Evaluation for infection before hematopoietic cell transplantation

INTRODUCTION — The infusion of hematopoietic cells to re-establish marrow function in an individual who has had his or her bone marrow ablated with chemotherapy and/or radiation has become standard therapy for many malignant and nonmalignant diseases. The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of hematopoietic cells from any source (eg, bone marrow, peripheral blood, umbilical cord blood). (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Patients can develop bacterial, fungal, viral, and/or parasitic infections following HCT, particularly following allogeneic HCT (figure 1). Infection in such patients is associated with high morbidity and mortality. Thus, prevention of infection is a major goal involving determination of risk, careful selection of donors, infection control measures, and prophylactic and pre-emptive antimicrobial therapy.

This topic review will discuss appropriate pretransplantation screening tests. An overview of the infections that can occur in association with HCT and prophylaxis against some of these infections are discussed separately.

●(See "Overview of infections following hematopoietic cell transplantation".)

●(See "Prevention of infections in hematopoietic cell transplant recipients".)

●(See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies".)

●(See "Prevention of viral infections in hematopoietic cell transplant recipients".)

PRETRANSPLANT EVALUATION — The pretransplantation evaluation is designed to prevent post-transplant infections by excluding unsuitable donors and by defining specific infection control policies and antimicrobial prophylaxis and therapy, which will be necessary after transplantation.

History — The donor and recipient must have a comprehensive history for recent or past infectious disease exposure, particularly when an allogeneic hematopoietic cell transplantation (HCT) is considered.

Donor — Donor screening should be performed within six months prior to stem cell donation [1]. In the United States, specimens for laboratory testing should be obtained up to 30 days before donation of peripheral blood stem cells or bone marrow. For lymphocyte and umbilical cord blood donations, a specimen should be obtained for testing within seven days before or after donation. The following issues are important in evaluation of the donor:

●Presence of active infection

●Infectious disease exposures

●Medical history including transfusions, hepatitis, toxoplasmosis, tuberculosis, and others

●Travel history or residence in areas of the world with endemic infections, especially within the recent past (see 'Endemic pathogens' below)

●Vaccination history

●Social history including sexual history, illicit drug use, and travel

Certain infections in the donor are contraindications to transplantation. These are discussed below. (See 'Contraindications to stem cell donation' below.)

Recipient — The history for the HCT candidate should include the same questions as for the donor and the following additional information:

●Type and intensity of previous chemotherapy and/or radiotherapy; status of the underlying cancer (first or second remission, relapse)

●Infectious complications during previous cancer therapy (febrile neutropenia, pneumonia of unknown origin, response to antifungal therapy, other documented infections [particularly invasive aspergillosis], antimicrobial susceptibility of each pathogen isolated and the treatment received)

●Type of immunosuppression (neutropenia, lymphopenia, CD4 count <200 cells/microL, hypogammaglobulinemia, asplenia, exposure to large doses of glucocorticoids, and others)

●Dental history within the last six months

●Structural abnormalities (eg, cardiac valvular disease, cavitary lung disease, prosthetic biomaterials such as vascular grafts, artificial joints, hemodialysis access fistula)

●Evidence of recent or current infection, including upper respiratory infections, which are often caused by community respiratory viruses (see 'Community respiratory viruses' below)

Physical examination — A complete physical examination should be performed with special attention to areas likely to become infected including the upper and lower respiratory tracts, the perioral and perirectal regions, skin, and site(s) of intravascular catheters and bone marrow biopsies.

Pathogen-specific testing — Laboratory testing for evidence of past infectious exposures is performed to detect asymptomatic infection in the HCT donor or candidate. Some tests are recommended for all HCT donors and candidates, whereas others are appropriate in selected individuals with epidemiologic risk factors (table 1) [1,2]. Serologic testing is used as an indicator of significant past exposures. In some cases (human immunodeficiency virus [HIV]-1 and hepatitis C), viral load testing is also indicated. Relevant pathogens that may be transmitted by the graft include the following:

●HIV-1 and -2

●Hepatitis B

●Hepatitis C

●Cytomegalovirus (CMV)

●Epstein-Barr virus (EBV)

●Herpes simplex virus (HSV)

●Varicella-zoster virus (VZV)

●Syphilis

●Human T cell lymphotrophic virus–I and –II (HTLV-I and -II)

●Toxoplasma gondii

●West Nile virus

There are US Food and Drug Administration, state, and other regulatory body requirements for donor screening that change over time [2]. All HCT donors and candidates should be screened for a variety of pathogens (table 1).

