Transplant patients – bone marrow transplant

What are key concepts of infections associated with bone marrow transplants?

Infections associated with bone marrow or human stem cell transplantation (BMT or HSCT) are the result of 3 factors:

• Infections acquired from endogenous pathogens at the time of conditioning and primary bone marrow (and immunologic) ablation;

• Infections acquired from environmental exposures; and

• Infections acquired in the setting of immunosuppression.

This can be broken down further to include:

• Primary immunosuppression related to the underlying condition e.g., secondary hypogammaglobulinemia in multiple myeloma;

• Secondary immunosuppression following treatment for lymphoma or receipt of agents such as rituximab;

• CD4 and CD8 depletion as a result of lymphocyte-directed therapies such as fludarabine, high dose corticosteroids, or biologics such as gemtuzumab or alemtuzumab.

Mitigation of these secondary side effects may be provided by passive administration of pooled immunoglobulin as in the case of hypogammaglobulinemia, or with the use of prophylactic antimicrobial agents used to augment the immunologic deficits, such as acyclovir for herpesviridiae suppression, trimethoprim-sulfamethoxazole for Pneumocystis jirovecii and toxoplasma secondary prevention, or a variety of antibacterial agents including quinolones or rifaximin for enteric gram-negative coverage in neutropenia.

The focus of this chapter, however, will be on factor two above and minimizing environmental risks during and immediately following bone marrow transplantation.

What infection control principles related to bone marrow transplant patients are necessary for effective infection control?

Understanding the pathophysiology of infection during this highly vulnerable period serves to better underscore the need to adherence to strict infection control guidelines. This includes:

• Colonization and community versus hospital environmental exposures as they may affect endemic colonization or latent infections (e.g., exposure to environmental factors such as Aspergillus or Fusarium through gardening; yeasts such as Saccharomyces through well meaning but ill-informed holistic health approaches pre-bone marrow transplantation; and vaccinations of family members to seasonal conditions such as influenza).

• Understanding the primary barriers to infection are disrupted with bone marrow conditioning as well as means for agent delivery. This includes the following: loss of mucosal integrity due to mucositis; loss of the normally present monocytoid/lymphoid and granulocyte primary responses to ingested or translocated pathogens across the bowel wall, as well as loss of normal respiratory epithelial function and pulmonary macrophages upon receipt of the marrow conditioning regimen and/or radiation ablative therapies; changes in alimentary flora from repeat hospitalizations and antimicrobial exposures and pressures; and disruption of integument with central venous access placement.

Therefore, principles for infection control practices in bone marrow transplant units are focused to protect fully immunosuppressed patients from exogenous pathogens in a manner that is not dissimilar to contact, respiratory, and airborne isolation for general infection control practices.

Environment focused

• Room ventilation to minimize spore inhalation.

• Room cleaning and equipment to minimize exposure to nosocomial organisms transmitted to or from fomites, plants, or flowers, and in the setting of pediatrics, play areas and toys to minimize pathogen exposure.

• Attention to construction and renovations to minimize spore inhalation.

Patient focused

• Hand hygiene.

• Isolation precautions.

• Barrier precautions.

• Healthcare personnel screening.

• Visitor screening.

• Patient skin/integument and oral care.

Healthcare delivery

• Intravascular catheters.

• Specific healthcare-associated infections with attention to Clostridium difficile infection (CDI), staphylococci, vancomycin-resistant enterococci (VRE), multi-drug-resistant (MDR) gram-negative bacilli, Legionella, and community-associated viral infections including common respiratory and gastrointestinal viral infections.

What clinical trials or meta-analyses related to bone marrow transplant patients guide infection control practices?

Clinical trials including double-blind controlled or placebo controlled trials exist with regards to antimicrobial prophylaxis and empiric or directed therapies during persistent fever and neutropenia in this population. However, very few prospective clinical trials or meta-analyses exist with regards to environmental controls to limit infectious complications in bone marrow transplantation.

Those interventions supported by well designed clinical trial or epidemiologic studies include the following:

Patient focused

• Intravenous catheter maintenance – please refer to the chapter on preventing intravascular catheter-associated infections as the practices and principles are the same in this population.

• Hand hygiene including the use of alcohol-based hand sanitizers and standard hand washing with plain or antimicrobial soap and water. The chapter on hand hygiene is more extensive, but the proven key elements are:

• Using an alcohol-based hand sanitizer prior to and following entry into a patient’s room if hands are not visibly soiled (this is superior to the use of an antimicrobial soap and water); and

• Standard hand washing with soap and copious water when hands are visibly soiled with blood or body fluids.

