Patients who undergo hematopoietic stem cell transplantation (HSCT) are at risk for developing bacterial, fungal, viral, and/or parasitic infections, particularly those who receive allogeneic transplants. Infections in these patients are associated with high rates of morbidity and mortality; therefore preventative strategies are of outmost importance.
For the purpose of this chapter, the term HSCT includes receipt of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (allogeneic or autologous) or cell source (bone marrow, peripheral blood, or umbilical cord blood). However, the risk of infection between types of HSCT differs depending on factors such as the patient’s net immunosuppression, the presence of tissue or organ damage, and the rate of immune reconstitution after transplant. Reconstitution is typically faster in autologous HSCT recipients than in allogeneic HSCT recipients and differs between the different types of allogeneic transplant. The differential impact on and recovery of the immune system by HSCT type is discussed in detail in Chapter 2 .
Infections during the course of HSCT may be derived from the patient’s microbial flora, a reactivation of a latent infection from either the recipient or donor, or from primary infection. Three periods of risk for infections in HSCT recipients have been traditionally described based on the time since transplantation. The three periods are pre-engraftment (from transplantation to neutrophil recovery, approximately day 20 to 30), early postengraftment (from engraftment to day 100), and late post engraftment (after day 100). During each of these periods, patients are at risk of developing bacterial, fungal, viral, and/or parasitic infections. Allogeneic HSCT recipients are considered to be at high risk for infection during all three periods (see Fig. 2.1 ), whereas autologous HSCT recipients are most vulnerable during the pre-engraftment and immediate postengraftment periods.
Measures to prevent infections during HSCT include determination of recipient risk, appropriate selection of donors, infection control measures, and targeted prophylactic and preemptive therapy. This chapter provides a general overview of infection risk and prevention in pediatric HSCT recipients, including guidance for a comprehensive infectious disease pretransplant evaluation. Specific infection control measures are addressed in Chapter 12 , and prophylactic and pre-emptive approaches are addressed in pathogen-specific chapters (see Chapter 14, Chapter 15, Chapter 16, Chapter 17, Chapter 18, Chapter 19, Chapter 20, Chapter 21, Chapter 22, Chapter 23, Chapter 24, Chapter 25, Chapter 26, Chapter 27, Chapter 28, Chapter 29, Chapter 30, Chapter 31, Chapter 32, Chapter 33, Chapter 34 .
Pretransplant evaluation
The pretransplant infectious disease consultation is an important component of infection prevention in HSCT recipients. The goal is to evaluate the donor and recipient for acute infections, relevant exposures, latent infections, and colonization with resistant organisms. The assessment should include a review of the history and laboratory results of both the donor and the recipient. The history should be accompanied by a detailed physical examination and comprehensive imaging of the recipient. Documentation of this information in a detailed pretransplant evaluation note can prove to be a valuable guide should concerns about infection in the posttransplant period develop.
Recipient evaluation
History.
Areas of focus for history taking in the recipient and donor are presented in Box 6.1 . A primary goal of this clinical encounter is to elicit any symptoms that may be concerning for the presence of an active infection or recent exposure to an infectious disease that could preclude proceeding to transplantation in the recipient. An equally important goal is to review the recipient’s medical history, social history, and laboratory results from both the recipient and donor to identify gaps in prior preventative measures (i.e., incomplete vaccination), document concomitant comorbidities, identify the presence of latent viruses or colonizing resistant organisms, and document possible social behaviors that may place the patient at risk for future infection.
Evaluation
Donor and recipient
Evidence of active infection
Infectious disease exposures (including tuberculosis, animals, foods)
History of transfusions
Travel history or residence in areas of the world with endemic infections
Vaccination history
Social history including sexual history, illicit drug use
Recipient
Type and intensity of previous chemotherapy and/or radiotherapy
Status of the underlying cancer (first or second remission, relapse)
Infectious complications during cancer therapy (bacterial, fungal, viral, others)
Colonization or infection with resistant organisms
Dental history
Structural abnormalities (cardiac defects, prosthetic biomaterials, hemodialysis access fistula)
Evidence of recent or current infection, including upper respiratory tract or gastrointestinal viruses infections
Documentation of all current foreign bodies
Transplant information.
Details regarding the type of graft, conditioning regimen, and plans for graft versus host disease (GVHD) prophylaxis are important for understanding the risk of infections in HSCT candidates. Clear documentation of these elements in the pretransplant evaluation makes them easily available if complications arise during the course of transplant.
The type of graft and number of stem cells to be infused should be noted as each of these factors may affect the time to recovery of the immune system after transplant, which will alter infection risk. For example, recovery of neutrophils after an umbilical cord transplantation takes significantly longer compared with receipt of a peripheral stem cell product. Additionally, manipulation of the graft product can also alter infection risk. T-cell–depleted grafts can help reduce the risk of GVHD but will also delay complete immune reconstitution of T-cell function, which can increase the risk for viral or fungal infection in the postengraftment periods. T-cell depletion can be achieved by ex vivo manipulation of the graft product or in vivo administration of a lymphocyte depleting agent such as anti-thymocyte globulin at the transplant. The latter is referred to as serotherapy. Discussions of these graft-specific features with the primary transplant team and the family before transplant can help frame the risk for infection and guide decisions for prophylaxis approaches.
