Sarah H. Appel

The two-edged sword of large-dose steroids for spinal cord trauma

ObjectiveIn 1990, large-dose steroid administration was advocated in spine-injured patients to lessen neurologic deficits. The authors undertook both prospective and retrospective studies to evaluate the response of such profound pharmacologic intervention. Summary Background DataOf all sources of nonfatal injury, spinal cord trauma remains the most devastating in both cost and impact on the quality of the patients life. One study found that routine large-dose steroid administration after injury lessened the extent of neurologic injury. After uncommonly promp‡ and broad lay press publicity, this practice was widely accepted. Biased by knowledge of the known immunosuppressive effects of steroids, the authors suspected that pneumonia was both more frequent and severe in steroid-treated patients. MethodsThirty-two patients with cervical or upper thoracic spinal injuries (C3–6, 20 patients; C6–7, 6 patients; and T1–6 6 patients) were studied at an urban level I trauma center from January 1987 to February 1993. Complete spinal cord injury was present in 22 of 32 patients; 14 patients received steroids postinjury. There was no difference in mean age, cord level, age-adjusted injury severity score, or the percent of injury severity score caused by the spinal injury. ResultsThe length of hospital stay was longer in steroid-treated patients (S) than in nonsteroid (NS) patients, that is, 44.4 days versus 27.7 days, respectively (p = 0.065). Seventy-nine per cent of S patients had pneumonia compared with 50% of NS patients (p = 0.614). There was no statistical difference in the episodes of pneumonia per patient between the two groups (p > 0.05). Prospectively, the authors evaluated sequentially several parameters known to be important in human immune responses to bacterial challenges in nine S and five NS patients. In S patients, both the per cent and density of monocyte class II antigen expression and T-helper/ suppressor cell ratios were lower than in NS patients. However, S patients did have an initially higher, earlier boost in some host defense parameters that rapidly declined, and their subsequent response was both blunted and delayed. These differences became even clearer when stratified according to cord level and incomplete versus complete cord status. Not surprisingly, infected patients, whether S or NS, had lower levels of monocyte antigen expression, CR3, and helper/ suppressor ratios. ConclusionsThese data do not permit a judgment to be made whether neurologic status was improved by S administration. It is known that vital immune responses were adversely affected, that pneumonia was somewhat more prevalent, and that hospitalization was prolonged and costs therefore increased by an average of

Experimental and clinical significance of endotoxin-dependent HLA-DR expression on monocytes

51,504 per admission. Further clinical studies will be needed to determine to what extent these observations offset the putative benefits of large-dose steroids in the treatment of spinal trauma.

Pneumonia in the surgical intensive care unit: Immunologic keys to the silent epidemic

For much of the last decade, an increasing number of surgeons have been interested in objective assessment of cellular contributors to host defense function. In order to study many of these processes, it is apparently desirable that the cells be isolated to the extent feasible for the purpose of analyzing a more or less pure population of cellular elements. The purpose of this paper is to describe the physiologic activation of mononuclear cells that occurs as a result of the isolation process. Therefore, it follows logically that such cells are therein intrinsically less responsive to further physiologic manipulation in vitro. Analyses of such data without an awareness of this intrinsic aberration will undoubtedly lead to misinterpretation of the capacity of such cells for further modulation by immunostimulants or by the intrinsic processes related to injury, anesthesia, and operation. Furthermore, it may indicate that certain agents, e.g., cytokines, are unable to stimulate cellular function when, in fact, the defense function of the cell has been initially stimulated by the isolation procedure. Fractionation of human peripheral blood over Hypaque-Ficoll and subsequent purification of monocytes by adherence to plastic lead to an increase in the relative density of HLA-DR on monocytes. This increase occurred when carried out in endotoxin lipopolysaccharide (LPS)-contaminated or LPS-depleted reagents. LPS, added experimentally to whole blood, enhanced HLA-DR expression on monocytes without further manipulation. Monocyte HLA-DR expression measured in whole blood was reduced in patients with major sepsis (n = 19) compared to normal subjects (n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of protein malnutrition and immunomodulation on immune cell populations

ObjectiveThe authors undertook a prospective study of trauma victims in the intensive care unit (ICU) to investigate the clinical course of pneumonia and the local and systemic immune responses to the pneumonia. Summary Background DataThe silent epidemic of pneumonia has been and “unappreciated killer” in terms of being overlooked in surgical ICUs for the past 5 years, and specifically, the most common major infection after severe trauma. Little is known about the immune response to an acute pulmonary infection. MethodsThe authors studied 50 consecutive, critically ill trauma patients, with a mean injury severity score of 28 ± 2, who developed pneumonia while ventilated mechanically. Patients were observed clinically, and specific immunologic parameters, including major histocompatibility antigen HLA-DR, complement receptor (CR3), and Fc receptor (FcRIII), were measured in circulating and local alveolar leukocytes for up to 30 days. Eleven patents provided unique clinical data via bronchoscopy for unilateral pneumonia, with collection of bronchoalveolar lavage (BAL) fluid from both the infected and uninfected sides. ResultsPatients developed clinical pneumonia 5.3 ± 0.4 days after admission to the ICU. At diagnosis, mean temperature was 101.4 F, white blood cell count was 16,000/mm3. arterial oxygen tension was 104 ± 14, fraction of inspired oxygen was 0.47, and positive end-expiratory pressure was 5. Thirty patients (Group A) recovered relatively promptly; 20 patients had prolonged illnesses (Group B), 15 of whom ultimately survived, and five of whom died. Patients with poor outcomes had greater leukocytosis (p < 0.05) and temperature elevation (p < 0.05) after 5 days of pneumonia. Immunologically, peripheral leukocyte expression of HLA-DR, FcRIII, and CR3 was equivalent in both groups. However, the expression of all three antigens on local alveolar leukocytes was decreased to a greater extent in the poor outcome group compared to the good outcome group, evident before any clinical differentiation between the two outcome groups. ConclusionsPneumonia prolonged duration of mechanical ventilation, ICU and hospital stay, and overall infectious morbidity. Although immune suppression has been recognized as a result of initial

