Changes in the transplantation procedure and the implementation of effective supportive care strategies have decreased the incidence of infectious complications early after conditioning therapy for allogeneic hematopoietic stem cell transplantation (HCT) and have extended the duration of risks later. Therefore, the types of infections that cause significant morbidity and the timing of risks have changed. These late infections are caused by all types of organisms, bacterial, viral, and fungal, but risks are predictable and surmountable with the use of tailored prevention strategies. Specifically, recent studies document prolonged risks for bacterial infections in the setting of GVHD, especially those caused by encapsulated organisms and those secondary to impaired Ab responses. Both prophylaxis and vaccination strategies can be used as a means to prevent infections, which typically manifest in the respiratory tract. Multiple viruses cause infection later after HCT, including several herpesviruses (eg, CMV and varicella zoster virus) and other respiratory viruses such as influenza and adenovirus. These infections can cause severe disease with diagnostic challenges, but prevention strategies using enhanced monitoring and/or prophylaxis may be effective. Finally, fungi also cause disease late after HCT, especially filamentous fungi (eg, Aspergillusspecies and Mucormycoses) and Pneumocystis jiroveci; prophylactic strategies may be used successfully to prevent invasive infection.
Epidemiology and risks: general
Infections have constituted a major threat since the introduction of hematopoietic stem cell transplantation (HCT) more than 40 years ago. In fact, infections are a main obstacle to the success of HCT, along with relapsed malignancy and GVHD. The development of preventative regimens and strategies were introduced as tools became available. Some major improvements in outcomes were associated with application of drugs and molecular tests to detect and prevent early bacterial infections, HSV, CMV, and preengraftment candidal infections. In fact, a large review comparing more than 2500 patients who received allogeneic HCT in Seattle over 2 different time periods (1993-1997 vs 2003-2008) showed lower risks for death associated with infection over the latter years. Differences were notable in risks associated with CMV and those associated with gram-negative bacteria and fungi (both Candida species and molds).We have made strides in preventing these infections, largely due to more aggressive prophylaxis strategies that use quinolone antibiotics and fluconazole and early screening strategies using molecular methods and radiology to detect and prevent CMV infection from causing end-organ disease.
Although our strategies have decreased the impact of early infections, limitations in preventative strategies and changes in transplantation methods now favor the development of later infections after HCT. Drug toxicities and limitations in molecular screening methods do not allow for effective application in some outpatient arenas. Changes in hosts and conditioning regimens that have reduced toxicity but extended durations of GVHD have effectively altered the predicted epidemiology of infection, with risks now occurring later after engraftment. Similarly, the use of alternative stem cell products such as peripheral blood rather than BM may be associated with later risks for infection during the GVHD period.
Large population-based studies have shown that the spectrum of bacterial infections has changed over time, with a notable shift from gram-negative bacteria causing bloodstream infection to gram-positive organisms as a primary cause of disease. This is thought to be due to prevention regimens and maintenance of prolonged intravascular catheters. The center-based studies have failed to demonstrate how changes in transplantation modalities have affected the epidemiology of bacteremia.
A major risk during the late transplantation period is respiratory acquisition of “pneumonia pathogens.” During the late period of poor Ab and cellular immunity, encapsulated bacteria such as S pneumoniae can cause the rapid development of pneumonia and/or meningitis with the potential for high morbidity. Both prophylaxis with trimethoprim-sulfamethoxazole and Pneumococcus vaccinations are at least partially effective in preventing disease. A review from the M.D. Anderson Cancer Center summarized S pneumoniae infections during the long period from 1989-2005. During this time, the calculated incidence of infection was 7 per 1000 HCTs performed. The infection typically did occur late, at a median day of diagnosis of 443 days, with underlying lymphoma and receipt of corticosteroids playing a role in increasing risks.7 Another population-based surveillance study performed in Toronto in 1994-2005 documented that the risk for S pneumoniae infections in HCT recipients was 347 per 100 000 person-years compared with 11.5 per 100 000 person-years in the general population. Results of this study emphasized the limitations of our prevention strategies, because the major serotypes that caused disease would typically have been protected by the available vaccine, which was not given in many people. Although trimethoprim-sulfamethoxazole can prevent some infections, this center also reported high rates of drug resistance in infecting isolates, further emphasizing the importance of timely vaccination.
Much has been written about the morbidity of the increasingly complicated multidrug-resistant (MDR) bacteria, both gram-positive and gram-negative. Organisms such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus(MRSA), Pseudomonas aeruginosa, and MDR Enterobacteriaceae (ESBL and KPC-producing gram-negatives) have become problematic at variable frequencies in different transplantation centers. These organisms can be acquired through the gastrointestinal (GI) tract early after HCT and later through multiple different routes, especially in people in whom endogenous flora have been altered due to prolonged or recurrent antibiotic exposure.
Risks for MDR organisms are important to understand given the implications on initiation of effective empirical antibiotic therapies. One large multicenter study performed in Brazil documented the scope of these pathogens. Prospective surveillance performed among 13 centers between March and November 2004 documented bacteremia in 91 of 411 patients (27%).Thirty-seven percent of these infections were caused by MDR pathogens.
Both Mycobacterium tuberculosis and atypical (rapid and slow growing) mycobacteria are a significant cause of disease late after HCT, especially in people with poor T-cell immunity. Rates of reactivation tuberculosis (TB) after HCT have historically been reported to be low, but rates are variable according to endemicity and pre-HCT seropositivity. However, many centers now observe devastating outcomes of previously unrecognized latent pulmonary TB in association with increased rates in certain endemic areas or transplantation of people from endemic regions.Discussion of how to prevent this occurrence is ongoing. Because recognition of latent infection based on skin test positivity has relatively poor sensitivity in people with hematologic malignancies, several investigators suggest enhanced pre-HCT screening of people at high risk using more sensitive methods of testing (eg, IFN-gamma release assays) in adjunct to the purified protein derivative skin test. Recognition of latent infection allows for the administration of effective treatment.
Viruses that cause infection after HCT can be classified as typically latent or “episodic” in nature, with the latter acquired typically after exposure rather than as a result of a reactivation event. It is important to understand the difference in viral pathogenesis because it has an impact on the type of preventative strategy that one would employ. Screening for reactivation with preemptive treatment and application of prophylaxis in seropositive recipients plays a role in preventing disease caused by latent herpesviruses such as CMV, HHV-6, and varicella zoster virus (VZV). Vaccinations have been developed to enhance protective responses to infection caused by episodic viruses such as influenza. Select viruses and prevention strategies are discussed in the following sections.
HSV and VZV
Reactivation HSV-1 and HSV-2 can occur both early and late after HCT, but the actual risk has been decreased dramatically by the generous use of acyclovir prophylaxis after allogeneic HCT. Acyclovir resistance has been described in severely T cell–depressed patients who have had prolonged or recurrent prior exposure, although it does not appear to be common.
CMV infection is common in the general population, and seropositivity in the donor and/or a HCT recipient is the norm. Reactivation of virus, potentially resulting in organ disease, causes morbidity and death if not managed appropriately. Prevention strategies have shown that prophylaxis with ganciclovir and preemptive therapy based on viral detection (using either antigen or PCR) decreases the risk for disease effectively, with some limitations to both strategies.