Hospital Epidemiology and Infection Control in the Transplant Center
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Both solid organ and hematopoietic stem cell transplant candidates and recipients are at high risk for healthcare-associated infections due to their underlying diseases, comorbid conditions, as well as the receipt of augmented immunosuppression to prevent rejection. Partnership between transplant physicians, institutional leaders, and infection preventionists allows for the accommodation of this growing vulnerable patient population into institutional risk assessments and hazard analyses. In addition, advancements in diagnostics and molecular typing have provided important information regarding sources of transmission of multidrug-resistant or opportunistic pathogens, thus informing strategies for mitigating risk and controlling outbreaks. Here we review common healthcare-associated infections and strategies for source control, prevention, and curbing outbreaks when detected.
KeywordsInfection control Surgical site infections (SSIs) Clostridioides difficile multidrug-resistant organism Influenza Respiratory syncytial virus Hand hygiene Legionella Nontuberculous mycobacteria (NTM) Central line-associated bloodstream infection (CLABSI) Catheter-associated urinary tract infection (CAUTI) Opportunistic premise plumbing pathogens (OPPP)
Despite significant advancements in immunosuppression, prophylactic strategies, and pre- and posttransplant management, candidates and recipients of both solid organ and hematopoietic stem cell transplants continue to be at higher risk for healthcare-associated infections when compared to other patients. Prolonged wait times and new allocation systems leave some patients reliant on indwelling devices like central venous catheters, ventilators, and urinary catheters both before and after transplantation, and the hospital environment itself serves as a potential source for infections with opportunistic pathogens. Improved access to molecular diagnostics and molecular typing has improved the ability to identify outbreaks and address source control. In addition, application of process improvement techniques and partnering between institutional and transplant leadership and infection prevention and control have led to a remarkable improvement in outcomes that were once considered inherent to transplant including healthcare-associated infections.
Here we review select infection prevention strategies that are applicable to transplant patients and review specific pathogens that pose risk to both candidates and recipients. General infection prevention practices are applicable to these vulnerable patient populations and include hand hygiene, respiratory hygiene, vaccination promotion, adherence to care bundles, and antimicrobial stewardship. In addition, patient placement and targeted surveillance for specific pathogens and syndromes may have a pivotal role in the prevention of infection with certain infections.
Hand hygiene is one of the most basic yet important aspects of infection prevention and control. Viruses, bacteria, and fungi can all be spread to and from the environment, staff, and patients via the hands of healthcare personnel (HCP). Hand hygiene prevents horizontal transmission of multidrug-resistant organisms (MDROs), including Clostridioides difficile, and reduces the risk of healthcare-associated infections (HAI). Despite this knowledge, HCP hand hygiene is poor even when working with vulnerable transplant recipients , highlighting the need for targeted interventions. Clinical staff and patients should have easy access to sinks and alcohol-based hand rub (ABHR) as part of a comprehensive strategy to improve compliance . Prospective monitoring through direct observation or electronically assisted monitoring with real-time feedback can increase hand hygiene compliance [3, 4].
Patient hand hygiene is also important for infection prevention. Patient hand contamination with MDROs is common, and this can be transmitted to and from their environment . An observational study of transplant recipients confirmed that hand hygiene compliance among patients is low, possibly contributing to pathogen transmission . Visitor hand hygiene is important because visitors frequently touch surfaces in the healthcare environment that are also touched by both patients and HCP, thereby increasing the risk of transmission of nosocomial pathogens . Thus, patient and visitor education encouraging hand hygiene and instructing the proper way to perform hand hygiene should be incorporated into a multimodal program addressing infection prevention.
Central Line-Associated Bloodstream Infections
Central venous catheters (CVCs) are used frequently in the pre- and posttransplant period for hemodynamic monitoring, blood sampling, and administration of medications and blood products. In addition to the convenience of direct venous access, they confer a risk of infection due to bypassing of the protective barrier of the skin. Central line-associated bloodstream infections (CLABSI) are a dangerous complication of CVCs, conferring increased length of stay, increased healthcare costs, and increased mortality risk [8, 9].
Transplant recipients and those awaiting transplant are at high risk for CLABSI, due to high prevalence of CVCs, prolonged hospital lengths of stay, prolonged duration of CVCs, and compromised immunity. Patients awaiting heart transplant frequently have pulmonary artery catheters, which allow for continuous monitoring of left ventricular filling pressures and confer a high urgency status for transplantation. At one institution, the CLABSI rate for patients with pulmonary artery catheters was five times higher than the CLABSI rate for intensive care unit (ICU) patients .
Patients who are pre- or immediately post-hematopoietic stem cell transplantation (HSCT) are at additional risk for bloodstream infections secondary to mucosal barrier injuries due to prolonged neutropenia. Single-center studies focusing on HSCT patients report a 20–60% incidence of bloodstream infections in the immediate posttransplant period and higher incidence in patients with acute graft-versus-host disease (GVHD) compared with rates prior to development of GVHD [11, 12]. HSCT candidates undergoing conditioning and HSCT recipients should perform oral hygiene throughout the day to reduce the risk of oral mucositis and secondary bacteremia .
A care bundle is a group of evidence-based practices which when performed together are associated with improved outcomes. Each included intervention is considered good practice. Compliance with care bundles should be audited, and feedback should be given to improve compliance and address barriers to compliance. Bundled interventions have proved to decrease CLABSI in ICUs and prompted a paradigm shift. CLABSI now were considered avoidable, and in many centers transplant populations are highlighted for increased incidence of CLABSI .
Indeed the majority of CLABSI are likely preventable. In a pivotal statewide trial, the implementation of a CVC insertion bundle including hand hygiene, full barrier precautions, cleaning the insertion site with chlorhexidine gluconate (CHG), avoiding the femoral site, and removing unnecessary CVCs resulted in a 66% sustained decrease in CLABSI in the ICU setting . Additional strategies to prevent CLABSI focus on maintenance of the necessary CVC. These include daily CHG bathing to reduce the bacterial load on the skin and daily patient hygiene [12, 16]; disinfection of catheter hubs prior to access, needleless connectors, and injection ports; dressing changes with CHG-impregnated dressings every 5–7 days or sooner if visibly soiled, wet, or loose; use of antibiotic-impregnated catheters; and use of ethanol-impregnated disinfection caps [17, 18, 19, 20, 21, 22].
