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Infections After Hematopoietic Stem Cell Transplantation

Sections Infections After Hematopoietic Stem Cell Transplantation
Overview
Risk Factors for Infection
Assessment of Infection Risk in Donor and Recipient
Transplantation Risk Periods
Prophylaxis and Treatment
Outcome
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References

Overview

Hematopoietic stem cell transplantation (HSCT) results in the alteration of several components of the immune system. Transplantation can result in granulocytopenia as well as impairment of barrier defenses, cell-mediated immunity, and humoral immunity. These changes lead to profound immunocompromise. Microorganisms (even those with limited pathogenicity) can cause infection more easily, and the infections that occur are more likely to be invasive or severe.

Patients who undergo HSCT experience a sequential suppression of host defenses, resulting in varying infectious risk at different phases of the transplantation process. Risks of infection also vary with the type of transplant, the indication for transplantation, and other host factors.^{[1, 2, 3, 4]}

The transplant procedure requires the harvesting of hematopoietic stem cells from a donor. The stem cell source may be bone marrow, peripheral blood, or umbilical cord blood. In autologous transplantation, the donor and recipient is the same individual. When the donor is someone other than the recipient, the procedure is described as allogeneic transplantation.

Autologous transplantation is feasible when the patient's bone marrow is normal and there are no relevant genetic conditions.^{[5, 6]} Allogeneic transplants are required to treat patients who have depleted or abnormal bone marrow. Allogeneic transplantation is also used for the management of certain genetic abnormalities.^{[7, 6, 8, 9]}

Donors for allogeneic transplants may be related or unrelated to the recipient. In syngeneic transplants, the donor is the identical twin of the recipient.

Allogeneic transplants are further categorized by the degree of human leukocyte antigen (HLA) match between the donor and recipient. The three main categories of allogeneic transplantation are HLA identical, HLA mismatched, and haploidentical. In haploidentical matches, there is one identical HLA haplotype and mismatches for a variable number of HLA genes on the unshared haplotype.

The greater the mismatch between donor and recipient, the higher the risk of graft versus host disease (GVHD). In GVHD, the donated stem cells view the recipient cells as foreign and attack recipient cells. Transplants from HLA–matched siblings are associated with a lower risk of GVHD and faster recovery of the recipient’s immune system following transplantation.^{[1, 3, 5]}

GVHD has been reported after syngeneic and autologous transplantation but is rare.^{[10, 11]}Importantly, GVHD increases the risk of infection, particularly during the first few months after HSCT. Risk of all types of infections is elevated, but there is a particularly clear association with increased risks of cytomegalovirus (CMV), fungal, and pneumococcal infections.^{[12, 13, 14]}

In preparation for receipt of the stem cells, recipients undergo myeloablation to eliminate their own myeloid cells. Myeloablation is accomplished by high-dose chemotherapy with or without irradiation.^{[1, 3]}

The harvested stem cells are processed before infusion into the recipient. This processing consists primarily of testing for infectious agents and determination of cell count but may include additional modifications or evaluations.^{[1, 3, 9, 15]} The donor graft may be depleted of T lymphocytes, which are the main effectors of GVHD. However, T-cell depletion is associated with higher rates of graft rejection and increased vulnerability to viral and fungal infections while the T-cell population is diminished.^{[8, 16]}

Although outcomes after HSCT have improved markedly since transplants were first utilized, infection remains an important source of morbidity. Infection is a leading cause of non-recurrence–related mortality^{[17, 18]}One study reported a 30-year cumulative incidence of infection of approximately 10.7%. In a single-center review of first matched-allogeneic HSCT in 1131 recipients transplanted between 2013–2017, CMV disease occurred in 4%, gram-negative bacteremia in 7%, invasive mold infection in 4%, and invasive Candida infection in 1%.^[18]

This article focuses on the common infections in patients who have undergone HSCT, the risk factors for these infections, and the approaches to their prevention and treatment.

Risk Factors for Infection

Certain risk factors place patients undergoing HSCT at increased risk for infections. These include the following^{[8, 14, 1, 3, 12]}:

Host factors
Type of transplant (allogeneic vs autologous) and degree of HLA mismatch
Stem cell source (peripheral blood vs bone marrow vs umbilical cord blood)
Immunosuppressive regimen
T-cell depletion

The baseline medical status of the HSCT recipient can influence the patient's susceptibility to infection. Underlying medical diagnoses, previous immune status, prior colonization, prior infections, and medications all contribute to the recipient's baseline infectious risk.^{[1, 3]}

In addition, certain genetic polymorphisms in the donor or the recipient may affect susceptibility to infections. For example, the risk of invasive aspergillosis after HSCT may be increased in recipients whose donors have haplotypes S3 or S4 of TLR4, the gene that encodes the toll-like receptor protein 4 (TLR4).^[19] In contrast, certain genotypes of activated killer immunoglobulin-like receptors (aKIR) in the donor have been found to protect from CMV reactivation.^{[20, 21, 12]}Recipients with mutations or polymorphisms in MBL2 (the gene that encodes mannose-binding lectin [MBL]) that result in low serum levels of MBL may be at increased risk of viral infections and mortality in the first 6 months after transplantation.^[20]

The risk of infection is higher in patients with malignant conditions than in those with nonmalignant conditions because of the immunosuppression associated with malignancy. Patients who are undergoing transplantation for immunodeficiency or other medical conditions should be evaluated to determine baseline immune status before myeloablation, as immune status is critical to infection risk. Patients who have undergone prior transplantation procedures have a higher risk of infection than persons undergoing first transplants. Older patients and patients with a history of resistant infections are also expected to be at higher risk of infection.^[22]

A risk assessment should be performed for specific infections. 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. The risk of reactivation of these viruses is elevated in HSCT recipients. Caregivers and close contacts should be immunized and should avoid contact with the stem cell recipient if they have any sign or symptom suggestive of infection.^[22]

Previous colonization with organisms such as bacteria and Candida species is a risk factor for developing bacteremia or candidemia when mucosal barriers become compromised.^{[22, 12]}Latent infections, such as tuberculosis, can reactivate during immunosuppression. Medications, including corticosteroids, that produce immunosuppression will also increase the risk of infection.

