone marrow transplantation (BMT). [3] These guidelines are a good resource for reviewing the variety of techniques available for preventing these infections.

Hospitals that perform BMTs should have appropriately designed facilities that have rooms with more than 12 air exchanges per hour and point-of-use high-efficiency particulate air (HEPA) filtration. [3] The HEPA filters should be able to remove particles down to at least 0.3 µm in diameter. [3] Laminar airflow rooms, in which air moves in one direction, have been shown to protect patients from Aspergillus infections during outbreaks. [52, 53] 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 that 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. [3]

Strategies of safe living posttransplantation after discharge home are also important to discuss with BMT recipients. This should include a discussion of 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. [3]

Bacterial infections

The use of prophylactic antibiotic therapy in BMT is controversial. [3] During the preengraftment period, fluoroquinolones have been used to decrease the incidence of gram-negative bacteremia, and beta-lactams and macrolides have been used to reduce the incidence of gram-positive bacteremia. [4, 20] Studies show that fluoroquinolones have been effective in the reduction of cases of gram-negative bacteremia. [13, 54] However, no studies have shown an improved survival rate with the use of any of the prophylactic antibiotic regimens. [54, 55, 56]

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. [55, 57] Streptococcal species are showing increased resistance to penicillin, ciprofloxacin, and imipenem. [15] Pseudomonas species have been found to be more resistant to agents such as ceftazidime. [15] Another concern with the use of prophylactic antimicrobial therapy is the increase in C difficile as a pathogen.

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 S pneumoniae vaccine. [3] However, the role of this vaccine in infants and younger children is absent or limited, as it is ineffective in this age group. The role of the newer conjugate pneumococcal vaccines in younger children who have undergone 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 have not been influenced. [5, 58, 59, 21] Granulocyte transfusion does not appear to be beneficial, even in the presence of profound neutropenia.

The treatment of bacterial infections in the preengraftment phase is usually empiric, with broad-spectrum antibiotic therapy begun upon the onset of any fever. Treatment is tailored upon 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. Knowledge and consideration of the local antimicrobial resistance patterns of the institution are 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)
  • Graft versus host disease (GVHD)
  • Total parenteral nutrition
  • Severe mucositis

More than 80% of patients who develop fungemia are infected with either Candida or Aspergillus species. [30]

Fluconazole prophylaxis has been shown to be effective in reducing the number of infections with C albicans and the patient mortality rate after BMT. [60, 61, 62] The dosage of fluconazole for prophylaxis is as follows: [3]

  • Children aged 6 months to 13 years: 3-6 mg/kg/d PO/IV once daily, not to exceed 400 mg/d
  • Children 14 years or older: 400 mg/d PO/IV once daily

Fluconazole has been recommended as a prophylactic agent in patients who have undergone BMT. However, with more widespread use of prophylactic fluconazole, an increase has occurred in infections secondary to resistant C albicans and in the isolation of Candida species (ie, C glabrata, C krusei) that are not usually sensitive to fluconazole. [4, 5, 21, 33] Fluconazole possesses no significant activity against Aspergillus; thus, increased infections with Aspergillus are emerging.

The agent micafungin is also approved for prophylaxis of Candida infections in BMT recipients as young as 4 months old. The dose for prophylaxis is 1 mg/kg IV once daily; not to exceed 50 mg/day.

With improved CMV control, Aspergillus species are now the most common cause of infectious mortality in BMT. [63] Fungal prophylaxis must be addressed, with a focus on the fungi and molds now observed and the resistance patterns. New antifungal agents (eg, voriconazole, caspofungin), which are effective against the resistant candidal species and have activity against Aspergillus, are likely to play a role in future prophylaxis measures.

The risk of fungal infection is particularly increased after 5-7 days of continuous neutropenia, and most centers begin empiric therapy for fungi after this period if fever has occurred during antibiotic therapy. Previously, fungal infections had been treated with either conventional or liposomal amphotericin B. Newer agents have increased the treatment armamentarium available for invasive fungal infections. Voriconazole (Vfend) is a new triazole antifungal agent that has been shown to be effective in vitro against Candida species, including C krusei and C glabrata, as well as Aspergillus species. This agent has been used with good effect (40% efficacy) as rescue therapy when amphotericin was not effective or was limited by toxicity. [64, 65, 66, 67, 68, 69, 70, 71, 72, 73]

Voriconazole, in a randomized controlled trial by Herbrecht et al, has been shown in patients 12 years of age or older to be a better agent than amphotericin B for Aspergillus infections, with both better response (voriconazole: 52.8% vs amphotericin B: 31.6%) and survival (at 12 weeks, voriconazole: 70.8% vs amphotericin B: 57.9%). [74]