Compliance with central line insertion and maintenance bundles is associated with lower CLABSI rates [23, 24, 25]. In order to ensure CVC bundled care, compliance is sustained on a patient, unit, and health system level; audit and reminders of bundle elements may increase consistency and subsequently reduce the risk of bloodstream infection .
Bundled CVC care has been shown to reduce CLABSI rates in transplant recipients as well. Implementation of process improvement strategies including standardization, monitoring with feedback, and plan-do-study-act cycles contributed to a 61% decrease (4.2–1.8 per 1000 CVC days) in a liver transplant ICU . Implementation of a CVC maintenance bundle resulted in a significant CLABSI reduction in pediatric HSCT patients . Identification of drivers for a rising CLABSI rate in a pediatric hematology-oncology unit and rapid development of interventions, such as identification of patients at high risk for CLABSI and involvement of senior nurses to assist less experienced nurses in dressing changes, resulted in a CLABSI rate reduction from 2.03 to 0.39 per 1000 CVC days .
Catheter-Associated Urinary Tract Infections
Catheter-associated urinary tract infection (CAUTI) is a common HAI, resulting in increased cost  and increased length of stay . Like CLABSI, CAUTI are largely preventable. The greatest risk factor for CAUTI is prolonged duration of indwelling urinary catheterization. Urinary catheters are often placed unnecessarily and remain in place longer than needed. Prevention measures include limiting insertion of indwelling urinary catheters, use of aseptic technique for insertion by a trained provider, regular perineal care, maintaining unobstructed flow of urine, and removal of the catheter as soon as it is no longer necessary.
CAUTI disproportionately affect solid organ transplant (SOT) recipients, with the most data available for kidney transplant recipients. In an analysis of kidney transplant recipients in the United States from 2002 to 2012, 7.5% of kidney transplant recipients developed CAUTI . Patient-specific risk factors for CAUTI in kidney transplant include age, female sex, and pre-transplant loss of function. Several studies confirm that prolonged duration of indwelling urinary catheter in kidney transplant recipients is a risk factor for both CAUTI and bacteremia [30, 31, 32].
Hospitals can reduce urinary catheter utilization by developing and implementing criteria for acceptable indications for indwelling urinary catheter use, such as when there is acute urinary obstruction, to assist in healing of pressure ulcers, or for select surgical procedures like kidney transplantation . There are several approaches to facilitate compliance with facility-specific utilization guidelines. A nurse-led approach incorporating multidisciplinary rounds on inpatient units that focused on appropriate indications for insertion and timely removal of urinary catheters was effective in reducing the number of catheter days on several units . Reminders for indwelling urinary catheter removal and stop orders embedded within the electronic health record have been effective in decreasing catheter use and significantly reducing CAUTI rates in multiple studies . Since limiting duration of urinary catheters is recommended, the risk of early catheter removal in kidney transplant must be balanced with the potential risk of perioperative urologic complications. The optimal duration of catheterization in this population remains controversial; however early removal should be considered in the appropriate patient [36, 37]. A multidisciplinary team focused on CAUTI-prevention education of nurses and other clinical staff led to a reduction in the CAUTI rate in the transplant care unit where rates had been higher than in the general hospital population .
There are no specific differences in the recommendations for maintenance of indwelling urinary catheters in transplant recipients compared with other patient populations. The Centers for Disease Control and Prevention (CDC) recommends use of aseptic technique with sterile equipment for urinary catheter insertion . In a recent randomized controlled trial in Australia, use of chlorhexidine solution for meatal cleaning at the time of catheter insertion resulted in a decreased incidence of CAUTI compared with use of sterile saline . For maintenance after insertion, however, meatal care with antiseptic solutions has shown no demonstrable benefit over routine perineal hygiene .
In addition to routine hygiene, maintenance efforts to reduce CAUTI focus on ensuring unobstructed flow of urine. Preventing kinking in catheter tubing allows for free flow of urine from the urethra to the collection bag. Lastly, keeping the collection bag below the level of the bladder and regular emptying of the collection bag prevent reflux of urine from the unsterile bag to the urethra . Involving ancillary HCP (e.g., transporters and physical therapists) in an interdisciplinary promotion of urinary catheter maintenance is important as all members of the healthcare team may be involved in the maintenance of necessary urinary catheters .
Clostridioides difficile infection (CDI) causes a spectrum of disease ranging from asymptomatic colonization or diarrhea due to mild infection to ileus, megacolon, bowel perforation, and septic shock. It is the most common HAI and poses unique infection control risks due to the environmental persistence of infectious spores.
Risk factors for CDI include frequent contact with healthcare settings, receipt of antimicrobials, hospitalization on inpatient units with high rates of overall antimicrobial use , immune compromise, poor hand hygiene compliance, and lapses in environmental disinfection. Thus it is not surprising that SOT and HSCT recipients have significantly higher rates of CDI than do general medical or surgical inpatients [44, 45].
Up to 29% of hospitalized patients are colonized with C. difficile . This colonization rate may be higher in HSCT patients and is not well described in SOT recipients . Patients who are colonized are more likely to subsequently develop symptomatic CDI . Antimicrobial stewardship, hand hygiene, and environmental disinfection are important strategies to reduce rates of both symptomatic infection and transmission.
Recommended commercial testing modalities for C. difficile include a stool toxin test as part of a multistep algorithm or nucleic acid amplification test (NAAT) alone. There are drawbacks to each type of test; two- or three-step algorithms that include a stool toxin test have relatively low sensitivity, while NAAT without patient-specific symptoms to guide testing does not differentiate between colonization and symptomatic disease. Diagnostic testing should be considered in patients with three or more unformed stools in 24 h or less, who have not had prior testing within the preceding 7 days and who do not have alternative causes of diarrhea, such as laxative use. Testing of asymptomatic patients is not recommended , and there are no recommendations to use contact precautions for patients who are asymptomatically colonized. Test of cure should not be performed to guide either treatment duration or cessation of transmission-based precautions.