Central venous access catheters are a portal for bloodstream and catheter site infections. The type of catheter, location of the catheter, history of catheter infection, and management of the central venous line may contribute to increased risk for infection.^{[23, 24, 25]}

The risk of infection is greater after allogeneic transplantation than after autologous transplantation. The increased risk of infection after allogeneic transplantation is multifactorial, but is primarily due to later engraftment (durable resolution of severe neutropenia) and higher incidence of graft versus host disease (GVHD).^{[3, 1]}

The presence of GVHD increases the risk of infection in several ways. GVHD treatment involves immune suppression, which increases the risk of infection directly. GVHD is also associated with immune deficiency caused by defective humoral and cell-mediated immunity and functional asplenia. Furthermore, select infections are thought to be implicated in the pathogenesis of GVHD.^{[26, 13]}

Stem cell source contributes to the risk of infection. Compared with stem cells from bone marrow, peripheral blood stem cells lead to faster hematopoietic cell reconstitution, with a reduced potential for recurrence of initial disease. Peripheral blood contains more progenitor cells and lymphocytes, which may facilitate engraftment. Severe infectious complications continue to be a leading cause of morbidity and mortality in umbilical cord blood transplant recipients, at least in part due to the reduced number of hematopoietic cells in these grafts and the delayed or incomplete immune reconstitution that occurs after cord blood transplants.^[27]

The risk for acute GVHD has not been shown to differ by stem cell source. However, chronic GVHD may be more common in recipients of peripheral blood transplants.^{[26, 13]}

The transplant preparation regimen influences the risk of infection. Cytoreductive regimens are tailored to the condition being treated and to the recipient. Myeloablative regimens are intense regimens utilized to destroy abnormal cells, such as malignant cells. Total body irradiation (TBI) may be used in combination with chemotherapy to achieve myeloablation. TBI is associated with delayed neutrophil engraftment.^[28]

Patients undergoing HSCT for non-malignant conditions do not require ablative cytoreduction and typically receive less intense conditioning.^{[1, 3, 8]}

Certain specific therapeutic agents also contribute to the risk of infection. Antithymocyte globulin (ATG), which is used to reduce the risk of graft rejection or to ameliorate GVHD, causes a profound T-cell defect and increases the risk of several infections, including Epstein-Barr virus (EBV)–associated post-transplant proliferative disorders.^{[29, 30]}Methotrexate causes mucosal injury and delayed neutrophil engraftment.^[31]

Assessment of Infection Risk in Donor and Recipient

All prospective stem cell donors should be thoroughly evaluated with a complete history (including infection exposure history), physical examination, and serologic testing.^{[1, 3, 9]}The initial screening and physical examination should be performed 8 weeks or less before the planned transplantation. Serologic testing should be conducted 30 days or less beforehand. Some experts suggest that serologic testing be repeated within 7 days before transplantation. All donors should be in good general health; any acute or chronic illness in the donor must be investigated to determine the etiology.^{[1, 3, 9]}

The following should be obtained in the medical history of prospective stem cell donors to evaluate their eligibility:

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: Identify whether the donor has resided in or traveled to geographic regions (foreign or domestic) with endemic infectious disease that can be transmitted by stem cell transplantation. This includes bacterial, viral, fungal, mycobacterial, and parasitic infections (eg, Chagas disease, leishmaniasis, malaria). For assessment of risk specific to the United States, local transmission information can be obtained from state departments of health.
History of the donor's plasma or blood being denied for donation
History of viral hepatitis or of symptoms suggestive of 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-Jakob disease (CJD)

Risk factors for acquisition of a blood-borne pathogen should also be assessed. Patients at high risk for that include the following:

Men who have had or are having sex with other men
Intravenous drug users
Persons with disorders of hemostasis who have received human-derived clotting factor concentrates
Inmates of correctional centers
Individuals who have received treatment for any sexually transmitted infection in the preceding 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:

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, reverse transcription polymerase chain reaction (RT-PCR) for CMV
Syphilis serology
COVID-19 testing, using reverse transcription polymerase chain reaction (RT-PCR)

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

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 infection during HSCT. The serology results serve 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). Before harvesting, autologous HSCT recipients should also undergo serologic testing, including for the herpes group of viruses, hepatitis viruses, and HIV.

Transplantation Risk Periods

A well-recognized and predictable sequence of events occurs in recipients of HSCT 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 the classification of HSCT-related infections into the following 4 distinct stages:

Pretransplantation
Preengraftment (approximately 0-30 days post-transplantation)
Early post-engraftment (approximately 30-100 d post-transplantation)
Late post-transplantation (≥100 d post-transplantation)

Pretransplantation

Infections during the pretransplantation period are very heterogeneous. Baseline host factors contribute significantly to infectious risk during this period. Key factors are the indication for transplant, medications, compromised barrier defenses, and immune status.