The IV dose for voriconazole in adults and children older than 2 years is 6 mg/kg q12h for 2 doses, then 4 mg/kg q12h. The oral dose of voriconazole for patients weighing 40 kg or more is 400 mg PO q12h for 2 doses, then 200-300 mg q12h. In patients who weigh less than 40 kg, the dose is 200 mg PO q12h for 2 doses, then 100-150 mg q12h. Voriconazole has also been used with good efficacy to treat less common fungal Infections by Cryptococcus, Fusarium, Trichosporon, Penicillium, and Scedosporium. [75, 76] Voriconazole has been used in the pediatric population with good success in invasive fungal infections, although the optimal dose in children younger than 12 years is not well established owing to different pharmacokinetics. [76, 77]

In a recent randomized controlled trial, voriconazole was compared to placebo as prophylaxis against invasive fungal infections in patients receiving chemotherapy for AML. [78] Lung infiltrates were found to be less common in the voriconazole group than in the placebo group (0% vs 33%, P =0.06), as was hepatosplenic candidiasis (0% vs 27%; P =0.11), but neither significantly. [78] However, this trial was terminated prematurely when a separate study found that posaconazole used as antifungal prophylaxis reduced mortality rates, making the use of a placebo unethical. [78]

Caspofungin (Cancidas) is the first agent in a new class of antifungal agents, the echinocandins. This agent has been shown in vitro to be effective against Candida and Aspergillus. [70, 79, 80, 81, 82, 83] The added advantages of the echinocandins are that they appear to be fungicidally similar to amphotericin B (all azole antifungals are fungistatic), and they have a new site of action; therefore, synergy may exist with the use of this agent and other antifungals. [83]

Caspofungin has been compared to amphotericin B in randomized controlled trials in the treatment of candidal infections, including invasive disease and esophagitis. [84, 85, 86] Caspofungin has been found to be equally effective for the treatment of candidal infections as amphotericin B, with much fewer adverse effects. [84, 85, 86] Caspofungin has been used in salvage therapy in patients with Aspergillus infections in whom amphotericin B therapy failed, with a favorable response in approximately 45% of patients. [87, 88] Pediatric populations have been treated successfully with caspofungin, with few side effects. [89]

Caspofungin pharmacokinetic studies for children have been performed, and standardized dosing guidelines have been established, as follows:

  • Children aged 3 months to 17 years
    • Loading dose: 70 mg/m2/d IV on day 1; not to exceed 70 mg/d
    • Maintenance dose: 50 mg/m2/dose IV; not to exceed 50 mg once daily
  • Adults aged 18 years or older
    • Loading dose: 70 mg IV on day 1
    • Maintenance dose: 50 mg IV once daily

To improve the poor response seen with conventional therapy, combination therapy has been used in the treatment of invasive aspergillosis. The basis of these regimens has been in vitro studies revealing synergy of the antifungals against Aspergillus. [83, 90, 91, 92] There has been no randomized controlled trial to address the efficacy of this approach. Studies consist of case reports and case series. [93, 94, 95, 96] With no proof that this is a better regimen in terms of efficacy or survival, important considerations arguing against the use of combination therapy include the additive toxicity, as well as the added costs of therapy.

When febrile neutropenia persists for more than 5-7 days despite empiric therapy, most centers currently rely on amphotericin B (0.5 mg/kg/d IV once daily for systemic candidiasis, 1-1.5 mg/kg/d once daily for invasive aspergillosis) or an equivalent dose of a liposomal formulation. [97, 98] This therapy is continued until the fever has abated and, generally, until the neutrophil count has recovered. Search for fungi must go hand in hand with empiric therapy.

When Candida is isolated from the bloodstream, look for dissemination of this fungus to different sites. Common sites of dissemination include the head, eyes, renal parenchyma (fungal balls), liver, and spleen. Adjunctive surgery is rarely required in invasive fungal infections secondary to Candida, with the possible exception of the patient with an isolated splenic candidal infection. [99] Aspergillus infections often require adjunctive surgery for successful therapy. This exogenous mold often enters through the sinuses, and sinus drainage is occasionally required. In addition, isolated lung nodules can be removed. Surgical therapy should be used as an adjunct to antifungal therapy, not as replacement therapy. [99]

