Infection Prevention and Control in Hematopoietic Stem Cell Transplant Patients
Leilani Paitoonpong
Dionissios Neofytos
Sara E. Cosgrove
Trish M. Perl
BASIC CONCEPTS OF HEMATOPOIETIC STEM CELL TRANSPLANTATIONS
Bone marrow or hematopoietic stem cell transplantation (HSCT) is a lifesaving therapy for many malignancies and genetic or acquired hematologic syndromes. Worldwide, over 25,000 allogeneic and 30,000 autologous HSCTs were performed in 2009 (1). HSCTs are the transfer of hematopoietic stem cells from one individual to another (allogeneic HSCT) or the return of the previously harvested cells to the same individual (autologous HSCT) (1). HSCT is used in the treatment of numerous conditions, including hematologic and other malignancies and nonmalignant disorders (i.e., bone marrow failure syndromes, congenital immunodeficiencies, enzyme deficiencies, and hemoglobinopathies) (1,2). Prior to transplantation, the recipient’s own marrow is fully or partially ablated to allow the engraftment of new bone marrow (1,2). Recipients receive a conditioning regimen that usually includes high-dose chemotherapy with or without total body radiation. After the conditioning regimen is completed, the graft is infused. At this point, the host is usually granulocytopenic and the peripheral neutrophil count has reached its nadir. The patient remains granulocytopenic and profoundly immunosuppressed until the donated or reinfused stem cells engraft. The time to engraftment depends on a number of factors and usually takes 2 to 4 weeks. Recovery of marrow function is accompanied by a prolonged, progressive restoration of the recipient’s immunologic competence (1,2).
The most serious complication of allogeneic transplantation is graft versus host disease (GVHD), which occurs when immunologically competent cells target antigens on the recipient’s cells (3,4). The potential immunologic phenomena that accompany foreign cell transplantation are minimized by closely matching the human leukocyte antigen (HLA) of the donor and recipient (5,6). In patients undergoing allogeneic HSCT, additional immunosuppression, such as cyclosporine, corticosteroids, and antithymocyte globulin, or other therapies, may be required to minimize the immunologically mediated complications, such as GVHD (3, 4 and 5,7, 8 and 9). Some degree of GVHD is desirable, because it produces a graft versus tumor effect, which results in lower relapse rates (10). GVHD occurs in acute or chronic forms and primarily affects the skin, liver, and gastrointestinal tract (3,4).
High-risk HSCT for GVHD includes stem cell source (unmatched or unrelated donor-recipients), types of manipulation to the stem cells, and conditioning regimens. For instance, nonmyeloablative conditioning regimens, also known as reduced-intensity conditioning (RIC) regimens, have been increasingly used (2,11). In these procedures, patients undergo less aggressive chemotherapy or immune-suppressive therapy prior to allogeneic transplant, so there is not complete ablation of the bone marrow (11). This strategy decreases chemotherapy-related toxicities such as mucositis and end-organ toxicity and the ability to treat older or sicker patients. However, as the recipient’s bone marrow is not fully ablated, the risk for GVHD has become a significant problem (9,12, 13 and 14).
The recipient serves as his own donor in autologous HSCT transplants. Bone marrow stem cells are collected prior to treatment for the underlying disease. The most serious complication of this type of HSCT is relapse of the underlying disease. Purging is a technique that eliminates malignant cells from the recovered marrow and is used to prevent this complication.
In the past, bone marrow stem cells were obtained directly from the marrow space by repeated aspiration from the iliac crest. More recently, stem cells circulating in the peripheral blood are collected as there may be more rapid engraftment and, in some studies, higher recipient disease-free survival (15, 16, 17 and 18). The major limitation of allogeneic peripheral blood stem cell transplantation is the high risk of developing GVHD, since approximately a 10-fold greater number of T cells can be found in peripheral blood grafts than in the bone marrow (19). Umbilical cord blood grafts, collected from the umbilical vessels in the placenta at the time of delivery, may also be used for HSCT. Umbilical cord blood graft cells are considered naïve hence associated with lower GVHD risk (20). The major disadvantages of blood as the HSCT source are the limited cell dose and delayed engraftment (1,21).
RISK FACTORS FOR INFECTION
Risk factors for infection among HSCT recipients can be classified as endogenous, including those related to the host and recipient, and exogenous, including those related
to administered conditioning regimens and high-dose steroids for GVHD and the environment of care.
to administered conditioning regimens and high-dose steroids for GVHD and the environment of care.
Host and Pretransplant Factors
The patients’ overall state of health is often compromised at the time of transplant with a predisposition to infection from either their underlying illness or any previous treatments received (22). Age considerably increases the risk of GVHD in allogeneic transplantation, and therefore the risk of infection (23). The recipient’s underlying disease may be associated with immune function impairment; for instance, chronic lymphocytic leukemia and multiple myeloma are associated with deficient humoral immunity (24,25). The more advanced the patient’s underlying disease at the time of transplant, the higher the risk of infection may be (1). The intensity of previously administered regimens may also influence the host’s immunity (1).
Transplant-Related Factors
Types of conditioning regimens, transplant source, and donor-recipient matching are the major transplant-related variables that dictate the risk for infectious complications. Conditioning-related mucositis and degree or/and duration of cytopenias represent the major risk factors for infection during the pre-engraftment period. Nonmyeloablative conditioning regimens have been associated with lower infection risk compared to fully ablative regimens, in part because of shorter duration of neutropenia and less mucosal damage (26). The above observations appear most likely in the early period after HSCT. However, during the late posttransplant period, mostly correlating with GVHD, the risks for late (after engraftment) viral and fungal infections persist (26,27). In addition, stem cell source may impact the risk for infectious complications: lower in peripheral blood graft and higher in cord blood transplants, in part, due to slower engraftment in the latter (28). The type of transplant may also affect the risk of infection: higher risk with unmatched or unrelated allogeneic (in part due to higher risk for GVHD and associated treatments) and lower risk with autologous or matched related allogeneic HSCT (1). Stem cell manipulation, such as T-cell depletion, may lead to higher rates of infections (1,29, 30 and 31).
Environmental Factors
During the preparative and early posttransplant periods, HSCT recipients are usually hospitalized; hence, the hospital environment represents a major potential source for infections. The source can be related to the facility and the physical environment, the care provided including treatments and equipment, and personnel, visitors, and other human interactions.
Based on serial surveillance cultures and cultures from normally sterile body sites obtained over a 2-year period among patients with acute myeloid leukemia, most infections developed from the patients’ endogenous flora; however, 47% of patients became colonized with healthcare-associated microorganisms (32). Ultimately, 39/43 (91%) patients who developed bacteremia were colonized with the implicated microorganism prior to developing a bloodstream infection (32).
Healthcare workers’ hands are another potential source of microorganisms. Schimpff et al. (32) found that the hands of 43 out of 126 (34%) healthcare workers caring for leukemic patients were colonized with gram-negative microorganisms or Staphylococcus aureus. Hands can become contaminated by lotions or contaminated soaps (33). For example, 12 of 25 (48%) HSCT recipients became colonized or infected (9 of 25; 36%) with Paecilomyces lilacinus after exposure to a contaminated, pharmaceutically prepared skin lotion (34). Healthcare workers and other patient contacts transmit microorganisms in other ways. Contact with such infected or colonized visitors and staff, many of whom may be asymptomatic, increases the risk of respiratory viral infections. Clearly, the season of the year the patient receives their HSCT and transplant-related care would dictate the risk of developing these infections (35, 36, 37 and 38).
Treatments and the environment can also lead to infections in this population. For instance, institutional water is a potential source of microorganisms such as gramnegative rods, Pseudomonas species, Legionella species, and Mycobacterium species and fungi (39, 40, 41, 42, 43, 44 and 45).
At another institution, seven of eight immunocompromised patients developed Pseudomonas aeruginosa septicemia (46). The microorganism was also isolated from mouthwash used by the patients, the water, and two sinks (46).
One outbreak of Stenotrophomonas maltophilia infections among allogeneic HSCTs was linked to a single room on the unit, although no source was found (47).
Heating and air conditioning systems can aerosolize and facilitate the spread of Aspergillus conidia. Arnow et al. (48) demonstrated that the mean concentration of A. fumigatus and A. flavus spores in the air correlated with the incidence of invasive aspergillosis (IA). When the Aspergillus concentration was 0.02 colony-forming units (CFU)/m3 of air, the incidence of invasive Aspergillus infections among high-risk patients was 0.3% (48). However, when the Aspergillus concentration rose to 1.1 to 2.2 CFU/m3 of air, the incidence of Aspergillus infections among highrisk patients rose to 1.2% (48). Notably, it is not entirely clear what the minimum concentration of Aspergillus spores in the air is to cause disease. Rhame et al. (49) reported that 5.4% of HSCT recipients developed IA when the mean concentration of A. fumigatus was 0.9 CFU/m3. Sherertz et al. (50) did not identify any cases of IA when 0.0009 CFU/m3 of Aspergillus was measured in air samples. Thio et al. (51) noted that air samples obtained on units that house highrisk patients must be obtained using appropriate high-volume samples. Multiple outbreaks of Aspergillus infection reported in the literature have illustrated the risks associated with construction and/or renovation and suboptimal maintenance, cleaning, and protection of the environment. Patients housed outside of a high-efficiency particulate air (HEPA)-filtered laminar airflow environment are at a 10-fold higher risk for developing healthcare-associated Aspergillus infection (50).
By the time HSCT recipients return home, their immune systems have been partially reconstituted, although environmental sources remain an ongoing potential source of infection. Clearly, the variety of exposures and variables makes it very difficult to study the effect of environmental factors for an infection after discharge. Prospective, well-designed studies are required to be able to make any further conclusions.