Clinical signs and symptoms of infection must be evaluated thoroughly. The etiology of any suspicious finding may be infectious, noninfectious, or multifactorial.

Diarrhea evaluation should include examination for uncommon pathogens and for typhlitis if the patient is at risk of neutropenic enterocolitis.

The catheter site should be monitored for signs of infection. Any febrile episodes should be thoroughly investigated.

Infections with aerobic gram-negative bacilli, such as Klebsiella species and Escherichia coli, are seen at increased rates during this period.^[12]

Preengraftment

Engraftment is defined as the point at which the absolute neutrophil count (ANC) remains above 500/µL and the platelet count exceeds 20,000/µL, for at least 3 days. Definitions may vary slightly by the transplant center. The preengraftment phase is generally longer in allogeneic HSCT than in autologous HSCT. Infections can occur, however, in recipients of autologous transplant patients.^[4]

In the preengraftment period, the increased risk of infection is due principally to neutropenia, altered barrier defenses, and vascular access catheters.^[22]The principal sources of pathogens during this period are the patient's skin, oral, and gastrointestinal (GI) tract flora. The disruption of the normal barrier defenses allows microorganisms that normally colonize these areas to become invasive.

Different conditioning regimens are employed for different transplant indications and lead to different risks of infection.

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, which is mostly used for hematologic malignancies to achieve full cytoreduction, is associated with a higher incidence of bacteremia and herpes zoster than conditioning with chemotherapy alone.^[32]

Bacterial infections

Pulmonary infections usually occur later in the course of the transplant. As with pneumonia in the immunocompetent patient, recovery of an organism is rare (< 20%). The empiric use of broad-spectrum antibiotic therapy for febrile episodes in the patient undergoing HSCT reduces the incidence of pneumonia.^{[33, 34]}

Typhlitis is enterocolitis associated with severe neutropenia.^[35] It is characterized clinically by fever, abdominal pain, nausea, and vomiting. There are characteristic ultrasound and computed tomography (CT) scan findings. The etiology of the bowel inflammation observed in typhlitis is polymicrobial. Normal GI flora (ie, gram-negative organisms, anaerobes, Candida species) become pathogenic in the immunocompromised state. Typhlitis has a reported mortality rate of 50-100%.^[35]

The treatment and prevention of bacterial infection are discussed later in this article (see Prophylaxis and Treatment: Bacterial infections, below). 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 results in Clostridioides difficile–associated disease.^[22]

Enterocolitis caused by C difficile has significant morbidity and mortality. Prevention strategies include antimicrobial stewardship and vigilance. Some institutions utilize probiotics.

Fungal infections

Elevated risk of early invasive fungal infection (ie, occurring before day 40) has been reported in allogeneic HSCT recipients of grafts from an unrelated donor or utilizing umbilical cord blood. These patients typically have prolonged neutropenia, and have received broad-spectrum antibiotic therapy with or without corticosteroids. Fungal infection risk is also associated with the use of parenteral nutrition.

The risk of developing a fungal infection is directly proportional to the duration of neutropenia and is particularly increased after approximately 5-7 days of sustained neutropenia. Two pathogens 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. Candida infections occur in approximately 11% of patients undergoing HSCT.^[22]

Aspergillus infections occur in 4%-20% of HSCT recipients, and the incidence of these infections in this setting appears to be increasing.^{[36, 37]}These fungi are ubiquitous in the environment, but increased concentrations are found around areas of recent construction within hospitals. Aspergillus is acquired through inhalation of spores. The most common clinical syndromes associated with Aspergillus are pulmonary and sinus disease. However, in immunocompromised patients, this mold can invade the circulation and disseminate widely.

Fluconazole (400 mg daily) is the recommended choice for prophylaxis against Candida infections in HSCT recipients.^{[37, 38]}Unfortunately, fluconazole has no activity against Aspergillus. Therefore, some transplant centers use second-generation triazoles (eg, posaconazole, voriconazole) for antifungal prophylaxis, especially in patients at high risk of Aspergillus infection.^[37]

With the use of newer triazoles, pathogens of the class Zygomycetes have emerged in more transplant centers. Zygomycosis (mucormycosis) has been found at incidence rates of up to 8% in autopsied leukemia patients and 2% in allogeneic HSCT patients. This infection is acquired by inhalation, ingestion, or trauma and has a mortality of up to 80% in transplant recipients. Numerous other fungi have been reported to cause infection in HSCT recipients.

Viral infections

The virus most commonly documented during the preengraftment phase is HSV, and the usual mechanism is the reactivation of prior latent infection. A large proportion (80%) of patients who were seropositive for HSV before the transplantation develop clinical disease if prophylaxis is not provided.^[22]The most common clinical presentation in this phase (85%) is gingivostomatitis. 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 fever during the preengraftment period. VZV infections, although less common during this phase, may also reactivate.

Post-engraftment

The post-engraftment period is heralded by the resolution of the severe neutropenia that is present before engraftment and continues to day 100 after HSCT. The barrier defenses that were compromised in the prior phase, because of induction chemotherapy and radiotherapy, have begun to heal at this phase. The major determinants of immunosuppression in this period include impairment of cell-mediated and humoral immunity, as well as diminished phagocyte function.

