Infection Control, Prophylaxis, and Vaccinations in Hematopoietic Cell Transplantation Recipients


Overview

Hematopoietic cell transplant (HCT) recipients are at a heightened risk of a wide range of new infections or the reactivation of latent or remote infections given the extent of immunosuppression and immune dysregulation caused by chemotherapy, immunosuppressive medications for graft-versus-host diseases (GVHDs), and environmental exposures. HCT consists of the administration of hematopoietic progenitor cells (HPCs) collected from three major sources (bone marrow, peripheral blood, and umbilical cord blood) and used to reconstitute the bone marrow of the recipient. HCT is autologous when HPCs are harvested from the patient before myeloablative chemotherapy and allogeneic when HPCs are collected from a donor or a relative with identical, haploidentical, or mismatched human leukocyte antigens. Allogeneic HCT recipients are at a greater risk of infections than autologous HCT recipients and have higher rates of morbidity and mortality. Therefore the prevention of infection in HCT recipients requires a multidisciplinary approach that takes into account potential sources of infections, as HCT recipients may be exposed to endogenous infections arising from the reactivation of a remote infection (viral, bacterial, parasitic, or fungal) or to exogenous infections. The determination of infection risk necessitates a comprehensive selection and review of graft donors, preemptive and prophylactic antimicrobial therapy measures, vaccination, and implementation of strict infection control measures. To minimize exogenous sources of infection, careful attention must be paid to patients’ environments (hospitals and ambulatory treatment clinics), foods, pets, and daily activities. Infection control measures should also be incorporated into outpatient settings, and patients should be educated regarding best practices for preventing infection.

Infection Control Strategies Within Healthcare Facilities

Infection control practices have become fundamental and integral elements of care for patients with oncologic diseases and comprises aspects related to the patients, healthcare environment—including healthcare workers—and the community. Early during the peritransplant period, HCT recipients are frequently hospitalized; therefore the principal exogenous source of infections, remains hospital settings.

Room Ventilation and Protective Environments

All allogeneic HCT recipients should be placed in rooms with protective environments, and such arrangements are preferable for autologous HCT patients. Protective environment rooms are characterized by a wide range of interventions, including the management of ventilation by positive air flow inside the rooms relative to the air flow in the adjacent spaces, bathrooms, anterooms, and corridor. The rooms should have 12 or more air changes per hour. They should also use high-efficiency particulate air filters, which decrease the risk of healthcare-associated invasive aspergillosis. Studies have shown that these filters remove around 99.97% of particles larger than 0.3 mm.

Construction, Renovation, and Cleaning in the Healthcare Setting

When construction, renovation, or maintenance projects occur within healthcare settings, specific precautions must be implemented given the greater risk of exposure to fungal microorganisms (primarily Aspergillus or Legionella species). Infectious particles can be released from the water supply or during the construction, destruction, or renovation of buildings. Whenever possible, HCT recipients should avoid construction as well as renovation areas. Importantly, hospital construction areas should maintain negative air pressure relative to the air pressure in the patient care areas, and the air should be released outside the hospital milieu or filtered with high-efficiency particulate air filters. Special attention should be given to cleaning, as it is indispensable during and after any construction activity. Also, HCT units should be cleaned once per day using hospital disinfectant and, importantly, should be kept dust-free.

Hand Hygiene

Appropriate hand hygiene is the single most essential practice for preventing the transmission of nosocomial infections and limits the spread of many infectious agents within healthcare settings. All healthcare workers should wash their hands in a systemic fashion before entering and after leaving patient rooms. Similarly, HCT recipients and their household members should be encouraged to practice handwashing hygiene with antimicrobial soap and water.

Isolation and Barrier Precautions

Barrier precautions and isolation measures should be implemented in all HCT centers to prevent patients and healthcare workers from acquiring communicable or infectious diseases. Hospital isolation practices encompass two levels of protection: standard precautions that apply to all patients and expanded precautions that are tailored according to the nature of microorganism transmission. Contact, droplet, and airborne precautions are commonly implemented in addition to standard measures to ensure protectiveness based on potential infections (see later for the isolation precautions for specific pathogens).