Risk Periods of Infectious Complications
The risk periods for infectious complications are traditionally divided into pre-and postengraftment. The former includes the time from initiation of the conditioning regimen to the infusion of the transplant and extends through engraftment. The latter starts from engraftment and is commonly divided into the early (up to 100 days after HSCT) and late phases (>100 days after HSCT).
Pre-Engraftment Host Risks
The major risk factors during the pre-engraftment period include mucositis and neutropenia associated with the administered chemotherapy and skin breakdowns from central venous catheters (1). Infections appear at a median of 6 days after the transplant, with 10% of the infections occurring in the pretransplant period (52). During this early period after HSCT, most patients develop neutropenic fever and 35% to 71% of patients may develop an infection, with an estimated overall infection rate during this period of 18 infections per 1,000 patient days (52, 53 and 54). Engels et al. (54) reported that 30% and 55% of autologous and allogeneic HSCT recipients, respectively, developed infections during the early phase of HSCT (p < .01), and the risk of infection correlated with the severity of neutropenia. Among 35 autologous HSCT recipients with early infectious complications, the following factors were found to be independent mortality predictors: male gender, total body irradiation, low pretransplant albumin, and mucositis or diarrhea (53).
Neutropenia Innate immunity is disrupted early in HSCT manifested primarily by the conditioning-associated neutropenia that occurs in the immediate posttransplant period and that coincides with the period when the patient’s natural barriers to infection are most likely to be breached (22). In addition to being decreased in numbers, the neutrophils are functionally impaired and display decreased chemotaxis (22). The risk of infections is related to both the duration and degree of neutropenia, with the risk of infection increasing sharply when the absolute neutrophil count (ANC) falls below 500 mm3 (55). In one study, the risk of serious infections was 5 and 43 infections per 100 admissions when the ANC was above and below 500 cells/mm3, respectively (55). Granulocytopenia allows for otherwise minor localized infections to disseminate. Prolonged neutropenia may predispose to infections due to pathogens resistant to multiple antimicrobial agents (e.g., S. maltophilia, Acinetobacter species), which may in part be due to the selective pressure of antibiotic therapy administered earlier in the course of the neutropenia.
Mucositis Conditioning-related oral and gastrointestinal mucositis occur in the vast majority of patients undergoing HSCT (56, 57 and 58). Additionally, it can be induced by regimens used to prevent GVHD (59). Breaches are created in the normal mucosal barrier of the oropharynx and gut that results in translocation of bacteria or fungi (mainly Candida species) (60,61). Mucositis-associated candidemia and viridans Streptococcus bacteremia post-HSCT are well described (61, 62, 63, 64, 65, 66, 67, 68 and 69). In a prospective study involving severe oral mucositis among autologous HSCT recipients, severe mucositis was associated with higher rates of fever and microbiologically confirmed infection, duration of antibiotic administration, and use of total parenteral nutrition (TPN) (70).
Postengraftment Host Risks
Several factors influence the degree of immunosuppression experienced after HSCT following recovery of neutrophil function. In allogeneic HSCT, the presence of GVHD greatly increases the risk of infection by prolonging the impairment in cellular immunity, by virtue of GVHD itself and the associated treatments (71). After the resolution of neutropenia, defects in acquired immunity become apparent as the spectrum of infections switches to include those ordinarily prevented by intact humoral and cellular immunity. Both allogeneic and autologous HSCTs are associated with quantitative decreases in lymphocyte counts (72). Furthermore, CD8+ suppressor cell populations recover sooner than the CD4+ helper cells (22). Thus, although the absolute lymphocyte count recovers to normal by the second month posttransplant, cellular immunity remains impaired by an abnormal CD8+/CD4+ ratio for at least a year after transplantation (72). In certain cases, the immune deficiency state can be prolonged for several years after transplantation (1). In addition, B-cell recovery may take up to 6 months posttransplant (1). In fact, an association between chronic GVHD and pneumococcal infections has been reported (73,74). Notably, Witherspoon et al. demonstrated that HSCT recipients 180 days posttransplant without chronic GVHD, had antibody responses indistinguishable from those of normal donors compared to patients with chronic GVHD (75). Other infections can occur during this period primarily due to impaired cell-mediated immunity, including infections caused by Aspergillus species, CMV, VZV, and Pneumocystis jiroveci (1)
INCIDENCE AND PREVALENCE OF HEALTHCARE-ASSOCIATED INFECTIONS
The incidence and prevalence of healthcare-associated infections among patients undergoing HSCT have not been well studied. In an early study, 12% of patients hospitalized in an oncology center developed a healthcare-associated infection (76). The highest incidence of healthcare-associated infections occurred among patients with acute myelogenous leukemia, 30.5 per 1,000 patient days (76). Among patients with acute lymphocytic leukemia, non-Hodgkin’s lymphoma, Hodgkin’s disease, and breast cancer, the reported rates were lower, 16.7, 13.4, 5.4, and 3.3 per 1,000 patient days, respectively. Carlisle et al. performed a prospective observational study over a 42-month period among neutropenic patients with leukemia and solid organ malignancies, of whom 8% had undergone an HSCT (77). Four hundred and forty-four infections were identified among 920 patients during 9,582 days of neutropenia. Overall, 48.3 infections occurred per 100 neutropenic patients (46.3 infections per 1,000 days of risk). The rates of site-specific healthcare-associated infections per 100 neutropenic patients were 13.5 for bloodstream infections, 5.7 for urinary tract infections, 5.5 for respiratory tract infections, and 3.4 each for skin and gastrointestinal infections. In 88% of infections, pathogens were identified; 35% of pathogens were classified as gram-positive cocci,
27% as gram-negative bacilli, 18% as Candida species, 9% as gram-positive bacilli, 6% as viruses, and 4% as Aspergillus. Dettenkofer et al. (78) reported 48% of 351 German HSCT recipients developed healthcare-associated infections. The most common cause of infections were catheter-related bloodstream infection, pneumonia, and gastroenteritis (78). The main pathogens were coagulase-negative staphylococci (36.3%), Clostridium difficile (20.4%), and enterococci (78).
27% as gram-negative bacilli, 18% as Candida species, 9% as gram-positive bacilli, 6% as viruses, and 4% as Aspergillus. Dettenkofer et al. (78) reported 48% of 351 German HSCT recipients developed healthcare-associated infections. The most common cause of infections were catheter-related bloodstream infection, pneumonia, and gastroenteritis (78). The main pathogens were coagulase-negative staphylococci (36.3%), Clostridium difficile (20.4%), and enterococci (78).
Infections that occur more than 3 months after HSCT have not been well studied, as the vast majority of those patients have been discharged by that time. Hoyle and Goldman canvassed 18 of 22 centers performing HSCT in the United Kingdom to determine the prevalence of infections that developed at least 3 months after transplant (79). Six percent of HSCT recipients were readmitted for a serious infection. The most common microorganisms causing serious infections included cytomegalovirus (CMV), Pneumocystis jirovecii, Streptococcus pneumoniae, Pseudomonas species, and Aspergillus species (79). Other groups have shown that 6 months or more after HSCT, recipients remain at increased risk for S. pneumoniae infections and Pseudomonas pneumonia (80,81). More prospective studies are needed to determine the risk of healthcare-associated infection among recipients of HSCTs and bridge the inpatient/outpatient care model that is being adopted by many HSCT centers.
SITE-SPECIFIC INFECTIONS
Bacteremia and Catheter-Related Infections
Bacteremia or bloodstream infection (BSI) is reported to be the most common infections in HSCT recipients. The incidence is estimated to be 38.6% per 100 patients based on a 249 episodes of bacteremia occurring over 4 years among 172 patients followed longitudinally (82). In this series, 82% of these infections occurred within 30 days of HSCT, whereas 18% occurred after this time period. The most common microorganisms included coagulase-negative staphylococci and viridans streptococci (82). Similarly, Almyroudis et al. (83) demonstrated that 170 BSI occurred among 298 HSCTs. Twenty-two percent of all HSCT recipients developed a BSI during the pre-engraftment period, while 19.5% developed a BSI after engraftment (83). The most common pathogens during pre-engraftment and postengraftment were viridans streptococci, Enterococcus faecium, and coagulase-negative staphylococci (83). All except one patient in this study had an indewelling intravascular catheter (83).
In a study from Spain, intravascular catheters were the source of BSI in 44% of HSCT recipients (84). Vascular access catheters are used in HSCT patients for an extended period of time. Most HSCT recipients have central venous access especially in the pretransplant phase and the preengraftment phase for delivery of conditioning regimens, stem cells, and other supportive treatments (85,86). However, it is difficult to determine the risk of infection because of variations in the definitions of infection employed, host and treatment factors as mentioned above, and the types of catheters used. In a study of 123 patients who underwent HSCT, 139 double-or triple-lumen catheters were placed and a catheter-related infection occurred in 22 (15.8%); 127 of the 139 catheters were placed and remained in place for a mean of 65 ± 55 days (87). The most common microorganisms causing BSI in most series were gram-positive bacteria, especially coagulase-negative staphylococci (78,85,88, 89 and 90). HSCT recipients with tunneled catheters are also at risk for catheter-related bloodstream infection, most commonly due to coagulase-negative staphylococci (91, 92 and 93). Among 242 HSCT recipients with indwelling, tunneled catheters who had daily blood cultures drawn, 5.28 patients per 1,000 catheter days developed a catheter-related bloodstream infection and 2.59 per 1,000 catheter days developed an exit site infection. Sixty-five percent of these infections occurred during neutropenia (94). Although subcutaneous ports are believed to be associated with lower infection rates, studies are needed to document this finding in HSCT patients (95).
