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

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/m
2
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 hyper
eosinophilic
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, a
nd 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]