Donor screening is recommended to be performed within 6 months prior to hematopoietic progenitor cell collection and should include the evaluation of ongoing infection, medical history of hepatitis, toxoplasmosis, tuberculosis (TB), and blood products transfusion.⁴ Obtaining vaccination and sexual and travel history is fundamental as well.

Recipient evaluation is similar to donor screening, but the HCT candidate should be further evaluated for history that includes the following: type and intensity of conditioning
chemotherapy and cancer status (relapse, remission), and prior documented infectious complications such as invasive aspergillosis (IA), respiratory viral infections, multi-drug-resistant bacterial, or viral infections during chemotherapy. Other risk factors such as type of immunosuppression, dental history within the last 6 months, and structural heart abnormalities or prosthetic joints also need to be assessed.

Since multiple pathogens could be transmitted by the graft, detecting previous infectious exposures is important in HCT donor and recipient.⁴ Laboratory testing should include HIV-1, HIV-2, hepatitis B, hepatitis C virus (HCV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), Toxoplasma gondii, syphilis, human T cell lymphotropic virus (HTLV)-I and HTLV-II, and West Nile virus in selected individuals with risk factors. Also, HCT candidates should be evaluated for TB, and those who have traveled or lived in certain endemic areas should be screened for Strongyloides stercoralis, Trypanosoma cruzi, Malaria, Histoplasma capsulatum, and Coccidioides species.

The infectious risk depends upon the state of immunosuppression (type, degree, and duration), exposure to pathogens and to foreign bodies (ie, central venous catheters), presence of organ damage post HCT (ie, mucositis, respiratory distress, and kidney failure), and the time elapsed since transplantation.

Host and Pretransplant Factors The risk of infection is higher in patients who are older, have high HCT comorbidity index, have iron overload, have history of prior HCT, or have history of prior infections in the donor and/or the recipient (pretransplant immunity against CMV, HSV, VZV, and/or EBV).⁵ Certain underlying diseases with prior prolonged chemotherapy agents could contribute to higher risk of infection as well,^6,7 such as an HCT candidate with multiple myeloma disease who had received extensive therapy with glucocorticoids.⁶

Transplant-Related Factors Allogeneic HCT recipients are at greater risk for all type of infections (particularly invasive fungal and herpes virus infections) compared with those receiving autologous HCT, mainly secondary to the delay in B- and T-cell immune reconstitution and the presence of unrelated or mismatched allogeneic donor grafts.⁵ Moreover, the same can be applied to graft manipulation with T-cell depletion, as HCT recipients have higher risk for graft rejection and slower cellular immunity recovery. On the other hand, intensive CRs lead to pronounced mucosal barrier injury and a prolonged neutropenic period that increases the risk for neutropenic fever and enterocolitis. Furthermore, using methotrexate as part of CR is associated with an increased incidence of mucositis and longer time to neutrophil count recovery and antithymocyte globulin, leading to additional T-cell deficiency. Methotrexate also increases the risk of invasive fungal and herpes virus infections. Another element playing a role in predisposing for opportunistic infections is the various gene polymorphisms. Examples include the role of toll-like receptor (TLR) polymorphisms in conferring a risk of IA such as TLR 4 gene polymorphisms.⁸

Environmental Factors During the pretransplant and early posttransplant periods, HCT candidates and recipients are usually hospitalized; hence, the hospital setting represents a principal potential source for infections. The source can be related to the facility and the physical environment, the care provided including treatments and equipment, and healthcare personnel (HCP), visitors, and other human interactions. Based on serial surveillance cultures and cultures from normally sterile body sites obtained over a 2-year period among patients with acute myeloid leukemia, most infections developed from the patients’ endogenous flora; however, 47% of patients became colonized with healthcare-associated microorganisms.⁹ Ultimately, 39/43 (91%) patients who developed bacteremia were colonized with the implicated microorganisms prior to developing a bloodstream infection.⁹ Hands of HCP are another potential source of microorganisms. Schimpff et al. study demonstrated that the hands of 43 out of 126 (34%) HCP caring for leukemic patients were colonized with Gram-negative microorganisms or Staphylococcus aureus.⁹ Hands can become contaminated by lotions or contaminated soaps.¹⁰ For example, 12 of 25 (48%) HCT recipients became colonized or infected (9 of 25; 36%) with Paecilomyces lilacinus after exposure to a contaminated, pharmaceutically prepared skin lotion.¹¹ HCP and other patient contacts transmit microorganisms in other ways. Contact with such infected or colonized visitors and HCP, many of whom may be asymptomatic, increases the risk of respiratory viral infections. Clearly, the season of the year the patient receives their HCT and transplant-related care would dictate the
risk of developing these infections.^12,13,14,15 Heating and air conditioning systems can aerosolize and facilitate the spread of Aspergillus conidia. Arnow et al.¹⁶ demonstrated that the mean concentration of Aspergillus fumigatus and Aspergillus flavus spores in the air correlated with the incidence of IA. When the Aspergillus concentration was 0.02 colony-forming units (CFU)/m³ of air, the incidence of invasive Aspergillus infections among high-risk patients was 0.3%.¹⁶ However, when the Aspergillus concentration rose to 1.1-2.2 CFU/m³ of air, the incidence of Aspergillus infections among high-risk patients rose to 1.2%.¹⁶ Although this study demonstrated a dose-response curve for Aspergillus levels in the air and infection, the data across multiple studies does not allow one to construct a dose-response curve and delineate a threshold above which infections increase. Thus, routine measure of Aspergillus spore levels in the air is not indicated. Multiple outbreaks of Aspergillus infection reported in the literature have illustrated the risks associated with construction and/or renovation and suboptimal maintenance, cleaning, and protection of the environment. Patients housed outside of a high-efficiency particulate air (HEPA)-filtered laminar airflow (LAF) environment are at a 10-fold higher risk for developing healthcare-associated Aspergillus infection.¹⁷