For patients with diarrhea, contact precautions including gowns and gloves should be initiated preemptively pending C. difficile test results and continued if positive until 48 h after diarrhea resolution to prevent transmission to other patients from HCP hands, clothing, and mobile medical equipment. It is preferable to have patients with CDI in single-patient rooms with separate toileting facilities. In the setting of space limitations, incontinent patients should be prioritized for single-patient rooms. If cohorting is required, patients with the same strain of CDI (e.g., two patients with the C. difficile B1/NAP1/027 strain) rather than different strains can be cohorted . This information, however, may not be readily available. Shedding of C. difficile spores in the stool may be prolonged even after symptom resolution. In centers where there are high rates of CDI, maintaining contact precautions until discharge may be warranted.
Use of ABHR or handwashing with soap and water is recommended when caring for patients with CDI. Compliance with ABHR is higher than with traditional handwashing; however ABHR is not sporicidal and thus may pose a higher risk of transmission of C. difficile spores despite good compliance. In settings where there are outbreaks or sustained high rates of CDI, hand hygiene with soap and water is preferred.
Bleach or other sporicidal surface disinfectants are needed to eliminate environmental persistence of spores. Daily and terminal room cleaning with a sporicidal agent may help reduce the risk of transmission of C. difficile to patients, especially when there are high baseline rates of CDI . The addition of ultraviolet light terminal disinfection may reduce the risk of C. difficile transmission, although studies have shown mixed results [50, 51]. Despite environmental disinfection interventions that result in objective measures of improved environmental cleaning, a multicenter randomized study found no effect of this on the incidence of healthcare-associated CDI . This highlights that there are many other important factors that affect the incidence of CDI, including pre-existing C. difficile asymptomatic colonization, antimicrobial use and overuse, testing stewardship, hand hygiene, disinfection of shared mobile medical devices, and compliance with contact precautions.
Surgical Site Infections
Despite improvements in perioperative management, surgical site infections (SSIs) continue to threaten SOT recipients early after transplantation. Healthcare and antimicrobial exposures are ubiquitous in SOT, and with increased wait times, there is a parallel increased risk for MDROs. The highest rates of SSI are reported in intestinal and multivisceral abdominal organ transplants .
Evidence-based strategies aimed toward SSI reduction in the general surgical population can be applied to SOT . These include close attention to maintenance of sterility, surgical technique, minimizing operative time, and minimizing transfusion requirements. The role of the anesthesiologist has been defined and includes reducing environmental contamination, catheter and airway management, as well as perioperative temperature, oxygenation, and glycemic management [54, 55]. Organ-specific risk factors for SSI have been recently reviewed .
In centers with increased incidence of S. aureus infections, there may be a role for active surveillance and decolonization with mupirocin and/or CHG. Decrease in S. aureus SSIs has been demonstrated in cardiac and lower joint surgeries when decolonization is included as part of a care bundle . Although not specific to SSI prevention, predictive models suggest utility in thoracic transplantation with the goal of decreasing posttransplant S. aureus infections . Decolonization of SOT candidates can be problematic as durability is incomplete , and unless a live donor is available, the timing of transplant remains unpredictable.
Perioperative antimicrobial selection should be determined by the transplanted organ. Preferred antimicrobial regimens tend to be heterogeneous and transplant center-specific . Organ-specific risk factors may require modification or augmentation of regimens (i.e., addition of antifungal prophylaxis) . Although not systematically studied, alteration in prophylaxis based on donor and recipient microbiology as well as institutional antibiograms is likely warranted. Societal recommendations for dosage, including weight-based dosing, and timing including re-dosing are applicable . Extended durations are rarely warranted and should be discouraged.
Recently, the need for patient engagement in HAI prevention has been highlighted . The role of the patient and caregiver may be paramount in SSI prevention . Smoking cessation, diabetes management, and hygiene including compliance with hand hygiene and bathing can influence infection risk. Both patients and their caregivers should be encouraged to promote HCP hand hygiene and appropriate wound care. In addition, educating patients about signs and symptoms of infection can prompt early identification of potential SSIs that may prevent morbidity.
Preventing Infections Associated with the Healthcare Environment
Transplant recipients are not only at risk for the same wide variety of infections that affect patients with intact immune systems; they are also at a unique risk for infections related to bacteria, mycobacteria, and molds found in the healthcare environment. While HSCT guidelines outline specific infection prevention and control practices , there are no standard infection prevention and control strategies among SOT programs . Limiting exposure to environmental molds, such as Aspergillus, and water-related opportunistic pathogens, such as Legionella species and nontuberculous mycobacteria (NTM), should be a focus of infection prevention and control efforts in the healthcare settings. In addition, access to molecular typing may aid in the identification of potential sources and inform mitigation strategies.
Nosocomial mold infections among transplant recipients result from respiratory exposure to fungal spores. Air and water can be sources of pathogenic fungi. Opportunistic molds such as Aspergillus and Fusarium can be present in a hospital’s water supply and may be ingested or inhaled when in water droplets formed from hospital showers or sinks. Water damage to sheetrock from leaks can lead to mold growth and subsequent aerosolization of mold spores within the hospital. Plants, unwashed fruits and vegetables, and fresh or dried flowers can harbor Aspergillus. Elevator shafts may pose an additional risk, as shaft surfaces are hard to clean, air moving within the shaft can harbor mold spores, and patients may be exposed during transit within the hospital.
There have been several published reports of environmental mold infections in immune-compromised patients, including transplant recipients, related to hospital linens. Outbreaks of Rhizopus have been linked to hospital linens that have been washed in low temperatures, stored in humid and/or dusty conditions, or stored in bins exposed to dust [64, 65]. Facilities supplying linens to the healthcare setting should wash, store, and transport linens in a clean environment, use high wash temperatures, and ensure linens are completely dry prior to packaging. Hospitals should prevent dust contamination of linens during transport, keep linen storage bins clean, and not top off linens prior to patient use (first in, first out premise) .
