Incidence and Risk Factors of Late-Occurring Infections in a Contemporary Cohort of Hematopoietic Cell Transplantation Survivors

Abstract

<h3>Introduction</h3> There is a paucity of information on late-occurring (≥1y) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT). Addressing these knowledge gaps can help tailor post-HCT infection surveillance and proactive immune reconstitution practices in this growing population. <h3>Method</h3> Patients were eligible if they underwent a first HCT at City of Hope between 2010 and 2013, and were alive and in remission at 1y post HCT; 696 were eligible and included in this study. Standardized (national guidelines) definitions were used to determine the occurrence of late-occurring (≥1y after HCT) severe/life-threatening/fatal bacterial, viral and fungal infections. Infections that occurred within 4 weeks of a previous one were considered polymicrobial. Follow-up was censored at relapse, subsequent malignancy, death, or December 31, 2017, whichever occurred first. Chronic GVHD (cGVHD) was categorized as none, mild, moderate/severe at 1y post HCT. We determined the cumulative incidence of: first, polymicrobial, vaccine-preventable, and subsequent infection (>4 weeks from initial infection), taking into consideration competing risk. We used multivariable regression (hazard ratio [HR], 95% confidence interval [CI]) to adjust for relevant covariates. <h3>Results</h3> Median age at HCT was 53.3y (range, 0.7y-78.1y); 58.5% were male; 73.1% were non-Hispanic white; 57.2% underwent allogeneic HCT; 42.8% were at high risk of relapse; 69.1% received myeloablative conditioning. Overall, 194 (27.9%) developed a late infection; 75 (10.8%) had at least one vaccine-preventable infection. Median time to first infection was 1.8y (range, 1.0-6.6y) from HCT. The 5y cumulative incidence of a late infection was 28.6%; 5y incidence of vaccine-preventable infection was 11.7%; 5y incidence of polymicrobial infection was 6.4%; and there was a steep increase in the incidence of each subsequent infection (Fig 1). Survivors of allogeneic HCT had a significantly higher 5y incidence (Fig 2), and the incidence was highest in patients with moderate/severe cGVHD at 1y post-HCT (Fig 3). Overall, there was a four-fold risk among allogeneic compared to autologous patients (HR 4.11; 95%CI 2.83-5.97; p<0.001). Mild cGVHD at 1y was associated with a 1.96-fold (95% CI 1.06-3.61) risk, while moderate/severe cGVHD was associated with a 3.61-fold (95% CI 1.98-6.58) risk of developing a late-occurring infection (reference: no cGVHD). <h3>Conclusion</h3> Nearly one third of long-term HCT survivors developed a severe/life-threatening/fatal infection, and one in ten developed a vaccine-preventable infection. Allogeneic HCT survivors had a higher risk than autologous survivors, due in part to cGVHD and its management. There was a steep increase in risk of subsequent infections with each infectious episode, emphasizing the need for closer monitoring and prevention strategies in these patients.