Infection due to the Zygomycetes (mucormycosis) is very difficult to treat, with high mortality rates despite treatment. Treatment currently involves early recognition and initiation of high-dose amphotericin B, often lipid complex, 5 mg/kg IV once daily (or higher), in combination with colony stimulating factors to shorten the duration of neutropenia, and adjunctive surgical resection when possible. The use of voriconazole as primary or secondary prophylaxis against fungal infections is emerging as a risk factor for the development of breakthrough zygomycetous infections. [100]

Newer agents that have activity against the class Zygomycetes are on the horizon, including posaconazole (a new triazole) and new echinocandins. [101, 102] Posaconazole (Noxafil) was recently approved by the US Food and Drug Administration (FDA) for use in children aged 13 years and older and adults for prophylaxis of invasive Aspergillus and Candida infections who are at high risk because of severe immunosuppression. The dosage information and safety of posaconazole in younger children has not yet been studied. [103]

In two recent randomized controlled trials, prophylactic posaconazole was compared to (1) fluconazole and itraconazole in patients receiving chemotherapy for AML and myelodysplastic syndrome and to (2) fluconazole in patients with severe GVHD who have undergone allogeneic BMT. [104, 105] Patients with AML and myelodysplastic syndrome who received posaconazole were found to have a significantly reduced incidence of invasive fungal infection (2% vs 7%, P < 0.001) compared to those receiving fluconazole or itraconazole. [104] Invasive aspergillosis was also observed less frequently in patients receiving posaconazole (1% vs 7%, P < 0.001). [104] In addition, mortality rates were lower in the posaconazole group than in the itraconazole or fluconazole group (P =0.04). [104]

In patients who developed severe GVHD after undergoing allogeneic transplantation, posaconazole therapy and fluconazole therapy were associated with similar rates of invasive fungal infections (5.3% vs 9%, P =0.07). [105] However, patients receiving posaconazole developed fewer proven or probable cases of aspergillosis than those receiving fluconazole (2.3% vs 7%, P =0.006). [105] The overall mortality rate was similar in the two groups, but deaths attributable to invasive fungal infections were less common in the posaconazole group (1% vs 4%, P =0.046). [105]

Viral infections

Reactivation of HSV infection can occur at any time following transplantation. The use of prophylactic acyclovir has been shown to be very effective at reducing the rate of HSV reactivation from 80% to less than 5% in HSV seropositive recipients. [21] 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 engraftment has occurred. [3]

Acyclovir (5-10 mg/kg IV q8h for 7-14 d) is also the treatment of choice when HSV infection does develop. [106] When patients do not respond to acyclovir, foscarnet (80-120 mg/kg/d IV divided q8-12h) is used until infection resolves. [106] 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 has profoundly decreased severe CMV disease. The highest risk for disease is in recipients who are CMV negative and who received transplantation from a donor who is CMV positive. The group at next highest risk is 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). [3, 4] One approach is to administer prophylaxis with ganciclovir to every patient at risk for CMV disease. (Administer ganciclovir by loading with 5 mg/kg IV q12h for 1 wk; then, administer 5 mg/kg IV once daily for 5 d per week from time of engraftment to 100 d after BMT. [3] ) The prophylactic approach has been shown to be very effective in patients who are CMV seropositive (29% reactivation in placebo arm vs 0% in ganciclovir arm, P < 0.001). [107]

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 (pp 65) or by PCR. [3] Because of the side effects of prophylactic medication and good tests on which to base early preemptive therapy, the preference at most transplant centers is to use this preemptive approach.

Weekly surveillance is performed in patients who are CMV seropositive or in those who are CMV seronegative and receiving a BMT from a donor who is CMV seropositive. The trend in CMV diagnostics is toward CMV PCR viral load over the antigenemia assay. PCR yields better quantitation, less assay variability, and increased sensitivity (has potential to prevent disease that is currently missed). [108, 109, 110] Once CMV is detected (≥5 cells per slide or ≥2 consecutively positive PCR test results), early preemptive therapy with ganciclovir is initiated: 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. [3]

Oral ganciclovir (ie, the prodrug valganciclovir [Valcyte]) is not currently recommended. Valganciclovir has been used in adult patients for the maintenance phase of CMV therapy (and in preemptive therapy for solid organ transplant patients). However, not enough studies have been performed to make these recommendations in pediatric patients. [111]

A recent study in T-cell depleted allogeneic stem cell transplant recipients revealed that preemptive treatment with PO valganciclovir or IV ganciclovir led to similar reductions of CMV DNA load. [112] A good effect on CMV DNA load (reduction below 3.0 log(10) copies/mL) was observed in 75.7% of ganciclovir and 80% of valganciclovir treatment courses. [112] There were no severe adverse effects, and CMV disease did not occur. [112] However, the percentage of patients receiving RBC transfusion was higher in the group of patients receiving ganciclovir (41% vs 20%, P =0.116). [112]

CMV viremia develops at rates in autologous BMTs that are as high as with allogeneic BMTs, but much less CMV disease occurs; therefore, patients with autologous BMT are not administered prophylactic therapy. [3] However, patients with autologous BMT do need ongoing screening and early therapy upon evidence of CMV reactivation.