Other important causes of impaired immunity include acute GVHD and the use of immunosuppressive agents as part of the management of GVHD episodes in allogeneic transplantation. GVHD prevents recovery of immune function and damages epithelial cells in multiple organ systems, leading to further breakdown of barrier defenses.^[39]

Bacterial infections become less frequent during the post-engraftment period, except in patients with continued central venous line access. These patients remain at risk for central line infections secondary to staphylococcal bacteria and less common pathogens.

The most important pathogens during the post-engraftment phase 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 HSCT who acquire CMV infection, 15%-20% die. CMV pneumonia is associated with a case-fatality rate of 80%-90%.

CMV disease due to infection occurs more commonly in allogeneic HSCT than in autologous HSCT. Risk factors associated with CMV disease include the following:

Recipient seropositivity
Histocompatibility differences (between donor and recipient)
T-cell depletion of the donated stem cells
Unrelated donor as graft source
Older age
Intense GVHD prophylaxis
Intense cytoreductive conditioning regimen

To prevent the development of CMV disease, transplant centers have used both prophylaxis and early empiric therapy of CMV viremia (see Prophylaxis and Treatment: Viral infections, below). The risk for acquiring CMV in seronegative patients comes not only from the transplant donor but also from transfusion of blood products and close sexual contact in adolescents in the post-engraftment phase of transplant.

Allogeneic transplant recipients with GVHD who have received therapy with high-dose corticosteroids are at risk for Aspergillus infection (late-onset aspergillosis) and Candida infections. GVHD and its treatment also place the patient at increased risk of viral infection with CMV and VZV.

With diminished cell-mediated and humoral immunity, other viral infections also occur in the post-engraftment period of transplantation. Adenovirus can lead to significant morbidity and mortality. In the immunocompromised patient, adenoviral infections result in systemic illness of increased severity and longer duration than in patients with normal immune systems. Adenovirus can cause hepatitis (with or without hepatic necrosis), pancreatitis, colitis, hemorrhagic cystitis, pneumonia, nephritis, and disseminated disease. Case reports of adenoviral meningoencephalitis have been documented. Adenoviral infection has been reported to occur in 4.9%-20.9% of patients undergoing HSCT.^[40]

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

Community-acquired respiratory viruses, such as respiratory syncytial virus (RSV), influenza, parainfluenza, and picornaviruses, can cause disease in the post-engraftment phase. In immunocompromised individuals, respiratory viruses may be nosocomially acquired, often have a prolonged course and progress to pneumonia, and are associated with a high mortality rate.^[22]Human metapneumovirus is increasingly recognized as a significant etiologic agent in patients with lower respiratory tract disease, with an associated mortality rate of up to 50%.{ref89-INVALID REFERENCE}

Respiratory virus infections were found to be a common problem (11%) in a pediatric HSCT population and were associated with substantial morbidity (28% developed pneumonia, approximately 5% had complications with croup), and mortality (9.4%). Parainfluenza type 3 was found to be the most common.^[40]Risk factors for the acquisition of respiratory viral infections depend on the type of HSCT (higher risk with allogeneic than with autologous transplantation) and the degree of GVHD present. Enteroviral infections have also been reported to occur in the post-engraftment period of transplantation.

Studies have focused on another virus in the herpes group, HHV-6. In immunocompetent persons, this infection is generally asymptomatic, but it may also be a self-limited febrile illness with roseola rash, otitis media, and other clinical manifestations. In HSCT recipients, HHV-6 infection mostly leads to asymptomatic seroconversion, but it can be associated with prolonged febrile illnesses and CNS syndromes, such as encephalitis. HHV-6 has also been linked to interstitial pneumonitis, early and late graft failure, and bone marrow suppression. Asymptomatic reactivation appears to occur commonly throughout the post-HSCT period. HHV-7, another beta-herpesvirus (related to CMV), has also been associated with febrile illness.^[41]

Hemorrhagic cystitis is a well-known complication of HSCT and is known to be caused by two viruses: adenovirus (as previously discussed) and BK virus (a polyomavirus). BK virus is an emerging pathogen in the HSCT population and can be identified by polymerase chain reaction (PCR) testing. Some studies have reported that hemorrhagic cystitis may be more likely to be associated with BK virus than with adenovirus. There is no established therapy for BK virus infection, but cidofovir has in vitro activity against polyomaviruses and has been used with success in case reports.^[42]

Parasitic infections also tend to occur during this period. Pneumocystis jirovecii pneumonia (PCP) was once 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.Toxoplasmosis has also been described in a small number of patients during this phase of transplantation.

Late post-transplantation

The late post-transplantation period is heralded by the recovery of cell-mediated and humoral immunity. This phase begins at day 100 and continues until the HSCT recipient stops all immunosuppressive medication for GVHD, which is approximately 18-36 months post-transplantation.^[22]In the absence of chronic GVHD, infection is unusual in this period.

Adequate reconstitution of the cellular and humoral immune systems occurs within 6-12 months after autologous HCT and can take 2 years or more in allogeneic HCT recipients. Reconstitution can be further delayed in patients who develop GVHD. 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. Therefore, late infections are an important cause of late morbidity and mortality in these patients.

Patients needing long-term immunosuppression for ongoing chronic GVHD are particularly at risk and are susceptible to infections by encapsulated bacteria (eg, Streptococcus pneumonia, Neisseria meningitides, Hemophilus influenzae), fungi (eg, Aspergillus spp, Candida spp, and P jiroveci) and viruses (eg, CMV, VZV), and need appropriate prophylaxis. Vaccinations should begin at 6-12 months after transplantation and should follow consensus recommendations for infection prevention in HCT recipients.^[43]

Infection in this phase is generally localized to the skin, the upper respiratory tract, and the lungs.^[22]Viral infections, especially with VZV, are responsible for more than 40% of infections during this phase, bacteria are responsible for approximately 33%, and fungi cause approximately 20%.

