1. Alterations in the immune system following major burns are deleterious to the patient.

2. The adverse effect on the host is burn size related and this has been shown in many experimental systems.

3. The exact reasons why these changes occur are currently still poorly understood.

4. EXPERIMENTAL WORK OVER THE LAST SEVERAL YEARS HAS DEMONSTRATED THAT, FOLLOWING INJURY:

• Lymphocyte responses to mitogens is suppressed

• The mixed lymphocyte response is suppressed

• The spread of experimental malignancies is accelerated

• Positive skin tests (e.g., tuberculin test) turn negative

• The graft-versus-host response is abrogated

The remainder of this discussion will follow the outline of the previous section, i.e., that of the normal immune response

Lymphocytes undergo both phenotypic and functional changes following thermal injury. The most immediately apparent of these is a reversal of the normal T4/T8 cell ratio from 2:1 to 1:2, so that there is a relative decrease of helper T4 cells and a relative increase in T8 suppressor cells. Some of this is due to redistribution of cells between the circulating blood and the tissues, but some is real, and the net result is: IMMUNOSUPPRESSION.

Some of the lymphocyte receptors and products also undergo critical changes: compare the figures below with Figures 1-2 in the introductory section. The T4 helper lymphocyte becomes strongly induced, overproduces the IL-2 receptor which is shed into the surrounding medium, and is no longer effective against a number of antigens. Again, the net result is: IMMUNOSUPPRESSION.

B-Lymphocytes undergo little change as a result of thermal injury except to participate in the reduction of MHC Class II receptor expression of all lymphocytes and macrophages: however, their most important products, the opsonizing antibodies IgG and IgA, leak out of the circulation together with other serum proteins, and are not available at the local site of injury in sufficient concentration to sustain the bactericidal activity of neutrophils, leading to more IMMUNOSUPPRESSION. See Figure 9.

The macrophage is strongly up-regulated following injury, and within minutes, the production of proinflammatory cytokines is induced. The first of these to appear in the circulation are Interleukin-1, Tumor Necrosis Factor, and Interleukin-6. As detailed in the Table in the first section, the biological effects as seen clinically are increased capillary permeability, fever, proteolysis, increase in activity of adhesion molecules, and induction of acute-phase protein production by the liver. As a normal reaction to injury, these effects would mediate improved delivery of neutrophils and antibodies to sites of infection, and fever would increase the efficiency of bacterial killing. In major burns, however, there appears to be an overreaction of these normal systems, leading to excess fluid loss, shock, catabolism, and the threat of death. There is also increased expression of the complement-binding receptors and a downregulation of expression of the MHC (major histocompatibility complex) Class II receptors, essential for many macrophage functions.

Compared with the resting phase, adhesion molecules are up-regulated, and the expression of BPI and IL-8R are downregulated (Figure 10). The phagolysozome is stimulated to release its contents into the surrounding tissues thereby losing some capacity for bactericidal activity intracellularly. In addition, there is an increase in necrotic cell death as opposed to apoptotic or programmed cell death, leading to damage to normal surrounding tissues as well. The result: IMMUNOSUPPRESSION and TISSUE DAMAGE.

Translocation is the term applied to the movement of microorganisms and their products from the gastrointestinal tract through the intestinal wall, the mesentery, the portal system, and eventually, the systemic circulation. Few dispute the fact that translocation occurs in a steady-state of normal health and that it is vastly increased following injury, but its precise role in the pathogenesis of complications of burns and trauma is still not clear. The theory of the impact of translocation is illustrated in the next Figure:

THE ROLE OF TOXIC METABOLITES

A discussion of toxic metabolites such as superoxide and nitric oxide, which play a key role in the final common pathway of cell damage and death following thermal injury, is beyond the scope of this section and the reader is referred to other sections for details of these mechanisms.

THE ARACHIDONIC ACID CASCADE

Tissue levels of prostaglandin E-2 increase markedly, as do levels of Thromboxane B-2. The etiology of these changes is due both to increased production, and decreased clearance because of changes in enzymatic activity, as illustrated:

These changes are immunosuppressive, promote increased capillary leakage, probably are instrumental in the induction of the Adult Respiratory Distress Syndrome through local release of prostanoids from alveolar macrophages, and increase translocation.

The search for intervention aimed at restoring immune function in burn patients has frustrated researchers for over thirty years, and still appears elusive. However, with our increased understanding of the mechanisms of failure, there is renewed hope that therapeutic modalities might yet be found. This review will focus on several aspects of intervention which have been attempted in animal models and in man: these are vaccination, stimulation of cellular elements and their receptors, intervention in the arachidonic acid cascade, and the neutralization of endotoxin.

Because of neutrophil defects, loss of serum antibody, and the frequency of wound sepsis caused initially by Pseudomonas, later by Staphylococcus, attempts at passive and active vaccination were made.

These are summarized in the following Table:

The basic problem with vaccination is that although it provides antibody for opsonization, it does not improve intracellular killing mechanisms in the neutrophil, nor abrogate the inflammatory cytokine cascade. In addition, burn patients are prone to infection by so many pathogens that to provide specific immunoprophylaxis would be a logistical impossibility.

This area of intervention has excited a great deal of interest in the last ten years since the discovery of the role of the inflammatory cascade in immunosuppression, and because of the well-documented suppression of cell-mediated immunity following major burns.

The results of many classical experiments can be illustrated by this one, where supernatant from cultured lymphocytes obtained from Pseudomonas-infected rats was administered to burned rats infected with a lethal strain of Pseudomonas, in an attempt to transfer immunity:

As can be seen, more of the treated animals survive for longer, but eventually all the animals succumb.

The following Table shows examples of reports dealing with immuno modulation:

In some animal models, depending on the timing, dosing and route of administration, biologically active agents can have similar or opposing effects. The above table shows only a few of the hundreds of experiments reported in which this statement holds true. Because of this, no consistent, reproducible immunomodulatory agent which could be readily applicable in man has been found to this point.

A great deal of work has been done in preventing and treating endotoxemia. The techniques have included:

All of the above methodologies have some beneficial effect in reducing measurable plasma endotoxin concentration, reducing pro-inflammatory cytokine levels, and at least temporarily improving patients’ clinical septic status. Unfortunately, no improvement in final survival has been demonstrated. Similarly, a recent series combining polymyxin B with ibuprofen, aimed at both reducing endotoxemia and prostaglandin E production, had similar results.

Figure 14 is an illustration of the actual measurements in a patient who survived. Note the steep fluctuations, at various stages of the clinical course, in cytokines and endotoxin. The dilemma is to know what to administer, when, and for how long, given these variations and given that we do not yet understand fully the function of the components of the inflammatory reaction.

Conclusion

It is most likely that multiple interventions will be necessary to deal with the immuno-suppression of the thermally injured patient. There will be agents to interrupt the cytokine and arachidonic acid cascades given together with an antiendotoxin agent, perhaps systemically as well as locally such as in the lung. These developments must await future research.