Immune Modulation and Immunotherapy in Critical Illness

Mark W. Hall

Jennifer A. Muszynski

KEY POINTS

Abnormal regulation of the immune response—overactivity or underactivity of the immune system—is the cause of adverse outcomes in many forms of critical illness.

Therapies aimed at reducing levels of proinflammatory mediators in human sepsis by specifically targeting lipopolysaccharide (LPS), tumor necrosis factor (TNF)-α, IL-1β, and others have been overwhelmingly unsuccessful in improving outcomes.

The role of methylprednisolone in the treatment of acute respiratory distress syndrome (ARDS) continues to be controversial, with recent evidence suggesting that its use beyond the second week of ARDS may be harmful.

Innate immune function is dynamic following a proinflammatory insult, such as trauma or sepsis. A subsequent or concurrent compensatory downregulation of innate immune function can be expected and, when severe, is termed immunoparalysis.

Immunoparalysis can be quantified through measurement of HLA-DR expression on circulating monocytes, with increased risks of adverse outcomes if <30% of monocytes are HLA-DR⁺. Another important measure of innate immune function is the capacity of whole blood to produce TNF-α when stimulated ex vivo. Severe reduction in the ex vivo TNF-α response is similarly associated with adverse outcomes.

Immunoparalysis can be reversed through the use of immunostimulatory agents, including interferon (IFN)-γ or granulocyte-macrophage colony-stimulating factor (GM-CSF), or by withholding exogenous immunosuppression, likely with beneficial effects of outcome.

Critically ill patients with persistent neutropenia should be treated with granulocyte colony-stimulating factor, and consideration should be given to the use of prophylactic therapy for pneumocystis pneumonia and fungal infections.

Adaptive immune dysfunction, including lymphopenia, anergy, and skewing toward anti-inflammatory T cells, is associated with increased risk of death in sepsis and multiorgan dysfunction syndrome. Use of appropriate prophylaxis against pneumocystis pneumonia and fungal infections, avoidance of lymphotoxic drugs, and treatment of hypogammaglobulinemia with IV immunoglobulin (IVIG) are important aspects of care for the critically ill lymphopenic patient.

To date, immunonutrition with n-3 polyunsaturated fatty acids or arginine has no role in the PICU.

Critical illnesses themselves and most of the therapies used to treat critically ill children have effects on the immune response. The development of routine immune monitoring protocols, including measurement of cell counts and immune function (e.g., HLA-DR expression or ex vivo TNF-α response), will be crucial to the identification of patients with overactive or underactive immune systems so that individualized treatment plans can be implemented.

The immune response and its regulation by the host is critical for the mounting of a successful defense against invading pathogens and for facilitating healing and repair of injured tissues. Much of the morbidity seen in the ICU, however, is a direct consequence of abnormal regulation of this immune response. The classic example of this maladaptive scenario is the case of septic shock, whereby an overly robust proinflammatory response causes far more tissue damage than the original infection that initiated it. At the same time, it is important to appreciate that pathology also occurs when the pendulum swings in the other direction. It is intuitive that children with underactive immune systems as the result of chemotherapy or treatment with immunosuppressive medications are at high risk for the development of infectious complications. Perhaps less intuitive is the notion that an overactive endogenous compensatory anti-inflammatory

immune response can follow or accompany a proinflammatory insult and can result in significant morbidity and mortality without the influence of exogenous immunosuppressants. The restoration and maintenance of a responsive immune system with a homeostatic balance between proinflammatory and antiinflammatory forces should be a goal of modern critical care medicine and has, thus far, proven difficult to achieve.

Historically, attempts at immunomodulation in the ICU have been largely focused on the abrogation of the proinflammatory response in such conditions as sepsis and acute respiratory distress syndrome (ARDS). It should be remembered that a great many patients suffer from iatrogenic immunosuppression as the result of treatment for malignancy, transplantation, or autoimmune disease. The history and role of immunomodulation and special considerations for the management of immunocompromised patients will be reviewed in this chapter.