Theoretically, active infection in HCT candidates should be treated before proceeding with stem cell transplantation. However, the decision of the appropriate timing of HCT must be made on a case-by-case basis and based on the risks and benefits of the procedure as many patients have malignant underlying diseases associated with high mortality rate and require a timely HCT.⁴ Also donor selection is essential in reducing the risk of post HCT complications that increase the infectious risk including GVHD, graft failure, and delayed immune reconstitution. HCT from donors cells that are not fully histocompatible are associated with higher risks of GVHD and graft failure.^18,19 On the other hand, avoidance of excessive immunosuppression and myelosuppression when possible remains the ultimate goal post HCT.

Definitions The practices to the prevention of infection in HCT recipients encompass primary prophylaxis, secondary prophylaxis, and preemptive therapy. The timing of antimicrobial initiation should be typically started with the CR or at the time of the hematopoietic progenitor cells infusion.

Approaches for Bacterial Infection Prevention During the preengraftment period, antibacterial prophylaxis with a fluoroquinolone is preferred, particularly with levofloxacin, as this has been associated with reduction of neutropenic fever episodes, all-cause mortality, infection-related mortality among allogeneic HCT recipients, and high-risk neutropenic patients including those receiving induction chemotherapy for acute leukemia.^4,20,21,22 The antibacterial drug should target Pseudomonas aeruginosa and other Gram-negative bacilli, and in HCT recipients, levofloxacin is preferred since they are at risk for oral mucositis-related viridans group streptococcal infection.²³ The addition of antibacterial agent against Gram-positive organisms (ie, vancomycin) is not indicated.²⁴ In the setting of match-related allogeneic HCT with reduced-intensity CRs protocol, that is, associated with a shorter period of neutropenia, an antibiotic prophylaxis is not typically advocated.²⁵ However, antibacterial prophylaxis is considered on a case-by-case basis for autologous HCT recipients since the degree of mucosal damage secondary to CRs is less pronounced and associated with a shorter time to neutrophil recovery and engraftment comparing to allogeneic HCT recipients.⁴ The duration of antibacterial prophylaxis is usually the period of expected neutropenia. However, patient who have received allogeneic HCT and developed GVHD are at higher risk for encapsulated bacterial infection, particularly Streptococcus pneumoniae, and HCT recipients should receive prolonged antibacterial prophylaxis.⁴ Antibacterial agents active against encapsulated bacteria are penicillin, levofloxacin, and trimethoprim-sulfamethoxazole and the choice of antibiotic should be driven based on local epidemiological data.⁴ The optimal duration of antibiotic prophylaxis is not clear and should be continued as long as active GVHD immunosuppressive therapy is administered.²⁶

Approaches for Fungal Infection Prevention HCT recipients are at greater risk of invasive fungal infections (IFIs) secondary to yeasts and molds during the preengraftment period and in those with advanced GVHD. In the era prior to the routine use of antifungal prophylaxis, Candida spp. were responsible for the majority of fungal infections followed by Aspergillus spp. But more recently, Aspergillus spp. has become the main cause of IFIs in HCT recipients.²⁷ In allogeneic HCT, most IFIs are secondary to Candida spp. in the preengraftment period, whereas IA is greater in postengraftment period and mainly in patients with GVHD receiving a prolonged course of corticosteroids.^28,29,30 In allogeneic HCT patients, the incidence of IA varies between 8% and 15% compared with an incidence of 1%-2% among autologous HCT recipients.³¹ Among mold infections, mucormycosis is the second most common described fungus in HCT recipients.³²