Risk factors for healthcare-associated BSIs among HSCT recipients include an allograft from a matched unrelated or partially matched family donor, GVHD prophylaxis without methotrexate (MTX), presence of a tunneled catheter, and duration of TPN. A Dutch multicenter study on high-dose chemotherapy followed by peripheral stem cell transplantation in high-risk breast cancer patients demonstrated that factors predictive of BSI were duration of neutropenia >10 days, use of catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN (85). An outbreak of catheter-related polymicrobial bloodstream infections among 13 HSCT outpatients was reported in one study (96). Risk factors included use of predrawn saline flush solution in which multiple doses were obtained from single-dose preservative-free vials (96).
The Centers for Disease Control and Prevention (CDC) has developed guidelines for the prevention of catheterrelated BSI, and these should be followed for all HSCT patients with intravascular catheters (97). Recommendations in these guidelines should be followed when catheters are inserted and maintained. Given that many patients are discharged home with indwelling catheters, education regarding prevention of catheter-associated infection should be provided to patients and caregivers, including the recommendation that contact with tap water at the catheter site should be avoided (97) (see also Chapter 17).
Pneumonia
Pulmonary complications occur during the early and late periods after HSCT and are associated with significant morbidity and mortality. They can be either noninfectious or infectious in origin. For infectious processes, the source may be from endogenous reactivation, acquired from the environment or from person-to-person contact. The most common early-onset complication is interstitial pneumonitis, occurring in 10% to 40% of patients and usually associated with CMV coinfection (98,99). During the first 100 days after HSCT, only 20% of pneumonias are caused by bacteria, and these are usually due to gramnegative bacilli (91). Sinopulmonary infections caused by other microorganisms and obstructive airway disease associated with chronic GVHD are among the late-onset problems.
HSCT patients are at a higher risk than general hospital patients for developing healthcare-associated pneumonia, and 40% to 60% develop adverse pulmonary sequelae (100,101). Pulmonary fungal infections, primarily Aspergillus species, develop in up to 16% of allogeneic HSCT patients (102,103). Healthcare-associated pneumonia in immunocompromised hosts can be caused by inhalation of aerosols carrying Legionella species or Aspergillus species, or exposure to individuals with RSV, influenza, or parainfluenza virus. These microorganisms are important pathogens in HSCT recipients, and outbreaks of healthcareassociated pneumonia have been documented (104, 105, 106, 107, 108, 109 and 110). Among nonbacterial causes of pneumonia in recipients of allogeneic HSCTs, CMV pneumonia has the highest mortality rate, 91% (111). Diffuse interstitial pneumonia caused by CMV during the postengraftment period occurs in 30% to 40% of the cases (22).
Gastrointestinal Infections
Gastrointestinal illness in HSCT patients can be both an infectious and noninfectious process. HSCT patients can develop gastrointestinal symptoms from the conditioning regimen, radiation, acute GVHD, or medications (112, 113 and 114). A number of microorganisms including viruses, bacteria, protozoa, and helminthes can cause gastrointestinal infection (112,115, 116, 117 and 118). Diarrhea may be caused by endogenous reactivation such as with CMV or acquired by various mechanisms such as respiratory transmission (e.g., adenovirus, influenza H1N1), ingestion (e.g., Salmonella), or contact transmission (e.g., C. difficile). The likely etiology of diarrhea following HSCT depends on the timing after transplantation (119). Early after transplantation, intestinal damage due to chemotherapy is a common cause. Later onset, 20 to 100 days after HSCT the differential diagnosis includes acute GVHD (120). In a cohort of 296 HSCT patients with diarrhea, Cox et al. (121) found that infectious pathogens accounted for only 13% of cases, whereas acute GVHD accounted for 48%. No etiology was identified in 39% of diarrheal episodes. Among patients with infections, the most common infecting microorganisms identified were viruses (12/126 patients; 9.5%) and C. difficile (6/126 patients; 4.8%). Another study reported identification of an infectious cause of diarrhea in up to 40% of episodes (122). Of the 31 patients where a pathogen was identified, 12 (39%) had adenovirus, 12 (39%) had C. difficile, and 9 (29%) had rotavirus. More importantly, the mortality rate was 55% among patients with a pathogen isolated and only 13% among those patients who did not develop infectious diarrhea (p < .0001). Likewise, Blakey et al. (116) identified the cause of diarrhea in children undergoing HSCT. Enteric pathogens caused diarrhea 52% of the time; 14% of cases of diarrhea were caused by C. difficile. Interestingly, other Clostridial species including cytotoxin-negative C. difficile and C. innocuum were excreted in 90% of diarrheal episodes when no enteric pathogen was identified.
Typhlitis or neutropenic enterocolitis is a complication following chemotherapy that is commonly found in patients with hematologic cancer and patients undergoing autologous HSCT (123,124). One study demonstrated that 75% of patients with typhlitis had at least cultured blood growing at least one microorganism at some time during their illness (125).
If infectious diarrhea is suspected in HSCT patients, Contact Precautions should be applied, because many of these pathogens such as adenovirus, rotavirus, and C. difficile can be healthcare-associated (126,127).
Details about specific microorganisms can be found below.
Sinusitis
Approximately 1.7% of HSCT patients, most commonly allogeneic grafts, develop sinusitis (128,129). Among 41 cultures of the paranasal sinuses obtained from 18 HSCT patients with sinusitis, the most common microorganisms identified were gram-negative bacteria (56.7%), grampositive bacteria (26.7%), and fungi (16.6%) (130). With the increasing use of high-risk HSCT and new cytotoxic chemotherapy, more cases of sinusitis due to less frequently identified pathogens have been reported including invasive fungi such as Aspergillus species, the Zygomycetes, and other filamentous microorganisms, which is a potentially lethal complication of HSCT-induced neutropenia. A mortality rate of 62% is reported despite appropriate antifungal therapy and surgical debridement (128).
MICROORGANISMS
We review those microorganisms that require infection prevention and control interventions or have implications for healthcare workers or the environment. Certain infections characteristically occur at different time periods following HSCT. This pattern, however, has evolved as the management of HSCT patients had changed, including the use of prophylactic antibiotics and antiviral agents. The risk of developing a blood-borne infection (HIV; hepatitis A, B, C, D, E, G, and H; malaria; Chagas’ disease; etc.) also exists in this population.
Infections in the early posttransplant period are usually due to the host’s own flora colonizing the skin and mucous membranes and the urogenital or alimentary tracts. Medical therapies and the hospital environment, however, may alter the profile of microorganisms that colonize individual patients. Owing to the liberal use of broad-spectrum antibiotics in HSCT units, acquisition of highly resistant microorganisms, such as vancomycin-resistant Enterococcus (VRE), multidrug-resistant gram-negative rods, and S. maltophilia, is common. The profound immunosuppression allows these patients to acquire potentially pathogenic microorganisms from sources that are of little concern in other hosts, such as uncooked foods and water. Free-living microorganisms, such as Pseudomonas species, normally colonize fresh fruits and vegetables and plants; institutional water sources are potential sources of microorganisms such as Pseudomonas species, Legionella species, fungi, and Mycobacterium species (39). Similarly, construction and renovation in and around healthcare institutions have been associated with infection due to Aspergillus spp. and other molds (51). During the neutropenic phase immediately following transplantation, pathogens whose removal is dependent on phagocytic function predominate. It is estimated that 60% of febrile episodes in neutropenic patients are accompanied by bacteremia, but there have been important shifts in the microorganisms responsible
for these infections (131). In the 1970s, gram-negative septicemia often caused by P. aeruginosa, Escherichia coli, Enterobacter cloacae, and Klebsiella species resulted in high mortality of febrile neutropenic patients (132,133). More recent prophylactic regimens have led to the emergence of fluoroquinolone resistant gram-negative rods and fungi. Driven by the extensive use of prophylactic and empiric antibiotic regimens active against gram-negative microorganisms, gram-positive microorganisms have now emerged as the most common pathogens (134). Gram-positive microorganisms now account for 60% of bacteremias in HSCT centers (134,135). Most of these infections are caused by Staphylococcus epidermidis and other coagulase-negative staphylococci. Wade et al. (134) found that the incidence of S. epidermidis infections increased from 2.0 per 1,000 patient days in 1972 to 14.6 per 1,000 patient days in 1979. Increased use of long-term indwelling venous catheters has also been implicated in the increase in gram-positive infections (134,135). Streptococci, in particular alpha-hemolytic strains, commonly found in the oral flora have been recovered with increasing frequency owing to the poorer activity of fluoroquinolones against these microorganisms (54). Furthermore, many gram-positive bacteremias, especially those due to S. epidermidis, now occur after engraftment (136). The proportion of gram-positive and gram-negative bacterial infections varies from study to study due to the variation of timing of study period, antibiotic prophylaxis use, and type of center performing transplantation. Between 2004 and 2007, Cattaneo et al. (137) performed a prospective surveillance study in Italy analyzing microbiological isolates of all infectious episodes at a hematology unit that also included autologous HSCT recipients. Gram-negative bacteria caused 49.3% of infections, gram-positive bacteria caused 40.9% of infections, and fungi caused 8.9% of infections in this series (137). These authors used levofloxacin for antibacterial prophylaxis in patients with expected neutropenia more than 7 days.
for these infections (131). In the 1970s, gram-negative septicemia often caused by P. aeruginosa, Escherichia coli, Enterobacter cloacae, and Klebsiella species resulted in high mortality of febrile neutropenic patients (132,133). More recent prophylactic regimens have led to the emergence of fluoroquinolone resistant gram-negative rods and fungi. Driven by the extensive use of prophylactic and empiric antibiotic regimens active against gram-negative microorganisms, gram-positive microorganisms have now emerged as the most common pathogens (134). Gram-positive microorganisms now account for 60% of bacteremias in HSCT centers (134,135). Most of these infections are caused by Staphylococcus epidermidis and other coagulase-negative staphylococci. Wade et al. (134) found that the incidence of S. epidermidis infections increased from 2.0 per 1,000 patient days in 1972 to 14.6 per 1,000 patient days in 1979. Increased use of long-term indwelling venous catheters has also been implicated in the increase in gram-positive infections (134,135). Streptococci, in particular alpha-hemolytic strains, commonly found in the oral flora have been recovered with increasing frequency owing to the poorer activity of fluoroquinolones against these microorganisms (54). Furthermore, many gram-positive bacteremias, especially those due to S. epidermidis, now occur after engraftment (136). The proportion of gram-positive and gram-negative bacterial infections varies from study to study due to the variation of timing of study period, antibiotic prophylaxis use, and type of center performing transplantation. Between 2004 and 2007, Cattaneo et al. (137) performed a prospective surveillance study in Italy analyzing microbiological isolates of all infectious episodes at a hematology unit that also included autologous HSCT recipients. Gram-negative bacteria caused 49.3% of infections, gram-positive bacteria caused 40.9% of infections, and fungi caused 8.9% of infections in this series (137). These authors used levofloxacin for antibacterial prophylaxis in patients with expected neutropenia more than 7 days.
