Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: characteristics of respiratory and catheter-related infections.

Over a 20-year period, 40 nontuberculous mycobacteria (NTM) were isolated from 6259 hematopoietic stem cell transplant (HSCT) recipients (0.64%), of which 28 were considered to have probable or definite infection (0.44%). Only 3 of 15 lower respiratory isolates obtained by bronchoalveolar lavage (BAL) and/or biopsy; (Mycobacterium avium complex [n = 2] and M. gordonae [n = 1]) caused definite or probable lower respiratory tract disease, whereas 12 of 15 were considered to cause possible lower respiratory tract disease according to Centers for Disease Control and Prevention definitions. The median time to diagnosis was 251 days following HSCT. All 3 patients with definite NTM disease were successfully treated with 3 antimicrobials for several months. Twenty-three patients had catheter-related infections, including exit site infection (n = 5), tunnel infection (n = 7), and catheter-related bacteremia (n = 11). All were caused by rapidly growing mycobacteria. The median time to diagnosis was 61 days following HSCT. All patients with catheter-related infections were successfully treated with an average of 2 antibiotics for a median of 3 weeks for exit site infection and 6 weeks for tunnel infection and catheter-related bacteremia. Soft tissue debridement was performed in all cases with tunnel infection. The catheter was removed in 21 of 23 patients with catheter-related infections. Two additional patients were diagnosed, one with lymphadenitis and one with skin lesion, due to NTM. In conclusion, NTM infections are infrequent in HSCT recipients and carry a good clinical prognosis. In the majority of lower NTM respiratory isolates obtained by BAL, a pathogenic role could not be established. However, lower respiratory tract disease can occur late after HSCT and should be considered if patients fail to respond to the treatment of concomitant infections or if evidence of tissue infection or concomitant bacteremia is present. Therapy should be performed with 2 to 3 antimicrobials, guided by antimicrobial susceptibilities, with additional surgical debridement in patients with tunnel infection.

Inhibition of in vivo neutrophil transmigration by a novel humanized anti-CD11/CD18 monoclonal antibody.

Leukocyte adhesion receptors, including the beta-integrin (CD11/CD18) family, play an important role in inflammation via their regulatory effects on leukocyte adhesion, transmigration, and function. A randomized, placebo-controlled, double-blind study was conducted in healthy volunteers to evaluate the in vivo effects of a humanized anti-CD11/CD18 monoclonal antibody, Hu23F2G, on leukocyte activation and transmigration. Neutrophil migration to a site of cutaneous inflammation in vivo, as measured by the skin chamber technique, was significantly reduced in subjects 24 hours after Hu23F2G administration. At 96 hours, neutrophil migration was not significantly different in subjects who received Hu23F2G or placebo. In contrast, delayed-type hypersensitivity (DTH) testing, which involves activation and migration of T lymphocytes and macrophages, was unaffected by the Hu23F2G treatment. These responses to Hu23F2G in vivo are similar to the clinical phenotype of leukocyte adhesion deficiency (LAD) type 1, a congenital disorder of CD18 deficiency. The in vivo properties of Hu23F2G suggest therapeutic potential for use in the treatment of acute non-infectious inflammatory disorders mediated predominantly by neutrophils.

Modulation of neutrophil-mediated activity against the pseudohyphal form of Candida albicans by granulocyte colony-stimulating factor (G-CSF) administered in vivo.

Renewed interest in neutrophil transfusions has emerged with the development and clinical use of granulocyte colony-stimulating factor (G-CSF). G-CSF not only increases neutrophil (polymorphonuclear leukocyte, PMNL) production but also modulates various physiological properties of PMNL. The effects of G-CSF on PMNL-mediated fungicidal activity were evaluated by administration of G-CSF (300 micrograms/day subcutaneously) to 5 healthy volunteers for 6 days. G-CSF significantly enhanced PMNL-mediated damage of Candida albicans pseudohyphae by 33% (P=.007) on day 2 and by 44% (P=.04) on day 6 at a 10:1 effector:target ratio. In contrast, the ability of PMNL to induce damage of hyphae from either Fusarium solani or Aspergillus fumigatus did not significantly change during the study period. These data demonstrate that G-CSF administered in vivo modulates PMNL-mediated fungicidal activity against the pseudohyphal form of C. albicans, thereby suggesting potential utility of G-CSF as a biologic response-modifying therapy in some opportunistic fungal infections.

Comparison of interferon-gamma, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor for priming leukocyte-mediated hyphal damage of opportunistic fungal pathogens.

Proinflammatory cytokines have been proposed as adjunctive therapeutic agents to enhance the host immune response during infections caused by opportunistic fungi. The study compared the differential in vitro priming effects of interferon-gamma (IFN-gamma), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) on hyphal damage of opportunistic fungi mediated by isolated neutrophils (polymorphonuclear leukocytes, PMNL) and buffy coat cells (polymorphonuclear leukocytes/peripheral blood mononuclear cells, PMNL/PBMC) from healthy donors. IFN-gamma (1000 U/mL) effectively primed both PMNL and PMNL/PBMC for enhanced hyphal damage of Aspergillus fumigatus, Fusarium solani, and Candida albicans. G-CSF (100 ng/mL) increased hyphal damage mediated by both PMNL and PMNL/PBMC against F. solani, and GM-CSF (100 ng/mL) augmented the antifungal activity of PMNL/PBMC against hyphal forms of both F. solani and C. albicans. IFN-gamma may be superior to G-CSF or GM-CSF for enhancing the microbicidal activity of PMNL and PMNL/PBMC against opportunistic fungi.

Murine model of recurrent group G streptococcal cellulitis: no evidence of protective immunity.

Despite the well-known tendency of cellulitis due to beta-hemolytic streptococci to recur, little is known regarding the mechanisms of human immunity to this infection. We established cellulitis in mice by using a strain of group G streptococcus (1750) originally isolated from the bloodstream of a patient with acute cellulitis. This strain, which has been studied extensively in our laboratory, expresses M protein structurally and functionally analogous to that of group A streptococci, and we have cloned and sequenced the gene encoding this protein (emmMG1). Mice injected with 5 x 10(7) CFU of strain 1750 developed nonlethal necrotic skin and soft tissue infections that healed spontaneously after 14 to 16 days. After healing, the mice were repetitively reinoculated three times with the same challenge dose of 1750. Lesion size did not decrease in severity, size, or time to healing after repetitive challenge. The maximum lesion size and tissue concentration of microorganisms increased between the first and fourth challenges. Pretreatment of 1750 cells with opsonic antisera to MG1 diminished neither the maximum lesion size nor the time course of evolution of the lesions. Thus, in the mouse model used here, there was no evidence of acquired protective immunity to experimentally induced cellulitis.