Conditioning regimens include myeloablative conditioning, reduced intensity conditioning, or nonmyeloablative regimens. The risk for toxicity increases with the intensity of the regimen. Myeloablative conditioning regimens are associated with profound immunosuppression and increased risk of mucositis that will predispose a child to bloodstream infections. Radiation-containing regimens increase the likelihood of mucosal and skin breakdown in the recipient. GVHD prophylaxis in HSCT is usually achieved using calcineurin inhibitor–based therapy (i.e., cyclosporine, tacrolimus), sometimes in combination with mycophenolate mofetil. The use of these immunosuppressant therapies increases the risk of infections and has been associated particularly with viral and fungal infections. Use of posttransplant cyclophosphamide for prevention of GVHD may also delay engraftment and count recovery.
When documenting the planned conditioning and GVHD prophylaxis regimens, attention should be given to the possibility of drug-drug interactions with anti-infective agents that might be used in prophylaxis or preemptive strategies. For example, the triazole antifungal class is often leveraged in prophylaxis pathways, but these agents can have significant interactions with many other drug classes, some of which might be used for conditioning or GHVD prevention. Therefore it is important to discuss these details with the transplant team in advance of the transplant.
Physical examination.
The recipient should undergo a complete physical examination, with an emphasis on sites that could become infected or serve as an entry for infection. These include the oral cavity, perirectal region, skin, central venous catheter sites and any foreign bodies, and the upper and lower respiratory tracts. Any signs of active infection should be noted followed by appropriate workup and management. Additionally, these signs of infection should be discussed immediately with the transplant team as they may preclude the ability to move forward with conditioning.
Pathogen-specific testing.
Laboratory testing for evidence of past infectious exposures is performed to detect asymptomatic persistence of certain pathogens in the HSCT candidate and the donor. Some tests are recommended for all HSCT donors and candidates, whereas others depend on epidemiologic risk factors ( Table 6.1 ). Serologic tests are typically used to investigate past exposures for a multitude of pathogens; however, in some cases, screening using polymerase chain reaction (PCR) assays is indicated (i.e., human immunodeficiency virus (HIV) and hepatitis C virus [HCV]). When relying on serology results to determine past pathogen exposures, the clinician must be aware of the possibility for false-positive detection secondary to passive receipt of antibodies (e.g., young infants, recent receipt of immunoglobulin or packed red blood cells). Alternatively, false-negative serology results may be present in patients with an underlying primary immunodeficiency disorder or those who are secondarily immunosuppressed. In these clinical scenarios, a greater reliance on PCR diagnostics may be necessary but does not always allow for the establishment of latent pathogen presence.
| Pathogen | Laboratory Test | Donor | Recipient | Notes |
|---|---|---|---|---|
| CMV | CMV IgG or CMV total Ab, CMV PCR | Yes | Yes | CMV PCR in recipient |
| EBV | EBV VCA IgM and IgG Ab, EBNA, EBV PCR | Yes | Yes | EBV PCR in recipient |
| HBV | HBsAg, HBs Ab, HBc Ab, HBV NAT | Yes | Yes | |
| HCV | HCV AB, HCV NAT | Yes | Yes | |
| HIV | HIV-1/2 Antigen and Abs assay, HIV NAT | Yes | Yes | |
| HSV 1/2 | HSV1 AB, HSV2 Ab | N | Y | |
| HTLV-1/-2 | HTLV-1/2 Ab | Yes | Yes | |
| VZV | VZV IgG | Yes | Yes | |
| WNV | WNV serology, WNV NAT | Yes | Yes | |
| Syphilis | RPR or syphilis Ab | Yes | Yes | |
| Toxoplasma | Toxoplasma serology, PCR | Yes | Yes | |
| Additional Screening Depending on Exposure History or Local Epidemiology | ||||
| Respiratory viruses | Respiratory virus PCR | No | Yes | |
| Chagas | Trypanosoma cruzi Ab | Yes | Yes | |
| Histoplasma | Histoplasma serology, antigens | No | Yes | |
| Blastomyces | Blastomyces Abs | No | Yes | |
| Coccidioides | Coccidioides Abs | No | Yes | |
| Malaria | Malaria screen, blood smear, PCR | Yes | Yes | |
| Strongyloides | S. stercolaris Abs | Yes | Yes | |
| Tuberculosis | Risk factor assessment, TST, IGRA | Yes | Yes | |
| Zika virus | Risk factor assessment, Zika PCR | Yes | Yes | |
| Ova and parasites | Stool test | No | Yes | |
| Additional Screening by Some Institutions | ||||
| Surveillance cultures | Perianal swab, nasal swab | No | Yes | For infection control purposes |
| Adenovirus | Blood and stool PCR | No | Yes | Active disease and risk of dissemination |
Imaging.