Viral Infections
Respiratory Virus Infections
Respiratory viruses cause infections in approximately 19% of HSCT patients each season (generally considered to be from November to May in the Northern Hemisphere). Respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza virus, adenovirus, picornaviruses, coronavirus, human metapneumovirus, and rhinovirus have been described as agents that affect HSCT patients (138,139). These viruses commonly cause upper respiratory tract infections and can lead to serious lower respiratory tract infections associated with significant morbidity and mortality in this population. Adenovirus can lead to disseminated visceral syndromes (140). Suspicion for respiratory virus infection should be maintained throughout the year, because parainfluenza and adenovirus occur yearround. While respiratory viruses are frequently acquired in the community, hospital transmission is well described. One group reported that 48% of these types of infections were acquired within the hospital (138). A study of HSCT patients with respiratory symptoms who had cultures and direct fluorescent antibody examination of nasopharyngeal wash/throat specimens demonstrated that the most common community-acquired respiratory agent was RSV (35%), followed by parainfluenza virus (30%), rhinovirus (25%), and influenza (11%) (141). Adenovirus was not included in the study because of the difficulty in differentiating new infection from reactivation of latent disease. Patients with radiographic evidence of pneumonia underwent bronchoalveolar lavage; 49% of patients with RSV had pneumonia and 22% of patients with parainfluenza had pneumonia, but pneumonia due to influenza and rhinovirus was uncommon (<10% of patients). In contrast, a more recent study reported the results of direct immunofluorescence assays performed on respiratory specimens from 179 HSCT patients who had 392 episodes of upper respiratory illness (142). Of the 68 (38%) in whom virus was detected, respiratory syncytial virus was detected in 18 patients (26.4%), influenza A or B in 28 (41.2%), and parain-fluenza in 7 (10.3%). Fourteen patients (20.6%) had multiple viruses isolated. RSV pneumonia developed in 55.5% of the patients with RSV upper respiratory infections. One of the 15 patients (6.7%) with RSV pneumonia died. Influenza pneumonia was diagnosed in three patients (7.3%). These investigators report a lower mortality than previously reported.
HSCT recipients or candidates who have symptoms of respiratory tract infection should be placed on Droplet Precautions and sometimes on both Droplet and Contact Precautions to avoid transmitting to other patients (127,143). Optimal isolation precautions should be modified after the causative agent is identified and the epidemiology understood (143). In some cases, prolonged shedding of virus is described requiring prolonged use of barrier precautions (144, 145, 146, 147 and 148). Diagnosis and the cause of upper respiratory infections should be established in HSCT patients, because they can progress to serious complications, some can be treated with antiviral agents, and others require precautions and rarely prophylaxis of exposed healthcare workers (143). HSCT candidates with upper respiratory tract symptoms, if possible, should postpone conditioning therapy until symptoms resolve (143) (see Table 59-1).
Adenovirus Adenoviruses are nonenveloped, doublestranded DNA viruses 70 to 90 nm in diameter (149). At least 7 human adenovirus subgroups, including 52 serotypes, have been documented (150). The incidence of disease in HSCT patients ranges from 5% to 27% in different studies (151, 152, 153, 154, 155, 156 and 157). Among HSCT recipients, especially children, the common serotypes that cause disease are 31 in subgroup A; 7, 11, 34, and 35 in subgroup B; 1, 2, 5, and 6 in subgroup C; and 4 in subgroup E (158). One group found that subgroup B serotype 35 was the most prevalent adenovirus strain in their institution, and half of the adult patients infected with this strain had the same serotype recovered from cultures prior to HSCT (152). Most of reported cases were diagnosed during the first 100 days posttransplant; however, the onset of adenoviral disease after 100 days has also been reported (152,154,159). HSCT patients who develop adenovirus infections can present with upper and lower respiratory tract illness, acute hepatitis, gastrointestinal disease, acute hemorrhagic cystitis, nephritis, conjunctivitis, and central nervous system disease (140,149,159, 160, 161, 162, 163 and 164). Patients who have recently undergone transplantation have an increased risk of severe disease (OR = 2.7) (165).
Disseminated adenovirus infection, in which two or more organ systems are involved, is associated with a 60% mortality rate (140,163,166). The mortality rate may be as high as 70% in patients with pneumonia and disseminated disease (154,167,168). Lymphopenia (<300 per µL) is one of the significant risk factors for severe disease, because lymphocytes play an important role in clearance of adenovirus viremia (154,169,170). Receipt of an allogeneic transplant, presence of GVHD, and receipt of concurrent immunosuppressive therapy are risk factors for disseminated infection (163,171). In addition, others have reported that the incidence of adenovirus is higher in children than adults (172).
Disseminated adenovirus infection, in which two or more organ systems are involved, is associated with a 60% mortality rate (140,163,166). The mortality rate may be as high as 70% in patients with pneumonia and disseminated disease (154,167,168). Lymphopenia (<300 per µL) is one of the significant risk factors for severe disease, because lymphocytes play an important role in clearance of adenovirus viremia (154,169,170). Receipt of an allogeneic transplant, presence of GVHD, and receipt of concurrent immunosuppressive therapy are risk factors for disseminated infection (163,171). In addition, others have reported that the incidence of adenovirus is higher in children than adults (172).
TABLE 59-1 Prevention and Control Strategies for Respiratory Virus Infections | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The diagnosis of adenovirus infection has traditionally been made by isolation of the virus in culture or by documentation of adenovirus in tissue. PCR is emerging as a promising diagnostic modality that provides a more rapid diagnosis and can be a monitoring tool for the virus (156,173, 174, 175 and 176).
Because they are nonenveloped viruses, adenovirus are highly resistant to chemical and physical agents and can remain infectious at room temperature for prolonged periods of time, up to 49 days on plastic and up to 35 days on metal (150,177). They are stable at low pH and resistant to gastric and biliary secretions allowing them to replicate and achieve high viral loads in the gastrointestinal tract (150).
Transmission can occur by inhalation of aerosolized droplets, direct and indirect contact, fecal-oral spread, or exposure to infected tissue or blood (126,159). In general, type-specific immunity develops after a self-limited, 2-week illness, although latent infection may be established in lymphoid tissue (149). Outbreaks have been reported primarily in pediatric HSCT patients (167,178, 179 and 180). The clinical presentation described in these outbreaks is diarrhea (178, 179 and 180).
Because the microorganism can be transmitted from person to person, attention to infection control practices is important. Recommendations for isolation precautions in a hospital setting depend on the type of clinical syndrome (126). Patients with diarrhea should be placed on Contact Precautions for at least the duration of illness (127). Since immunocompromised hosts may have asymptomatic shedding of adenovirus for months after infection, precautions should be continued for the duration of hospitalization or viral shedding to prevent transmission (126). For respiratory disease, conjunctivitis, or disseminated infection, Droplet and Contact Precautions should be maintained for at least the duration of illness (126,127).
Environmental cleaning with approved disinfectants such as a chlorine-based product, ethyl alcohol, or ethanol mixed with quaternary ammonium compounds is important to prevent spread of the microorganism (126). High-level disinfectants maybe used for instruments when applicable (181).
Influenza Influenza is a segmented RNA virus with three subtypes, A, B, and C. The former two most commonly cause infection in humans. The virus is characterized by its hemaglutinin (H) and neuraminisase (N) moieties. Beyond the hemaglutinin and neuraminidase, minor genetic variations occur annually so that hosts can be susceptible to any strain that emerges each year (182). Influenza causes a febrile syndrome characterized by the sudden onset of fever, myalgias, cough, and sometimes gastrointestinal complaints (182, 183 and 184). It can lead to viral pneumonia, encephalitis, myocarditis, rhabdomyolysis, and other disseminated processes (185, 186, 187, 188, 189 and 190). Secondary bacterial infections with S. pneumoniae, S. aureus, and methicillin-resistant S. aureus (MRSA) are well described (191, 192, 193 and 194). Immunocompromised patients receiving HSCT are considered to be at high risk for healthcare-associated influenza. Hospital outbreaks of influenza often occur during community epidemics and can be explosive among hospitalized high-risk patients and have been documented with the same frequency among neutropenic and nonneutropenic and autologous and allogeneic HSCT recipients (195). Whimbey et al. (195) found that almost one-third (29%) of the hospitalized adult HSCT recipients had influenza type A cultured after developing respiratory symptoms. Hospital transmission was responsible for 60% of these 68 infections. Seventy-five percent of the cases were complicated by pneumonia and 17% (1/6) of these patients died (195).