VZV infections in HSCT recipients are most likely to occur during the late post-transplantation period and are usually secondary to reactivation. The median time for the occurrence of VZV is 5 months after transplantation. Eighty-five percent of patients develop shingles, while approximately 15% develop chickenpox. Patients who develop chickenpox are at an increased risk of systemic dissemination (eg, leading to pneumonia), but dissemination can also occur with shingles.

Systemic fungemia is not commonly observed at this stage. However, oropharyngeal candidiasis and Aspergillus sinopulmonary and disseminated infections may occur.

A rarely described opportunistic pathogen in recipients of HSCT is Nocardia. These atypical bacteria are gram-positive aerobic actinomycetes that are found in soil and decaying organic matter. A review of 27 cases of nocardiosis in recipients of bone marrow transplantation (BMT) described isolation of the bacteria from blood, brain abscess, sputum, bronchoalveolar lavage (BAL) washings, open lung biopsy specimens, and skin (eg, catheter access sites and abscesses). Most commonly, Nocardia infection was associated with a pulmonary illness; 56% of the patients had documented abnormal findings on chest radiographs, with nodules and in some cases with pulmonary infiltrates. Median time to the diagnosis of nocardiosis was 210 days after BMT.

Prophylaxis and Treatment

The Centers for Disease Control and Prevention (CDC), Infectious Disease Society of America (IDSA), American Society of Blood and Marrow Transplantation (ASBMT), and inernational gorups have sponsored guidelines for preventing, diagnosing, or treating opportunistic infections.^{[44, 38, 45, 46, 47]}There are also guidelines for the management of individual infection types or individual microorganisms and trial reports or case series that are useful resources.^{[48, 2, 49, 12, 44, 38]}

Hospitals that perform HSCTs must have appropriately designed facilities with relevant engineering controls. It has been recommended to house immunodeficient patients in rooms with more than 12 air exchanges per hour and point-of-use high-efficiency particulate air (HEPA) filtration. The HEPA filters should be able to remove particles down to at least 0.3 µm in diameter. Laminar airflow rooms, in which air moves in one direction, have been shown to protect patients from Aspergillus and other infections during outbreaks. Rooms should have positive air pressure compared with the hallway unless it is housing a patient who has an active disease with a pathogen that has airborne transmission; in that case, a negative pressure room is recommended.

Daily bathing with chlorhexidine-impregnated washcloths decreased the risk of acquisition of multidrug-resistant organisms and the development of hospital-acquired bloodstream infections in transplant recipients in a randomized trial.^[12]

Policies and procedures should be developed to address isolation and barrier precautions. Hand washing should be strongly emphasized to reduce 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 infections. Healthcare workers should follow an appropriate policy concerning employee vaccination.

Visitor policies should be developed with attention to ongoing local, regional, and global infection and transmission patterns. Current trends should not be used exclusively, however, because changes in the epidemiology of infections are common over time. Mutations, resistance trends, and other factors should inform the development of a dynamic response to emerging or ongoing epidemics. Adherence to guidelines from national and international agencies may not be sufficient to reduce infection in populations that are at very high risk for infection. Preventive measures should exceed the minimum standards, if necessary, and should be tailored to individual hospital infection patterns and individual patient factors.

Oral and skin care should be stressed to patients throughout the HSCT process. All patients undergoing HSCT should receive a dental evaluation before the initiation of the conditioning phase of transplantation. Patients with mucositis during conditioning or post transplantation should maintain a regimen of proper oral care with frequent evaluation. Urogenital and perianal lesions should be reported and evaluated promptly, as should any sign or symptom of infection.

Strategies of safe living after discharge home are also important to discuss with HSCT recipients. This should include a discussion of the following^{[1, 3]}:

How to avoid infectious exposures from the environment
Safer sex practices
Pet safety
Food and water safety
Travel safety
Use of masks
Avoidance of infected persons
The need for vaccination

Bacterial infections

The use of prophylactic antibiotic therapy in HSCT is controversial, but regimens have been established and instituted in several cooperative groups and individual facilities.

Antimicrobial prophylaxis is associated with several adverse effects. It results in C difficile infection, resistant organisms, and drug-drug interactions. Evidence suggests that alteration of the microbiome caused by antimicrobial prophylaxis increases the risk of GVHD.

Current studies are exploring highly individualized risk assessment with tailored prophylaxis based on host factors. For suitable recipients, these regimens may include probiotic use, the use of non-absorbable antimicrobials, and fecal microbiota transplantation, in addition to pharmaceutical therapy. Risk stratification involves genetic risk assessment, medical history, demographics, and fecal microbiome analysis.^{[50, 51]}

Studies show that fluoroquinolones have been effective in preventing gram-negative bacteremia but a clear survival advantage has not been demonstrated.

For treatment of C difficile infection (initial or recurrent), the IDSA suggests using fidaxomicin, but considers vancomycin an acceptable alternative.^[44] Bezlotoxumab, a human monoclonal antibody against C difficile toxin, may be beneficial in combination with standard-of-care antibiotics.^[44]Fecal microbiota transplantation is an emerging therapy for recurrent C difficile infection that does not respond to antibiotics alone, but it has not yet received regulatory approval.^[51]

Traditional empiric coverage consists of one or more antipseudomonal agents, either alone or in combination with an antistaphylococcal antibiotic.