Endemic pathogens — Certain other pathogens should be tested for in HCT candidates (and, in some cases, donors) who have resided in or traveled to an endemic area (table 1):

●Strongyloides stercoralis

●Coccidioides species

●Histoplasma capsulatum

●Trypanosoma cruzi

●Malaria

Screening for tuberculosis — HCT candidates should be evaluated for latent or active tuberculosis (TB); the evaluation should include obtaining a history of [1]:

●Prior active TB

●Exposures to contacts at high risk for TB

●Results of prior tuberculin skin tests (TST) or interferon-gamma release assays (IGRA)

In the 2009 guidelines for preventing infectious complications among HCT recipients, there was no consensus about whether all HCT candidates should undergo TST or IGRA prior to HCT [1]. We favor screening for TB with either one of these tests in all HCT candidates with risk factors for TB. It should be noted that false-negative TST and IGRA results may occur in immunocompromised patients. (See "Epidemiology of tuberculosis", section on 'Risk factors' and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)" and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

Since transplanting stem cells from a donor with latent TB poses no known risk of TB in the recipient, screening donors for latent TB is not necessary [1]. Potential donors with signs or symptoms of active TB should be evaluated for TB, and donation should be deferred until the TB is well controlled.

Community respiratory viruses — Community respiratory virus infections are common among patients receiving HCT and are more prevalent during periods of community outbreaks [3,4]. Accordingly, healthcare workers and visitors with symptoms of upper respiratory infection should be restricted from having contact with HCT candidates. The presence of a community respiratory virus infection in an HCT candidate is of particular concern because these viruses can progress to pneumonia following HCT. Respiratory syncytial virus (RSV) and other respiratory viruses, such as influenza, parainfluenza viruses, adenovirus, and metapneumovirus, can progress to pneumonia in HCT recipients. Because infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be asymptomatic and subsequent clinical illness can result in devastating complications, transplant centers test potential HCT recipients for this virus by polymerase chain reaction on nasopharyngeal swab specimens prior to initiating the conditioning regimen.

Any HCT candidate with signs and/or symptoms of an upper respiratory tract infection should be tested promptly for the presence of community respiratory viruses. The optimal specimens for testing are nasopharyngeal aspirates, washings, and swabs. The optimal diagnostic test (viral culture, rapid antigen testing, fluorescent antibody testing, polymerase chain reaction [PCR]) varies depending on the virus. (See "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Laboratory confirmation' and "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Upper respiratory illness' and "Human metapneumovirus infections", section on 'Diagnosis' and "COVID-19: Diagnosis".)

It is unclear how to best manage asymptomatic patients who test positive for SARS-CoV-2, but we prefer to avoid transplantation until the PCR is negative for preferably one month, when possible.

MANAGING INFECTIONS PRIOR TO HCT — Active infections in the hematopoietic cell transplantation (HCT) candidate should be eliminated or suppressed prior to transplantation, whenever possible. Even asymptomatic infections can evolve into overwhelming sepsis following transplantation. Similarly, donors with active infections should be treated prior to donating cells. Infections in the donor that are contraindications to stem cell donation are discussed below. (See 'Contraindications to stem cell donation' below.)

Decisions regarding the timing of HCT following initiation of therapy for infections in the HCT donor or candidate must be made on a case-by-case basis. Since many HCT candidates with malignant conditions have a high mortality rate if their underlying disease is not treated expeditiously with HCT, it may be appropriate to proceed to HCT even when the donor is known to have an infection that could be transmitted to the recipient [1]. The risks and benefits of using potentially infected donor cells must be weighed carefully in this situation.

When HCT candidates have infections with pathogens that can be treated fully prior to HCT (eg, bacteremia or bacterial pneumonia), it is optimal to do so. In some cases, continuing treatment through the high-risk period is indicated. The decision of when it is safe to proceed to HCT must be made on a case-by-case basis.

Cytomegalovirus — Patients with profound T cell immunodeficiency have a higher risk for cytomegalovirus (CMV) infection, even prior to commencing the conditioning regimen. These patients should undergo testing with CMV quantitative polymerase chain reaction (PCR) two weeks prior to commencing the conditioning regimen and should receive anti-CMV therapy if found to have CMV viremia.

The development of CMV infection prior to allogeneic transplantation is associated with a high risk of death after HCT [5]. Active CMV replication in a HCT recipient can portend particularly high risk for CMV disease when the patient is CMV seropositive and is transplanted from a donor who is CMV seronegative or with cord blood stem cells [6]. In these high-risk situations, it has been suggested that the patient be treated with an antiviral agent (eg, intravenous [IV] ganciclovir, oral valganciclovir, IV foscarnet) to prevent CMV disease, and the conditioning regimen should be delayed until the CMV infection is controlled (ie, until evidence of decline of CMV viral load in the absence of CMV disease). The conditioning regimen may then be started during antiviral therapy. However, ganciclovir or valganciclovir should be switched to foscarnet no longer than two days prior to starting the conditioning regimen to prevent the myelosuppressive effects of ganciclovir and valganciclovir. Foscarnet may be stopped if CMV PCR or antigenemia become undetectable and if there is no evidence of CMV disease. However, close monitoring should continue and foscarnet resumed at the first evidence of CMV reactivation or CMV disease. Letermovir is alternative agent to consider for this purpose, but to date, has not been studied for this purpose. Prevention of CMV disease is discussed in detail separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Cytomegalovirus'.)