Pandemic H1N1 influenza, which emerged in 2009, has also been associated with morbidity and mortality in HSCT patients (145,196, 197 and 198). Five of thirteen HSCT recipients infected with H1N1 influenza had lower respiratory tract involvement that occurred when they were profoundly neutropenic (196). Only one patient with lower respiratory tract infection survived, whereas all with upper respiratory tract infections were alive at follow up through 100 days (196).
Infection prevention and control of influenza in the HSCT population can be challenging, because many of these patients have prolonged infection and viral shedding. Gooskens et al. (144) evaluated eight immunosuppressed patients with prolonged influenza virus infection. Virus was shed for more than 2 weeks and it was found that shedding was associated with lymphocytopenia, lower respiratory tract infection, and development of drug resistance during oseltamivir treatment (144). Although patients who received antiviral treatment had clinical improvement, lymphocyte reconstitution was required for complete viral clearance (144). A similar finding has been noted in patients with pandemic H1N1 influenza infection (145). Tramontana et al. reported on 17 HSCT patients and 15 oncologic patients with laboratory-confirmed pandemic H1N1 influenza. All HSCT patients <100 days posttransplant or with severe GVHD required ICU admission, and the inhospital mortality rate was 21.9% (145). Virus was shed up to 28 days during oseltamivir therapy. An H275Y mutation developed in four of seven patients who were PCR positive after 4 days of oseltamivir therapy (145). These studies suggest that HSCT patients should not be removed from Droplet Precautions until it is documented that they are no longer shedding influenza virus (145).
Outbreaks of influenza among hospitalized patients including HSCT patients are commonly reported (108, 199, 200, 201, 202 and 203). Healthcare workers are often implicated as potential sources of transmission demonstrating the importance that all healthcare personnel who work in HSCT units receive annual influenza vaccination (201, 202 and 203). Additional interventions in the setting of an outbreak include strict infection prevention and control precautions. These include enforcing barrier precautions, masking universally, minimizing the number of staff entering the unit and patients’ rooms, screening of visitors and other personnel, delaying nonessential admissions to the unit, surveying
actively for respiratory virus infection in all patients and unit staff, and using antiviral chemoprophylaxis for HSCT patients regardless of earlier vaccine status for the duration of the outbreak (108,143).
actively for respiratory virus infection in all patients and unit staff, and using antiviral chemoprophylaxis for HSCT patients regardless of earlier vaccine status for the duration of the outbreak (108,143).
Influenza vaccine should be administered to patients prior to transplantation, because response to influenza vaccine is extremely limited for at least 6 months after transplantation (204). Influenza vaccine does not fully protect patients until 2 years following HSCT. All family members and close or household contacts of HSCT recipients should continue to be vaccinated annually as long as the HSCT recipient remains immunosuppressed (143) (see also Chapter 42).
Parainfluenza Parainfluenza viruses are divided into four serotypes (205). Of the four types, parainfluenza 3 is the most common, followed by serotypes 1 and 2 (205). Parainfluenza virus can cause serious lower respiratory tract disease in both adults and children who undergo HSCT (206). Significant risk factors for progression from upper to lower respiratory tract infection have included corticosteroids use and lymphopenia (205,207,208). Parainfluenza outbreaks in HSCT recipients have been reported (109,110,209,210). These outbreaks were caused by introduction of parainfluenza 3 virus strains from a community reservoir into the HSCT population with subsequent person-to-person transmission within the unit (110,211). Some studies revealed that, most likely, transmission occurred initially in the outpatient setting (209, 210 and 211). The mortality rate in HSCT patients infected with parainfluenza has been reported to be 33% to 38.5% (110,208,210). Infection prevention and control measures much like those described for influenza are the most important strategy for preventing parainfluenza infection and transmission among HSCT recipients. Many outbreaks report the need for prolonged enforcement of surveillance, isolation, cohorting, and other infection prevention issues (210,211). The outpatient setting should also be included in these prevention strategies.
Respiratory Syncytial Virus RSV accounts for one-third to one half of community-acquired respiratory viral infections among HSCT recipients (138,141). Healthcare-associated transmission has been well documented among HSCT recipients, and the risk of healthcare-associated infection increases during community outbreaks (106,107,212). Almost 60% (19/33) of the RSV infections in HSCT recipients are complicated by pneumonia, with an associated mortality between 51% and 80%. This infection may be complicated by pneumonia, and the risk of progression to pneumonia is greater in patients who are pre-engraftment, who underwent HSCT <1 month prior to infection, who are lymphopenic, and who have preexisting obstructive airway disease (103,143). RSV spreads via large droplets from respiratory secretions or by contamination of hands or surfaces and subsequent contact with the mucous membranes of the eyes and nose. Prevention of this viral infection is the best strategy given the limited therapeutic options and the tremendous morbidity associated with these infections. Comprehensive programs that include surveillance and isolation have been shown to prevent transmission among children (213). A multifaceted infection control strategy is essential in the event of a healthcare-associated RSV outbreak; prompt identification of cases with active screening, cohorting, isolation of infected patients, screening of staff and visitors for upper respiratory tract symptoms, cleaning of equipment, and educating staff have been demonstrated as effective measures in controlling outbreaks on HSCT units (214).
Coronavirus Coronaviruses are a family of single-stranded RNA viruses that cause respiratory disease among humans. Until the 2002 to 2003 respiratory virus season, two coronavirus strains, OC43 and 229E, were known to cause respiratory disease (215). Patients generally present with mild upper respiratory symptoms, although pneumonia has been described (215,216). Limited data are available about the clinical syndromes among HSCT patients. In a case series of two patients who had received autologous transplants, both developed pneumonia characterized by a dry, nonproductive cough and interstitial infiltrates on radiographs (139). Milano et al. (146) conducted a prospective surveillance study in allogeneic HSCT recipients and reported that the incidence of coronavirus infection among these patients was 11.1%. Nine of twenty-two patients were asymptomatic and 3/22 patients had prolonged viral shedding (146).
In 2003, severe acute respiratory syndrome was described, which has rejuvenated interest in this virus and the clinical syndromes it causes. Published reports from several cohorts of patients noted a febrile syndrome characterized by cough, myalgias, dyspnea, and occasionally diarrhea with some patients going on to develop respiratory failure (217, 218 and 219). The spectrum of disease in HSCT patients is not well described.
Human Herpes Viruses Infections
Cytomegalovirus Cytomegalovirus (CMV), a doublestranded DNA herpes virus, is a major cause of morbidity and mortality among HSCT patients. Asymptomatic infection or symptomatic disease can result from either newly acquired infection from CMV-infected bone marrow or blood products or reactivation of previous infection. Risk factors for symptomatic CMV disease in HSCT patients include CMV seropositivity in the HSCT recipient, receipt of CMV seropositive hematopoietic stem cells or blood products by a CMV-seronegative recipient, allogeneic HSCT, use of T-cell-depleted graft, use of a mismatched or unrelated donor, the development of GVHD, prolonged immunosuppression, lymphopenia following transplantation, use of high-dose corticosteroids, alemtuzumab, fludarabine, or 2-chlorodeoxyadenosine, and failure of development of a CMV-specific cellular immune response (22,91,220, 221, 222, 223, 224 and 225).
Serious CMV disease most frequently results in interstitial pneumonitis (143). Other manifestations include gastroenteritis, hepatitis, and encephalitis; retinitis has also been reported in HSCT recipients (226,227).
Quantitative polymerase chain reaction (PCR) for CMV DNA or RNA is the most sensitive method for detecting CMV and has been used to determine the need for preemptive therapy (143,225,228). CMV pp65 Ag in leukocytes (antigenemia) can also be used, but the test may be falsely negative in patients with neutropenia (143,229,230).
Despite treatment with ganciclovir and IVIG, mortality from CMV pneumonia remains as high as 20% to 75% (231, 232, 233 and 234). Among autologous HCST patients who developed
CMV pneumonia, all were previously CMV seropositive and all except two had underlying hematologic malignancies (235). Most cases (n = 11) occurred <30 days posttransplant, although five cases occurred >100 days posttransplant. Thirty-one percent of patients died. New infection with CMV among CMV-seronegative HSCT patients has dramatically decreased since the use of CMV seronegative or leukocytereduced blood products have been implemented. In one study, the rate of exogenous infection was 23% compared to 0% in seronegative patients receiving CMV-seronegative red blood cell and leukocyte-depleted platelets (236). CMV-seronegative blood products are felt to be comparable to filtered leukocyte-reduced blood products with regard to risk of CMV transmission (236).
CMV pneumonia, all were previously CMV seropositive and all except two had underlying hematologic malignancies (235). Most cases (n = 11) occurred <30 days posttransplant, although five cases occurred >100 days posttransplant. Thirty-one percent of patients died. New infection with CMV among CMV-seronegative HSCT patients has dramatically decreased since the use of CMV seronegative or leukocytereduced blood products have been implemented. In one study, the rate of exogenous infection was 23% compared to 0% in seronegative patients receiving CMV-seronegative red blood cell and leukocyte-depleted platelets (236). CMV-seronegative blood products are felt to be comparable to filtered leukocyte-reduced blood products with regard to risk of CMV transmission (236).
The overall incidence of developing CMV pneumonia in the first 100 days after transplantation is 7% (91). CMV infection is much less likely to cause serious disease following autologous HSCT (237). The incidence of CMV infection is 38.8% to 61%; however, only 0.8% to 6.9% of patients develop end-organ disease (230,237,238). A review of CMV pneumonia in autologous HSCT recipients at one institution reported that 2% (16/795) of autologous HSCT patients developed CMV pneumonitis (235). However, historically, 45% to 87% of allogeneic HSCT patients develop CMV infection and 21% to 43% develop disease (237,239). The current standard of care in patients who are seropositive or have received seropositive transplants is to receive prophylactic antiviral therapy or preemptive antiviral therapy after detection of CMV reactivation with diagnostic testing. The rates of CMV disease in HSCT patients are now 5% to 18% (143,222,240).
