The “cytokine storm” has recently been a headline topic because of the COVID-19 pandemic. Cytokines are small proteins secreted by cells for diverse autocrine, paracrine, and endocrine cell signaling functions. In the setting of injury or illness, cytokines regulate immune and inflammatory host responses, and specific cytokines called chemokines recruit immune cells to the site of injury or infection. However, perturbations in cytokine production and/or signaling can cause systemic increases in inflammation, recruitment of leukocytes to organs not originally affected by the injury or illness, and resultant remote organ damage. The National Institutes of Health defines a cytokine storm as “a severe immune reaction in which the body releases too many cytokines into the blood too quickly” because of a bacterial or viral infection, autoimmune condition, or other disease. Several different types of cytokines exist that are involved in the cytokine storm/cascade including interferons, interleukins (ILs), chemokines, colony-stimulating factors (CSFs), and tumor necrosis factors (TNFs).1,2 Although this cytokine storm is associated with high mortality in severely affected patients with COVID-19, it is also relevant in the inflammatory cascade typical of polytrauma patients. Understanding this phenomenon helps explain the role of damage control orthopaedics after trauma.
Cytokines in Critical Illness
The cytokine storm is believed to be a large contributing factor to the severity of pathology seen in critically ill patients with COVID-19.3,4 Patients requiring hospitalization and admission to intensive care unit with COVID-19 are more likely to display high levels of proinflammatory cytokines such as IL-6, IL-1β, TNF-α, interferon-γ, inducible protein-10, monocyte chemotactic protein-1, and IL-2R compared with patients with moderate disease.5-7 The excessive cytokines and chemokines attract nonspecific inflammatory and immune cells such as neutrophils and monocytes, which infiltrate lung tissue and cause pulmonary and interstitial lung tissue damage. They also result in apoptosis of lung epithelial and endothelial cells in the airways and the alveoli of the lungs. This results in vascular leakage and alveolar edema in the lungs and, ultimately, the hypoxia and subsequent respiratory distress is seen in patients.4,5 Thus, collectively, the proinflammatory cytokines and chemokines that are in excess contribute to the notable lung damage and pathogenesis of acute respiratory distress syndrome, the leading cause of death, seen in severe patients with COVID-19.5
Cytokine storm proinflammatory effects can result in a reduction of physiological anticoagulants in the body. This can predispose a patient with COVID-19 to disseminated intravascular coagulation and resultant multiorgan dysfunction.4 All of this contributes to the consistently high D-dimer levels seen in many patients with COVID-19.4 Finally, the “cytokine storm” contributes to the severe depletion of the patient's T cell cohort.6 One study illustrated how the coronavirus can directly infect and destroy T cells and how the myriad of inhibitory cytokines released by the body, such as TNF-α and IL-10, also directly contribute to this decline. CD4 T cells, CD8 T cells, natural killer cells, memory and regulatory T cells, and B cells were all shown to be decreased because of COVID-19 and its subsequent “cytokine storm.”8 Lymphopenia is one of the most noticeable markers of a patient infected with COVID-19, and decreased lymphocyte counts have been shown to be closely linked to the severity of the disease experienced. These complications are seen in patients with COVID-19 despite a declining viral load, supporting the role of the vigorous host immune response in severe outcomes rather than viral virulence itself.5
Cytokines in Polytrauma Patients
Although the COVID-19 pandemic has highlighted the postinfectious cytokine storm phenomenon, any surgeon who has performed damage control orthopaedics (DCO) would recognize a parallel within their trauma patients. The same type of inflammatory cascade can be stimulated by polytrauma. Endogenous tissue damage products after trauma, such as oxidized phospholipids or extracellular matrix fragments, result in initiation of inflammatory signaling. This acute increase in inflammation is systemic in trauma patients (systemic inflammatory response system, SIRS) and should subside alongside the increase in anti-inflammatory mediators (compensatory anti-inflammatory response system) (reviewed in Refs. 9,10). However, in severe trauma patients, a prolonged and hyperactive SIRS overlapping with an immune compromised state in compensatory anti-inflammatory response system can result in secondary infection, hypercoagulability with deep vein thrombosis and pulmonary thromboembolism, multiple organ dysfunction syndrome, and death.11 Thus, the concept of DCO is based on the goal to perform as little surgical trauma possible to stabilize long bone and pelvic fractures so that surgical trauma does not add to the existing and evolving systemic inflammation experienced by polytrauma patients. In Pape's landmark work on DCO, acute respiratory distress syndrome complications were reduced by provisional external fixation of femur fracture rather than internal fixation in polytrauma patients with chest injury.12