Plants, Toys, and Play Areas

To reduce the risk of mold or bacterial nosocomial transmission, live plants and flowers should be excluded from HCT patients’ hospital rooms. Studies have shown that plants and flowers may contain numerous microorganisms such as Pseudomonas aeruginosa , Burkholderia cepacian , and Aeromonas hydrophila . It is also noteworthy that the water from flower vases may harbor pathogenic fungi and multiresistant infectious agents. Special attention should also be given to pediatric patients’ toys and play areas, as previous outbreaks of rotavirus and norovirus have been linked to communal toys. P. aeruginosa infection from water-retaining bath toys has been described as well. Therefore cleaning and disinfecting toys and play areas are essential in pediatric HCT units.

Dietary Principles and Food Safety

To prevent food-borne diseases, HCT recipients’ food should be prepared carefully and attention should be given to the food types offered and their appropriate storage and handling. HCT patients should avoid unwashed vegetables and fruits, undercooked or raw meat, seafood, and eggs. The U.S. Department of Agriculture’s food safety recommendations for patients with cancer advises consuming only pasteurized dairy products and washing hands with soap and water before handling, preparing, and eating foods. Stricter restrictions have been recommended for HCT recipients and patients with neutropenia (those with an absolute neutrophil count below 500 cells/mm 3 ) include the avoidance of raw fruits and vegetables, undercooked meat, and unpasteurized milk and cheese. Recent data, however, have shown that there is no major reduction in infectious risk in patients who followed the strict neutropenic diet recommendations after HCT compared to those who followed a general hospital diet.

Preventive Practices for Relevant Infections in Hematopoietic Cell Transplant Recipients

Central Line–Associated Bloodstream Infections

Central line–associated bloodstream infections (CLABSIs) are a major cause of hospital-associated infections. Only competent and well-trained healthcare personnel should be allowed to insert, maintain, and care for central venous catheters (CVCs), and they should adhere to evidence-based guidelines. Cancer patients, including HCT recipients, are at greater risk of CLABSIs secondary to host-related factors—such as sex, age, and the presence of mucositis—and nonhost-related factors mainly related to prolonged hospitalization, prolonged central line use, and the use of multilumen CVCs. The Centers for Disease Control and Prevention’s guidelines for the prevention of CLABSIs call for practices such as: a) the insertion of CVC bundles, which entails the use of aseptic measures (e.g., hand hygiene, barrier precautions, and the use of chlorhexidine during catheter placement); b) the use of maintenance or postinsertion CVCs bundles, which involves daily assessment of the catheter insertion site, cleaning the infusion hub, dressing changes, and assessing the need for CVCs; c) the use of antimicrobial-impregnated CVCs; and d) the use of sutureless devices for securing CVCs.

Legionella Species

Legionnaires’ disease should always be in the differential diagnosis of nosocomial pneumonia in HCT recipients and is associated with substantial morbidity and mortality. Legionella species are commonly found in aquatic environments and may contaminate hospital water systems. The factors that enhance proliferation of the bacteria are mainly water stagnation and sedimentation and the conditions in man-made water environments. The principal mechanism of transmission is through the inhalation of contaminated aerosols generated by room-air humidifiers, showers, faucets, respiratory therapy equipment, or cooling towers. The primary preventive measures for Legionnaires’ disease rely on the periodic and routine culturing of water samples to quickly detect contamination of hospital water systems (i.e., ≥ 30% of samples are positive for Legionella bacteria). Therefore the common practice is to preserve water systems free of detectable organisms. Other routine measures to reduce the risk of contamination include chlorinating water and maintaining water temperatures at greater than or equal to 50 °C or less than 20 °C at the tap.

Methicillin-Resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) screening practices for HCT recipients are not well standardized and the current guidelines do not recommend routine screening for MRSA carriage. The data on MRSA carriage, screening, and outcomes in HCT patients are limited. A large, retrospective cohort study evaluated the prevalence of MRSA in patients before HCT showed that pretransplantation MRSA colonization was not associated with postransplantation MRSA-related complications. This finding was unexpected, given that HCT recipients have multiple risk factors for MRSA acquisition, including prolonged hospital stays, frequent antibiotic exposures, and common usage of intravascular devices.

All healthcare personnel in HCT units should apply the standard isolation and precautionary measures for patients with MRSA infection or colonization, including frequent handwashing between patients and use of gloves and gowns when in contact with MRSA-infected or colonized patients. For patients with a history of recurrent MRSA infection and colonization, decolonization via chlorhexidine baths and the application of 2% mupirocin ointment should be considered.