Historically, the majority of CMV infections occur between 30 and 100 days following transplantation, with a median day of onset between the 40th and 50th day (22,237). However, the risk of developing CMV disease later after transplantation appears to be increasing as prophylaxis and preemptive strategies are employed early after HSCT. The trend where CMV infection develops in HSCT cases at longer intervals after the transplant may be related to delayed reconstitution of CMV-specific T-cell immunity in the face of ganciclovir prophylaxis. Strategies for preventing late CMV disease in HSCT patients with high risk include use of continued surveillance and preemptive antiviral therapy. No precautions beyond Standard Precautions are recommended.
Herpes Simplex Virus Herpes simplex virus (HSV) infection is an important cause of morbidity in HSCT patients due to the severe mucocutaneous lesions produced by reactivation of latent virus (136). Prior to the routine implementation of prophylaxis, HSV was the most common viral infection seen after HSCT, occurring in up to 80% of seropositive individuals in the first 50 days after HSCT (136,241). Shedding of the virus is most frequent from days 14 through 28 after HSCT (136). In contrast, only 1% of previously seronegative patients excrete the virus. The disease most often involves the oropharynx, but can manifest itself by limited or disseminated cutaneous disease. Less frequently, HSV may produce keratitis, pneumonitis, hepatitis, or encephalitis (136). Importantly, healthcare-associated transmission of HSV from infected patients to healthcare workers and family members is reported (242,243). Several outbreaks suggest that immunocompromised patients with herpes simplex pneumonia are most likely to transmit the virus (242,243). In one of these studies, molecular typing of strains confirmed that the patients’, healthcare workers’, and family members’ strains were genetically identical (242). An emerging concern is the increasing frequency of HSV strains that are resistant to acyclovir (244, 245, 246, 247, 248 and 249). One study demonstrated that 7% (14/196) of patients undergoing allogeneic HSCT were infected with acyclovir resistant HSV-1; seven cases were also resistant to foscarnet. Standard Precautions are recommended for all patients. In addition, patients with lesions should be placed on Contact Precautions (127). In instances with HSV pneumonia, Droplet Precautions should be considered.
Varicella-Zoster Virus Varicella-zoster virus (VZV) is caused by a DNA virus in the herpes family. It is the cause of varicella (chicken pox), which represents primary infection, and herpes zoster (shingles), which represents reactivation of latent VZV infection (250). Although varicella is generally a mild disease in children, serious morbidity and mortality are common if infection occurs in immunocompromised patients (251). Among patients developing varicella while receiving chemotherapy for malignancy or immunosuppressive therapy following transplantation, severe disease has been reported in 36% and death in 13% (252,253). Encephalitis has also been reported in allogeneic HSCT patients (254,255). In children, 28% not treated with antivirals develop pneumonia (251). The skin lesions may form for up to 2 weeks and crusting may require 3 to 4 weeks (251).
The majority of VZV infections in adults are due to reactivation of latent virus. In contrast to HSV infections that usually develop in the first month after HSCT, VZV-seropositive HSCT recipients develop VZV reactivation during the 3 to 12 months after HSCT (median = 5 months) (252,256, 257, 258, 259, 260, 261, 262, 263 and 264).
Risk factors for reactivation of VZV include chronic GVHD, a diagnosis of leukemia and other lymphoproliferative disorder, CD4 lymphocyte count of <800 cells/L, HLA mismatch, a myeloablative regimen with total body irradiation, CD34+ cell-selected allogeneic and autologous peripheral blood HSCT, and age >50 years (252,258,260,265, 266, 267 and 268). Although most patients present with a dermatomal rash, cutaneous dissemination occurs in 6% to 23% of patients, encephalitis occurs in 5% of patients, and visceral involvement is noted in up to 14% of patients (261,264,268, 269 and 270). Visceral involvement most commonly involves the lungs and liver, and abdominal symptoms such as pain, nausea, and vomiting can precede the development of vesicular rash by several days (271). Although antiviral suppression is standard of care for HSV disease, the role of antiviral suppression for the prevention of VZV has not been established in HSCT patients. While oral acyclovir for 6 months after transplant suppressed VZV reactivation, patients have developed rapid onset of VZV infections after the cessation of therapy (256,268,272). The concerns about development of resistant strains of herpes viruses may outweigh the utility of prophylaxis. Regardless of VZV serologic status, HSCT candidates and recipients should avoid exposure to persons with active VZV infections and to persons who develop a rash after VZV vaccine (143). In hospital such patients should be placed on Airborne and Contact Precautions as immunocompromised hosts with VZV shed virus from the respiratory tract and lesions and transmission
to other patients is documented (273). VZV-seronegative HSCT patients who are exposed to VZV or a vaccinee with a rash and are not immunocompetent should receive VZIG within 96 hours of exposure (143,274). A recent study by Hata et al. (275) demonstrated that inactivated varicella vaccine given before autologous HSCT and during the first 90 days after significantly reduced the risk of herpes zoster; 33% of unvaccinated patients compared to 13% of vaccinated patients developed zoster.
to other patients is documented (273). VZV-seronegative HSCT patients who are exposed to VZV or a vaccinee with a rash and are not immunocompetent should receive VZIG within 96 hours of exposure (143,274). A recent study by Hata et al. (275) demonstrated that inactivated varicella vaccine given before autologous HSCT and during the first 90 days after significantly reduced the risk of herpes zoster; 33% of unvaccinated patients compared to 13% of vaccinated patients developed zoster.
Varicella is extremely contagious, with secondary attack rates of >90% (276,277). The incubation period of varicella ranges from 8 to 21 days, but most patients develop disease between 14 and 16 days after exposure. Patients with varicella become infectious 24 to 48 hours prior to the onset of rash, and viral shedding is prolonged by 2 days in the immunocompromised host (251). Transmission is thought to be due to direct contact with infectious persons. However, based on several outbreaks where patients and/or healthcare workers with no exposure developed varicella, airborne transmission is presumed (273,278, 279 and 280). Sawyer et al. (281) used PCR technology to determine whether VZV could be transmitted by aerosol spray. VZV DNA was detected in 64 of 78 (82%) air samples from hospital rooms housing patients with varicella infections and 9 of 13 (69%) rooms of patients with herpes zoster (281). VZV was detected from infected patients’ beds for 1 to 6 days following the onset of rash, and on some occasions could be detected outside of the patients’ rooms. Interestingly, this study contradicts investigators who suggest fomites are not important in the transmission of VZV (276).
Airborne transmission is suspected to be a primary mechanism of transmission of disease among patients with hematologic malignancy and patients undergoing HSCT (273,278, 279 and 280). Leclair et al. (279) described an outbreak of varicella that occurred in a pediatric hospital. Twenty-four of thirty-two patients hospitalized on an infant ward were exposed and susceptible to varicella. Ultimately 15 (62.5%) patients developed chickenpox after an index case requiring mechanical ventilation was hospitalized. Studies of distribution of air documented increased airflow to those rooms where a higher number of cases occurred. These investigators suggest that increased concentrations of virus and droplets were expelled from the exhaust loop of the ventilator. In a similar instance, Gustafson et al. (280) demonstrated that the risk of children developing varicella was related to how near they came to the index case’s room. Eight (11%) exposed children developed varicella. The attack rate was higher for children exposed to the patient early in his disease (8/28; 28.6%) (280). Based on airflow studies, the pressure in all rooms was positive relative to that of the outside corridor. Moreover, 10% of a tracer gas released in the patient’s room was measured in corridor air (280). Furthermore, airborne transmission may occur with herpes zoster that involves more than one dermatome. For instance, an adult patient developed herpes zoster after receiving high-dose steroids, and three nurses developed varicella (273). Two of the three nurses had no contact with the patient. HSCT recipients with primary varicella infection or disseminated herpes zoster should be placed on Airborne and Contact Precautions (127). Patients with localized herpes zoster should also be placed on Airborne Precautions until disseminated infection is ruled out, because most HSCT recipients are in an immunocompromised state (127). The precautions should be maintained until lesions are dry and crusted (127). In HSCT recipients with varicella pneumonia, precautions should be maintained for the duration of the illness (127). Susceptible healthcare personnel should not enter the room if immune caregivers are available (127). For susceptible nonimmunized healthcare personnel who are exposed to a varicella patient, postexposure prophylaxis with vaccine is recommended as soon as possible but within 120 hours; for susceptible exposed personnel for whom vaccine is contraindicated, Varicella Zoster Immunoglobulin (VZIG) should be provided within 96 hours. Use Airborne Precautions for exposed susceptible persons and furlough exposed susceptible healthcare personnel beginning 8 days after the first exposure until 21 days after the last exposure or for 28 days if VZIG was given (127).
Hospital transmission of varicella is well recognized. Healthcare personnel should have evidence of immunity to varicella (274). Institutions should establish protocols and recommendations for screening and vaccinating personnel and for management personnel after exposures in the work place (274) (see also Chapter 43).
Epstein-Barr Virus Epstein-Barr virus (EBV) has been associated with various clinical syndromes. It can cause primary infection, reactivation, and chronic active infection in HSCT patients (264,282). Most EBV reactivations are asymptomatic; however, the complications such as encephalitis/myelitis, pneumonia, and hepatitis can occur (264). The role of EBV as a cause of posttransplant lymphoproliferative disorder (PTLD) is well described (264,282). This disorder occurs predominantly in recipients with profound T-cell cytopenia such as a T-cell-depleted graft (143,283). Other risk factors include unrelated donor HLA mismatch, use of antithymocyte globulin, and use of anti-CD3 monocloncal antibodies for GVHD prophylaxis (282, 283 and 284).