Patients with a history of CMV disease (ie, pneumonia, gastrointestinal disease, and retinitis) within six months preceding HCT should be given IV foscarnet throughout the pre-engraftment period.

Community respiratory viruses — There is limited information concerning whether HCT candidates with documented community respiratory viruses should have the transplant procedure delayed [3,7,8]. If possible, HCT candidates with upper respiratory tract symptoms at the time that the conditioning regimen is due to begin should postpone the conditioning regimen until the illness has resolved [1].

This recommendation is supported by a prospective study in which pre-HCT and weekly post-HCT nasal washes were obtained through day 100 following HCT from patients with or without symptoms [8]. The following findings were observed:

●Of 458 patients, 116 (25 percent) had respiratory viruses detected prior to HCT.

●Patients with a respiratory virus detected prior to HCT had fewer days alive and out of the hospital and lower survival at day 100 compared with patients with negative samples.

●An elevated risk of death was present when rhinovirus was detected but not when influenza or respiratory syncytial virus (RSV) was detected. A possible reason for this is that most patients with RSV or influenza either received antiviral therapy or had a delay in transplantation, whereas fewer patients with rhinovirus had a delay in transplantation and therefore remained positive at conditioning.

●Among symptomatic patients, those with respiratory viruses detected had increased overall mortality compared with patients without viruses detected; among asymptomatic patients, detection of respiratory viruses was not associated with increased mortality.

A separate study that included 37 HCT candidates with documented RSV infection has also suggested that it is important to delay HCT in such patients [7]. The following outcomes were noted:

●HCT was delayed in 31; two of these patients developed recurrent RSV infection following HCT, with no fatalities.

●Three patients with documented RSV infection during conditioning had HCT delayed; two developed possible RSV pneumonia and both recovered.

●Three patients with documented RSV infection during conditioning did not have their procedure delayed; two developed RSV pneumonia and one of whom died.

There are insufficient information as how to approach patients with active, recovering, or asymptomatic severe acute respiratory syndrome coronavirus 2 infection prior to HCT. We prefer delay until acute symptoms, if present, have resolved and the PCR is negative, followed by an interval of several weeks, preferably one month.

Invasive fungal infections — In HCT candidates who have had infections that are likely to recrudesce following HCT, secondary prophylaxis during the period of increased risk is appropriate. Examples of such infections include invasive aspergillosis and disseminated candidiasis (hepatosplenic candidiasis). This is discussed in detail separately. (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients", section on 'Secondary prophylaxis' and "Treatment and prevention of invasive aspergillosis", section on 'Secondary prophylaxis for prevention of relapse' and "Chronic disseminated candidiasis (hepatosplenic candidiasis)".)

Tuberculosis — HCT candidates with untreated latent tuberculosis (TB) should begin receiving prophylaxis prior to undergoing HCT [1]. Similarly, HCT candidates who have been exposed to an individual with active smear-positive pulmonary or laryngeal TB should begin receiving prophylaxis prior to transplantation. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Tuberculosis prophylaxis'.)

CONTRAINDICATIONS TO STEM CELL DONATION — It is important to exclude certain infections in the donor (table 1). Examples of infections in the donor that are considered contraindications to transplantation include [1]:

●HIV infection

●Acute cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection

●Acute hepatitis A infection (as determined by a positive hepatitis A IgM)

●Zika virus – Potential HCT donors should be considered ineligible for HCT donation if they have been diagnosed with Zika virus infection over the past six months, resided in or traveled to an area with active mosquito-borne Zika virus transmission, or had sexual contact with a man who meets either of these criteria. Potential umbilical cord blood donors should be considered ineligible for donation if the birth mother has been diagnosed with Zika virus infection at any point during the pregnancy, resided in or traveled to an area with active Zika virus transmission at any point during the pregnancy, or had sexual contact at any point during the pregnancy with a man who meets either of these criteria. (See "Zika virus infection: An overview".)