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. [113] Leflunomide, an immunosuppressive agent, has been used in an allogeneic BMT recipient with CMV resistant to ganciclovir, foscarnet, and cidofovir. [114]

CMV-specific immunoglobulin (CMVIG) has been used in addition to ganciclovir in recipients of allogeneic BMT who are CMV seronegative. Randomized controlled trials that examined CMV prophylaxis with CMVIG have shown conflicting evidence regarding benefit. Meta-analysis of the literature has been completed. [115, 116] The meta-analysis by Messori reviewed 5 randomized controlled trials and found a benefit in using CMVIG. 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 randomized controlled trial included patients with CMV pneumonitis, but not exclusively. [116]

A second meta-analysis, by Wittes in 1996, [115] described a very heterogenous group of patients. Patients who have undergone BMT as well as solid organ transplants were included in the meta-analysis. Randomized controlled trials, 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. The benefit of 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). 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).

Varicella infections can occur in the late posttransplantation period. Although prophylaxis is not recommended in this period, prevention should be attempted following exposure. Varicella zoster immunoglobulin (VZIG), at a dose of 125 units (1.25 mL) per 10 kg, should be given to patients less than 24 months following BMT and to those more than 24 months after BMT who are on immunosuppressive therapy or have chronic GVHD. [3] VZIG should ideally be administered within 48-96 hours after exposure to a person with chickenpox or shingles. Patients who have undergone 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). [106]

Treatment for the respiratory viruses and adenovirus in the patient who has undergone 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. [117, 118, 119, 120, 121] However, studies have also shown that treatment with ribavirin makes no difference in infections secondary to adenovirus. [122, 123, 124, 41, 125] 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. [125, 126, 127, 128, 129]

The respiratory viruses (eg, RSV, influenza, parainfluenza, rhinovirus) do not have a standard treatment protocol. Ribavirin treatment has been attempted (15-20 mg/kg/d IV divided q8h or the inhalation form). [130] But the success of ribavirin in treating these infections has been inconsistent. [130, 131, 132, 133, 134]

In two recent studies, the addition of RSV immune globulin (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. [135, 136]

Rimantadine or amantadine has been used for prophylaxis or early preemptive therapy for influenza A infections. However, circulating influenza A viruses worldwide have rapidly developed resistance to these agents over the past several years, and these medications are no longer recommended for influenza prevention or treatment. Amantadine and rimantadine are not recommended by the CDC for the 2008-2009 influenza season because of resistance. Preliminary CDC data from the 2007-2008 influenza season showed resistance to amantadine remains high among influenza A isolates, with approximately 99% of tested influenza A (H3N2) isolates and approximately 10% of influenza A (H1N1) isolates resistant to amantadine (CDC Prevention and Control of Influenza 2008).

In a study from Brazil, influenza A and B infections were found in 39 patients (influenza A in 18, influenza B in 23, 2 with both). [137] Thirty-eight BMT patients were treated with oseltamivir, 75 mg twice a day for 5 days, (all within 48 h of symptom onset) and 3 with amantadine, 100 mg twice a day for 5 days. [137] Only two patients developed pneumonia (5.1%), and none died. [137] Oseltamivir (Tamiflu) proved to be safe and appears to have played an important role in the prevention of complications of influenza infection. [137]

The dosage of oseltamivir is weight based, as follows:

  • Less than 15 kg - 30 mg PO bid for 5 days
  • 15-23 kg - 45 mg PO bid for 5 days
  • 23-40 kg - 60 mg PO bid for 5 days
  • More than 40 kg - 75 mg PO bid for 5 days

HHV-6–associated meningoencephalitis has been treated both with ganciclovir and foscarnet. [138, 139, 140, 141, 142] Ganciclovir has also been used as prophylaxis to prevent HHV-6 disease. [143, 138] There are no randomized controlled trials to prove treatment or prophylaxis with ganciclovir is effective.