Primary antifungal prophylaxis Practices regarding antifungal prophylaxis vary across medical centers and in part depend on the local epidemiologic data and resistance rate. A meta-analysis comparing an antimold primary prophylaxis to fluconazole primary prophylaxis in hematological malignancy or HCT recipients showed a risk reduction of IA and fungal infection-related mortality in the antimold prophylaxis group compared to fluconazole prophylaxis
group, whereas no difference in overall mortality was seen between both groups.³³

Allogeneic HCT recipients receiving myeloablative CRs with no indications for mold prophylaxis and autologous HCT recipients are at high-risk for candida infections (severe oral and/or gastrointestinal mucositis, particularly those who have received cyclophosphamide plus either busulfan or total body irradiation as part of CRs). In these patients, fluconazole 400 mg once daily is recommended.^4,22 Fluconazole is well tolerated, inexpensive, available as oral and intravenous formulations, and is associated with a smaller degree of drug interactions; however, it has several downsides, including narrow activity against Candida spp. compared to echinocandins, multiple cases of fluconazoleresistant Candida species breakthrough infections that have been reported, and lack of antimold activity. Therefore, other agents are considered appropriate alternatives, including echinocandins (caspofungin, anidulafungin, and micafungin), itraconazole (many drug-drug interactions and poorly tolerated), voriconazole, and posaconazole.²²

An antimold prophylaxis is indicated, ideally with voriconazole 200 mg twice daily, in the following patients: allogeneic HCT recipients with an underlying acute myelogenous leukemia, allogeneic HCT recipients with GVHD requiring prolonged corticosteroids at a dose of 1 mg/kg or greater for longer than 3 weeks, those who have undergone HCT but have a prolonged neutropenia prior to stem cell infusion such as patients with aplastic anemia, patients anticipated to have a slow engraftment period >28 days, or those with graft failure.^34,35 If voriconazole cannot be given, posaconazole is an appropriate alternative followed by isavuconazole. Lipid formulations of amphotericin B have been studied for antimold prophylaxis with conflicting efficacy results.³⁶

Secondary antifungal prophylaxis Prior history of mold infection was previously considered a contraindication for HCT due to the high-risk of infectious-related complications. However, secondary prophylaxis (either continuation or reinitiation of antifungal therapy) can prevent fungal infection reactivation and allow for bone marrow transplantation.^23,37,38 The choice of antifungal agents is similar to the above (section of primary antifungal prophylaxis), but voriconazole is considered the front line antimold therapy.

Approaches for Viral Infection Prevention Viral infection in HCT recipients is associated with a high rate of morbidity and mortality, and therefore, an antiviral prophylaxis or preemptive therapy is advocated. The viruses of concern in HCT recipients include herpesviruses (cytomegalovirus [CMV], herpes simplex virus [HSV], varicella-zoster virus [VZV], Epstein-Barr virus [EBV], and human herpes virus 6 [HHV6]), respiratory viruses (influenza, respiratory syncytial virus [RSV], metapneumovirus, parainfluenza, and adenovirus), and hepatitis viruses (Hepatitis B virus [HBV], HCV).⁴

Cytomegalovirus Although CMV reactivation could occur in autologous HCT recipients, the risk is remarkably more significant in allogeneic HCT patients. The CMV serostatus of donor and recipient impact on CMV reactivation risk following HCT, with the lowest risk of post-HCT CMV reactivation in CMV-seronegative recipients receiving a progenitor stem cells from a CMV-seronegative donors (CMV D-/R-).

CMV-seropositive recipients are at higher risk of post-HCT CMV reactivation, particularly if the grafts were received from CMV-seronegative donors (CMV D-/R+), in light of the absence of donor memory T-cells against CMV.³⁹ Ideally, prevention of post-HCT CMV reactivation relies on the selection of a CMV-seronegative donor for CMV-seronegative recipients when feasible and also transfusing blood products obtained from CMV-seronegative donors.⁴ Therefore, CMV-seropositive HCT recipients should be followed closely for CMV reactivation and should be given CMV therapy prophylactically (primary or secondary) or preemptively.

PREEMPTIVE THERAPY Most transplant centers prefer a preemptive rather than a prophylactic approach to reduce antiviral drugs toxicity and consider treating only those who develop CMV viremia based on serial CMV PCR testing in the whole blood or plasma.⁴ The frequency and duration of CMV monitoring depends on the risk of CMV reactivation (eg, allogeneic HCT vs autologous HCT). In addition, the timing of preemptive therapy initiation is not well defined and depends mainly on the patient risk group with a threshold of CMV viral load ≥500 (high risk) or ≥1000 copies/mL (low risk).⁴⁰ As antiviral therapy (induction initially then maintenance therapy if CMV remains detectable at 2 weeks), one of the following agents may be considered: ganciclovir, valganciclovir, or foscarnet.⁴ There are no studies supporting the use of letermovir in HCT recipient as preemptive therapy; however, in renal transplant recipients, letermovir has shown promising results.⁴¹

