Etoposide treatment in secondary hemophagocytic syndrome: impact on healthcare-associated infections and survival

Hemophagocytic syndrome (HS), or hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition, with high overall mortality rates in the ICU [1]. The pathophysiology relies on defective cytotoxicity in T-CD8 lymphocytes and NK-cells [2], resulting in uncontrolled macrophage activation and cytokine release after antigen stimulation, leading to multiple organ dysfunction [3‐7]. HS is traditionally characterized as being either familial (fHS) or secondary (sHS), the latter being most prevalent in the setting of an adult ICU population, resulting from infectious (viral, bacterial and parasitic) and non-infectious triggers (malignancy, autoimmune disease), with underlying immune suppression [1]. Diagnosis is often challenging and the most widely used diagnostic classifications are the HLH-2004 criteria [8] and the HScore [9], even if significant overlap occurs with common ICU entities such as sepsis [10]. Importantly, early recognition and trigger identification [11] are crucial in improving patient survival. Apart from cause-specific treatment and supportive care, etoposide, a type 2 topoisomerase inhibitor, is the frontline therapy for managing the sickest patients. Etoposide selectively depletes hyperactivated T-CD8 lymphocytes and quickly reverses the cytokine storm [12]. Its efficacy is notorious in pediatric familial HLH [13] and EBV-related HLH [14]. In adult patients, use of first-line etoposide therapy was associated with increased survival in a retrospective study [12].

Healthcare-associated infections (HAIs) are common in the ICU. According to the European Center of Disease Control (ECDC) [15], critically ill patients present with up to 8.3% of at least one HAI. Healthcare-associated pneumonia (HAP) is the most frequently reported (6.3%), followed by bloodstream infections (BSI, 3.7%) and then urinary tract infections (UTIs, 2%). HAIs lead to impaired clinical course with higher mortality rates, prolonged hospital stay [16], as well as increased antimicrobial use, and antimicrobial resistance [15].

To date, data on the rate of HAIs in ICU patients with sHS are scarce. However, sHS patients present a high risk of developing such infections, due to both intrinsic (immunosuppression with specific or drug-induced protracted neutropenia) and extrinsic factors [devices such as endotracheal tube or central venous catheters (CVC)]. In a retrospective study on secondary HS, HAIs were independently associated to worse prognosis [17]. Additionally, whether the administration of early immunosuppressive drugs—namely etoposide—to control macrophage activation increases the risk of HAI in ICU patients is unclear although clinically relevant. The main objective of this study was to assess the influence of etoposide administration on the rate of HAIs in critically ill patients with sHS, and to evaluate whether etoposide is associated with mortality.

In this cohort of critically ill patients with sHS, using a competing risk survival model, the occurrence of HAIs was associated with decreased cumulative survival. Interestingly, etoposide administration was associated with an increased rate of microbiologically documented HAIs in the ICU, without influencing survival outcomes.

To date, few studies have focused on HAIs in critically ill immunocompromised patients. In a retrospective study, Velasco et al. demonstrated a high rate of HAIs in immunocompromised ICU patients, with an overall rate of 91.7 per 1000 patient-days, with pneumonia, urinary tract infections and bloodstream infections being the most frequent [24]. More recently, in a large cohort of cancer patients, Stoclin et al. reported a cumulative incidence of ventilator-associated pneumonia (VAP) and secondary BSI of 58.8% and 15.1%, respectively, during the first 25 days of exposure [25] and HAIs were not associated with higher ICU mortality. In our cohort, we report a cumulative incidence of HAIs of 25% at day 15 after ICU admission, in the setting of sHS patients. HAIs were associated with a decreased survival rate. Most common causes of in-hospital death included multi-system organ failure (MOF), progressive underlying onco-hematological disease, and acute respiratory distress syndrome (ARDS) (Additional file 1: Table S5). Even though our study found an association between HAIs and increased mortality, final causality of death is hardly solely attributable to HAIs in these patients. In a pooled analysis of 661 ICU patients with sHS, overall mortality was 57.8%, with a higher mortality rate of 63.2% in patients with a malignant trigger [1, 26, 27]. In our study, we report a lower ICU mortality rate of 28.5%. This difference can be explained, in part, by a center effect, since our center is specialized in managing oncohematology patients, with shortened diagnosis and treatment delays which are correlated to better prognosis [11]. We may also hypothesize that sHS patients represent a particular group of patients within the immunocompromised ICU population, presenting with severe organ failures at ICU admission (median SOFA score at 8 [6–12]), explaining why the onset of HAIs is associated with a poorer outcome. Further studies with larger cohorts are needed to confirm our findings.

Etoposide constitutes a frontline therapeutic in the management of sHS in the most severe patients, to promptly limit organ failure, as it effectively reverses the cytokine storm by significantly reducing T lymphocyte activation. Early administration of etoposide has shown efficacy in pediatric patients [13, 14]. In adult patients, no randomized study has been conducted. Nevertheless, etoposide was associated with increased survival in a retrospective study [12]. Etoposide may promote the occurrence of HAIs, but data regarding the impact of etoposide on the incidence of HAIs in sHS patients are scarce. In one retrospective study, Apodaca et al. found that HAIs were independently associated with mortality. However, this cohort included a small number of patients and the rate of HAIs was very high (42%) [17]. To our knowledge, this is the first study assessing that the incidence of HAIs is higher in critically ill patients with sHS receiving etoposide. Nevertheless, while HAIs are associated with a poor outcome in the whole population of the study, survival in patients who received etoposide is not impacted. These results may either reflect increased risk of HAI with balanced risk benefit ratio in terms of mortality or a limited statistical power precluding the identification of an association between etoposide and mortality. Such infectious risk should be known to promptly detect and treat infections in these patients with frequent underlying immunosuppression. Current guidelines suggest antiviral, antifungal and pneumocystis prophylaxis for sHS patients needing etoposide administration [28]. Further studies to evaluate the benefit of broader prophylaxis with antibiotics are warranted for these patients.

This study suffers, however, from several limitations. First, this was a single center and retrospective study. Second, the primary event of interest was the first microbiologically documented HAI, which may have led to an underestimation of nosocomial events. Then, even if we used propensity score-based weighting of our population for etoposide exposure, and although groups seemed to be balanced on measured covariates after weighting, we cannot rule out that unmeasured parameters would differ between groups. Among these, EBV replication status, which mostly reflects the depth of immunosuppression, can also influence etoposide response. However, in our cohort, we only reported 4 (2.4%) EBV-associated lymphoproliferations with specific treatment requirements and follow-up. Third, corticosteroids represent a well-known risk factor associated with the occurrence of HAIs. However, we could not analyze this variable in the model, as an interaction exists between steroids and etoposide administration in a sensitivity analysis. Additionally, 25% of HAIs occurred before or on the day of etoposide administration. Since etoposide was administered at ICU admission in most patients, we do not believe that this could affect our results. Finally, as most patients received etoposide in our study, the small sample size of patients who did not received etoposide led to limited statistical power. The lack of benefit of etoposide on survival needs to be interpreted cautiously.

In summary, our study shows that etoposide treatment is associated with a higher incidence of HAIs in the ICU in severe patients with sHS. While HAIs were independently associated with a poor outcome, etoposide administration was not associated with a decreased survival. These results confirm that the use of etoposide to reverse organ failures is feasible assuming an increased risk of nosocomial infection that should be considered and monitored.