Risk infection to spare bleeding? The quandary of splenectomy for immune thrombocytopenia
Authors: Michelle Zeller, Donald M. Arnold
Journal: American Journal of Hematology (2015)

Choosing between medical management and splenectomy for the treatment of immune thrombocytopenia (ITP) presents a difficult decision for patients. To opt for medical management means regular, often daily medications, frequent clinic visits and, if disease control is poor, a 1% risk of intracerebral hemorrhage 1. On the other hand, splenectomy may provide a prolonged platelet count response or “cure” for to up to 70% of patients 2, but is associated with a 1% lifelong risk of severe infection. Evidence to guide this decision is limited, and no comparative trials of medical versus surgical treatment have been done. In addition, no consistent predictor of splenectomy success has been identified apart from younger age 2, even although previous reports have found an association with response to high-dose intravenous immunoglobulin 3. Thus, ITP patients and their doctors continue to struggle with the decision as to whether or not to proceed with splenectomy 4. Rituximab is another second line therapy for ITP and may be a suitable alternative to splenectomy for some patients because of its association with lasting remissions 5. Rituximab was quickly adopted into practice because of early experiences showing benefit in patients with refractory ITP 6; however, data from randomized trials are less optimistic. In a recent meta-analysis, rituximab plus standard of care was more often associated with a complete platelet count response (platelets > 100 × 109/L without rescue treatment) compared with standard of care alone (46.8% vs. 32.5%; p = 0.002); however, responses were often not sustained past 12 months 7. The efficacy of rituximab in ITP is thought to be related to the rapid and profound depletion of autoantibody-producing B-cells or to downstream effects on regulatory T-cells 8. Toxicities of rituximab include infusional reactions, hepatitis B reactivation, and a possible association with progressive multifocal leukoencephalopathy 9. Bacterial infection is the most feared complication of splenectomy. The risk of overwhelming post-splenectomy infection is approximately 1%–3%. In a population-based Danish cohort study of 3,812 patients who underwent splenectomy, the overall incidence rate of infection was 7.7 per 100 person-years [odds ratio compared with unsplenectomized patients with an indication for splenectomy, 1.7 (95% confidence interval, 1.5–2.1) in the first 90 days] 10. In a review of the literature up to 1996, the frequency of infection was 2.1% and mortality was 1.2% among 484 patients who had splenectomy for ITP 11. Life-threatening infections may occur many years after splenectomy, suggesting that the risk of severe infection may persist 12. To reduce the risk of bacterial infection, all patients who undergo splenectomy should receive vaccinations against the encapsulated bacteria Streptococcus pneumoniae, Haemophilus influenza type B (HIB), and Neisseria meningitidis. Likewise, patients who are due to receive rituximab should also receive pre-splenectomy vaccines because some patients will eventually require splenectomy and treatment with rituximab may impair vaccine responses. Reduced vaccine responses were demonstrated in a substudy of a randomized trial comparing rituximab or placebo: All patients received the S. pneumoniae polysaccharide vaccine and the HIB conjugate vaccine 6 months after rituximab or placebo infusions. One month after vaccination, an adequate antibody response to the S. pneumoniae vaccine was achieved by three of 14 (21%) patients in the rituximab group and four of six (67%) patients in the placebo group 13. Similar results were obtained with the HIB vaccine. A recent meta-analysis in patients with rheumatoid arthritis also showed that rituximab lowered antibody responses to S. pneumoniae and influenza vaccines 14. The study by Moulis et al. 15 in this issue of the American Journal of Hematology addresses the topic of how often and when vaccinations are currently being administered to patients with ITP before splenectomy or rituximab. This national database study from France identified ITP patients, exposure to splenectomy, rituximab, and vaccination retrospectively. The study showed that vaccination rates for S. pneumoniae, HIB, and N. meningitidis were 70.2%, 47.0%, and 11.9%, respectively, for patients treated with splenectomy; and 32.4%, 18.9%, and 3.8% for patients treated with rituximab. Only 30% of patients received vaccines in the recommended 2-week time frame before rituximab. For splenectomy patients previously treated with rituximab, over half of the vaccinations were administered after rituximab and during the period of maximal B-cell depletion. The authors conclude that adherence to vaccination guidelines is poor and timing of vaccination is suboptimal. Other surveillance studies have shown similar results 16, 17. Several strategies for improving vaccination uptake have been tested, including community education, standard order sets for providers, and provider reminder systems 18. In a systematic review, provider reminder systems were shown to be the most effective 19. These interventions were designed to alert providers when individual patients were due for specific vaccinations. Implementation of these systems included notations in patient charts, automatic chart prompts, and electronic checklists. Combining interventions, for example, improving patient access to vaccines plus provider-based interventions, were also effective. Population-level strategies that have been recommended by the US Task Force on Community Preventive Services in collaboration with the Centers for Disease Control and Prevention include increased community awareness of the importance of vaccinations through education, improved access to vaccines by reducing (or eliminating) costs, and at-home vaccination programs 20. In the broader field of knowledge translation, facilitating the implementation guidelines into practice can often be achieved with clinical decision support systems 21. Examples include manual or computer-driven physician reminders or electronic order entry systems 22, 23. Linking health information from hospital visits, vaccine dispensation, and diagnostic codes could be used to develop a standardized, integrated decision support system for ITP patients who require vaccinations. Electronic reminders can be used to prompt hematologists or surgeons about the need for and timing of vaccines; a decision support system can be designed to disallow booking of splenectomies or rituximab infusions before proof of vaccination is provided; and preprinted order sets for rituximab could include vaccine dose and administration schedules. An alternate strategy is to vaccinate all ITP patients as soon as the diagnosis is made. The study by Moulis et al is a wake-up call for ITP treaters. Although there is some doubt as to the effectiveness of vaccinations in preventing post-splenectomy infection 24, improved uptake of vaccinations before splenectomy and rituximab would likely reduce infection risks to rates that would increase patients' and providers' comfort with splenectomy as an acceptable treatment choice.