PRIMARY PROPHYLAXIS Several antiviral agents have been frequently used for CMV prophylaxis including ganciclovir (most effective and commonly used), valganciclovir, letermovir, foscarnet, and to a lesser extent high-dose acyclovir and valacyclovir.⁴ Interestingly, letermovir has gained an essential role in prevention of CMV infection in recipients of allogeneic hematopoietic cell transplants, since it provides a potent anti-CMV activity with a novel mechanism of action and an acceptable safety profile.⁴² Other investigational drugs have been studied in HCT recipients including brincidofovir and maribavir.^43,44 Allogeneic HCT recipients who are at greater risk for CMV disease may benefit from CMV prophylaxis in early post engraftment period. However, there are no guidelines to favor preemptive vs prophylactic approach, and decisions should be made on a case-by-case basis.⁴ Given the close monitoring of CMV PCR and the prophylactic and preemptive approaches, the majority of CMV disease arises during the late post engraftment phase (more than 100 days post HCT).⁴⁵ However, at present, no routine prophylaxis during this period is advocated. Nevertheless, CMV PCR monitoring is warranted in high-risk HCT patients.

SECONDARY PROPHYLAXIS HCT recipients with history of CMV end-organ disease (such as pneumonitis, retinitis, gastrointestinal disease) over the last 6 months prior to HCT are at increased risk for CMV reactivation following stem cell transplantation.⁴⁶ Therefore, those patients should receive anti-CMV therapy as secondary prophylaxis after completion of treatment for CMV disease. Routine practices for secondary prophylaxis consist of initiation of ganciclovir IV before HCT and then switching to one of the following agents: foscarnet, letermovir (not well studied in secondary prophylaxis), or high-dose valacyclovir during the preengraftment period in attempt to reduce the myelosuppression induced by ganciclovir and valganciclovir.

Herpes simplex virus As standard of care, all HCT candidates should be tested for serum anti-HSV-1 and HSV-2 immunoglobulin G (IgG) prior to stem cell transplantation.⁴ All HCT candidates who are seropositive for either HSV-1 and/or HSV-2 should be offered an antiviral prophylaxis during the early post-transplant period to prevent HSV reactivation.⁴ The choice of HSV prophylaxis is one of the following antiviral agents: acyclovir IV 5 mg/kg IV every 12 hours or oral acyclovir (400 or 800 mg twice daily), or valacyclovir 500 mg twice daily. HSV prophylaxis should be given from the time of CR initiation until engraftment or until mucositis resolves, whichever is longer. Nevertheless, longer course of HSV prophylaxis is indicated in case of a history of recurrent HSV infection or in VZV-seropositive HCT patients. Of interest, anti-HSV prophylaxis should be held if patients are receiving anti-CMV therapy with ganciclovir, valganciclovir, or foscarnet, except letermovir, because these agents are active against HSV infection.

Varicella-zoster virus VZV infection can lead to multiple diseases in immunocompromised patients and is mainly secondary to reactivation of endogenous virus in seropositive HCT recipients. HCT patients remain at risk for VZV reactivation for at least 1 year following stem cell transplantation, and this period may extend longer in those receiving immunosuppressant agents, including corticosteroids.⁴⁷ Therefore, antiviral prophylaxis is indicated, and the main antiviral agents used are the following: valacyclovir 500 mg twice daily or acyclovir 800 mg twice daily for at least 1 year following autologous and allogeneic HCT, or longer if patients are receiving corticosteroids for GVHD, alemtuzumab, or other T cell-suppressive chemotherapy.⁴ In the case that HCT recipients are exposed to VZV through contact with contagious, infected patients, a VZV post exposure prophylaxis is advocated. For VZV-seronegative HCT patients and also VZVseropositive HCT recipients (highly immunosuppressed), a varicella-zoster immune globulin (VariZIG) should be offered within 10 days of exposure.^4,48 If this is not available, patients should receive valacyclovir 1 g three times daily for at least 3 weeks duration following VZV exposure.⁴

Human herpes virus 6 HHV-6 reactivation is associated with several syndromes following allogeneic HCT including graft failure, myelosuppression, and encephalitis, which are mainly secondary to HHV-6B. HHV-6 reactivation with end organ disease is associated with high morbidity and mortality rates. However, there is no indication for routine screening for HHV-6 post HCT or for any prophylactic or preemptive therapy in any context, as HHV-6 reactivation often coincides with the onset of disease.^49,50 Similarly, a prospective multicenter study showed no difference in the development of HHV-6 encephalitis at 60 days posttransplant in HCT recipients receiving prophylactic foscarnet compared with historical control group.⁵¹