●Acute toxoplasmosis

●Active tuberculosis (until it is well controlled)

●An acute tickborne infection, such as Rocky Mountain spotted fever, babesiosis, anaplasmosis, ehrlichiosis, Q fever, or Colorado tick fever

●Active or past history of Chagas disease

●Acute or recent West Nile Virus infection

A donor with known active coronavirus disease 2019 (COVID-19) infection or who asymptomatically tests positive should preferably avoid donation. There is limited published experience [9] with small numbers of donors who were noted to have a positive SARS-CoV-2 test in the peri-donation period (some who became symptomatic shortly after donation). Some donors who developed COVID-19 during stem cell mobilization had their collection stopped; others, particularly early during the pandemic when testing was not readily available, completed donation. Importantly, there was no SARS-CoV-2 transmission to recipient, no effects on recipient engraftment, no adverse events attributed to SARS-CoV-2 to the recipient, and no effects on six-month survival. However, in view of the limited experience, no recommendation can be made and generally it is advisable for donors with known COVID-19 infection to avoid donation until resolution of infection.

The decision of whether or not to exclude a potential donor who is at risk for or who has other infectious diseases should be made on a case-by-case basis [1].

Hepatitis B-seronegative HCT candidates should not receive stem cells from HBsAg-positive or hepatitis B deoxyribonucleic acid (DNA)-positive donors if another suitable donor is available [1]. However, donation is not strictly contraindicated since viral transmission is not universal and the recipient can receive antiviral prophylaxis. Hepatitis C-infected HCT candidates for whom there is no alternative donor can receive a transplant from a hepatitis C-positive donor provided that they understand the risk involved. When possible, hepatitis B- or C-infected donors can be treated with antivirals to reduce the transmission risk. This is discussed in greater detail separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Hepatitis viruses'.)

Donors who have traveled to a malaria-endemic area should defer donation for one year following their return [1]. Former or current residents of endemic areas should defer donation for three years. If this is not feasible, the donor should be treated empirically for malaria prior to donation. If the donor is diagnosed with active malaria, collection of stem cells should be delayed if possible until treatment has been completed and negative confirmatory testing obtained. If this is not feasible, pre-emptive treatment of the HCT recipient is reasonable, although there is no evidence regarding the safety or efficacy of this approach.

Blood banking standards recommend deferral for a past history of Q fever or babesiosis because these infections can be chronic and Babesia parasites might persist despite appropriate therapy [1]. Based upon these concerns, we also suggest the avoidance of stem cell donation from individuals with a history of Q fever or babesiosis.

VACCINATION — Following transplantation, HCT recipients typically lose immunity to pathogens against which they were previously immunized. Thus, HCT recipients should be immunized against a number of pathogens following the return of immune competence. Other strategies for preventing infections in HCT recipients include pretransplant vaccination of HCT candidates with the usual vaccines that are indicated based upon age, vaccination history, and exposure history; and vaccination of household contacts. These issues are discussed in detail separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients" and "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Considerations in patients with cancer", section on 'COVID-19 vaccination'.)

SUMMARY AND RECOMMENDATIONS

●Risk of infection after HCT – The infusion of hematopoietic cells to re-establish marrow function in an individual who has had his or her bone marrow ablated with chemotherapy and/or radiation has become standard therapy for many malignant and nonmalignant diseases. Patients can develop bacterial, fungal, viral, and/or parasitic infections following hematopoietic cell transplantation (HCT) (figure 1). Infection in such patients is associated with high morbidity and mortality. Thus, prevention of infection is a major goal involving determination of risk, careful selection of donors, infection control measures, and prophylactic and pre-emptive antimicrobial therapy. (See 'Introduction' above.)

●Importance of the pre-transplant evaluation – The pretransplantation evaluation is designed to prevent post-transplant infections by excluding unsuitable donors and by defining specific infection control policies and antimicrobial prophylaxis and therapy, which will be necessary after transplantation. The donor and recipient must have a comprehensive history for recent or past infectious disease exposure, particularly when an allogeneic HCT is considered. (See 'Pretransplant evaluation' above.)

●Laboratory screening tests – Laboratory testing for evidence of past infectious exposures is performed to detect asymptomatic infection in the HCT donor or candidate. Some tests are recommended for all patients, whereas others are appropriate in selected individuals with epidemiologic risk factors (table 1). (See 'Pathogen-specific testing' above.)

●Treating active infections before HCT – Active infections in the HCT candidate should be eliminated or suppressed prior to transplantation, whenever possible. Even asymptomatic infections can evolve into invasive disease or overwhelming sepsis following transplantation. Decisions regarding the timing of HCT following initiation of therapy for infections in the HCT donor or candidate must be made on a case-by-case basis. (See 'Managing infections prior to HCT' above.)

●Secondary prophylaxis – In HCT candidates who have had infections that are likely to recrudesce following HCT, secondary prophylaxis during the period of increased risk is appropriate. Examples of such infections include invasive aspergillosis and disseminated candidiasis (hepatosplenic candidiasis). (See 'Invasive fungal infections' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Elias Anaissie, MD, and Kieren A Marr, MD, who contributed to earlier versions of this topic review.