Neutrophil chemotactic defects can be excluded by the presence of neutrophils at the site of infection. The Rebuck skin window is a 4-hour in vivo test for neutrophil chemotaxis thatis not performed routinely by most laboratories. In vitro studies of neutrophil migration are available in specialized laboratories.Flow cytometry for the presence of adhesion molecules, such as CD18 or CD15, can help diagnose leukocyte adhesion defects.Point mutations that affect the function of the adhesion molecule but do not alter antibody binding are missed using flow cytometry. CGD can be diagnosed by the flow cytometry-based test usingdihydrorhodamine 123 or the nitroblue tetrazolium test (seeChapter 72). Light microscopy of neutrophils for the presence ofgiant granules can help diagnose Chédiak-Higashi syndrome.
Therapy for neutropenia depends on the underlying cause. Patients with severe bacterial infections require broad-spectrum antibiotics; the resolution of neutropenia is the most important prognostic factor. Most patients with severe congenital neutropenia or autoimmune neutropenia respond to therapy with G-CSF. Granulocyte transfusion should be reserved for life-threatening infection. Chronic mild neutropenia not associated with immunosuppression can be managed expectantly with prompt antimicrobial treatment of softtissue infections, which usually are caused by S. aureus or group A streptococcus.
Frequent courses of antibiotics, including trimethoprim-sulfamethoxazole prophylaxis, and surgical débridement of infections are required in CGD. Because A. fumigatus can cause serious infection in patients with CGD, moldy hay, decomposing compost, and other nests of fungi must be avoided, and prophylactic antifungals can be helpful. The frequency of infection in CGD is lessened by treatment with recombinant interferon-γ administered subcutaneously three times a week. Stem cell transplantation (see Chapter 76) may be lifesaving in CGD, LAD-1, and Chédiak-Higashi syndrome.
The prognosis depends on the particular defect. Milder and transient defects in neutrophil numbers have a better prognosis. Prolonged absence of neutrophils or their function has a poor prognosis, especially with the risk of bacterial and fungal sepsis. Treatment with prophylactic antibiotics and interferon-γ has improved the prognosis of patients with CGD. Stem cell transplantation is the only currently available mode of therapy that can reverse the poor prognosis of severe neutrophil defects. As in other genetic defects, prenatal diagnosis and genetic counseling are possible for all known gene mutations.
The complement system consists of plasma and membrane proteins that function in the innate immune response as well as facilitate adaptive immunity. Complement proteins can kill pathogens with or without antibodies, opsonize pathogens
LECTIN PATHWAY CLASSIC PATHWAY ALTERNATIVE PATHWAY (Antibody independent) (Antibody dependent) (Antibody independent) C4 C1 (C1q, C1r, C1s) C3
B, D, P C2b
Figure 75-1 Complement component cascade involving the classic, alternative, and lectin pathways. The initiating events for the pathways differ, but they result in the production of C3 cleaving enzyme activity, which is the pivotal step as the three pathways converge to the terminal activation sequences. Ag-Ab, Antigen-antibody complex; B, factor B; D, factor D (factor B clearing enzyme); P, properdin.