Hospitalized HSCT recipients should be placed in protective environment (PE) rooms [13, 67]. Use of PE rooms for SOT recipients, including lung transplant recipients, is variable among transplant centers . PE rooms are designed to protect severely immune-compromised patients from human and environmental airborne pathogens. These rooms have positive air pressure in relation to the hallway, with high-efficiency particulate air (HEPA) filtration to remove particles ≥0.3 μm in diameter that can pose an infectious risk and ≥12 air exchanges per hour to bring in fresh air and remove stale air. In a tertiary care hospital setting, patients with HSCT or hematologic malignancy who had significant exposure outside of the PE room during their hospitalization had higher risk for invasive mold infections .
The differential in air pressure should be monitored continuously, ideally by automated systems that alert appropriate staff when the pressure difference is lost. In order to prevent air containing spores from outside the room getting in, and to maintain positive pressure, PE rooms should be sealed, with filling in of gaps between walls, floors, ceilings, windows, and doors .
Use of HEPA filtration is especially important when construction is conducted within or near the hospital. A heightened risk to immune-compromised patients comes from the aerosolization of mold spores during construction within or in proximity to a hospital, and outbreaks of healthcare-associated environmental mold infections have occurred in relation to adjacent construction in hospitalized immune-compromised patients .
Construction plans should include measures to control mold and should be made in conjunction with the hospital’s infection prevention and control department, who can develop an infection control risk assessment (ICRA). ICRAs in this scenario focus on measures to control and minimize airborne dissemination of fungal spores, such as resealing of hospital windows, use of portable HEPA filters in rooms of susceptible patients, use of N95 particulate respirators for patients during travel within and outside of the hospital, and planning for staff caring for susceptible patients to enter and exit the hospital away from the site of construction [66, 70].
Due to multiple potential environmental sources, hospitals should perform surveillance for healthcare-associated mold infections particularly during and after construction events and in highly susceptible patients. This can include utilization of the electronic health record or surveillance software to identify patients with radiographic changes consistent with invasive mold infections; regular review of microbiology laboratory reports for growth of Aspergillus and other opportunistic molds; monitoring of therapeutic antifungal use; and location tracing of infected patients to identify high-risk environmental exposures . Additionally, scheduled environmental assessments for water damage and dust, and environmental sampling for identification of mold, can be used to target mitigation efforts .
In addition to invasive mold infections, transplant recipients and other immune-compromised patients are at higher risk for infections due to waterborne pathogens. The hospital water supply is increasingly identified as a source of nosocomial acquisition , likely related to the size and complexity of healthcare facility water systems and the vulnerability of patients treated in these facilities. Outbreaks of infections related to water exposure within a hospital have included Legionella species, nontuberculous mycobacteria, Pseudomonas aeruginosa, and other Gram-negative bacteria. These organisms are often referred to as opportunistic premise plumbing pathogens (OPPP). Sources identified in outbreak investigations include potable water, sinks, aerators, showers, immersion tubs, ice and ice machines, and decorative fountains. Transmission of pathogens occurs through both direct and indirect contacts, ingestion, aspiration, and/or aerosolization.
Legionella, atypical mycobacteria, as well as Pseudomonas aeruginosa and other Gram-negative bacteria are normal inhabitants of drinking water. These bacteria may be chlorine- and heat-resistant and can form biofilms on plumbing surfaces, making them difficult to eradicate from a hospital’s water supply once detected . Older water systems can promote stagnation, corrosion, and the biofilm formation, thus propagating the growth of OPPP.
Healthcare-associated reservoirs for opportunistic premise plumbing pathogens and potential risk mitigation strategies in the setting of healthcare-associated cases or isolation of potential pathogens during routine sampling
Mitigation strategies for high-risk units
Potable (tap) water
Ensure that semicritical devices including respiratory devices are not rinsed in tap water (use sterile water)
During water disruptions refrain from using or drinking tap water (e.g., showering, rinsing, or ingesting)
Periodic sampling of water for Legionella spp. especially in high-risk units including organ transplant units and hematopoietic stem cell transplant units
Remove aerators or develop an appropriate maintenance and disinfection plan for high-risk units especially in the setting of detected Legionella spp. in water samples or evidence of hospital-onset disease
Discourage automated faucets due to the inability to achieve high outlet temperatures and inability to flush
Discourage decorative water features (e.g., fountains)
Discourage showers or develop an appropriate maintenance and disinfection plan of shower heads
If basins are used for bathing, a plan should be in place for disinfection of basins or the basins should not be reused
Potential disinfection methods include copper ionization, hyperchlorination, superheating, and filtration – a water management plan should be in place and reviewed periodically with infection prevention and control and facilities experts
Heighten awareness and surveillance for legionellosis, unusual nontuberculous mycobacterial infections, and increased incidence of hospital-onset respiratory infections with Gram-negative bacteria
Gram-negative bacteria including carbapenem-resistant Enterobacteriaceae
Ensure separation of handwashing sinks from sinks where contaminated waste may be disposed (e.g., hopper or utility sink)
Ensure a maintenance and disinfection plans for sinks (including drains) located in patient rooms where aerosolization or splashing may occur
Ensure that maintenance and disinfection are occurring as per manufacturer’s instructions
Heighten awareness and surveillance for nontuberculous mycobacteria after cardiac surgery including transplant
Position the device to allow vent to exhaust away from the surgical field
Plumbing design to limit dead-end pipes and subsequent water stagnation can help limit OPPP overgrowth . Other interventions include use of reverse osmosis filters on faucets and shower heads, maintaining circulating water at high temperatures with addition of cold water at the point of use (sinks, showers), or periodic superheating of the water system to limit bacterial growth in circulation [79, 80].