• Adherence to CDC guidelines regarding prevention of healthcare-associated infections including close adherence to the use of contact, airborne, and droplet precautions, and very careful screening of healthcare personnel and visitors with restriction of entry onto the unit or to the recipient’s room if they have a condition that is potentially transmissible to the patient (including respiratory or diarrheal infections). These guidelines are outlined and summarized in detail elsewhere.

• Cleaning, disinfecting, or sterilizing equipment and devices that enter a bone marrow recipient’s room. This includes use of approved hospital disinfectants, which are discussed in a separate section.

• Good oral and dental hygiene prior to transplantation and maintained for at least 1 year after.

• Family members should receive standard vaccines as recommended; when efficacy is equivalent, the use of inactivated agents is preferable.

Environment focused

• Construction control that limits dust exposure to only within the construction area, isolating air handling from construction zone from air handling to actively used patient areas, construction air systems being negative pressure relative to the actively used patient care areas, and terminal cleaning and disinfection with approved disinfectant of the construction site prior to patient use.

• Prevention of Aspergillus and other fungal outbreaks by limiting exposure to and prevention of bird nesting near hospital air-intake.

Those interventions supported by strong theoretic rationale include:

Patient focused

• Patient and family recommendation on infection control practices including hand hygiene during hospitalization and at discharge.

• Minimizing the use of previously opened dressing supplies.

• Daily changes of arm boards when used.

• Care and cleaning/disinfection of toys and play areas in pediatric units and following published recommendations.

• Disinfecting and cleaning toys between play with other children.

• In children who put toys into their mouths, not allowing the sharing of toys with other children.

• Disposal of toys or other common items when used by patients on contact precautions.

• Healthcare worker adherence to vaccines for transmissible and preventable diseases.

• Patients should be encouraged to take daily showers or baths with mild soap.

• Maintaining good perineal care.

• Removal of oral devices or appliances such as dentures and bridges during transplantation.

• Protecting not totally implantable intravascular devices (e.g., peripheral intravascular central catheters or PICC lines) from tap water.

Environment focused

• Central point-of-use high-efficiency particular air filters (HEPA) with minimum 99.7% efficacy in removing particulate matter greater than or equal to 0.3 microns.

• American Institute of Architects recommendation for greater than or equal to 12 air exchanges per hour.

• Bone marrow transplant recipient rooms maintained at positive pressure relative to the hallway greater than or equal to 2.5 Pa, and other air handling practices.

• Use of portable HEPA filters during construction or in non-traditional rooms such as intensive care unit rooms.

• Daily cleaning and dust control using pre-moistened mop heads and cloths with approved hospital disinfectants to avoid dust dispersal.

• Daily use of approved disinfectant for environmental disinfection.

• Addressing environmental leaks within 72 hours to avoid mold development with attention to all surfaces – wall coverings, floor, ceiling tiles, and cabinetry.

• Limiting or not using false ceilings.

• During construction, having the air handling sealed.

Those recommendations with insufficient evidence to fully support generalized recommendation include:

Transplant recipient use of N95 respiratory or masks when outside of their rooms.

Routine environmental sampling of rooms and patient care areas for bacteria and fungi.

Discontinuation of methicillin-resistant Staphylococcus aureus (MRSA) isolation precautions with three negative screens on 3 consecutive days.

Use of foam oral brushes or tooth swabs.

Those interventions required by state or federal regulations include:

• American Institute of Architects (AIA) guidelines as minimum standards for ventilation.

• Engineered humidity controls in HVAC (heating, ventilation and air conditioning) systems and monitoring controls.

What are the consequences of ignoring key infection control principles and concepts?

The consequences of ignoring the key principles and infection control practices outlined above include significant morbidity and mortality for the BMT patient, as he or she is neutropenic, with continued complications post-engraftment. This includes:

Bacterial infections with multi-drug-resistant organisms, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci or Clostridium difficile

Methicillin-resistant Staphylococcus aureus

BMT centers should follow published recommendations regarding the prevention of healthcare-associated transmission of MRSA.

The key elements include:

• Adherence to and maintenance of hand hygiene as described above.

• Adherence to the use of appropriate contact precautions.

• Adherence to standard environmental cleaning with an effective bactericidal disinfectant.

There are insufficient data regarding the use of routine screening for MRSA carriage in this population. However, BMT units should work very closely with their infection control program and infection control practitioners in the setting of high MRSA rates either within the BMT unit itself or in the hospital.

The use of decolonization strategies is being explored and in some settings appears to be useful. The center needs to be cognizant of the presence and prevalence of high-level mupirocin resistance as this may affect attempted decolonization.