Trimethoprim/sulfamethoxazole (TMP/SMZ) is not recommended due to its myelosuppressive effects. Levofloxacin appears to have the most favorable profile. If levofloxacin is not feasible, ciprofloxacin is an alternative, although it has less activity than levofloxacin against gram-positive bacteria, including the viridans group streptococci. Understanding local resistance epidemiology is critical to the decision of whether to implement fluoroquinolone prophylaxis. In addition to patient factors, local and hospital infection and colonization patterns should be used to help design the prophylaxis regimen.^[45]

In the late post-transplantation period, because of the increased infection rate related to encapsulated organisms, some centers suggest the use of prophylactic penicillin. The CDC has issued guidelines on the use of the pneumococcal vaccine in children and adults with immunocompromising conditions (including iatrogenic immunosuppression).^{[52, 46]} Pneumonia is the most common late infection. A variety of pathogens are implicated. Chronic GVHD is the most commonly identified risk factor.^[12]

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 once organisms have been isolated but should remain broad due to the profound immunosuppression of transplant recipients. Treatment with empiric antibiotics usually continues until neutrophil count recovery occurs.

Fungal infections

Because antifungal prophylaxis has been widely adopted, there has been a shift away from invasive candidiasis toward invasive mold infections, including breakthrough infections.^[2]Fungal infections in HSCT recipients can be life-threatening or fatal.^{[53, 54, 55]}Factors that increase the risk for invasive fungal infection following HSCT include the following:

Neutropenia
Broad-spectrum empiric antibiotic therapy
Immunosuppressive agents
GVHD
Parenteral nutrition
Severe mucositis

The majority of patients who develop fungemia are infected with either Candida or Aspergillus species.^{[56, 54, 55, 12]}

Fluconazole is effective in reducing C albicans infections and patient mortality after HSCT.^[12]The National Comprehensive Cancer Network (NCCN) guidelines recommend fluconazole or an echinocandin (micafungin, caspofungin, anidulafungin) for antifungal prophylaxis in autologous HSCT recipients with mucositis and in allogeneic HSCT recipients with neutropenia.^[38]

However, with the more widespread use of prophylactic fluconazole, an increase has occurred in infections with resistant C albicans and the isolation of Candida species (eg, C glabrata, C krusei) that are not usually sensitive to fluconazole.^{[22, 12]}Fluconazole possesses no significant activity against Aspergillus; thus, increased infections with Aspergillus are emerging.^[56]

Voriconazole is more effective than fluconazole in preventing fungal infections in transplant recipients.^[55]In HSCT recipients with significant GVHD who are receiving immunosuppressive therapy, NCCN guidelines recommend posaconazole, with voriconazole, an echinocandin, or amphotericin B products as alternatives to fluconazole.^[38]

Triazole antifungals are primarily metabolized by hepatic cyp450 enzymes and, therefore, are implicated in several drug-drug interactions. This drug class is also nephrotoxic and hepatotoxic. The echinocandin micafungin is approved for prophylaxis of Candida infections in HSCT recipients as young as 4 months old. One study utilized micafungin from the start of conditioning. At engraftment, the patients were switched to voriconazole prophylaxis if they had no history of fungal infection, or treated with itraconazole if they had a history of fungal infection. This approach proved safe and effective.^[57]Pediatric populations have been treated successfully with echinocandins, with few side effects.^{[55, 57]}

Infection due to Zygomycetes (mucormycosis) is very difficult to treat, with high mortality rates despite treatment.^[58]Treatment currently involves early recognition and adjunctive surgical resection when possible. Pharmacologic therapeutic options are amphotericin B and the triazole antifungal agents isavuconazole and posaconazole. Other agents, including fluconazole, voriconazole, and echinocandins, do not work against the fungi that cause mucormycosis.^{[59, 60]}

The use of voriconazole as primary or secondary prophylaxis against fungal infections is emerging as a risk factor for the development of breakthrough Zygomycetes infections. Newer agents that have activity against the class Zygomycetes include posaconazole and echinocandins. Posaconazole is 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, and also has orphan drug status for the treatment of invasive aspergillosis and zygomycosis.

Hyalohyphomycosis is an invasive fungal disease with an incidence rate than varies from 3% to 35% and a mortality rate approaching 90%. It is caused by non-pigmented molds, most frequently Fusarium spp. Risk factors include the patient's degree of immunosuppression and geographic location.^[61]Voriconazole is the usual first-line agent for hyalohyphomycosis, but many of these molds are resistant to various antifungal agents; susceptibility testing may guide therapy.^[47]

Pneumocystis jirovecii

P jirovecii, despite its classification as a fungus, is susceptible to several antibacterial and antiparasitic drugs. The agent most commonly used for prophylaxis is TMP/SMZ. Other agents that have activity against P jirovecii include dapsone, pentamidine, atovaquone, pyrimethamine, sulfadoxine, clindamycin, and primaquine in combination. Adverse effect profiles and patient factors should be used to determine the appropriate prophylactic regimen. TMP/SMZ is associated with leukopenia and may cause delayed engraftment.

