Growth Factors G-CSF and GM-CSF: Clinical Options

The body's immediate response to bacterial infection becomes clinically evident as an inflammatory reaction accompanied by an acute-phase response in the liver and hyperthermia. Activation of the immune system must be counterregulated to curb these processes and to prevent (or at least minimize) damage to the host tissue. The major part of this intricate regulation is performed by the cytokine mediator network, a relay of glycoprotein signals that first activate proliferation and host defense functions of immune cells and then control the return to a state of readiness when the infection is under control. Septic shock encompasses fulminant, and self-destructive activation of the defense system that is now understood as a systemic inflammatory reaction followed by multiple organ failure. This extreme activation of the nonspecific immune system is followed, provided the patient can be stabilized by intensive medical care, by corresponding massive counterregulation. The patient, whose immune system is exhausted, is left almost defenseless in a state termed immune paralysis, or anergy. A patient in this state is particularly susceptible to lifethreatening secondary infections. Granulocyte (G-CSF) and granulocyte/macrophage colonystimulating factors (GM-CS!'; (Table 64.1), central mediators of the endogenous response to infection and inflammation, have been cloned and are commercially available in forms approved for clinical use (Table 64.2). Both stimulate the proliferation and release of immune cells from the bone marrow, and so they were originally approved for the treatment of leukopenia. G-CSF, when given prophylactically or as substitution in situations of deficiency, has also been attributed with improved host defense paired with antiinflammatory effects. GM-CSF, on the other hand, is considered a potent immunostimulator and proinflammatory agent. Evidence from many animal studies and some clinical studies suggests that prophylactic treatment with G-CSF at the time a risk can be anticipated, such as before an operation, may offer protection from infections and lower the incidence of sepsis. GM-CSF therapy may find a place in reactivating the immune system of patients in a state of immune paralysis following septic shock, thereby reinforcing the patients' impaired defense system against secondary infections. (See Table 64.3 for approved and experimental indications.)