Chapter 061. Disorders of Granulocytes and Monocytes (Part 12)

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Patients with leukopenias or leukocyte dysfunction often have delayed inflammatory responses. Therefore, clinical manifestations may be minimal despite overwhelming infection, and unusual infections must always be suspected. Early signs of infection demand prompt, aggressive culturing for microorganisms, use of antibiotics, and surgical drainage of abscesses. Prolonged courses of antibiotics are often required. In patients with CGD, prophylactic antibiotics (trimethoprim-sulfamethoxazole) and antifungals (itraconazole) markedly diminish the frequency of life-threatening infections. Short courses of glucocorticoids may relieve gastrointestinal or genitourinary tract obstruction by granulomas in patients with CGD. ...

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Chapter 061. Disorders of Granulocytes and Monocytes (Part 12) Patients with leukopenias or leukocyte dysfunction often have delayed inflammatory responses. Therefore, clinical manifestations may be minimal despite overwhelming infection, and unusual infections must always be suspected. Early signs of infection demand prompt, aggressive culturing for microorganisms, use of antibiotics, and surgical drainage of abscesses. Prolonged courses of antibiotics are often required. In patients with CGD, prophylactic antibiotics (trimethoprim-sulfamethoxazole) and antifungals (itraconazole) markedly diminish the frequency of life-threatening infections. Short courses of glucocorticoids may relieve gastrointestinal or genitourinary tract obstruction by granulomas in patients with CGD. Recombinant human IFN-γ, which nonspecifically stimulates phagocytic cell function, reduces the frequency of infections in patients with CGD by 70% and reduces the severity of infection. This effect of IFN-γ in CGD is additive to the effect of prophylactic antibiotics. The
recommended dose is 50 µg/m2 subcutaneously three times weekly. IFN-γ has also been used successfully in the treatment of leprosy, nontuberculous mycobacteria, and visceral leishmaniasis. Rigorous oral hygiene reduces but does not eliminate the discomfort of gingivitis, periodontal disease, and aphthous ulcers; chlorhexidine mouthwash and tooth brushing with a hydrogen peroxide–sodium bicarbonate paste helps many patients. Oral antifungal agents (fluconazole or itraconazole) have reduced mucocutaneous candidiasis in patients with Job's syndrome. Androgens, glucocorticoids, lithium, and immunosuppressive therapy have been used to restore myelopoiesis in patients with neutropenia due to impaired production. Recombinant G-CSF is useful in the management of certain forms of neutropenia due to depressed neutrophil production, especially those related to cancer chemotherapy. Patients with chronic neutropenia with evidence of a good bone marrow reserve need not receive prophylactic antibiotics. Patients with chronic or cyclic neutrophil counts < 500/µL may benefit from prophylactic antibiotics and G-CSF during periods of neutropenia. Oral trimethoprim-sulfamethoxazole (160/800 mg) twice daily can prevent infection. Increased numbers of fungal infections are not seen in patients with CGD on this regimen. Oral quinolones such as levofloxacin and ciprofloxacin are alternatives. In the setting of cytotoxic chemotherapy with severe, persistent neutropenia, trimethoprim-sulfamethoxazole prevents Pneumocystis jiroveci
pneumonia. These patients, and patients with phagocytic cell dysfunction, should avoid heavy exposure to airborne soil, dust, or decaying matter (mulch, manure), which are often rich in Nocardia and the spores of Aspergillus and other fungi. Restriction of activities or social contact has no proven role in reducing risk of infection. Cure of some congenital phagocyte defects is possible by bone marrow transplantation (Chap. 108). However, complications of bone marrow transplantation are still serious, and with rigorous medical care many patients with phagocytic disorders can go for years without a life-threatening infection. The identification of specific gene defects in patients with LAD 1, CGD, and other immunodeficiencies has led to gene therapy trials in a number of genetic white cell disorders. Further Readings Horwitz MS et al: Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 109:1817, 2007 [PMID: 17053055] Klion AD et al: Approaches to the treatment of hypereosinophilic syndromes: A workshop summary report. J Allergy Clin Immunol 117:1292, 2006 [PMID: 16750989]
Nathan C: Neutrophils and immunity: Challenges and opportunities. Nat Rev Immunol 6:173, 2006 [PMID: 16498448] Puel A et al: Heritable defects of the human TLR signalling pathways. J Endotoxin Res 11:220, 2005 [PMID: 16176658] Rosenzweig SD, Holland SM: Phagocyte immunodeficiencies and their infections. J Allergy Clin Immunol 113:620, 2004 [PMID: 15100664] Segal BH et al: Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 79:170, 2000 [PMID: 10844936] Bibliography Diaz CA, Gulino AV: WHIM syndrome: A defect in CXCR4 signaling. Curr Allergy Asthma Rep 5:350, 2005 [PMID: 16091205] Doffinger R et al: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat Genet 27:277, 2001 [PMID: 11242109]
Dorman SE et al: Clinical features of dominant and recessive interferon-γ receptor 1 deficiencies. Lancet 364:2113, 2004 [PMID: 15589309] Etzioni A et al: Of man and mouse: Leukocyte and endothelial adhesion molecule deficiencies. Blood 94:3281, 1999 [PMID: 10552936] Filipovich AH: Hemophagocytic lymphohistiocytosis and related disorders. Curr Opin Allergy Clin Immunol 6:410, 2006 [PMID: 17088644] Goldbach-Mansky R et al: Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med. 355:581, 2006 [PMID: 16899778] Grimbacher B et al: Hyper-IgE syndromes. Immunol Rev 203:244, 2005 [PMID: 15661034] Luster AD et al: Immune cell migration in inflammation: Present and future therapeutic targets. Nat Immunol 6:1182, 2005 [PMID: 16369557] Medvedev AE et al: Cutting edge: Expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent
bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex. J Immunol 174:6587, 2005 [PMID: 15905496]