Legionella pneumophila and other Legionella species are opportunistic pathogens that can cause a life-threatening pneumonia in susceptible patients. Transmission occurs via inhalation of aerosols and can come from showers, faucets, or cooling towers in the community or healthcare setting. An outbreak of L. pneumophila serotype 3 among HSCT patients in a new bone marrow transplant unit in an Israeli hospital was linked to heavy contamination of potable water with the same serotype . Interventions implemented included restrictions on drinking tap water and showers for HSCT patients, in addition to superheating and hyperchlorination of the water system. An outbreak of Legionella micdadei pneumonia among kidney and heart transplant recipients at a US hospital was linked molecularly to L. micdadei isolated from hot water sources, including showers and sinks in patient rooms and the hospital-wide hot water recirculation loop . Mitigation strategies included superheating and subsequent chlorination of the water system. Legionella outbreaks have also been linked to decorative water fountains in the healthcare setting [77, 83]. Mortality from Legionnaire’s disease is 25% based on national surveillance data; however rates specific to transplant recipients are not known .
Nontuberculous mycobacteria can be found in soil, water, and dust, and these environmental sources can lead to community-acquired or nosocomial infection. NTM have been linked to multiple outbreaks in healthcare settings, often related to the hospital or municipal water supply. One such outbreak occurred among pediatric HSCT patients after the opening of a new hospital building. An increase in isolation of the rapidly growing mycobacteria M. chelonae from clinical cultures was traced to the new building’s water supply. Water samples collected from hospital faucets, showers, and ice grew M. chelonae and other NTM. Infection prevention and control efforts included use of only bottled water for consumption in HSCT patients and reinforcement of a policy to run showers for 2 minutes prior to patients entering to reduce the mycobacteria density in water . This policy had been put in place several years earlier in response to an outbreak of M. mucogenicum bacteremia linked to exposure of patients with central venous catheters to M. mucogenicum-contaminated shower water .
Another US hospital noted an increase in the incidence of M. abscessus isolated from respiratory sample cultures after opening a new hospital building, disproportionately affecting lung transplant recipients . Environmental cultures from biofilms of water sources in the hospital addition grew M. abscessus, and it was hypothesized that micro aspirations from tap water led to lung colonization and subsequent infection. Interventions to prevent and control further exposure to M. abscessus included use of sterile water instead of tap water for oral care, respiratory therapy, consumption, and enteral tube flushes for all lung and heart transplant recipients, ICU patients, and patients with disrupted GI tracts . The authors noted that low flow rates in the hospital addition’s water distribution system, put in place to conserve water, may have facilitated higher water concentrations of M. abscessus.
Disseminated NTM infections, specifically M. chimaera, have been associated with the use of extracorporeal circulation in cardiac surgeries . These heater-cooler devices (HCDs) are used ubiquitously in heart transplantation. Identification of the potential for these devices to aerosolize NTM as well as other waterborne pathogens led to several control efforts. These included revisions and a request for adherence to the manufacturers’ instructions for maintenance and disinfection of these devices; use of sterile or filtered water; and positioning the device in order to vent to exhaust away from the operative field. Although not previously routine practice, NTM should be considered in the differential diagnoses of otherwise unexplained infections in patients after cardiac surgery including SSI. Legionellosis and infections with Gram-negative bacteria have also been linked to HCDs.
An outbreak of Pseudomonas fluorescens-related febrile neutropenia in HSCT recipients was linked by molecular typing to a contaminated drinking water dispenser in a hospital in the United Kingdom. This hospital performed routine weekly pharyngeal screening for Pseudomonas carriage at baseline in hematology patients, allowing for identification of pharyngeal colonization in the absence of other positive clinical cultures . A hospital in Finland used pulsed-field gel electrophoresis to link 11 cases of Pseudomonas aeruginosa bacteremia in HSCT recipients to isolates from showers and sinks with the same PFGE pattern in their bone marrow transplant unit . No further cases of Pseudomonas aeruginosa infection with the same PFGE pattern occurred after implementation of infection control measures, which included hand disinfection, disinfection of shower pipes and shower heads, and use of hot water when cleaning. Similarly, other outbreaks due to other multidrug-resistant Gram-negative bacteria including carbapenem-resistant Enterobacteriaceae (CRE) have been linked to contaminated sinks using molecular typing including whole genome sequencing [91, 92, 93]. Separating handwashing sinks from areas used for disposal of contaminated waste and disinfection and/or reconfiguration of existing pipes or water systems are important strategies to address identified risks.
Similar to surveillance for other HAI such as CLABSI or CAUTI, use of the electronic health record to identify patients with nosocomial pneumonia can guide targeted interventions, such as testing for Legionella infection and other waterborne opportunistic pathogens in susceptible patients. Additionally, targeted environmental surveillance that includes culture of the hospital water supply in areas housing high-risk patients can identify the affected areas and guide eradication efforts . Special attention should be given to the performance of institutional hazard analyses and revisions of water management plans to ensure ongoing attention to the potential environmental risk to transplant populations and other susceptible hosts.
Colonization with Multidrug-Resistant Organisms
Multidrug-resistant organisms (MDROs) include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Gram-negative organisms including extended-spectrum β-lactamase (ESBL) or CRE. Candida auris, an emerging healthcare-associated yeast, is also considered a MDRO because of its antifungal resistance profiles, its unique ability to colonize the skin, and its persistence in the healthcare environment .
Enterococci are gastrointestinal common commensals. Gastrointestinal VRE carriage is the major reservoir of the organism in the healthcare setting. VRE can survive on surfaces, and transmission can occur via healthcare workers, mobile medical equipment, or shared toileting facilities . Similar to VRE, ESBL-producing and carbapenem-resistant Gram-negative bacteria can persist through gastrointestinal carriage.
Like VRE and multidrug-resistant Gram-negative organisms, patients tend to be the reservoir for transmission of S. aureus. S. aureus colonizes the nares and skin in up to 30% of healthy people. Patients with MRSA colonization are more likely to develop MRSA bacteremia than patients who are not colonized [96, 97]. Nosocomial MRSA infections are often associated with breaks in skin and mucosal barriers including intravascular catheters, endotracheal tubes, or recent surgery and confer significant morbidity and mortality risk [98, 99]. The epidemiology of MRSA in organ transplantation has recently been reviewed .