Vancomycin-Resistant Enterococci

Vancomycin-resistant enterococci (VRE) are now a major problem among allogeneic HCT recipients and are a primary cause of nosocomial bloodstream infections (e.g., bacteremia) at some transplant centers, particularly in the early posttransplant. Unlike MRSA carriage, VRE carriage in the pretransplant period is associated with VRE-related infectious complications posttransplantation, and VRE bacteremia has been reported in 11% to 34% of VRE-colonized patients. Therefore HCT candidates and recipients should be screened for VRE carriage during hospitalization to detect the bacteria early and minimize their transmission. To limit VRE transmission, strict adherence to infection control practices (e.g., washing hands with soap and water or alcohol-based solution) is essential. Patients with VRE should be placed under contact precautions until all antibiotics are discontinued and repeat cultures are negative. Patient rooms, including equipment and all surfaces, should be cleaned and disinfected daily.

Clostridium difficile Infection

The golden rule in controlling Clostridium difficile infection (CDI) is to administer antimicrobials for the shortest possible duration and improve the use of appropriate antibiotics. CDI is more prevalent in transplant recipients, including solid organ and HCT recipients, than in other hospitalized patients. Nosocomial CDI is primarily transmitted horizontally (spread from one individual to another) in hospital settings and the bacteria are often present on the hands of healthcare workers. All patients with CDI should be placed under contact precautions for the duration of infection; some centers isolate these patients for their entire hospital stay. Hospital personnel treating them should wear gowns and gloves and should focus on frequent handwashing with soap and water. CDI should be treated as recommended by the Infectious Diseases Society of America guidelines. Of interest, recent studies evaluated the effectiveness of CDI prophylaxis with oral vancomycin (125 mg given twice daily) on the incidence of CDI rates in HCT patients and found that oral vancomycin was highly effective in preventing CDI in allogeneic HCT recipients and did not increase the risk of GVHD or disease relapse.

Preventive Measures to Reduce Infection Risk

Despite innovations in diagnostic tools and therapeutic antimicrobial options, the incidence of infection-related mortality remains relatively high at around 8% and 17% to 20% in autologous and allogeneic HCT recipients, respectively. The time elapsed since the transplant is very important in stratifying risk factors because HCT recipients are prone to infection from specific microorganisms during three periods post-HCT. The first is the preengraftment period from HCT infusion until 30 days afterwards. The second is the early postengraftment period that lasts from engraftment to 100 days after HCT. Finally, the third is the late postengraftment period, defined as the time 101 days or more after HCT. Additional risk factors for infection include the patient’s net state of immunosuppression, the presence of intravascular devices, HCT recipient and donor exposure to pathogens (refer to Table 30.1 for pretransplant screening before transplant), and the presence of end-organ damage related to conditioning chemotherapy and myeloablative regimens. The infectious risk also depends on host and pretransplant factors and is greatest in those who are older, have iron overload, have a prior history of infections, or have had previous corticosteroid therapy. Transplant-related factors also play a major role in infectious risk as allogeneic HCT recipients are more predisposed to all types of infections than are autologous HCT recipients. Another risk is environmental, since HCT recipients are commonly hospitalized and, while receiving inpatient treatment, are exposed to many potential sources of nosocomial microorganisms (e.g., the facility, equipment, physical environment, visitors, and healthcare workers). Hence, preventing infection requires a multilevel approach that begins with donor selection—one of the main factors affecting graft failure, the reconstitution of the immune system, and the occurrence of GVHD—and ends by reducing, whenever possible, the use of myelosuppression and immunosuppression following HCT. The timeline elapsed from transplant, common microorganisms encountered in each phase, and overview of antimicrobials prophylaxis are summarized in Table 30.2 for autologous HCT and in Table 30.3 for allogeneic HCT recipients.

Table 30.1
Pretransplant, Pathogen-Specific Evaluation in Hematopoietic Cell Transplant Candidates
Infectious Agents Screening Tests
HBV Hepatitis B surface antigen and antibody; hepatitis B core antibody
HCV Hepatitis C antibody
HIV Fourth-generation immunoassay for HIV antibody
HSV 1 and 2 HSV1 and 2 antibodies
VZV VZV antibody
CMV CMV antibody
EBV EBV antibody
Syphilis Rapid plasma reagin
Mycobacterium tuberculosis T-spot or quantiFERON-TB
Toxoplasma gondii Toxoplasma antibody
HTLV-I and HTLV-II HTLV-I and II antibodies
WNV WNV PCR in selected individuals with risk factors
Coccidioides species Coccidioides antibody (residence in Southwestern USA and Northern Mexico)
Histoplasma capsulatum Histoplasma antibody (residence in Midwestern USA)
Strongyloides stercoralis Strongyloides antibody
Malaria Malaria PCR (residence in endemic areas)
Trypanosoma cruzi Chagas serology (residence in South and Central America or received blood transfusion in endemic area)
CMV , Cytomegalovirus; EBV , Epstein-Barr virus; HBV , hepatitis B virus; HCV , hepatitis C virus; HIV , human immunodeficiency virus; HSV , herpes simplex virus; HTLV , human T-cell lymphotropic virus; PCR , polymerase chain reaction; VZV , varicella-zoster virus; WNV , West Nile virus

