Infection is an everyday problem in orthopaedics and is quite common in open fracture management. To study this process and provide a basis to prevent infection, we developed a model that includes trauma (blunt fracture in the fashion of Bonnarens and Einhorn), surgical stabilization (standardized intramedullary K-wire fixation), and infection (Staphylococcus aureus inoculum). In this two-part study, we found that 10(2) colony-forming units of inoculum produced an optimal infection rate of 90-100%, which substantially challenged the immune system without overwhelming sepsis. We hypothesized that, in traumatic fractures, there is a specific immunological response that may lead to an increased rate of infection. In Part 2, we demonstrated immunosuppression (decreased Interleukin-12 levels) at days 6, 10, and 12 after fracture fixation versus nonfractured control groups (p < 0.05). This study describes a rat model of femur factures with osteomyelitis that allows investigation of posttraumatic immunosuppression.

The immune system undergoes numerous changes after traumatic and burn injuries, including a down-regulation of the TH1 response and up-regulation of the TH2 response.

The PubMed, Medline, and Ovid search engines were queried for relevant human studies. Bibliographies were also meticulously reviewed.

An interesting and potentially clinically relevant pattern of immune dysregulation exists after injury. The type 1 T-helper cell (TH1) response is suppressed as illustrated by diminished interleukin (IL)-2, interferon (IFN)-gamma, and IL-12 levels after major injury. The enhancement of the TH2 response is marked by elevated IL-10 and IL-4. Certain cytokine profiles, ratios, and polymorphisms may help identify patients at increased risk of systemic inflammatory response syndrome (SIRS), sepsis, multiple organ failure (MOF), and deep venous thrombosis. The most promising prognostic indicators to date are decreased production of the IL-12, elevated IL-10, soluble IL-2 receptor-a (sIL-2Ra), and IL-18 levels, IL-18 promoter polymorphisms, the IL-6:IL-10 ratio, and the degree of TH1 suppression as measured by diminished IL-2 and IFN-gamma. The Cytokine sections are subdivided into basic science, human studies, animal studies (when necessary), and directed therapeutics. The outcomes of sepsis, SIRS, or MOF are generally discussed together.

T-cell-specific immunologic changes occur after major injury. Identification of those TH1/TH2 cytokine profiles associated with worse prognosis may one day allow clinicians to risk stratify injured patients and identify those at increased risk of developing SIRS, sepsis, MOF, and deep venous thrombosis. Immune-targeted therapies may eventually serve as effective treatments in the acute setting to decrease morbidity and mortality, and to improve the management and prognosis of those patients at risk for developing postinjury complications.

The appearance of nucleated red blood cells (NRBC) in the circulation is associated with a variety of severe diseases, and indicates a relatively poor prognosis. Whether a malfunction of the bone marrow leads to this phenomenon is as unknown as the possible role that cytokines could play in this process. We analyzed erythropoietin, interleukin (IL)-3, IL-6, and IL-12p70 in the blood of 301 patients with circulating NRBCs. Two hundred fifty NRBC-negative patients served as controls. Multiple logistic regression revealed a significant association between the appearance of NRBCs in the blood and erythropoietin (odds ratio, 1.017; 95% confidence limits, 1.007-1.027; P < 0.001), IL-3 (odds ratio, 1.293; 95% confidence limits, 1.180-1.417; P < 0.001), IL-6 (odds ratio, 1.138; 95% confidence limits, 1.016-1.275; P < 0.05), and age (odds ratio, 1.019; 95% confidence limits, 1.009-1.030; P < 0.001), respectively. Gender and IL-12p70 were not significantly associated with the appearance of NRBC in the blood. To estimate the RBC production in the bone marrow, the increase in the reticulocyte concentration in blood was measured. The reticulocyte concentration in NRBC-positive patients was 69 +/- 2/nL, which was significantly higher than in NRBC-negative patients (60 +/- 2/nL; P < 0.01). Taken together, NRBC could be a marker that sums up hypoxic and inflammatory injuries. Thus, generally, the appearance of NRBC in blood is a valid parameter to identify patients at high mortal risk. Moreover, the increased number of reticulocytes in the blood of NRBC-positive patients may indicate that the appearance of NRBC is not associated with disturbed bone marrow function as far as the erythropoiesis is concerned.