The prevalence of MDRO in the healthcare setting has increased globally over the last several decades [101, 102, 103]. In data reported to the CDC’s National Healthcare Safety Network, MRSA and VRE are the most commonly identified MDRO associated with device-related infections or SSI [104, 105]. SOT recipients in particular have a high prevalence of CRE [106, 107, 108, 109], and VRE colonization is common in HSCT recipients  and organ transplant candidates and recipients . In terms of CRE risk, international travel and healthcare exposures including SOT and HSCT in other countries may potentially introduce novel mechanisms of resistance to transplant units .
Risk factors for MDRO acquisition are ubiquitous in transplantation. These include high rates of antimicrobial use for both prophylaxis and treatment, frequent and/or prolonged hospitalizations, invasive procedures, high device utilization rates, and medical comorbidities such as kidney failure .
As with MRSA, MDRO colonization often precedes invasive disease. In the setting of active surveillance, liver transplant candidates and recipients with asymptomatic MRSA or VRE colonization were at increased risk for invasive MRSA or VRE infection, respectively, when compared with patients who were not colonized, and VRE colonization was associated with an increased risk of mortality . A meta-analysis of 23 studies looking at the effect of MRSA and VRE colonization in liver and other SOT recipients found a similarly increased risk of infection with colonization in the pre- and posttransplant periods . Additionally, a prospective study of liver transplant recipients with active surveillance for rectal MDRO colonization found that even intermittent colonization was significantly associated with subsequent MDRO infection . In a retrospective study of liver recipients, carbapenem-resistant Klebsiella pneumoniae colonization was a significant risk factor for invasive carbapenem-resistant K. pneumoniae .
Interventions such as antimicrobial stewardship; monitoring of environmental disinfection – including disinfection of mobile medical equipment – monitoring of hand hygiene compliance; active surveillance; antiseptics applied to the skin, nares, and oral mucous membranes; and standard and contact precautions can help reduce MDRO colonization and prevent transmission to other patients . Measures to lower the risk of invasive infection include the instating and monitoring compliance with the aforementioned evidence-based bundles to insert and maintain vascular and urinary catheters and oral care and ventilator management to prevent lower respiratory tract infections in ventilated patients.
The CDC and European guidelines recommend the use of standard and contact precaution for patients with MDRO colonization or infection [115, 116, 117]. In select settings the role of contact precautions and the duration of contact precautions may require reexamination especially for ESBL producers [109, 118], MRSA and VRE. Two large trials found these precautions were no more effective than standard precautions in reducing MRSA or VRE transmission [119, 120]. A systematic review and meta-analysis of 14 studies found that discontinuing contact precautions for MRSA and VRE did not lead to increased infection rates . An additional meta-analysis of nine studies looking at infection prevention and control measures to reduce transmission of VRE found that improved hand hygiene compliance, but not contact precautions, decreased the VRE transmission rate . Additionally, contact precautions are associated with fewer bedside visits from healthcare personnel and more preventable adverse events . In the setting of outbreaks, the use of contact precautions may be warranted .
Active surveillance for MDROs in asymptomatic patients can identify patients at higher risk for invasive infection and facilitate targeted interventions, such as skin and mucous membrane antisepsis to reduce MDRO colonization or broader empiric antimicrobial management for sepsis. Recent publications have shown that active surveillance with implementation of standard plus contact precautions for carbapenem-resistant Enterobacteriaceae (CRE) reduces CRE colonization and infection [125, 126]. However, there is a lack of strong evidence that universal screening for CRE in asymptomatic pre- and posttransplant recipients is of benefit .
In a multicenter cluster randomized trial, daily chlorhexidine bathing of patients in ICUs and HSCT units reduced the risk of MDRO acquisition and subsequent bloodstream infection . A large cluster randomized trial of ICU patients in multiple hospitals found that universal decolonization with nasal mupirocin and CHG bathing and, to a lesser degree, targeted MRSA screening and decolonization were more effective than active MRSA surveillance with standard and contact precautions in reducing rates of MRSA colonization and bloodstream infection . In a single center, active surveillance for MRSA colonization in liver transplant recipients with targeted infection control interventions (i.e., contact precautions, cohorting, intranasal mupirocin for decolonization) reduced MRSA colonization and invasive infection .
Respiratory viral infections can contribute to significant morbidity in the immune-compromised host . During periods of intense immunosuppression, early after transplantation or in the setting of GVHD, both SOT and HSCT recipients are at increased risk of viral infection-related complications. These potential complications include progression from upper respiratory tract infections to lower tract infections and pneumonia, bacterial and fungal superinfections, and respiratory failure . In addition, respiratory viral infections have been associated with bronchiolitis obliterans in lung transplant recipients and long-term airflow decline in HSCT recipients.
Molecular diagnostic platforms provide both rapid and accurate results and should be utilized early. Staff should be encouraged to adhere to standard precautions including hand hygiene, disinfection of shared equipment, and respiratory hygiene and cough etiquette. Due to the high rates of morbidity observed in HSCT recipients, some centers recommend universal masking either year-round or during periods of increased community activity of respiratory syncytial virus (RSV) or influenza . Systematic evaluations have not been performed supporting universal masking, and controversy exists regarding the preferred mask [133, 134]. Moreover, contact precautions (use of gowns and gloves) are recommended for some respiratory viruses in addition to standard precautions .
Persistent and asymptomatic viral shedding is common in immunosuppressed populations . Thus, defining the optimal duration of transmission-based precautions in the inpatient setting is difficult, and variability exists between centers.
Although traditionally influenza season commences in the Fall and can persist well into Spring, novel influenza viruses with pandemic potential may emerge at any time. Indeed, many lessons were learned in 2009 with the emergence of H1N1 in both the community and healthcare settings [135, 136].
Nosocomial acquisition and healthcare-associated outbreaks among transplant recipients (both SOT and HSCT) have been reported. In general, an outbreak investigation is initiated in the setting of a single hospital-onset case. Updated guidance regarding outbreak control is available and is applicable to both the SOT and HSCT patients . In order to avoid nosocomial and/or sustained transmission, institutions are recommended to encourage vaccination, screen for symptoms, emphasize appropriate patient placement and early diagnostics, initiate early treatment, and establish a procedure for addressing ill healthcare personnel.