Vancomycin-resistant enterococci

BMT recipients will have many risk factors associated with VRE colonization. Bloodstream infection with VRE in this population greatly effects outcome, and historically is associated with significant complications. BMT centers should follow published recommendations to reduce risk of VRE infection when possible.

Multi-drug-resistant gram-negative bacilli

Emerging MDR and extended drug resistant (XDR) gram-negative organisms including carbapenemase producing Klebsiella, Stenotrophomonas and Acinetobacter as well as Enterobacteriaceae with inducible or constitutively produced extended spectrum beta-lactamases are being reported in BMT centers as well as many of our hospitals. Present guidelines include:

• Antibiotic stewardship that is focused on this specialized population as the tensions between the outcomes benefit from gram-negative coverage while neutropenic and duration of exposure to the agent with subsequent selection for emergence of one of these organisms are contraposed.

• As with VRE and MRSA, adherence to hand hygiene, appropriate contact precautions, and use of hospital approved bactericidal disinfectant in cleaning are recommended.

Clostridium difficile infection

The frequency of CDI in BMT populations is growing. Diarrhea is very common in this population as a result of mucositis and other chemotherapeutic side effects. C. difficile is a spore forming anaerobic organisms that spreads by spores and nosocomial transmission on fomites and hands. Vigilance in screening for CDI should be high given complications including typhlitis and ileocecitis, with management and control in an absolutely neutropenic population being very difficult.

Additionally, nosocomial transmission of CDI via transfer of spores is well reported. The BMT center should adhere strongly to published guidelines regarding infection control practices for CDI. These include:

• Strict adherence to contact isolation with donning of gloves and gowns upon entering the room.

• Contact precautions should be utilized at least until the patient is asymptomatic; some centers continue precautions until discharge.

• Strict adherence to hand hygiene– controversy exists regarding the use of waterless hand sanitizers versus standard hand hygiene with soap and water. While alcohol-based hand sanitizers are not sporicidal, except in extreme nosocomial outbreaks, there have not been documented reports of clinical ineffectiveness of continued use of these hand sanitizers in sporadic cases. Soap and water are not sporicidal, but will effectively remove spores from hands when hand washing guidelines are followed closely. However, the adherence to hand hygiene practices drops off significantly when traditional soap and water routines are recommended. Therefore, for sporadic cases, continued use of gloves with ongoing use of waterless (alcohol based) hand sanitizers is preferred. In outbreak situations, it is best to work with infection control and hospital epidemiology to develop a specific algorithm to which staff and visitors must adhere.

• Environmental cleaning and disinfection. This is another area of controversy as standard hospital approved disinfectants are not routinely sporicidal. Data exists suggesting use of 1:10 sodium hypochlorite solution left to dry effectively decreased the CDI rate in one hospital. The frequency of such cleaning as well as use in terminal clean is not well established. However, in outbreak situations, like hand hygiene, it is strongly recommended that environmental services, the BMT unit, infection control and hospital epidemiology work closely together to attempt to control and resolve the outbreak.

Nosocomial aspergillosis

The relationship between construction and nosocomial Aspergillus infection is well documented throughout the literature. Infection is largely through inhalation of spores aerosolized in the process of construction and subsequently contaminating air through the hospital ventilation intake or the patient room specifically, or in cases of cutaneous infection, contamination of pre-opened dressing materials or arm boards.

Practices that have in case series and observational data decreased spore transmission and nosocomial cases include the following:

• Isolation of BMT unit air handling from the rest of the hospital air handling system with backup power and redundant air management systems in emergencies and when maintenance requires the primary system to be shut down.

• Use of HEPA filtration with effective filtration to particle size greater than or equal to 0.3 micron.

• Isolation of air supply during construction both internal (room or area renovation) and external (large construction project).

• Ongoing careful environmental surveillance to ensure there is no bird nesting at air intakes.

• There are some data suggesting the use of anterooms to the actual patient room may help reduce certain infections.

• Specific data-derived or theoretical environmental controls well outlined below.

• Routine air sampling is also controversial. In a suspected outbreak of nosocomial aspergillosis or similarly transmitted fungal pathogen air sampling may be very beneficial, particularly as specific environmental controls are put into place. However, the utility in non-outbreak situations is not well established and may be very time and labor intensive with data that may not be of significant use. As such, at present, routine air sampling is not recommended.