The definition and application of DCO, however, is not practiced with consensus. One road block to fully understanding when and how to apply DCO may come with further understanding of the inflammatory response timeline experienced by polytrauma patients. Several studies show the association of trauma severity with a timeline of specific cytokine expression.13-16 Sousa et al demonstrated in a cohort of 99 young, predominantly male, trauma patients that high cytokine levels tapered over 72 hours after injury, but persistent elevation of cytokines IL6 and IL10 were associated with multiple organ dysfunction syndrome and death. In addition, IL6 levels correlated with Injury Severity Score, IL10 elevation was associated with SIRS with hypoperfusion, and high mobility group box 1 was associated with shock in patients on admission to the hospital. Binkowska et al followed a group of 32 patients where the levels of IL6 and IL1 receptor peaked during the third hour of hospitalization, regardless of injury severity. However, both were markedly higher in the Injury Severity Score >20 patients and in patients with complications.15
Implications for Musculoskeletal Tissues
Multiply injured orthopaedic patient exhibit impaired fracture healing compared with isolated extremity fracture patients. Impaired fracture healing has been associated with aberrant polymorphonuclear leukocyte number and function and prolonged IL6 expression in early fracture callus, demonstrating immune perturbations that affect bony healing.17 A recent animal study of fracture and polytrauma, modeled by concomitant thoracic blunt injury and burn injury, demonstrated that cytokine expression at the fracture site was similar to that seen in the fracture callus of patients with delayed fracture healing including high levels of IL-1, IL-6, and inducible protein-10/CXCL10.18 This is consistent with increases in inflammation that occurs after polytrauma. Overlying muscle injury exacerbates the immune dysregulation at fracture sites, and muscle tissue within a volumetric muscle loss injury demonstrates gene expression related to inflammation and fibrosis.19,20 Local cytokine and chemokine effects after muscle injury attribute to the continuance of fibrotic deposition and inhibition of satellite cells' regenerative capacity. Finally, muscle wasting and cachexia is associated with multiple chronic inflammatory states, including critical illness and trauma. Whether at a systemic or local level, immune and inflammatory perturbations do affect musculoskeletal tissue healing.
In summary, the recent COVID-19 pandemic has brought attention to cytokines and the phenomenon of cytokine storm into mainstream discussions. In this disease specifically, a cytokine storm overwhelming immune response contributes to the pathophysiology and mortality of the COVID-19 infection. Analogous perturbed immune reactions are experienced in polytrauma patients, compromising local tissue healing while threatening multiple organ systems. The practicing orthopaedic surgeon can appreciate the impact of severe trauma on a patient's tolerance of multiple surgeries, dictating damage control approaches. Furthermore, injuries and polytrauma still occur despite the COVID-19 pandemic. As a result, surgeons may see the effects of a heightened inflammatory state as in polytrauma settings when treating a spectrum of injury severity in COVID-19-positive patients. The expanding field of osteoimmunology should contribute to the orthopaedic community's understanding of how the immune system response, whether normal or pathologic, affects the whole body outcome of our patients. Efforts that mitigate damaging effects of an over exuberant immune response while maintaining the necessity of intact immunity are an important direction for critical care and trauma research and clinical care.
References printed in bold type are those published within the past 5 years.
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