Annual vaccination with inactivated influenza vaccine for patients and household contacts is strongly encouraged. It is important to note that both antibody- and cell-mediated immune responses are likely suboptimal early posttransplantation . However, vaccination of SOT and HSCT patients has been associated with improved outcomes . Potential strategies to improve immune response in the SOT population include offering booster doses or high-dose vaccine [140, 141]. Current recommendations include initiating annual influenza vaccine 6 months after HSCT. In the setting of increased community activity, vaccination can be offered as early as 3–4 months after HSCT .
During influenza season aggressive symptom screening of HCP, patients, and visitors is recommended. Many institutions limit nonessential visitors and enforce visitor age restrictions on high-risk units (i.e., HSCT units). Patients and visitors should be educated regarding symptoms, respiratory hygiene, and cough etiquette, and ill visitors should be excluded.
Influenza is transmitted through large droplets generated through talking, coughing, and sneezing. Transmission can occur through indirect contact with a contaminated environment and inoculation of mucosal surfaces. Airborne transmission can also occur especially in the setting of aerosolizing procedures, but the superiority of using respirators over surgical masks has not been established . Currently, in addition to standard precautions, droplet precautions are recommended to reduce the risk of transmission. Patients should be prioritized to a single room when influenza is suspected or confirmed. Cohorting of symptomatic cases based on strain type may be prudent; however cohorting strategies should be discussed with infection preventionists or public health authorities.
In the setting of sustained transmission, nonessential admissions should be delayed, and consideration should be given to redirecting new admissions. Patient transport and movement should be minimized. Symptom screening of staff should be performed daily, and ill staff should immediately mask and be removed from direct patient care. Current recommendations are to exclude these individuals from working with patients until afebrile for 24 h without antipyretics and no earlier than 5 days after illness onset. In the setting of HSCT, the CDC recommends work exclusion or temporary reassignment for as long as 7 days from symptom onset.
Chemoprophylaxis with a neuraminidase inhibitor (i.e., oseltamivir) should be offered to roommates and ward mates of patients with influenza, irrespective of vaccination status . Monitoring and audit of both hand hygiene and environmental disinfection should be prioritized. Patients should be empirically treated when influenza is suspected pending diagnostic results . HCP who are not vaccinated should be vaccinated and offered chemoprophylaxis for 2 weeks after vaccination. In the setting of antigenic drift of circulating virus from vaccine strains, chemoprophylaxis should be considered for all influenza-exposed HCP irrespective of vaccination status.
Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) has been associated with morbidity in both SOT and HSCT . The incidence of nosocomial RSV infections often mirrors that of increased community activity. Frequently increased activity is seen during the Fall and early Winter. Transmission is due to direct inoculation of mucous membranes and inhalation of droplets or by indirect inoculation by fomites from a contaminated environment. Outbreaks have occurred in both inpatient and ambulatory settings .
Despite evidence of droplet transmission, the routine use of masks is controversial. There has not been conclusive evidence suggesting masks decrease transmission even in the setting of an outbreak. The conjunctiva and nasal mucosa are major portals of entry, and the addition of masks and eye protection should be considered as part of standard precautions if exposure to respiratory secretions is anticipated . A recent systematic review suggested that eye protection was more effective at reducing transmission than the addition of a mask as part of a multiple component outbreak response . Patients with known or suspected RSV should be prioritized for single-patient rooms and placed in contact precautions. Cohorting, if necessary, should be coordinated with an institution’s infection prevention and control department.
In the absence of an effective vaccine or chemoprophylaxis, primary prevention of nosocomial transmission is paramount. Prophylaxis with palivizumab, a RSV-specific monoclonal antibody, is variable among surveyed SOT centers [146, 147]. The American Academy of Pediatrics offers guidance regarding the use of palivizumab in pediatric populations during RSV season [148, 149, 150]. Off-label use in adults in an outbreak setting has been described .
Like influenza, in the setting of an outbreak of RSV, aggressive screening of visitors, HCP, and patients should occur. Visitor limitations and age restrictions may be required. Cohorting of both patients and staff and restricting patient movement as well as augmented monitoring of hand hygiene and environmental disinfection are recommended. In addition, HCP and visitors are encouraged to practice respiratory and cough etiquette. Ill HCP should be immediately removed from patient care; however, the optimal duration of exclusion or reassignment remains unclear. It should be noted that often individuals can be asymptomatic and can serve as a source for ongoing transmission . Active laboratory surveillance in the absence of symptoms cannot be categorically recommended but can be considered in settings of sustained transmission .
Contrary to both RSV and influenza, adenovirus infections do not demonstrate seasonality . In immunocompetent hosts adenovirus causes a variety of infections depending on serotype. Infections can range from the asymptomatic or mild upper respiratory tract infection to epidemic keratoconjunctivitis and gastroenteritis. More serious infections that more often plague the immune-compromised host include pneumonia, hepatitis, hemorrhagic cystitis, encephalitis, and disseminated disease [153, 154].
Adenovirus is transmitted through direct contact with a patient’s environment or via fomites and respiratory secretions. Serotypes associated with gastroenteritis can be transmitted through the fecal-oral route. Adenovirus requires both contact and droplet precautions in addition to standard precautions. Due to prolonged shedding, it is recommended that patients remain in precautions for the duration of the hospitalization .
Like RSV, there are no proven prophylactic strategies to prevent adenovirus transmission in the setting of an outbreak. The strategies outlined for both influenza and RSV including symptom screening, visitor restriction, increased audit of hand hygiene, PPE compliance, and disinfection are recommended. Adenovirus can be quite tenacious, and evaluating the role of the environment and potentially contaminated shared equipment is vital in stemming a potential outbreak . The live vaccine currently available only to US military recruits is contraindicated in SOT and HSCT.