Legionella outbreaks

Nosocomial Legionella outbreaks including those in BMT units in hospital settings are well described. It is also well recognized that not all hospitals have nosocomial Legionellosis. The approach within BMT units is similar to recommended control guidelines for hospital settings. It is recommended that hospital centers that have BMT units follow published guidelines regarding monitoring for Legionella, and if monitoring reveals an outbreak, the institution follow published guidelines regarding the sampling, interventions, and prevention strategies for controlling Legionella.

Infection with a community acquired viral pathogen

These include respiratory viral pathogens (seasonally, influenza; parainfluenza, respiratory syncytial virus, and adenovirus are becoming less seasonal in presentation); Human metapneumovirus is becoming increasingly recognized as an important community respiratory viral pathogen, as well as more common gastrointestinal viral pathogens such as norovirus. Both may be transmitted to BMT recipients by either visitors or healthcare workers.

Respiratory viral infections

Standard infection control practice guidelines should be followed regarding isolation and testing of patients who have a syndrome consistent with a community respiratory viral pathogen including seasonal or avian influenza, parainfluenza, RSV or adenovirus. Pathogen specific isolation precautions should be followed when the pathogen is identified, e.g., contact and droplet precautions for RSV and adenovirus.

The BMT unit should remain vigilant when the infected patient recovers from the infection. BMT recipients may continue to actively shed virus for up to weeks following recovery from the active infection. As such, they remain a potential risk for the other patients and staff on the BMT unit. Well documented ongoing shedding for up to 6 weeks has been reported in BMT recipients infected with influenza A and parainfluenza,

Viral gastroenteritis

Transmission of viral gastroenteritis (e.g., rotavirus, norovirus, and adenovirus) is specifically through the fecal-oral route. BMT units should adhere to published guidelines regarding the isolation precautions, hand hygiene, and environmental cleaning for at least the duration of gastrointestinal symptoms. Attention should be made for diagnostic testing, and infection control practices should be sustained for the defined asymptomatic shedding period that can occur following patient clinical recovery of symptoms to prevent or limit nosocomial transmission.

Visitor screening

BMT centers should have written policy regarding the screening all visitors of transmissible or communicable diseases. This includes use of an entry point with screening for community-associated viral infections (respiratory viruses and diarrheal diseases like norovirus and rotavirus), but also conditions that can be transmitted through contact pathogens such as community-acquired MRSA skin, soft tissue infection, and varicella zoster.

The screening should also include recent receipt of any attenuated live viral vaccinations such as the nasal influenza vaccine, varicella, or zoster vaccine, MMR or in the case of very young children, their primary vaccinations that may also include rotavirus vaccination. Visitors with any of these conditions should not be permitted to have direct contact with the BMT recipient, particularly if the recipient is receiving conditioning chemotherapy.

Healthcare worker screening

The BMT unit and hospital should provide a comprehensive written policy regarding the vaccinations and conditions with which an employee entering the BMT unit to provide direct patient care should receive or may have. These are all well outlined in the 2003 HICPAC advisory.

In the BMT unit, when at all possible, the killed or component vaccines should be utilized if they have the same efficacy as a live-attenuated vaccine counterpart. If a live-attenuated vaccine is required, it is recommended that the healthcare worker not provide direct patient contact during the potential shedding period outlined by the vaccine manufacturer. While there are only theoretic risks of transmission of an attenuated live vaccine agent by healthcare workers in this setting, there are reports of transmission within household settings.

The BMT unit should also monitor staff for potentially communicable diseases, and limit patient exposure based upon the condition. These are well outlined in the 2003 HICPAC guidelines.

Skin care

Skin integrity should be assessed on a routine basis. This includes inspection of any intravenous catheter sites including tunneled catheters or implanted port devices. Infection may manifest only as local tenderness, surrounding poorly demarcated erythema or serous drainage. Purulence will not be present during absolute neutropenia. Standard skin care should be followed with specific care of the intravenous catheters to prevent exposure to tap water, and use of mild skin cleansers.

No pre-opened otherwise sterile dressings should be used to prevent risk of inoculation with spore forming organisms. Arm boards should be changed on a daily basis if they are in use.

Minimizing rectal examination with the insertion of devices (thermometers and suppositories) or fingers into the rectum is discouraged, though data on bacteremia from these practices are only in the case report or case series form.

Oral care

All BMT patients should maintain good oral care. This includes pre-BMT dental evaluations and addressing any dental needs prior to admission for BMT. Many case series document poor outcomes from oral infections, and poor mucositis healing or complications resulting from concurrent poor dental hygiene and chemotherapy-associated mucositis are well described. Adequate healing should be allowed after oral surgical procedures prior to admission for conditioning chemotherapy and BMT.

