Early Platelet dynamics during Staphylococcus aureus bacteremia is associated with dysregulated cytokine response and predictive of microbial persistence and mortality

BackgroundPlatelets play key roles in host immune response during sepsis. Microbial persistence and early dysregulated cytokine response predict poor outcomes in patients with Staphylococcus aureus bacteremia (SAB). Our objective was to determine the relationship between early platelet trends and cytokine response, microbial persistence and 30-day mortality in patients with SAB. MethodsA two-center observational study was conducted in hospitalized patients with monomicrobial SAB. Electronic medical records were reviewed for pertinent demographic, laboratory, and clinical information. Eligible subjects were grouped by platelet count at onset and Day 4 of SAB: normal platelet (NP, [&ge;] 150 x 109/L) and thrombocytopenia (TC, < 150 x 109/L). The groups were compared for clinical characteristics and outcomes. Results812 patients met inclusion criteria. The median age was 59 years with MRSA accounting for 34% of SAB. The most common comorbidities were hypertension followed by diabetes then renal disease. Thrombocytopenia (TC) occurred in 29% of patients at SAB onset: 15% (n = 120) were mild and 14% (n = 114) were moderate-to-severe (MS). Compared to patients with normal platelet (NP) at SAB onset (n = 578), higher proportion of patients with TC had alcohol use disorder (p = 0.015), active malignancy (p = 0.002), liver disease (p < 0.001), in addition to requiring intensive care unit (ICU) level of care during hospital stay (p < 0.001). TC patients had a longer duration of bacteremia (3 days vs 2 days; p = 0.008) and higher risk for 30-day mortality (18% vs 6%; p < 0.001) overall compared to those with NP. Changes in platelet count from SAB onset to Day 4 differed significantly between those with persistent (PB) versus resolving bacteremia (RB). Notably, patients who had NP at SAB onset but developed new onset of TC by Day 4 had a higher risk for 30-day mortality compared to those who maintained NP at Day 4 (20% vs 4%; p < 0.001). Those with recovery of their platelet count from TC to NP by Day 4 (n = 20) had their SAB shortened by one day (2 days vs 3 days; p = 0.413) and trended toward lower risk for 30-day mortality (5% vs 22%; p = 0.068) compared to those with sustained TC by Day 4 (n = 88). ConclusionOur results suggest that platelet dynamics during early course of SAB are associated with dysregulated cytokine response and predictive of 30-day mortality. Future studies should be conducted to assess the impact of utilizing platelet count within the first four days of S. aureus bacteremia to guide clinical interventions and to further investigate S. aureus virulence factors that impair recovery of platelet count in patients with thrombocytopenia. FundingNone Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPersistent S. aureus bacteremia is associated with high mortality and morbidity despite receipt of anti-staphylococcal agents with apparent in vitro activity. We have previously reported that early dysregulated host cytokine response biased towards an anti-inflammatory state (high IL-10/TNF ratio) during clinical course of S. aureus bacteremia is predictive of persistence and mortality. Additionally, we showed that mortality risk increases by 16% for each continued day with S. aureus bacteremia. In recent experimental models, others have shown that platelets play key roles in host immunity and bacterial clearance. Specifically, S. aureus virulence factor, -toxin, induced aberrant platelet aggregation resulting in thrombocytopenia and compromised bacterial clearance from the blood. We performed literature review using PubMed to identify any clinical studies published between January 1, 1996 and April 30, 2021 with the term "thrombocytopenia" AND ("Staphylococcus aureus" OR "S. aureus bacteremia" OR "persistent bacteremia" OR "duration of S. aureus bacteremia" OR "dysregulated immune response"). We identified three related clinical studies published previously: 1) a retrospective study with a main objective of identifying risk factors associated with thrombocytopenia at sepsis onset during S. aureus bacteremia, 2) another retrospective study aiming to evaluate the prognostic impact of thrombocytopenia at onset, Day 3, and Day 7 of methicillin-susceptible S. aureus bacteremia for predicting mortality, and 3) one prospective study that evaluated the association between ICU admission platelet count and host immune response but did not include infections with S. aureus. Added value of this studyTo extend the findings from the few earlier clinical studies by performing a more in-depth analysis of the relationship between platelet count, cytokine response, and outcome of bacteremia caused by both methicillin-sensitive and methicillin-resistant S. aureus in a large patient cohort. We examined early platelet dynamics by accounting for changes in daily platelet count over the course of initial 7 days of bacteremia which revealed that platelet count during the first three days of S. aureus bacteremia was significantly associated with a dysregulated cytokine response and predictive of 30-day mortality. Notably, for every 20 x 109/L drop in platelet count by day 4, the risk of death increased by 25%. Importantly, we observed a significant reduction in the risk of mortality in those with platelet count recovery to normal range by day 4 of bacteremia comparable to those whose platelet count remained normal throughout the course of infection, suggesting a critical window for early therapeutic interventions to mitigate platelet consumption and injury. Implications of all available evidenceOur observations provide strong clinical relevance to the experimental findings implicating the role of S. aureus -toxin in causing platelet injury as well as destruction and sequestration in the microvasculature leading to death in mouse models of bacteremia. The strong link between thrombocytopenia and mortality in S. aureus bacteremia support the need for close monitoring of platelets and a more timely and precise approach to S. aureus bacteremia management that is based on the host-pathogen interface. Considering the distinct patterns of platelet dynamics observed early during the course of S. aureus bacteremia associated with differential mortality risk and the significant improvement in survival among those with platelet recovery by day 4 of bacteremia, follow-up studies should focus on evaluating clinical microbiology procedures that could provide the -toxin phenotype of the infecting strains with prognostic significance to clinicians and investigating therapeutic agents that could mitigate -toxin-mediated insults to platelets to improve treatment outcome.