Some transplant centers begin PCP prophylaxis 14-20 days before transplantation. Prophylaxis against Pneumocystis should continue for several months after the transplantation. Continued prophylaxis (> 6 mo) is required in patients with chronic GVHD or patients receiving immunosuppressive therapy (eg, prednisone).^{[62, 63, 64]}

When agents other than TMP/SMZ are used for prophylaxis, a high index of suspicion for PCP should exist in all patients with respiratory signs or symptoms. The treatment of choice in the patient with PCP is high-dose TMP/SMZ. Second-line agents include intravenous pentamidine, intravenous trimetrexate plus oral folinic acid, oral trimethoprim plus oral dapsone, oral atovaquone, or oral primaquine plus clindamycin.^{[62, 64]}

Parasitic infections

Toxoplasmosis prophylaxis should be provided for allogeneic HSCT recipients who are seropositive and have active GVHD or have a history of previous Toxoplasma chorioretinitis. The recommended agent for prophylaxis is TMP/SMZ. Vaccines are in development. Toxoplasma can result in disseminated infection, including infection of bone marrow and brain.^{[65, 66, 67]}

Viral infections

Herpes simplex virus

Reactivation of HSV infection can occur at any time following transplantation. Prophylactic use of acyclovir is very effective at reducing the rate of HSV reactivation and should begin when the conditioning regimen is initiated. Prophylaxis should continue until mucositis has resolved and engraftment has occurred. HSV reactivation may occur at the same time as mucositis. The presence of mucositis should prompt testing for HSV. Acyclovir is the drug of choice for HSV. Live herpes zoster vaccination is immunogenic and safe in immunocompromised patients.^{[68, 32]}

A systematic review and meta-analysis concluded that antiviral prophylaxis directed against herpes viruses is highly effective and safe. Prophylaxis reduced all-cause mortality, HSV, CMV disease, and herpesvirus reactivations among HSCT recipients.^[69]

Epstein-Barr virus

EBV reactivation is primarily due to endogenous reactivation or transmission from the allograft.

Signs and symptoms of EBV infection are heterogeneous. Reactivation may be asymptomatic or present as mononucleosis. The most severe manifestation is EBV-related post-transplantation lymphoproliferative disorder (PTLD).

The risk of EBV-related PTLD varies. Several factors modulate risk. The risk is lower with post-transplant cyclophosphamide and higher with T-cell depletion cord blood transplantation.

High-risk patients should undergo weekly monitoring of EBV DNA by quantitative PCR in whole blood starting on the day of transplantation. Monitoring should generally be continued for three months but should continue for a longer period in those who had early EBV reactivation and those receiving treatment for GVHD.^{[70, 29]}

Cytomegalovirus

CMV was once the leading cause of morbidity and mortality in patients after HSCT. The advent of ganciclovir for prophylaxis has profoundly decreased severe CMV disease. The highest risk for disease is in CMV-negative recipients whosedonor who is CMV positive. CMV-positive recipients are at moderate risk. Minimal risk exists if a CMV-negative recipient of a CMV-negative graft receives filtered leukocytes and irradiated filtered blood products for all transfusions. Other factors conferring a high risk of CMV reactivation include umbilical cord blood transplantation, haploidentical transplants, HLA-mismatched transplants, T-cell depleted transplants, and corticosteroid treatment. Scheduled surveillance is indicated and involves measuring CMV pp65 antigenemia and CMV PCR viral load. If CMV is detected, early preemptive therapy with ganciclovir is initiated. Therapeutic drug monitoring and evaluation for resistance should be part ofthe treament plan.^{[71, 72]}

Ganciclovir for CMV prophylaxis and treatment is administered intravenously. Valganciclovir is administered orally.^[63]

Although CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in HSCT recipients, the use of these agents is often limited by toxicities and resistance. ^[73] Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, was approved in 2021 for post-transplant CMV infection/disease that has not responded to available antiviral treatment for CMV. Adoptive immunotherapy using third-party T-cells has proved safe and effective in preliminary studies. Vaccine development continues.^{[73, 74, 75, 76]}

Adenoviruses

Adenovirus, which generally causes a mild self-limited illness in the immunocompetent host, can be fatal in an immunocompromised host. A high index of suspicion is needed for all immunocompromised individuals.^[77]Adenoviral infections may include hemorrhagic cystitis, gastroenteritis, and pneumonitis.^{[78, 79, 80]}

Treatment for adenovirus infection in a patient who has undergone HSCT is not currently standardized. Virus-specific T-cells (VSTs) are available for the management of adenovirus and have proved safe and effective. Combination VSTs are useful in patients with polymicrobial infections. Scheduled administration of VSTs may considered.^{[81, 74, 82]}Effective live oral vaccines are available for some patient populations but management should be tailored to each patient based on history, immune function status, clinical course, and local virus behavior.^[80]

Varicella

Varicella infections can occur in the late post-transplantation period. Prevention should be attempted following exposure. Varicella-zoster immunoglobulin (VZIG), should be given to patients less than 24 months following HSCT and to those more than 24 months after HSCT who are on immunosuppressive therapy or have chronic GVHD. VZIG should ideally be administered within 48-96 hours after exposure to a person with chickenpox or shingles. Breakthrough infections occur and should be diagnosed and treated promptly. HSCT recipients who develop varicella should be managedwith intravenous therapy for 7-10 days.^[83]

Respiratory syncytial virus

Both mucosal and humoral antibodies are important for protection from RSV infection. Intravenous immunoglobulin containing high levels of RSV-specific neutralizing antibodies and the monoclonal antibody palivizumab that targets site II on the F glycoprotein provide some protection against severe RSV infection.^[84]