TARGETING PROINFLAMMATION

A detailed review of the immunology of inflammation can be found elsewhere in this text. To briefly review, the cytokines tumor necrosis factor (TNF)-α, IL-1β, and interferon
(IFN)-γ are proinflammatory cytokines released by innate immune cells (TNF-α, IL-1β) and lymphocytes (IFN-γ) in response to an inflammatory stimulus. The signaling pathways associated with the production of proinflammatory cytokines in immune cells include the mitogen-activated protein kinase and nuclear factor-κB (NF-κB) pathways. The cytokine that has been most reliably associated with adverse outcomes in the setting of proinflammatory disease is IL-6, likely because IL-6 is released in response to more potent proinflammatory cytokines and, therefore, serves as a marker for inflammation. IL-6, while an inducer of the acute phase response, has significant anti-inflammatory properties of its own. More potent anti-inflammatory cytokines, produced by both innate and adaptive immune cells, include IL-10 and transforming growth factor (TGF)-β. Innate immune cells include neutrophils, monocytes, macrophages, and dendritic cells, while adaptive immune cells include T and B lymphocytes.

Severe Sepsis and Septic Shock

The classic signs and symptoms of severe septic disease, including fever, altered vascular tone, and increased capillary permeability, are largely the result of the effects of proinflammatory cytokines rather than the offending pathogen itself. It is not difficult to understand, therefore, why a great deal of time and energy was spent in the 1980s and 1990s developing

and testing regimens to target proinflammatory mediators in severe sepsis and septic shock.

Anti-endotoxin Strategies

The first studies performed in this area focused on gram-negative lipopolysaccharide (LPS). First using pooled anti-sera rich in anti-LPS activity (1,2), then using monoclonal anti-LPS antibodies (3,4), investigators tried in vain to consistently demonstrate a survival benefit in septic adults. One phase III trial was stopped after interim analysis demonstrated a trend toward higher mortality in treated patients (5). Recombinant bactericidal/permeability-increasing protein (BPI), an endogenous antimicrobial peptide capable of neutralizing endotoxin, was evaluated in a phase III trial in children with meningococcemia. While recombinant BPI conferred no improvement in survival, functional outcome was better in the treated group (6).

Anti-cytokine Strategies

Recombinant IL-1 receptor antagonist (IL-1ra), a naturally occurring IL-1β antagonist, underwent two large phase III trials, both of which failed to show improvement in adult sepsis survival (7,8). TNF-α has been similarly targeted with neutralizing monoclonal antibody therapy. Four major anti-TNF antibody studies have been performed in septic adults to date, including the NORASEPT I and II and INTERSEPT trials (9,10,11), which demonstrated no improvement in 28-day survival in the treatment arms. The subsequent MONARCS trial showed a slight but statistically significant reduction in 28-day mortality in the subgroup of patients with plasma IL-6 levels of >1000 pg/mL (12), suggesting that the most profoundly inflamed patients may benefit from TNF-α depletion. Antagonists of bradykinin (deltibant) and platelet-activating factor (lexipafant) have also failed to show survival benefit in adults (13,14).

TABLE 85.1 RELATIVE POTENCIES OF CORTICOSTEROIDS

▪ DRUG	▪ ANTI-INFLAMMATORY (IMMUNOSUPPRESSIVE)	▪ MINERALOCORTICOID
Dexamethasone	30	0
Methylprednisolone	5	1
Hydrocortisone	1	5

Activated Protein C

It should be noted that significant overlap exists between the inflammatory and hemostatic pathways. Activated protein C (APC) is an endogenous protein with anti-thrombotic, profibrinolytic, and anti-inflammatory properties that has been studied in septic adults and children. Despite initially encouraging results in the subset of adults with the most severe illness (APACHE II scores ≥25 or ≥2 organ failure and an absence of risk factors for severe bleeding, including recent surgery) (15), the pediatric phase III trial that followed was stopped at its planned interim analysis for lack of efficacy (16). Recombinant human APC has subsequently been removed from the market for safety concerns, largely related to bleeding risk.

Corticosteroids

The role of corticosteroids in adult and pediatric critical illness remains controversial. It was once thought that methylprednisolone or dexamethasone would, by virtue of their antiinflammatory properties, have beneficial effects in the setting of the proinflammatory storm of sepsis. Two meta-analyses published in the mid-1990s concluded that the use of these drugs was associated with an increased risk of mortality from sepsis in adults (17,18). Two more recent meta-analyses demonstrated a survival benefit associated with the use of a 5- to 7-day course of low-dose hydrocortisone (200-300 mg/day) in adults with severe sepsis or septic shock (19,20). This difference may be explained by the fact that hydrocortisone has far less glucocorticoid (immunosuppressive) activity and far more mineralocorticoid (hemodynamic supporting) activity than either methylprednisolone or dexamethasone (Table 85.1). It should be noted that, while subsequent studies have demonstrated faster shock resolution with hydrocortisone use in sepsis, the mortality benefit has not been consistently seen (21). Hydrocortisone use for hemodynamic support in septic children has yet to be studied in a randomized, controlled trial.