Other Respiratory Viruses
Respiratory viruses frequently encountered in the healthcare setting and recommended transmission-based precautions and prophylaxis strategies
Transmission-based precautions in addition to standard precautions
Recommended duration of precautions
Contact and droplet precautions
Duration of hospitalization
Fall to Winter
24 h after resolution of fever and respiratory symptoms or 7 days after symptom onset whichever is longer – viral shedding can be prolonged
Vaccination of HCP, patients, and household contacts with inactivated influenza vaccine
Neuraminidase inhibitor (e.g., oseltamivir) prophylaxis in the setting of increased incidence or contraindication to vaccination
Neuraminidase inhibitor (e.g., oseltamivir) prophylaxis in the setting of exposure irrespective of vaccination status
Duration of illness
Depends on subtype, PIV3 more common in Spring and Summer but can be year-round
Duration of illness – viral shedding can be prolonged
Respiratory syncytial virus
Fall to early Winter
Duration of illness – viral shedding can be prolonged
Palivizumab recommended for high-risk patients as per AAP guidelines
Varicella may be transmitted through direct contact with the rash or through airborne transmission during primary or disseminated infection. Additional transmission-based precautions may be recommended for patients on minimal immunosuppression with uncomplicated dermatomal zoster that be covered; however standard precautions can be used once disseminated disease has been excluded. Patients with primary VZV or herpes zoster involving more than two adjacent dermatomes should be placed in airborne and contact precautions. Patients should remain in airborne and contact precautions until lesions are dry and crusted, which can take longer in the profoundly immune compromised.
The advent of the varicella zoster vaccine has been pivotal in the prevention of primary varicella infections (chickenpox), and the timing of vaccination in transplant candidates has been reviewed [140, 156, 157]. In HSCT, patients can be vaccinated if no longer on immunosuppression and if over 2 years from HSCT without evidence of GVHD [157, 158]. Household contacts should receive age-appropriate VZV vaccinations. Transplant recipients should be isolated from contacts recently vaccinated with live-attenuated vaccines who develop a varicella-like rash. HCP are considered immune to VZV with laboratory confirmed immunity or written documentation of receipt of two doses of varicella vaccine .
In the setting of an exposure to varicella, nonimmune household contacts are encouraged to seek immunization. In terms of herpes zoster vaccination, household contacts should preferentially be offered the inactivated subunit vaccine rather than the live-attenuated vaccine. A categorical recommendation regarding subunit herpes zoster vaccine in SOT cannot be given at this time; however safety and efficacy data are emerging and trials are ongoing .
In the setting of nonimmunity, administration of Varicella zoster immune globulin (VZIG) within 10 days of an exposure is recommended . Immunosuppressed patients with significant exposure may be required to furlough or be placed into airborne and contact precautions for 8–21 days postexposure. This period can extend to up to 28 days in the setting of receipt of VZIG. This recommendation is based on the average incubation of VZV being 2 weeks and transmission occurring 5–6 days prior to onset of the rash.
Use of antivirals for postexposure prophylaxis has not been systematically evaluated. It can be considered in the setting of patients unable to receive passive prophylaxis prior to 10 days postexposure. Current recommendations include a 7-day course of acyclovir or valacyclovir beginning 7–10 days after exposure. Many recommend longer durations.
In 2018–2019, the resurgence of measles worldwide after eradication in many countries has led to a refocus on the prevention of measles in the healthcare setting [161, 162]. Use of the live vaccine is contraindicated in SOT. In the setting of HSCT, vaccination is recommended in the absence of ongoing immunosuppression and GVHD. Current recommendations are to consider vaccination over 2 years from transplant. Irrespective of timing of SOT or HSCT, however, vaccination of household contacts is encouraged [140, 163].
Measles is highly contagious and requires immediate recognition and placement in airborne precautions. Patients are infectious 4 days prior to and 4 days after onset of the rash. The classic prodrome of cough, coryza, and conjunctivitis can be subtle and may be missed. In the setting of potential exposure and ongoing transmission, HCP should remain vigilant and err on the side of caution.
In the setting of an exposure where patients do not have documented immunity (defined as receipt of two doses of MMR vaccine or laboratory confirmation of immunity), transplant patients should receive immunoglobulin within 6 days of exposure . In most cases patients with exposure who do not have evidence of immunity will be asked to quarantine with monitoring for symptoms for 21 days after exposure if no receipt of postexposure prophylaxis and 28 days after exposure with receipt of immunoglobulin.
Healthcare Personnel Vaccination
HCP, like household contacts, are encouraged to receive all age-appropriate vaccinations including those where inactivated vaccines are not available. Currently, vaccination against influenza, varicella, measles, mumps, rubella, pertussis, and hepatitis B is recommended . In the setting of inadvertent exposures to communicable diseases, healthcare providers should contact their institutional infection prevention and control department and occupation health providers in order to determine the role of prophylaxis, reassignment, or furlough in the case of documented nonimmunity and significant exposure.
Recommendations for infection prevention and control practices in the general inpatient and ambulatory population are applicable to both SOT and HSCT populations. It should be noted, however, that these populations do pose additional infection prevention challenges due to endogenous and exogenous immunosuppression, frequent exposure to healthcare, and antimicrobial exposures. Promotion of vaccination of patients, families, and HCP affords some protections from viruses and bacteria; however, vaccine hesitancy continues to exist in some communities. It is important for institutional leadership, transplant leadership, and infection prevention and control experts to partner and ensure that these unique populations are included in process improvement initiatives including those directed toward HAI prevention.
Hand hygiene compliance plays a pivotal role in preventing healthcare-associated infections.
Care bundles and interdisciplinary teamwork have been associated with reduction in device-associated infections like central line-associated bloodstream infections and catheter-associated urinary tract infections in transplant patients.
Transplant candidates and recipients are at increased risk for infections with environmental and waterborne pathogens, and mitigation strategies are available including patient placement, infection control risk assessments at the time of construction, and comprehensive water management plans.
The use of molecular typing can aid in identifying the potential sources of outbreaks and inform mitigation strategies.
Vaccination of healthcare personnel, household contacts, and patients can prevent severe illness from communicable diseases like influenza and reemerging infections like measles.
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