Treatment of RSV infection is largely supportive. Ribavirin treatment in adult allogeneic BMT recipients was found to significantly reduce the risk of RSV-associated mortality, and viral load.^[85]The monoclonal antibody palivizumab is approved for the prevention of invasive RSV infection in high-risk patients.^{[84, 86]}

Influenza

HSCT recipients should receive annual influenza vaccination (see Vaccinations, below); however, the use of live attenuated nasal spray influenza vaccine (LAIV4) is contraindicated in these patients.^[87]CDC recommendations for antiviral treatment of influenza depends on several patient factors and may consist of oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir. Data suggest that baloxavir marboxil can be effective in treating neuraminidase inhibitor-resistant influenza in profoundly immunocompromised patients.^{[88, 89]}

Human herpesvirus 6

Reactivation of infection with HHV-6 (specifically, HHV-6B) occurs frequently after transplantation, affecting approximately 40% of subjects within the first few months. HHV-6B is the most frequent infectious cause of encephalitis in HSCT recipients and is associated with morbidity and mortality. HHV-6B is also implicated in the pathogenesis of acute GVHD and post-transplant pneumonia syndromes. Ganciclovir has been used as prophylaxis to prevent HHV-6 disease.

HHV-6–associated meningoencephalitis is treated with ganciclovir and/or foscarnet. Due to the toxicity of both agents, treatment is reserved for selected high-risk patients. HHV-6-specific T-cells have been effective and have demonstrated minimal adverse effects.^[90]

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2)

HSCT recipients with SARS-CoV-2 infection (COVID-19) experience high mortality. The principal goal should be avoidance of infection with strict isolation, quarantine, vaccination (see Vaccination, below), and testing protocols for all persons who come into contact with immunocompromised patients. PCR testing should be used instead of antigen testing because antigen testing is associated with a high false-negative rate. Scheduled surveillance testing is also indicated for all contacts and patients because most infected persons have only mild symptoms or are asymptomatic for days after they become infectious.^{[91, 92]}

Treatment for COVID-19 is evolving but consists primarily of supportive care and immune-modulating agents. Due to the high risk of severe infection in HSCT recipients, the response to exposure or infection should be aggressive. Therapy should be individualized to avoid drug-drug interactions.^{[93, 94]}The FDA has approved several agents for the treatment of COVID-19, including baricitinib, remdesivir, molnupiravir, nirmatrelvir, and paired monoclonal antibodies. However, the FDA has revised its authorizations for two paired monoclonal antibody treatments, bamlanivimab/etesevimab, and casirivimab/imdevimab, due to decreased effectiveness against SARS-CoV-2 variants that have emerged since the development of those antibodies. Additional experimental therapies are being developed.^{[93, 94]}

Parasitic infections

Toxoplasmosis, which is caused by the intracellular protozoan parasite Toxoplasma gondii, can be life-threatening in immunocompromised individuals. Environmental controls such as food safety and animal exposure should be discussed with outpatients and close contacts.

Toxoplasmosis prophylaxis should be provided for allogeneic HSCT recipients who are seropositive and have active GVHD or have a history of Toxoplasma chorioretinitis. The recommended agent for prophylaxis is TMP/SMZ.Progress has been made in designing a potential vaccine against T gondii but there are no feasible formulations.^[95]Prevention and early recognition are the foundations of management.

Common presentations of toxoplasmosis include fever, encephalopathy with mental status changes or seizures, and pneumonia. First-line therapy is with oral pyrimethamine, sulfadiazine, and leucovorin for at least 6 weeks, followed by secondary prophylaxis.^{[96, 97]}

Vaccinations

Reimmunization is required for most autologous and allogeneic HSCT recipients because they lose immunity. Immunization should be performed in the first and second years post-transplantation.^[22]All non-live vaccines should be administered, and boosters for diphtheria and tetanus toxoid should continue every 10 years.^[22]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.

A study in 15 children receiving a single dose of Varilrix (varicella vaccine) 12-23 months after BMT revealed antibody responses (measured using immunofluorescence assays) of 65% at 6 weeks, 90% at 6-12 months, and 65% at 24 months after vaccination.^[98]Adverse effects were minimal. Therefore, some centers are recommending varicella vaccination 24 months after HSCT unless the patient is receiving long-term immunosuppressive therapy.

HSCT recipients should receive lifelong seasonal influenza vaccinations. Although serologic conversion rates are lower in transplant recipients than in healthy controls, patients who receive influenza vaccine 6 months or more after HSCT are at a lower risk of developing virologically confirmed influenza.^[99]

Vaccination against emerging variants of SARS-CoV-2 may be feasible depending on patient factors, time from transplantation, and type of transplant. Although the immune response will be subpar in many HSCT recipients, some patients may benefit. The American Society of Hematology and the American Society for Transplantation and Cellular Therapy provide regularly updated information on COVID-19 vaccination recommendations for HSCT recipients.^[100]

Surveillance

In addition to surveillance for specific organisms as described above, early detection of fever by a wearable device may identify infection before symptoms develop.^[101]

Outcome

Infection is a major source of morbidity and mortality for patients who undergo HSCT. Prevention or management of infections is key.

HSCT can control and/or cure many malignant and non-malignant hematologic diseases, congenital and acquired diseases of the immune system, some solid tumors, and some inherited disorders of metabolism.

Among HSCT patients whose disease remains in remission for the first 2-5 years after transplantation, it is estimated that approximately 80-90% will be alive over the subsequent 10 years. Many patients have a good prognosis; aggressive prevention and management of infections should be considered the standard of care post HSCT.^[102]

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