Infections following allogeneic stem cell transplantation: New concepts, improved insights, and renewed hope for better outcomes

Keywords:

• Allogeneic stem cell transplantation
• fungal infections
• immune reconstitution
• immunogenetics
• immunotherapy
• microbiome
• viral infections

Allogeneic stem cell transplantation (ASCT) is a medical procedure widely used to treat diseases once thought incurable, such as malignant and non-malignant hematological disorders including leukemia, lymphomas, and aplastic anemia. The indications for ASCT continue to expand, including lately patients with HIV. Over 400,000 patients have received ASCT between 2006–2014 based on figures from the Worldwide Network for Blood and Marrow Transplantation- a consortium that compiles data from over 1516 transplant centers from 75 countries world-wide.¹ In the last 3 decades, we have witnessed tremendous changes in the field of ASCT. Specifically, with the development of novel techniques of transplantation such is reduced intensity conditioning, widening sources of stem cells including the use of cord blood and grafts selected for CD34+ cells, and new approaches toward graft-versus-host disease prophylaxis and the improvement of post-transplant supportive care with the management of transplant associated organ toxicities.² These changes have made ASCT feasible in an expanding number of patients, including older patients with comorbidities who could not tolerate myeloablative conditioning regimens of the past.

Despite all these improvements, ASCT continues to be associated with a profound humoral and cellular immune deficiency, predisposing patients to the development of opportunistic infections, such as severe viral infections (e.g., CMV, adenovirus, BK virus, community-acquired respiratory viruses), opportunistic fungal infections and multidrug resistant bacterial infections.³ These immune deficits commonly preexist due to the underlying systemic disease for which the patient is being transplanted, but become worse shortly after conditioning regimen and with the use of immunosuppressive therapy to control graft-vs.-host disease (GvHD). As a result, many patients may have persistent, quantitative and qualitative immune deficits that persists for years following transplantation.

Common infectious complications after ASCT often follow a predictable timeline.^3,4 Specifically, early on in the setting of neutropenia and mucositis complicating conditioning regimen, pathogens associated with mucosal injury such as Gram-positive or Gram-negative bacteria, Candida and herpes simplex virus predominate. CMV reactivation occurs typically around early post engraftment and coincides with profound defects in cellular immunity and the frequent occurrence of acute GvHD. Around that time, the cumulative immunosuppression post ASCT and/or the development GvHD result in an increased risk from opportunistic mold infections such as aspergillosis and community-acquired respiratory viruses such is Influenza and RSV. The continuous risk for opportunistic viral and mold infections, and infections caused by encapsulated bacteria such is Streptococcus pneumoniae are major concerns in patients with chronic GvHD.

Our understanding of the pathogenesis and treatment of these infections is evolving rapidly. Continuous improvements in our therapeutic armamentarium and in the diagnostics of many infections, as well as the increasing experimental sophistication in studying immune recovery, GvHD and its role and interaction with the host microbiome is changing how we define “immunosuppression” and the pathogenesis of major opportunistic pathogens encountered in the peri-transplant period. An increasing awareness of immunogenetic risk for infections and the pharmacogenetic variables affecting drug response and pharmacokinetics further contribute to the complexity of research in this area.

This special focus section in Virulence entitled Post-ACST infections is dedicated to some key concepts surrounding the modern landscape of the key infections seen post ASCT. All these articles complement one another and they are written by notable experts in their corresponding field, who put their content in context.

First, Metha and Rezvani, from the MD Anderson Cancer Center, start with an overview of the dynamic and interrelated phases of immune reconstitution post ASCT and its relationship to infection risk.⁵ Next, Wójtowicz and Bochud, from the University of Lausanne, Switzerland, expertly discuss the rapidly evolving and complex topic of the immunogenetic risk and infections following ASCT.⁶ They nicely elaborate on the difficulties of having immunogenetic profiling assist to the assessment of the dynamic nature of infectious risk. Taur, from Memorial Sloan Kettering, NY, critically discuss the emerging studies on the role of microbiome in GvHD pathogenesis and infectious complications post ASCT.⁷ We have just started scratching the tip of this “big data” iceberg, which now includes study not only of the microbiome but also of mycobiome and virome. Fuji and colleagues, from the University Hospital of Würzburg, Germany,⁸ address the major unmet need in treatment of opportunistic infections in ASCT, that of adjunct immune therapy to fight of opportunistic recalcitrant fungal and viral infections. The authors address different strategies and effector cell platforms, timing of intervention (e.g., prophylaxis vs preemptive vs salvage therapy), the drawbacks of each approach, and the challenges of clinical trial design and patient selection. Al-Bader and Sheppard, from McGill University in Canada,⁹ provide a thorough overview of our current understanding in immune a pathogenesis of Aspergillus fumigatus, the most common cause of fungal infection post ASCT. Further insight into how Aspergillus senses environmental cues, invades and evades immune system containment post ASCT would further enhance our understanding for that difficult to treat disease and bring new therapeutic strategies. Finally, Blythe and colleagues, from the University of Sydney in Australia,¹⁰ address the complex topic of CMV-specific immune-reconstitution following ASCT. The authors provide an excellent overview of the emerging clinical strategies for characterization of the immunogenetics of donor/ recipient and CMV reactivation post ASCT, as well as the promise of clinical tests to capture the kinetics of recovery of CMV immune responses.

In summary, major progress has been made both in the technical aspects and in understanding the biology of ASCT, as well as improvements in supportive care, including understanding of the immunopathogenesis and treatment determinants of major opportunistic infections. As the qualitative and quantitative elements of both immune recovery and reconstitution of microbial communities in mucosal surfaces of the ASCT recipients are quite complex, integrating these big data approaches to the classic, time honored risk factors of infections should be an obvious and challenging direction for future studies. Nevertheless, there is growing optimism that these modern concepts will be ultimately integrated into clinical practice to assess individual susceptibility to specific infections post ASCT. I hope that the readers of Virulence will enjoy reading this special focus section and learn a lot about what the future holds in these very exciting areas of modern medicine.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

DPK acknowledges the Frances King Black Endowment for cancer research.