Patients with multiple injuries have alterations in hemodynamic, metabolic, and immune responses that largely are orchestrated by endogenous mediators referred to as cytokines. At the molecular level cytokines act as architects constructing a blueprint which ultimately will become the clinical "Big Picture"; however, the exact role and extent each cytokine has is still in question. In addition, the surface of research opportunities has nearly been scratched regarding the best way to control or manipulate the cytokine response in efforts to improve care for the trauma patient. Systemically organisms respond to injury regardless of the cause (hemorrhage, ischemia, reperfusion, fracture, and tissue damage) by attempting to restore homeostasis, which involves a coordination of the immune, cardiovascular, endocrine, and nervous systems. This systemic response can result in severe immunologic compromise that threatens the survival of patients with trauma. It seems that it is this balance or imbalance of cytokines, along with other associative factors, that controls the eventual clinical pathway a patient will take. Blood mediator concentrations often parallel the inflammatory process, and high levels of cytokines can be followed by severe organ dysfunction. Certain cytokine levels, such as the interleukins, can be used in predictive ways to correlate organ failure in multiply injured patients. Although much more research must be done, there is great promise in the study of cytokines through basic science research and clinical trials.

Paradoxically, the host response to severe sepsis may lead to immunosuppression, thereby favoring nosocomial infections. We examined the role of the two IL-12 isoforms, bioactive IL-12p70 and regulatory IL-12p40, in 16 patients with severe sepsis. We compared the capacity of purified blood and alveolar phagocytes [polymorphonuclear neutrophils (PMN) and monocytes/macrophages] to secrete each isoform. Blood monocytes had normal basal secretions. In contrast, a marked imbalance was observed after ex vivo stimulation by lipopolysaccharide plus IFN-gamma, with significantly lower IL-12p70 production and higher IL-12p40 production. Conversely, stimulated IL-12p40 production by the patients' blood PMN tended to be impaired, as was their cell-surface beta2 integrin and L-selectin expression, known as markers of cell activation. In the patient's bronchoalveolar lavage fluid, the production of both IL-12 isoforms after ex vivo stimulation was significantly lower with alveolar macrophages than with autologous blood monocytes and significantly higher with alveolar PMN than with autologous blood PMN. This sheds new light on the potential role of PMN in local modulation of inflammation, via secretion of the anti-inflammatory IL-12 p40 subunit. The imbalance between the bioactive and regulatory IL-12 isoforms, which is probably designed to control excessive inflammation, may also make septic patients more susceptible to nosocomial infection.

To determine the effect of major trauma on the cytokine-producing activity of monocytes and CD4+ T cells in a homogeneous cohort of patients as well as to determine the relationship between monocyte and T-lymphocyte responses and clinical outcome.

Surgical intensive care units of a trauma center and flow cytometry and experimental laboratories at a teaching hospital.

Prospective cohort clinical study with measurements of white cell cytokine-producing activity on days 2, 5, and 10 postinjury. The number of cytokine-producing CD14+ monocytes, CD4+, and CD8+ T cells were determined in whole blood using flow cytometry combined with the intracellular cytokine staining method. Basal and lipopolysaccharide-stimulated interleukin (IL)-12, tumor necrosis factor-alpha, IL-6, and IL-1alpha production by monocytes as well as basal and phorbol 12-myristate 13-acetate plus ionomycin-stimulated interferon-gamma, IL-4, and tumor necrosis factor-alpha production by T cells were determined on days 2, 5, and 10 postinjury and compared with similar measurements made in healthy control subjects.

Twelve randomly selected black, male patients were enrolled in the study: mean injury severity score, 26; mean age, 35 yrs; mean Glasgow Coma Scale score, 13; systemic inflammatory response syndrome, 92%; sepsis, 42%; bronchial infection, 42%; and adult respiratory distress syndrome 25%.

After lipopolysaccharide stimulation, the number of IL-12-, tumor necrosis factor-alpha-, IL-1alpha-, and IL-6-producing CD14+ monocytes was 40% to 70% lower in trauma patients on postinjury days 2, 5, and 10 than in healthy control subjects. After phorbol 12-myristate 13-acetate stimulation, the number of IL-4-producing CD4+ cells increased three-fold in the trauma patients compared with healthy control subjects. In contrast, the number of interferon-gamma- or tumor necrosis factor-alpha-producing CD4+ and CD8+ T cells was not different between the patients and control subjects. The Th1/Th2 ratio was significantly lower in patients on all postinjury days than in the control subjects. A statistically significant inverse correlation was found between the number of IL-12-producing monocytes and IL-4-producing CD4+ T cells in trauma patients (p =.007, r2 =.47). This correlation was absent in control subjects. The degree of depressed capacity of monocyte IL-12 production on day 2 postinjury showed a statistically significant correlation with the development of adult respiratory distress syndrome, sepsis, or infections and also with the duration of systemic inflammatory response syndrome and sepsis.

Major trauma results in an early and marked decrease in monocyte cytokine-producing activity. The trauma-induced depression in IL-12 production by the mononuclear phagocyte system may promote T-cell commitment toward a Th2 pattern early after trauma. The appearance of the Th2 pattern is the result of elevated numbers of IL-4-producing cells without major alterations in T-cell interferon-gamma-producing capacity. The degree of alterations in monocyte and T-cell responses on day 2 postinjury correlates with the development of adverse clinical outcomes and the subsequent duration of the inflammatory response.