Parasitic infections

Prophylaxis against PCP should begin with engraftment and continue until 6 months after the transplantation. [3] Continued prophylaxis (>6 mo) is required in patients with chronic GVHD or patients receiving immunosuppressive therapy (eg, prednisone). [3] 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). [3]

A combination product that includes trimethoprim and sulfamethoxazole (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. [3] 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 once daily, not to exceed 100 mg/d), atovaquone, and aerosolized pentamidine (recommended dose for children < 5 y is 9 mg/kg/dose every mo; recommended dose for children >5 y is 300 mg every mo). [3]

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 in divided doses q6-8h). Second-line agents include intravenous pentamidine, intravenous trimetrexate plus oral folinic acid, oral trimethoprim plus oral dapsone, oral atovaquone, or oral primaquine plus clindamycin. [144]

Toxoplasmosis prophylaxis should be provided for allogeneic BMT recipients who are seropositive and have active GVHD or have a history of previous Toxoplasma chorioretinitis. 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. [3]

Vaccinations

Reimmunization is required for most autologous and allogeneic BMT recipients because they lose immunity to the common childhood illnesses. Immunization should occur in the first and second year posttransplantation. [21] All nonlive vaccines should be administered, and boosters for diphtheria and tetanus toxoid should continue every 10 years. [21, 3, 2] Patients should receive lifelong seasonal influenza vaccinations. [3] Live virus vaccines, such as measles, mumps, and rubella (MMR), should not be administered until at least two years following transplantation, and the patient should no longer have active GVHD and should not be on immunosuppressive therapy. [2, 3]

A study in 15 children receiving a single dose of Varilrix (varicella vaccine) 12-23 months after BMT revealed antibody responses (measured using IFA) of 65% at 6 weeks, 90% at 6-12 months, and 65% at 24 months after vaccination. [145] Adverse effects were minimal. [145] Therefore, some centers are recommending varicella vaccination 24 months after BMT unless there is need for chronic immunosuppressive therapy. [146]

Routine yearly vaccination with influenza vaccine is recommended in all transplant recipients. Although serological conversion rates are lower in transplant recipients than in healthy controls, patients who receive influenza vaccine 6 months or more after BMT are at a lower risk of developing virologically confirmed influenza. [147]

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Outcome

In 1993, approximately 15,000 autologous and allogeneic bone marrow transplantations (BMTs) were performed worldwide; in 1998, approximately 20,000 BMTs were performed in North America alone, with approximately 20% of them occurring in children. [1, 3, 5] 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. [1]

Infection remains a major cause of mortality in patients who undergo 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 a bone marrow recipient, the mortality rate is high. Pathogens that are benign in an immunocompetent host can lead to significant mortality in these patients.

A recent study out of Switzerland examined the mortality rate in patients after allogeneic BMT for early leukemias. [148] They analyzed transplant-related mortality in 4 time cohorts: 1980-1989, 1990-1994, 1995-1998, and 1999-2001. [148] They found that the survival rate increased from 52% at 5 years in 1980-1989 to 62% in 1995-1998 (P < 0.05). [148] Transplant-related mortality rates decreased from 36% to 26% (P < 0.05) owing to a reduction in infection-related deaths (P < 0.001). [148] Mortality due to graft versus host disease (GVHD), relapse, or other causes did not improve over the time cohorts. [148]

Aspergillus infection, which is generally benign in the immunocompetent host, carries a mortality rate of close to 100% in BMT recipients. [29] Adenovirus, which generally causes a mild self-limited illness in the immunocompetent host, can lead to a mortality rate of 18%-60%. [38] Appropriate management of infectious diseases in this population involves understanding transplantation techniques, clinical syndromes, the stages of immunosuppression, the natural history of certain infections, immune system reconstitution, early empiric therapy, and different antimicrobial agents.

Patients who have survived long-term generally have good health, stressing the importance of prevention and management of infectious diseases. In a survey of 798 patients who underwent BMT before 1985 and had survived more than 5 years, 93% were in good health and 89% had returned to work or school full time. [3, 149]

A study examined the neuropsychological and adaptive functioning of 76 children who had undergone BMT for an extracranial tumor without previous cranial irradiation. [150] Patients were observed and evaluated at least 5 years after the end of treatment. Overall, their performance and skills were in the normal range and their professional and academic outcomes were satisfactory. [150] However, deafness associated with the previous administration of cisplatin led to negative effects on verbal intelligence quotient (IQ). [150] Reading difficulties had arisen, possibly related to absence from school during hospitalization. [150] In the younger subgroup (< 3 y), visual-perceptual skills were found to be more affected than in older patients (>3 y). [150]

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