A biologic basis for altered host defenses in surgically infected abscesses.

Malnutrition has deleterious effects on immune functions, which predispose to an increased risk of infection. To study the effect of protein malnutrition on such immune functions and resistance to infection, we divided C57BL/6 mice into three groups: (1) control-standard diet, (2) protein-malnourished for 14 days, and (3) protein-malnourished for 14 days followed by standard diet for 3 days. The animals were further divided into subgroups: (1) an untreated group, (2) a muramyl dipeptide (MDP)-treated group, and (3) an interferon-gamma (IFN-gamma)-treated group before cecal ligation and puncture (CLP). Malnourished mice had significantly (P less than 0.05) lower body weight, serum albumin, spleen/body weight, percentage of splenic macrophages with Ia expression (%MOIa), increased splenic T suppressor cells, and greater mortality after CLP. Refeeding plus IFN-gamma or MDP significantly increased %MOIa (P less than 0.05) and also abrogated the increase in splenic lymphocytes seen in the malnourished animals. The increase in splenic suppressor T cells was not affected by refeeding or immunomodulation. Mortality after CLP was increased from 15% in the controls to 85% in the malnourished group and was significantly decreased by refeeding, MDP, and the combination of refeeding plus immunomodulators (P less than 0.05). These data show that 14-day malnutrition adversely affected the immune response to infection and increased mortality from CLP. Refeeding and immunomodulation restored macrophage Ia expression without CLP but not after the procedure, despite the significant reduction in mortality. The use of immunomodulation in protein malnourished conditions may serve as an adjuvant role to nutritional support.

The use of a new assay for detecting antibody to Staphylococcus aureus in severely injured patients.

ObjectiveThis study determines whether there are any differences in several immunologic parameters in circulating peripheral blood leukocytes, serum, and plasma compared with pus leukocytes, and supernatant of various types of abscess. Summary Background DataAlthough there have been reports of high lysozyme levels and low complement levels within pus, there has been no systemic comparison of concentrations of these substances and others within pus compared with those within peripheral blood. MethodsPeripheral blood and abscess pus were collected from 31 patients with abscesses and percent and mean channel of monocytes expressing complement receptor and major histocompatibility antigen HLA-DR, the percent and mean channel of polymorphonuclear leukocytes (PMN) expressing complement receptor, lysozyme level, and levels of total hemolytic complement, iC3b, C5b-9, and immunoglobulins were measured within both pus and peripheral blood. ResultsPercent of monocytes expressing HLA-DR and percent of monocytes and PMN expressing complement receptor, total hemolytic complement, and IgM were reduced within pus compared with peripheral blood, whereas the mean channel of monocytes expressing HLA-DR and the mean channel of PMNs expressing CR3, C5b-9, and lysozyme were increased in pus. ConclusionsThere are marked differences in immunologic parameters measured within pus of abscesses versus that seen in peripheral blood.

Murine Intraabdominal Abscess: Immune Modulation with Interferon-γ

Investigation of the antibody response to Staphylococcus aureus infection has been hindered by lack of a simple and specific assay. We report an enzyme-linked immunosorbent assay (ELISA) using a strain of S. aureus devoid of Protein A, a frequent cause of false positive results in ELISAs, and have used this assay to study antibody responses of 23 severely injured patients. This IgM ELISA had a diagnostic sensitivity for major Staphylococcal infection of 70% (seven of ten patients with major infection) and a specificity of 92% (12 of 13 patients without major infection). Of three patients with major Staphylococcal infections who mounted no IgM response, two died and the other developed severe chronic Staphylococcal infection, and hence prompt initiation of appropriate therapy was necessary. Furthermore, the ability to mount IgM response to Staphylococcal infections appears to contribute to an orchestrated host defense response against this organism.

Depressed Interferon Gamma Production and Monocyte HLA-DR Expression After Severe Injury

Investigations in our laboratory have focused on changes in major histocompatibility complex (MHC) antigen expression on monocytes occurring in association with injury and clinical infection [1]. Expression of class II MHC antigens on the surface of monocytes appears to be essential for antigen recognition and T-cell proliferation [2].