Although most HSCT recipients undergo pretransplant imaging, there are no defined standard of care protocols for imaging. Some institutions request imaging of the chest, abdomen, and sinuses for all recipients before transplant; others take a targeted approach based on past infectious history (i.e., fungal infection or pneumonia) and the site of infection. Recipients undergoing autologous or allogeneic HSCT for lymphomas or solid tumors routinely undergo chest and abdominal computed tomography (CT) imaging as part of their disease evaluation. Observational studies suggest that pre-HSCT routine CT imaging of the abdomen may not be warranted in other recipients who are asymptomatic and without previous infectious findings. , CT imaging of the sinuses is not routinely recommended as pre-HSCT radiographic findings have not been found to correlate with subsequent development of clinical sinusitis after transplant. Based on these data and to spare patients from unnecessary radiation, the decision to perform CT imaging should be based on a careful risk assessment, history, and physical examination.
Additional evaluations.
Consultation with other specialists may help detect or prevent infections in the recipient. Dental evaluation should be considered for all HSCT candidates to evaluate their oral health and perform any necessary dental procedures to decrease the incidence of oral mucosa–borne infections during periods of mucositis. Otolaryngologic evaluation should be considered in symptomatic patients or those with a history of sinusitis. A direct scope may detect existing infections or anatomic features that may increase risk for infections and identify patients who may need closer follow-up during their transplant course.
Donor evaluation
History.
Similar to history attainment for the recipient, the goal of the history obtained from the donor is to identify active infection or prior infectious disease exposures that would make the donor ineligible or pose a risk of infection transmission to the recipient. Many of the historical data to be captured for the donor are similar to those collected for the recipient (see Box 6.1 ). A standard approach to capturing this information is important so that no pertinent information is missed. A standardized checklist has been developed by an American Association of Blood Banks (AABB) task force and complies with all regulatory requirements. The checklist is available at the AABB website ( http://www.aabb.org/tm/questionnaires/Pages/default.aspx ) and can be used as a guide for collecting this information. Generally, the donor assessment should identify social risk factors (e.g., intravenous drug use, prior blood transfusions, pregnancies, abortions, and tattoos), document immunization history, and prior travel. Often the donor is not always available for interview by the clinical team; however, clinicians should familiarize themselves with the AABB donor screening tool to know which historical elements need to be assessed from the donors.
Pathogen-specific testing.
Requirements from the U.S. Food and Drug Administration (FDA), state, and other regulatory bodies for donor screening are frequently updated. In the United States, unrelated donors are required to comply with guidelines from the U.S. Food and Drug Administration, The Joint Commission, the AABB, the National Marrow Donor Program, and the Foundation for the Accreditation of Cellular Therapy. Some tests are required of all donors and some depend on exposure history (see Table 6.1 ). As in recipients, most are serologic tests to investigate past exposures, but PCR is used as indicated. Donor screening should be performed within 6 months before stem cell donation. Specimens for laboratory testing of peripheral blood stem cells or bone marrow should be obtained up to 30 days before donation and within 7 days for testing of lymphocyte or umbilical cord blood donation. For umbilical cord blood donation, mothers are screened for Hepatitis B virus (HBV), human immunodeficiency virus (HIV), syphilis, human T-lymphocyte virus (HTLV)-1/2, cytomegalovirus (CMV), West Nile virus, and Chagas disease.
Close attention should be paid to donor serology results, particularly CMV, Epstein-Barr virus (EBV), HBV, HCV, and Toxoplasma gondii as these results may lead to prevention and management strategies as discussed in the sections Prevention of Viral Infections and Prevention of Other Infections.
Active infections.
Donors with any evidence of an active infection should be treated for that infection with some assessment of treatment effectiveness, either by clinical examination or laboratory follow-up results, performed before product harvest. Specific examples would include donors with active tuberculosis (TB) or malaria. For the former, the donor should be treated and donation deferred until the infection is deemed to be controlled. Donors with active malaria should receive treatment and have a documented negative follow-up test result before donation. In certain circumstances, an identified suitable donor is identified but that donor retains an infection that may pose a risk to the recipient. In these circumstances, the risk of infection transmission needs to be weighed against the need to proceed with transplantation. It is possible in such scenarios that the infection risk can be reduced to optimize the balance of benefit over risk. For example, a suitable donor who is either HBV or HCV positive can be treated with antivirals to reduce the transmission risk (see the following special considerations section).
Special considerations and contraindications to donation.
Some infections in the donor are considered contraindications to stem cell donation ( Box 6.2 ). In other cases, the decision to exclude a potential donor should be made on a case-by-case basis, particularly when delaying transplant may lead to mortality.
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Management principles for patients with neutropenia
Bartonella, Legionella, Mycoplasma,and Ureaplasma
Respiratory viruses
Histoplasmosis, blastomycosis, and coccidioidomycosis
Clostridioides difficileinfection
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