Use of antimicrobial oral rinses has been shown to be effective in routine oral care. Use of a soft tooth sponge rather than a tooth brush is recommended but data are only in the case series format

Interestingly, data supporting the practice of removing oral apparatus like dentures from time of admission through to engraftment are very limited. However, observational data do exist linking the insertion of dentures at the time of meals with removal and soaking in antimicrobial rinse during neutropenia and mucositis with improved mucositis healing times.

Preventing intravenous catheter-associated infection

BMT units should follow established practices for the prevention of infections related to intravascular devices. These are well outlined in a separate section with well-demonstrated case control and other controlled studies.

What other information supports the key conclusions of research regarding bone marrow transplant patients, e.g., case control studies and case series?

With regards to the prevention of infection in the BMT patient population, most if not all of the case control studies regarding different interventions have been focused on the use of antimicrobial agents for prevention/prophylaxis, empiric, or directed therapy during fevers in neutropenia.

Summary of current controversies.

• Routine screening of patients for MRSA or VRE carriage is presently not recommended.

• Routine air sampling for fungal spores is presently not recommended.

• Hand hygiene practices in the setting of sporadic versus outbreak CDI is institutionally based and dependent on the balance between sustaining high rates of hand hygiene versus spore removal in outbreak situations.

• Very broadly balanced antimicrobial stewardship in the setting of absolute neutropenia should be established with a good understanding of the outcome benefits from specific gram-negative rods (GNR), gram-positive coccus (GPC), and yeast coverage during neutropenia, but carefully withdrawing agents to help limit emergence of MDR/XDR GNR, MRSA, and VRE.

• Careful attention to environmental control practices may be required largely through state or federal regulation or at a minimum from AIA guidelines have a good theoretic basis for air handling recommendations particularly in the setting of external construction, internal renovations, and air handling systems emergencies.

• Visitor policies should be established, but age limitation is not clear, as the emotional benefits from visits from one’s children or grandchildren or siblings may easily outweigh some of the theoretic risks. However, in those cases where children are allowed to visit, specific questionnaire and exclusion guidelines should be in place.

• Vaccinations should be followed, but the use of attenuated live viral vaccines in healthcare workers working in BMT units is discouraged for theoretic reasons.

What is the impact of controlling infections in bone marrow transplant patients relative to the control of infections in other patient populations?

Significant changes in the field of BMT continue to develop. Most of the changes have been in the areas of new and evolving strategies for the use of antimicrobial agents, particularly the development of well tolerated oral antifungal agents that have excellent activity against filamentous molds that traditionally carried extremely high mortality rates (Aspergillus and Rhizopus species).

Other changes include reduced intensity conditioning regimens that result in decreased loss of dendritic cell populations responsible for educating engrafting stem cells, increasing age in the BMT recipient, more frequent alternative source stem cells including cord blood derived stem cells, improving diagnostics with regards to screening for and diagnosing infectious pathogens, and modifications to approaches to the prevention and control of graft-verse-host disease in allogeneic HSCT/BMT recipients.

While a BMT patient has undergone extensive screening to rule out or treat many potentially transmissible conditions including MTB, acute community-associated infections such as respiratory virus infections like influenza, parainfluenza, RSV or adenovirus, or is not admitted for transplantation during acute HSV or VZV outbreaks, they may be colonized with MRSA or VRE or have prior CDI much like the standard hospital patient.

In most settings, these patients are not “new” to the BMT facility, but have extensive and intense relationships with the host hospital as these are frequently the centers that provide primary treatment for the underlying condition for which they are receiving the BMT. As such, they may require routine isolation precautions, in addition to the precautions developed to help protect them from exogenous transmissible pathogens in the setting of their transplant.

Therefore, the impact in this highly specialized population is not only to continue to protect other patients from nosocomial pathogens the BMT recipient may carry, but also to prevent or minimize exposure to pathogens that under immunocompetent circumstances may not result in significant disease but in BMT may result in significant morbidity and mortality.

The other caveat with this population is with regards to seasonal respiratory viral pathogens. It is now very clear that asymptomatic shedding of influenza A and B, parainfluenza, and RSV is prolonged for weeks or in some cases months in this population. As such, recognition and sustained precautions are necessary to protect not only the other patients on the BMT floor but also the staff to avoid iatrogenic transmission.

Overview of important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and bone marrow transplant patients.

BMT specific IC studies have largely been focused on air handling due to the high risk for nosocomial invasive aspergillosis (IA) infection. See Table I, Table II, and Table III. Other studies regarding the hospital-acquired pathogens such as CDI, MRSA, VRE, Legionella,and MDR/XDR GNR are discussed in detail elsewhere in the context of general infection control practices.