Multiple Organ Dysfunction Syndrome and Multiple Organ Failure in Pediatric ICU Patients:
The Potential Role of Immunophenotype Therapy
by Joseph A. Carcillo, M.D., Associate Director, Pediatric Intensive Care Unit, Children's Hospital of Pittsburgh, PA, US and Hans-Dieter Volk, M.D., Ph.D., Institute of Medical Immunology, Charité, Berlin, Germany

Intensive care units (ICUs) are now the leading consumers of healthcare costs in the industrialized world. Many administrators are striving for ways to reduce these costs. The average length of stay in ICUs is approximately three days. A substantial portion of patients who stay longer than three days do so because they have dysfunctional or failing organs. These patients are said to have multiple organ dysfunction syndrome (MODS) or multiple organ failure (MOF), depending on the degree of organ function remaining. Multiple organ dysfunction occurs in large part due to unchecked systemic inflammation.

Several cytokines have proved useful as serum markers of this inflammatory process. Tumor necrosis factor a (TNFa), interleukin 8 (IL-8), soluble Fas (a cell surface protein that inhibits apoptosis by blocking the binding of the Fas [APO-1, CD95] gene to Fas ligand, a membrane protein in the TNF family that is expressed on activated T and NK cells), and interleukin 6 (IL-6) are all markers of immune cell activation. IL-6 is also a marker of tissue injury: plasma levels correlate with severity of organ failure, length of ICU stay and patient mortality. As a result, IL-6 levels may be used to identify patients with systemic inflammation and MODS.

In the past five years, investigators have reported that systemic inflammation and MODS can be therapeutically reversed, with improved survival and reductions in the lengths of stay and associated costs.¹ IL-6 measurements are a critical first step in a simple algorithm for diagnosis and therapy (Table 1). Patients with systemic inflammation are initially identified based on increased plasma IL-6 levels, with the cause being determined through further immunophenotyping (immune response classification). The appropriate therapy is then administered, resulting in an improved clinical outcome. It should be noted that measurements are predictive after five days, not on ICU admission or at onset of illness.

Table 1. Algorithm summary for ARDS/MODS
Immune diagnostics
	Increased circulating IL-6 (> 20 pg/mL). Systemic inflammation is defined as IL-6 > 20 pg/mL.
	TNFa response to LPS < 200 pg/mL. Immune paralysis is defined as ex vivo TNFa response < 200 pg/mL.
Immunophenotype-directed therapies
	Give methylprednisolone for increased IL-6 and unresolving ARDS with normal TNFa response.
	Rapidly taper immunosuppression or administer GM-CSF/interferon g if unresolving MODS occurs with increased IL-6 levels and a TNFa response < 200.
Immune therapy endpoints
	Reduce circulating IL-6 to < 20 pg/mL, and increase ex vivo TNFa response to > 200 pg/mL.
Measurements are predictive after five days, not on ICU admission or at onset of illness.

Meduri and colleagues reported that patients with persistently increased TNFa and IL-6 levels, unresolving acute respiratory distress syndrome (ARDS, the pulmonary manifestation of MODS), and no infection, responded to intravenous treatment with 1 mg/kg of methylprednisolone every 6 hours.² The use of this anti-inflammatory glucocorticoid resulted in the resolution of ARDS, as well as normalization of TNFa and IL-6 levels. When administered at the same prescribed levels, this agent has also been shown to reduce inflammation and improve outcomes in patients with status asthmaticus (a sudden continuous and intense asthmatic attack). The 1 mg/kg dose is well tolerated and backed by vast clinical data to support its safety. Essentially, the excess inflammation that led to MODS in these patients was successfully treated with asthma-dose steroids.

An even larger group of patients with unresolving MODS is characterized by high IL-6 and interleukin 10 (IL-10) levels. They have a high likelihood of developing, and dying from, an unremitting secondary gram-negative bacterial and/or fungal infection. Volk and colleagues³ have immunophenotyped these patients and found that they have prolonged monocyte deactivation. The deactivated monocytes (macrophages, dendritic cells) are unable to kill bacteria or fungi. The immune systems of these patients are also unable to respond to foreign antigens (pieces of destroyed microbes) presented by the limited numbers of functional monocytes, an activity that normally stimulates the adaptive immune response. Ultimately, inflammation continues unchecked because infection cannot be controlled. This state of immune paralysis may be confirmed by testing expression of monocyte HLA-DR (a genetic marker on the surface of a white blood cell). HLA-DR expression on monocytes less than 30 percent (Becton-Dickinson) or an ex vivo whole blood TNFa response to lipopolysaccharide (LPS) less than 200 pg/mL (DPC, and Milenia Biotec) are indicators of immune paralysis. The cause of MODS in these patients is excess inflammation secondary to an inability to kill infection. Since reducing infection reduces inflammation, the treatment for this cause of MODS and inflammation is rapid tapering of immunosuppressives (e.g. tacrolimus, cyclosporine A, rapamycin) or, in patients not receiving immunosuppressive therapy, treatment with GM-CSF (granulocyte-macrophage colony-stimulating factor) or interferon g to reactivate the monocytes and restore the ability to kill infection. Hall and Carcillo⁴ have shown that this strategy results in normalization of IL-6 and IL-10 levels.

Results of immunophenotype-directed therapy in children with MODS at Children's Hospital of Pittsburgh demonstrate an odds ratio of survival 136 times greater when therapies are directed according to immunophenotype compared to when they are not (Table 2). These data indicate the potential value of MODS therapies directed at IL-6 and ex vivo TNFa response immunophenotypes.

Research in the cytokines arena is beginning to shed much needed light on some of the mysteries that surround immune dysfunction. In the case of MODS, monitoring cytokines such as IL-6 shows great promise in the management of these patients. The algorithm presented may someday improve care and reduce costs in the ICU.

1. Lynn W, Brealey D, Singer M. Multi-organ dysfunction in the critically ill: epidemiology, pathophysiology, and management. J Royal Coll Physicians 2000; 34(5): 424-7.

2. Meduri G, Headley A, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998; Jul 8;280(2):159-65.

3. Volk HD, Reinke P, Krausch D, et al. Monocyte deactivation-rationale for a new therapeutic stategy in sepsis. Intensive Care Med 1996;22 Suppl 4:S474-81.

4. Hall MW, Carcillo JA. The role for DPC immunophenotyping in pediatric multiple organ dysfunction syndrome [electronic slide presentation]. Presented at the 31st Critical Care Congress of the Society for Critical Care Medicine; 2002 Jan 27-29; San Diego, US.