Extracorporeal Therapies

Another approach to the restoration of immunologic homeostasis is the bulk removal of inflammatory mediators through hemofiltration, membrane adsorption, plasmapheresis, or plasma exchange [reviewed in (22)]. An advantage of most of these techniques is that no single mediator is targeted; rather, large concentrations of cytokines can be removed at once. Disadvantages include the need for dedicated large-bore IV access, exposure to blood products (plasma exchange), and the likely need for relatively long-term therapy. In fact, most prospective studies of extracorporeal therapies in sepsis have been small, involved shortterm treatment (1-2 days), and have been largely unsuccessful
in demonstrating improved outcomes. Of these therapies, plasmapheresis and plasma exchange have shown the most promise in prospective trials, perhaps because plasma exchange involves the replacement of patient plasma with donor plasma, thereby both removing unwanted mediators and replacing potentially deficient ones (23,24,25). In particular, restoration of plasma activity of von Willebrand factor-cleaving protease, ADAMTS13, via plasma exchange has been reported to improve outcomes in the setting of pediatric thrombocytopenia-associated multiple organ failure (TAMOF) (26).

Acute Respiratory Distress Syndrome

The immunomodulators that have been studied most extensively in the setting of ARDS are the glucocorticoids. Reduction of inflammation and inhibition of the fibroproliferative

phase of ARDS seem to be reasonable therapeutic goals in the management of this syndrome. In 1998, improved pulmonary function, reduction in organ failure, and improved survival were demonstrated in adults with unresolving ARDS at 7 days who received a prolonged course of methylprednisolone (27). Subsequent studies have questioned these findings, including a prospective study of 180 adults that failed to show a survival benefit and, in fact, showed increased mortality rates in patients whose methylprednisolone was started >14 days after the onset of ARDS (28). Yet another adult ARDS study, this time using lower doses and earlier initiation of methylprednisolone, demonstrated improvements in morbidity and mortality (29). To date, no studies have been performed to address this question in the pediatric population.

Cardiopulmonary Bypass

Exposure of leukocytes and complement to the tubing and membranes associated with extracorporeal procedures, including cardiopulmonary bypass (CPB), is known to induce a potent proinflammatory response. While significant advances have been made in the development of less bioreactive coatings for these devices, many practitioners continue to rely on systemic anti-inflammatory agents to attenuate this response [reviewed in (30)]. The administration of glucocorticoids to the patient and/or bypass pump has been shown to reduce neutrophil activation and proinflammatory cytokine release. Attempts to effect bulk removal of proinflammatory cytokines through modified ultrafiltration during CPB have yielded variable results. It should be noted that the impact of these strategies aimed at reducing the proinflammatory response to CPB on patient outcomes is far from clear. Multiple pediatric studies now suggest that a prolonged, severe anti-inflammatory response following pediatric CPB may, in fact, be harmful (31,32,33).

IMMUNOPARALYSIS

The recurrent failure of treatments targeting the proinflammatory response is coincident with burgeoning experimental and clinical evidence that an overactive anti-inflammatory response

frequently predominates in the ICU, is often occult, and can be highly pathologic. For many years it has been known that a major inflammatory insult typically results in a compensatory anti-inflammatory response syndrome characterized by reduction in cell-surface marker expression on innate immune cells and increased production of anti-inflammatory cytokines, including IL-10 (34,35). In the 1990s, investigators began associating severe depression of innate immune function with adverse outcomes following trauma, sepsis, and transplantation (36,37,38). This phenomenon, termed immunoparalysis, has been quantified in two major ways. First, surface expression of the class II major histocompatibility complex molecule HLA-DR, important in antigen presentation, has been shown to be reduced in circulating monocytes from patients with compensatory anti-inflammatory response syndrome. Severe reduction in HLA-DR expression, such that <30% of circulating

monocytes are strongly HLA-DR⁺ by flow cytometry, is characteristic of immunoparalysis. A more functional measure of innate immune capability is the ex vivo LPS-induced TNF-α production assay. In this test, an aliquot of whole blood is incubated with a standard concentration of LPS, and TNF-α production is measured in the supernatant. Patients with immunoparalysis will demonstrate a severe reduction in their ability to make TNF-α

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