HSCT donors and candidates should be tested for the presence of anti-EBV IgG antibody before transplantation to determine the risk for primary EBV after HSCT (143). Standard Precautions are used for this microorganism (127). No additional isolation is needed.
Human Herpes Virus Types 6 and 7 The scope of disease caused by human herpes virus type 6 or 7 (HHV-6 or HHV-7) in HSCT patients has yet to be fully elucidated. Both viruses are frequent causes of febrile infection in children and the etiologic agents of exanthem subitum. Primary infection usually occurs in the first year of life and seroprevalence in adults exceeds 90% (285). Following primary infection, the virus establishes latency in peripheral blood mononuclear cells as well as salivary glands and neural cells (286). Reactivation of latent virus is felt to be the source of infection in the majority of HSCT patients. Although HHV-6 cannot be cultured from the blood of healthy adults, roughly 40% to 50% of HSCT patients develop HHV-6 viremia 2 to 4 weeks after transplantation (287,288). Patients receiving allogeneic HSCT have been reported to be at higher risk for reactivation of HHV-6 (287). Although most HSCT patients with HHV-6 reactivation are asymptomatic, several studies have demonstrated a correlation between reactivation of HHV-6 and both maculopapular rash and fever following HSCT transplantation (287,289, 290 and 291). Other studies have
shown an association between central nervous system symptoms including encephalitis and detection of HHV-6 in cerebrospinal fluid (CSF) (288). Wang et al. (292) examined CSF from 22 allogeneic HSCT patients with central nervous system symptoms and found that 23% (5/22) had detectable HHV-6 DNA and no other potential pathogen identified. In addition, 11 of the 22 patients without detectable HHV-6 had other causes identified that explained central nervous system symptoms (292). Hospital transmission has not been reported to date. Standard Precautions are recommended for these patients.
shown an association between central nervous system symptoms including encephalitis and detection of HHV-6 in cerebrospinal fluid (CSF) (288). Wang et al. (292) examined CSF from 22 allogeneic HSCT patients with central nervous system symptoms and found that 23% (5/22) had detectable HHV-6 DNA and no other potential pathogen identified. In addition, 11 of the 22 patients without detectable HHV-6 had other causes identified that explained central nervous system symptoms (292). Hospital transmission has not been reported to date. Standard Precautions are recommended for these patients.
Viral Gastroenteritis
Rotavirus Rotavirus is a common cause of nonbacterial gastroenteritis in children. It has also been a significant cause of diarrhea in HSCT recipients (297,298). The symptoms of rotavirus infection in HSCT patients included diarrhea, vomiting, abdominal pain, and loss of appetite (298).
Several healthcare-associated outbreaks of rotavirus infection have been reported (299, 300, 301 and 302). One outbreak was reported to be related to shared toys in a playroom on a pediatric oncology floor (303).
Environmental contamination is common despite cleaning since rotavirus is a nonenveloped virus and can survive on nonporous surfaces for a long period of time (300,301,304, 305 and 306). Disinfectants that can be used for rotavirus include sodium hypochlorite, phenol-based products, and ortho-phenylphenol with alcohol (307).
Rotavirus was reported to have asymptomatic shedding, and prolonged shedding may occur in immunocompromised patients (126,303,308) (see also Chapter 50).
Norovirus Norovirus is the leading cause of outbreaks of nonbacterial gastroenteritis in the community and can be explosive in healthcare settings (126,309). Roddie et al. (310) retrospectively reviewed 12 HSCT recipients with norovirus infection. The median time after transplantation to the development of symptoms was 10.5 months (range 0.25-96 months). Patients present with fever, transient nausea, and vomiting. Diarrhea can be prolonged, lasting a median of 3 months (range = 0.5-14 months). Norovirus is highly transmissible by the fecal-oral route and by environmental and fomite contamination (309). Moreover, it can survive in chlorine and varying temperatures (freezing and heating to 60°C). Quaternary ammonium compounds and alcohols are ineffective as disinfectants (309,311). Hand washing with soap and water should be implemented. Routine alcohol-based hand rubs may be ineffective for preventing norovirus transmission (126,309). Newer alcohol-based products have been introduced and are effective in inactivating the virus (312).
Patients should be placed on Contact Precautions. The environment should be aggressively cleaned. A hypochloritebased cleaning agent is recommended for use on hard, nonporous environmental surfaces at a concentration of 1,000 ppm depending on the level of contamination and types of surfaces (126,313). Cohorting and symptom screening may be instituted if ongoing transmission occurs. Rapid and aggressive responses are important when this microorganism is suspected because of how explosive it can be in hospitals (309,314).
Other Viruses
Parvovirus B19 Parvovirus B19 is an uncommon pathogen in the HSCT population, occurring in 1.4% of transplant patients at one institution (315). Transmission via transplantation may occur (316). It has been associated with prolonged anemia and viral shedding in the peritransplant period as well as in patients with chronic GVHD (317, 318, 319 and 320). Parvovirus B19 has also been associated with rash, arthralgia, hepatitis, pneumonitis, and myocarditis (321). Multiorgan failure has also been reported (322). IVIG has been used for treatment in the absence of evidence from a randomized trial (321).
Polyoma Virus Two viruses warrant mention. First, Polyoma BK virus was first reported in renal transplant patients in 1971 (323). The isolation of BK virus in HSCT recipients most often correlates with secondary viral replication due to impaired polyomavirus-specific cellular immunity (143). Hence, viruria occurs in about 60% to 80% of patients after HSCT, usually within 2 months (324, 325, 326, 327, 328, 329 and 330). Approximately 20% of patients with viruria will develop hemorrhagic cystitis (324,331,332). Factors that may contribute to hemorrhagic cystitis include presence of pretransplant BK virus IgG antibody, type of conditioning regimen, allogeneic HSCT, type of donor, GVHD, and a high peak BK urine viral load (324,331,333). Hemorrhagic cystitis from BK virus typically occurs after engraftment and must be distinguished from hemorrhagic cystitis caused by other pathogens including adenovirus and CMV (143,324).
Second, Polyoma JC virus infection has also been reported to cause progressive multifocal leukoencephalopathy (PML) in HSCT recipients (334,335). Standard Precautions are used for patients with either polyoma virus infection.
West Nile Virus West Nile virus (WNV) is a mosquito-borne flavivirus that is indigenous to Africa, Asia, Australia, and southern Europe (336). It was first noted in North America in 1999, and the number of yearly cases in the United States has continued to increase since that time. It is of concern to caregivers of HSCT patients because of convincing evidence that it can be transmitted by blood transfusion and organ transplantation (337,338). Tests to detect viral nucleic acid within blood products are now available and are being used to assess the blood supply for WNV.
In the general population, approximately 20% of persons infected with the virus develop a mild febrile illness and only 1 in 150 develops meningitis or encephalitis (339). However, all of the patients who received organs from a donor who had received blood containing WNV developed clinical WNV; three of the four developed encephalitis and one died, suggesting that the disease is more virulent in immunocompromised hosts (338). The diverse clinical presentations of WNV neurologic disease include meningoencephalitis, meningitis, flaccid paralysis, ataxia, cranial nerve abnormalities, extrapyramidal signs, myelitis, polyradiculitis, optic neuritis, and seizures. The incubation period is 3 to 14 days, and most patients
demonstrate a CSF pleocytosis (339). At least two cases of WNV infection have been reported in patients who underwent HSCT (340). In both cases, the infection was fatal.
demonstrate a CSF pleocytosis (339). At least two cases of WNV infection have been reported in patients who underwent HSCT (340). In both cases, the infection was fatal.
This population is considered to be at increased risk of infection if they come from areas where WNV is endemic or because they receive blood products. WNV should be suspected in all HSCT patients who have received blood products or have exposure to mosquitoes and present with fevers and neurologic symptoms (337,341, 342 and 343).
Prevention strategies include avoiding exposure to mosquitoes and may include screening of the blood supply. Standard Precautions are used in these patients.
Bacterial Infections
Viridans streptococci Bacteremia caused by viridans streptococci is associated with a sepsis-like syndrome among HSCT and neutropenic patients (62,65). One investigator reported that streptococci cause 71% of bloodstream infections in children undergoing HSCT (344). Likewise, Heimdahl et al. (60) showed that oral microorganisms, particularly a-hemolytic streptococci, caused 24 of 59 infections that occurred in neutropenic patients early after HSCT. The important predisposing factors for viridans streptococcal bacteremia are severe neutropenia and oral mucositis. Besides mucositis, dental health also has impact on viridans streptococcal bacteremia in HSCT recipients. Graber et al. (345) demonstrated that HSCT recipients with streptococcal bacteremia were more likely to have severe intraoral pathology while neutropenic compared to patients without an identified focus of infection (26% vs. 0%) and slightly shorter interval between the last dental procedure and the onset of neutropenia (11 vs. 14 days). Risk factors for viridans streptococcal bacteremia include prophylactic administration of trimethoprimsulfamethoxazole, beta-lactams, or a fluoroquinolone and chemotherapy-induced gastrointestinal toxicity treated with H2 antagonists or antacids (67,346). Penicillin-, cephalosporin-, and quinolone-resistant strains of viridans streptococci have been reported (346, 347, 348, 349 and 350). Attributable mortality rate for pre-engraftment viridans streptococcal bacteremia is 6% to 30% (67). Empiric vancomycin therapy is recommended in HSCT patients with viridians streptococcal infection if penicillin resistance is suspected either because of local microbiologic data or host risk factors (351). Vancomycin should be narrowed based on final susceptibilities. The prudent use of vancomycin is needed to minimize vancomycin-resistant microorganisms in this patient group.
