Severe infection can lead to sepsis. In sepsis, the host mounts an inappropriately large inflammatory response in an attempt to clear the invading pathogen. This sustained high level of inflammation may cause tissue injury and organ failure. Later in sepsis, a paradoxical immunosuppression occurs, where the host is unable to clear the preexisting infection and is susceptible to secondary infections. A major issue with sepsis treatment is that it is difficult for physicians to ascertain which stage of sepsis the patient is in. Sepsis treatment will depend on the patient’s immune status across the spectrum of the disease, and these immune statuses are nearly polar opposites in the early and late stages of sepsis. Furthermore, there is no approved treatment that can resolve inflammation without contributing to immunosuppression within the host. Here, we review the major mechanisms of sepsis-induced immunosuppression and the biomarkers of the immunosuppressive phase of sepsis. We focused on reviewing three main mechanisms of immunosuppression in sepsis. These are lymphocyte apoptosis, monocyte/macrophage exhaustion, and increased migration of myeloid-derived suppressor cells (MDSCs). The biomarkers of septic immunosuppression that we discuss include increased MDSC production/migration and IL-10 levels, decreased lymphocyte counts and HLA-DR expression, and increased GPR18 expression. We also review the literature on the use of specialized pro-resolving mediators (SPMs) in different models of infection and/or sepsis, as these compounds have been reported to resolve inflammation without being immunosuppressive. To obtain the necessary information, we searched the PubMed database using the keywords sepsis, lymphocyte apoptosis, macrophage exhaustion, MDSCs, biomarkers, and SPMs.

Early in sepsis, a hyperinflammatory response is dominant, but later, an immunosuppressive phase dominates, and the host is susceptible to opportunistic infections. Anti‐inflammatory agents may accelerate the host into immunosuppression, and few agents can reverse immunosuppression without causing inflammation. Specialized pro‐resolving mediators (SPMs) such as resolvin D2 (RvD2) have been reported to resolve inflammation without being immunosuppressive, but little work has been conducted to examine their effects on immunosuppression. To assess the effects of RvD2 on immunosuppression, we established a model of macrophage exhaustion using two lipopolysaccharide (LPS) treatments or hits. THP‐1 monocyte‐derived macrophages were first treated with RvD2 or vehicle for 1 h. One LPS hit increased NF‐κB activity 11‐fold and TNF‐α release 60‐fold compared to unstimulated macrophages. RvD2 decreased LPS‐induced NF‐κB activity and TNF‐α production but increased bacterial clearance. Two LPS hits reduced macrophage bacterial clearance and decreased macrophage NF‐κB activity (45%) and TNF‐α release (75%) compared to one LPS hit, demonstrating exhaustion. RvD2 increased NF‐κB activity, TNF‐α release, and bacterial clearance following two LPS hits compared to controls. TLR2 inhibition abolished RvD2‐mediated changes. In a mouse sepsis model, splenic macrophage response to exogenous LPS was reduced compared to controls and was restored by in vivo administration of RvD2, supporting the in vitro results. If RvD2 was added to monocytes before differentiation into macrophages, however, RvD2 reduced LPS responses and increased bacterial clearance following both one and two LPS hits. The results show that RvD2 attenuated macrophage suppression in vitro and in vivo and that this effect was macrophage‐specific.

This case describes a rare instance of reversible dilated cardiomyopathy (DCM) in a 65-year-old Caucasian male with a significant past medical history of inflammatory rheumatoid arthritis (RA) controlled with rituximab and hydroxychloroquine (HCQ). The patient presented with acute onset of dyspnea on exertion and palpitations and was diagnosed with congestive heart failure in the context of DCM. Despite having no prior cardiac abnormalities, an EKG revealed a new left bundle branch block, and an echocardiogram demonstrated a severely reduced left ventricular ejection fraction (LVEF) of 10-15%. Left heart catheterization and coronary angiography revealed no evidence of coronary artery disease. Given the absence of an overt cause, drug-induced DCM was suspected; hence, rituximab and HCQ were discontinued. Other common causes of DCM, including alcohol abuse and virus-induced DCM, were excluded based on relevant testing. Seven to nine months after cessation of HCQ and rituximab, the patient’s RA progressed, and treatment was initiated with IV tocilizumab, resulting in a good clinical response. At the 26-month follow-up, a repeat echocardiogram revealed mild mitral regurgitation with an LVEF which improved to 55%. At this point, Takotsubo cardiomyopathy was considered a potential cause of this patient’s DCM due to its reversible nature. This case highlights the importance of comprehensive cardiac monitoring in symptomatic patients at high risk for cardiovascular disease, such as this patient with long-standing inflammatory disease. Physicians should work together to closely monitor and consider the serious potential risks of all treatment regimens.