Table 30.2
Phases of Potential Infections and Antimicrobial Prophylaxis in Autologous Hematopoietic Cell Transplant Recipients
Time Elapsed From the Transplant Bacterial Causes Antibacterial Prophylaxis Viral Causes Antiviral Prophylaxis Fungal Causes Antifungal Prophylaxis
Preengraftment phase a Gram-positive bacteria (gastrointestinal Streptococcus species, Clostridioides , and encapsulated bacteria) and gram-negative bacilli Quinolones (mainly Levofloxacin) HSV 1&2, respiratory viruses (e.g., influenza, respiratory syncytial virus, parainfluenza, and adenovirus) Acyclovir or valacyclovir Candida species Fluconazole
Postengraftment phase b Gram-positive, encapsulated bacteria None Respiratory viruses (e.g., influenza, respiratory syncytial virus, parainfluenza, and adenovirus), CMV, and VZV Pneumocystis jirovecii One of the following: TMP-SMX, aerosolized pentamidine, oral dapsone c or oral atovaquone
CMV , Cytomegalovirus; HSV , herpes simplex virus; TMP-SMX , trimethoprim-sulfamethoxazole; VZV , varicella-zoster virus

a The preengraftment phase is defined as the time from transplantation to neutrophil recovery (approximately day 20–30).

b The postengraftment phase is the time beyond engraftment.

c Check glucose-6-phosphate dehydrogenase levels before using.

Table 30.3
Phases of Potential Infections and Antimicrobial Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients
Time Elapsed From the Transplant Bacterial Causes Antibacterial Prophylaxis Viral Causes Antiviral Prophylaxis Fungal Causes Antifungal Prophylaxis
Preengraftment phase a Gram-positive organisms (gastrointestinal Streptococcus species and encapsulated bacteria) and gram-negative bacilli Quinolones (mainly Levofloxacin) HSV types 1 and 2 ; enteric and respiratory viruses (e.g., influenza, respiratory syncytial virus, parainfluenza, and adenovirus)
  • Acyclovir or valacyclovir;

  • CMV preemptive therapy; and some centers consider CMV prophylaxis (see text) e

Candida species; Aspergillus species and Mucorales
  • Fluconazole or antimold agent such as voriconazole or posaconazole (see text).

  • For PJP, add one of the following at day +30: TMP-SMX, aerosolized pentamidine, oral dapsone f or oral atovaquone

Early postengraftment phase b Gram-negative bacilli and encapsulated bacteria See footnote d HSV types 1 and 2 ; enteric and respiratory viruses; CMV; HHV-6; EBV (PTLD); BK virus; VZV (mainly late phase) Candida species; Aspergillus species and Mucorales ; Pneumocystis jirovecii
Late postengraftment phase c Encapsulated bacteria Acyclovir or valacyclovir Aspergillus species and Mucorales; Pneumocystis jirovecii

CMV , Cytomegalovirus; EBV , Epstein-Barr virus; HHV-6 , human herpes virus 6; HSV , herpes simplex virus; PJP , Pneumocycstis jirovecii ; PTLD , posttransplantation lymphoproliferative disease; TMP-SMX , trimethoprim-sulfamethoxazole; VZV , varicella-zoster virus

a The preengraftment phase is defined as the time from transplantation to neutrophil recovery (approximately day 20–30).

b The postengraftment phase is the time beyond engraftment.

c The late postengraftment phase is the time beyond day 100 after hematopoietic cell transplant (HCT). In addition, other infections could occur, such as parasitic diseases.

d Antibiotic prophylaxis is usually discontinued at neutrophil engraftment. However, HCT recipients who develop chronic graft-versus-host disease are at high risk of infection because of encapsulated bacteria and should receive prolonged antibiotic prophylaxis (i.e., penicillin).

e Add acyclovir or valacyclovir if the patient is receiving letermovir prophylaxis.

f Check glucose-6-phosphate dehydrogenase levels before using.

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