Vancomycin-Resistant Enterococcus Enterococci are commensal flora of the human gastrointestinal tract. In normal hosts, they may have limited pathogenicity, but in HSCT recipients VRE are associated with significant morbidity and mortality (352,353). Reported rates of colonization are variable (4.7-40.2%), although rates are increasing in some studies (352,354, 355 and 356). Kamboj et al. (357) noted that 27.5% of allogeneic HSCT had VRE colonization at pretransplant screening between 2008 and 2009. VRE were the most common cause of primary bacteremia (53.5% of all positive blood cultures) in the early posttransplant period (days 4-10 after HSCT), and only 53% of patients with VRE bacteremia had positive surveillance cultures growing at pretransplant screening. The independent risk factors for VRE bacteremia were VRE colonization and allograft with T-cell depletion. The mortality in this study was 4.4% compared to 15% in patients with non-VRE bacteremia (357). The increased incidence of VRE occurred after implementing vancomycin prophylaxis in the peritransplant period to prevent viridans streptococci infection in myeloablative HSCT (357).
Several studies have evaluated risk factors for VRE infection (132,133,358, 359 and 360). Independent risk factors for developing VRE infection include neutropenia for more than 1 week, the use of oral vancomycin, and mucositis severity (133,358). Zaas et al. (132) reported that the risk factors for infection in colonized patients included diabetes mellitus, gastrointestinal procedures, acute renal failure, and use of vancomycin for 7 days in the 60 days before admission. C. difficile-associated diarrhea has also been noted as a risk factor for VRE colonization and bacteremia (132,358).
Hospital factors that predict colonization and infection with VRE include location in a high-risk area such as the ICU or oncology unit, length of hospitalization, number of individual contacts with VRE carriers, and overall proportion of patients colonized with VRE on a unit (361, 362, 363 and 364). VRE can be transmitted by person-to-person spread or from the contaminated environment. Most hospital transmission occurs via the contaminated hands of healthcare workers. VRE survives on hands for at least 60 minutes after inoculation and are recovered on the hands in 10% to 43% of workers caring for VRE-colonized patients (241,365). In addition, case-control studies have shown that exposure to a healthcare worker caring for a VRE-infected or a VRE-colonized patient increases the risk of acquiring VRE (366). VRE can survive for long periods (up to 7 days) on dry surfaces and is recovered in 7% to 30% of environmental surfaces cultured during outbreaks of VRE (365,367,368). Environmental contamination increases twofold when patients have diarrhea or are colonized in multiple body sites (368,369). Not surprisingly, VRE outbreaks have been linked to many fomites including contaminated electronic thermometers and ear oximeters (370,371).
The relationship between antibiotic exposure and colonization and infection with VRE has been extensively studied. The most consistently recognized antimicrobials associated with VRE acquisition are vancomycin, extendedspectrum cephalosporins, and antianaerobic agents (363,372, 373, 374 and 375). Both the total amount of antimicrobials and the therapy are risk factors for VRE (364). There is a consistent epidemiologic association between previous use of oral vancomycin and subsequent development of VRE colonization, which is likely related to selection pressure in the gastrointestinal tract, leading to the recommendation that oral vancomycin not be used routinely in the therapy of C. difficile colitis (364). The relationship between intravenous vancomycin therapy and VRE colonization and infection is more controversial. Although several studies have noted an association between vancomycin and VRE, others have not found an effect (369,372, 373 and 374,376, 377, 378, 379, 380, 381 and 382). Although vancomycin therapy likely does not cause VRE to develop or increase the chance that a patient will acquire VRE, it likely exerts selective pressure in the gastrointestinal tract and increases the burden of preexisting VRE to a detectable level (364). Consequently, the prudent use of vancomycin
in patients at high risk for VRE, particularly HSCT patients, is highly recommended.
in patients at high risk for VRE, particularly HSCT patients, is highly recommended.
Extended-spectrum cephalosporins and antianaerobic drugs have also been strongly associated with VRE (376,381,383). Among HSCT patients, Edmond et al. (363) reported that patients who received metronidazole or imipenem were 2.5 times more likely to develop a VRE bloodstream infection. One group was able to reduce the VRE acquisition rate on a leukemia unit by substituting piperacillin-tazobactam for ceftazidime as therapy for febrile neutropenia with no change in vancomycin use (384). The theoretical mechanism of this observation is that extended-spectrum penicillins have some activity against enterococci whereas cephalosporins do not, allowing for some reduction of VRE overgrowth in the gastrointestinal tract (364). Some oncology centers have moved toward the use of extended-spectrum penicillins rather than cephalosporins as a means to reduce rates of VRE colonization and infection, but studies to date have not confirmed the benefit of this approach (385, 386 and 387).
VRE colonization may persist for up to 1 year (388). Among 253 immunocompromised patients, Lai et al. found 70% of patients were persistent fecal carriers for up to 303 days (median = 41) (389). Of the 49 patients whose later stool cultures no longer grew VRE, four patients became recolonized. Beezhold et al. (390) found that all patients with VRE bloodstream infections were colonized either in the gastrointestinal tract (100%) or on the skin (86%).
The impact of these infections cannot be underestimated in this population. VRE bacteremia is associated with increased mortality in HSCT patients. In a well-designed historical cohort study of 27 leukemic patients with VRE bacteremia, Edmond et al. (363) reported a mortality of 67%, compared to a 30% mortality in closely matched controls without VRE bacteremia. Several studies suggest that VRE infections not only increase hospital length of stay, but also consequently inflate the cost of care to both the hospital and the patient (363,391).
A number of outbreaks of VRE among HSCT units or hematological wards have been reported (376,392,393). Most implicate infection control breaches and antibiotic overuse (376,392,393). Approaches to outbreak control included staff education, weekly surveillance, isolation of colonized patients, hand hygiene, environmental cleaning, and changing antibiotic policies (376,392,393) (see also Chapter 33).
Methicillin-Resistant Staphylococcus aureus Resistance to methicillin among S. aureus was first noted in 1961, the first year that methicillin was available. Since the late 1980s, rates of MRSA in the hospital setting have continued to increase. Among HSCT patients, S. aureus is a significant pathogen, particularly as a cause of catheterrelated bloodstream infection (94). Risk factors for the acquisition of MRSA include previous or prolonged hospitalization, advanced age, recent surgery, enteral feedings, and open skin lesions (394, 395 and 396). The overall frequency of MRSA in a study of HSCT recipients was 5%, and was most commonly seen in unrelated-donor (9%), sibling allogeneic (6%), and autologous (3%) recipients. More than half (21/41) of the events occur 1 month to 6 years after transplantation, 15/41 occurred pretransplant and 5/41 were detected early posttransplant. The mortality rate was highest in the early posttransplant group with most patients presenting with bacteremia (397,398). Mihu et al. (397) reported a case fatality rate of 15% with an attributable mortality rate of 8%. Risk factors for late S. aureus bacteremia in allogeneic HSCT recipients included skin GVHD and prolonged hospital length of stay (397). MRSA is transmitted primarily on the hands of healthcare workers; thus, hand hygiene coupled with Contact Precautions form the backbone of the prevention of transmission of MRSA. One study suggested that the environment and common items in the environment may play a more important role than previously recognized (399). Many centers perform surveillance cultures of the anterior nares at the time of admission and weekly to facilitate the early identification of patients with MRSA. This strategy facilitates the identification and rapid isolation of patients who could be colonized with the microorganism. Given that many of these patients have been previously hospitalized and exposed to antibiotics, such a strategy may be cost effective in this population. For patients with recurrent MRSA infection, current guidelines suggest that eradication of the carrier state can be attempted by applying a 2% mupirocin calcium ointment to the nares, and by the use of topical antiseptics such as chlorhexidine for bathing (126) (see also Chapter 29).
S. aureus with reduced susceptibility to glycopeptides has been reported in HSCT patients (400). Current guidelines recommend that institutions should conduct routine surveillance for the emergence of Staphylococcus species strains with reduced susceptibility to vancomycin (126).
Antibiotic-Resistant Gram-Negative Microorganisms Gram-negative pathogens are described in detail in Chapters 34 and 35 “Enterobacteriaceae” and “Nonfermentative Gram-Negative Bacilli,” respectively. These microorganisms are significant causes of bloodstream infection in HSCT patients. Mikulska et al. (401) found a significant decrease in the gram-positive bacteria/gram-negative rods ratio from 2.4 to 1 between 2004 and 2007. Fluoroquinolone resistance was common (74%) among gramnegative microorganisms in this study, likely because all patients received fluoroquinolones for prophylaxis. In a prospective multicenter study from Brazil, it was found that bacteremia was caused by gram-negative bacteria in 37% of patients and by gram-positive bacteria in 47% of patients (402). Mixed infections were noted in 16% of patients (402). P. aeruginosa (22%), Klebsiella pneumoniae (19%), and E. coli (17%) accounted for the majority of gram-negative isolates and 37% were resistant to multiple antimicrobials (402).
A number of outbreaks of gram-negative microorganisms have been reported among HSCT patients and on hematologic units (47,403,404,405, 406, 407, 408, 409, 410, 411, 412 and 413). Most P. aeruginosa outbreaks are related to water sources such as shower heads, basins, sinks, bathtubs, faucets, bidets, water closets, and bath toys (403,405,407, 408, 409, 410, 411 and 412). Some studies have demonstrated microorganisms on healthcare personnel’s hands suggesting that poor hand hygiene plays a role in transmitting these microorganisms (414, 415 and 416). Infected healthcare personnel can also play a role in healthcareassociated P. aeruginosa infection. Healthcare personnel with intermittent otitis externa and onychomycosis have
been implicated in outbreaks (415, 416, 417 and 418). Artificial fingernails have also been associated with a P. aeruginosa outbreak (419).
been implicated in outbreaks (415, 416, 417 and 418). Artificial fingernails have also been associated with a P. aeruginosa outbreak (419).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
