Immunosuppression in Sepsis

Abstract

ABUNDANT EVIDENCE EXISTS IN BOTH ANIMALS AND humans with sepsis for the appearance of a “cytokine storm,” characterized by high plasma levels of proinflammatory cytokines and chemokines, clinical signs of fever, tachycardia, and tachypnea and followed rapidly by development of shock, multiorgan failure, and death. Additional evidence indicates that sepsis can be associated with a state of immunosuppression, broadly defined as lymphopenia and loss of immune function, though the timing, incidence, and nature of the immunosuppression remain poorly characterized, especially in humans. The study by Boomer and colleagues in this issue of JAMA is perhaps the most authoritative investigation exclusively involving humans and confirming the onset of immunosuppression developing during septic shock or severe sepsis (defined as a systemic response to infection complicated by acute organ dysfunction). The investigators evaluated 40 patients who had sepsis following bacterial peritonitis or ventilator-associated bacterial pneumonia, using “bedside autopsies” to obtain splenocytes and lung cells immediately after the declaration of death. Trauma patients undergoing splenectomy and brain-dead patients (often following intracranial hemorrhage) who had not had sepsis were included as controls. The observations in the current study provide compelling evidence for development of immunosuppression in patients with sepsis, albeit with the important caveat that all of the study patients died of sepsis—those who survived may well have had a different immunologic course. Splenocytes obtained from these patients and subsequently stimulated in vitro with bacterial lipopolysaccharide (LPS) or with agonist antibodies revealed markedly suppressed production of cytokines ( 10% compared with supernatant fluids from LPS-stimulated splenocytes obtained from sepsis-free donors). The reason for high cytokine blood levels in sepsis is not known but may be due to exposure of macrophages and other cytokine-producing cells to high levels of agonists released from the infecting organisms (bacteria, viruses, etc). In addition, the data clearly indicate that splenocytes from patients with sepsis showed reduced content of costimulatory molecules such as CD28 on T cells, indicating that these cells had defective immune function. Antigen-presenting cells, largely consisting of macrophages and dendritic cells, were deficient in the costimulatory molecule CD86 and expressed increased levels of HLA-DR and the inhibitory ligand PD-L1 and its receptor, PD-1. Furthermore, there was a buildup of inhibitory cells (regulatory T cells and myeloidderived suppressor cells) in spleens and in cells isolated from lungs obtained from patients with sepsis. In lung, alveolar epithelial cells and endothelial cells expressed multiple inhibitory receptors and ligands, suggesting that such cells bring about reduced responsiveness of nearby lymphocytes. Collectively, at least in lung and spleen, the cellular changes essentially reflected that the “stars were aligned” in a manner leading to profound immunosuppression. The reasons for such an undesirable constellation of changes are obscure. Preventing or reversing such outcomes in experimental sepsis may be achieved by use of inhibitors of apoptosis (synthetic inhibitors of caspases or other types of inhibitors), but in human sepsis, lymphopenia and immunosuppression are usually well advanced by the time the patient is admitted to the intensive care unit, raising the question whether such derangements can be reversed over a short period. There have been suggestions that orally administered protease inhibitors of the retroviral class improve survival in the murine model of sepsis induced by cecal ligation and puncture, with reduced plasma levels of proinflammatory cytokines and diminished apoptosis in thymic and splenic tissues. Another poorly understood outcome in sepsis is the extent to which development of multiorgan failure may be related to the cytokine storm. Furthermore, whether the cytokine storm has any linkage to the development of immunosuppression is also largely unknown. Devices that adsorb cytokines may be useful. For example, use of a hemoperfusion device with polymyxin B improved survival in 64 patients with abdominal sepsis. Whether the effects of such devices are limited only to removal of LPS