Robert L. Roberts

Treatment of chronic recurrent multifocal osteomyelitis with interferon gamma

Chronic recurrent multifocal osteomyelitis is characterized by recurrent episodes of painful swollen lesions of the bone and overlying skin with radiographic changes and an elevated sedimentation rate. It resembles infectious osteomyelitis but with negative findings on bacterial culture and no response to antibiotics. We treated a 13-year-old girl with interferon gamma for 3 months. She had 11 episodes of chronic recurrent multifocal osteomyelitis in 2 1/2 years before therapy and has had none in the 15 months since therapy, an outcome suggesting a favorable therapeutic response.

Slow subcutaneous human intravenous immunoglobulin in the treatment of antibody immunodeficiency: use of an old method with a new product.

Human intravenous immunoglobulin (IVIG) is a valuable therapeutic agent for antibody immunodeficiency and certain immunoregulatory disorders. However, for some patients, intravenous administration is not feasible because of poor venous access, severe side effects, or rapid IgG catabolism. This report demonstrates that the slow subcutaneous infusion of IVIG is a suitable alternative in these patients. Berger et al.1 first reported the use of 16.5% intramuscular immunoglobulin given by slow subcutaneous infusions for antibody replacement in immunodeficiency. Gardulf and associates2, 3 have used the subcutaneous route in immunodeficient adults in Scandinavia for many years, and they report that it is less expensive, better tolerated, and preferable to intravenous infusions by most patients. Abrahamsen et al.4 report a similar experience in eight children with primary immunodeficiency. Because mercury-free 16.5% intramuscular immunoglobulin is not available in this country, we used preservative-free 10% IVIG in eight antibody-deficient patients, all of whom tolerated subcutaneous infusions well, including three patients with prior severe adverse reactions to IVIG infusions.

Effect of interleukin (IL)-12 and IL-15 on activated natural killer (ANK) and antibody-dependent cellular cytotoxicity (ADCC) in HIV infection

The ability of IL-12 and IL-15 to enhance natural killer (NK) activity and antibody-dependent cellular cytotoxicity (ADCC) of mononuclear cells (MNCs) from HIV+ children and their mothers was investigated. MNCs from HIV+ patients were deficient in NK and ADCC activity compared to control MNCs against several target cells. Overnight incubation with IL-15 or IL-12 augmented NK activity of MNCs from both patients and controls, and the combination of IL-12 and IL-15 resulted in the greatest enhancement. ADCC in HIV+ patients against gp120-coated CEM.NKR cells or chicken erythrocytes could also be enhanced by IL-2 or IL-15 in overnight cultures. Culturing MNCs with either IL-2 or IL-15 for 1 week increased the NK activity in patients to levels of controls treated with these cytokines. However, the response to the combination of IL-12 and IL-15 was less than that to IL-15 alone in 1-week cultures. Culturing MNCs with IL-2 and IL-15 for 1 week also increased the percentage of CD16+/CD56+ cells in both patients and controls. Thus, IL-15 can restore the deficient NK activity in patients and may be a candidate for immunomodulative therapy in HIV+ patients.

Decreased superoxide anion and hydrogen peroxide production by neutrophils and monocytes in human immunodeficiency virus-infected children and adults.

ABSTRACT: The higher susceptibility to serious bacterial infections of patients, particularly children, infected with the human immunodeficiency virus (HIV) may be due in part to defective function of their phagocytic cells. We examined the ability of polymorphonuclear cells and monocytes of HIV-infected children and adults to generate superoxide anion (SO) and hydrogen peroxide (HP) and compared it with that of cells from normal children and adults. SO was measured by reduction of cytochrome c and HP by horseradish peroxidase-dependent oxidation of phenol red. The cells were incubated in 96-well plates at 37°C for 2 h before the assay and the nonadherent cells then removed. Readings for SO were taken at 10, 30, 60, and 120 min after stimulation with phorbol myristate acetate; HP production was assayed after 90 min. The SO and HP production by polymorphonuclear cells and monocytes from both HIV-infected children and adults was consistently found to be markedly lower than that of cells from age-matched controls. The magnitude of the difference in response between patients and control cells also increased with increasing incubation time. Thus, phagocytic cells from HIV-infected children and adults are defective in their ability to generate reactive oxygen intermediates, and this defect may make them more vulnerable to bacterial and fungal infections.

Human eosinophils are more toxic than neutrophils in antibody-independent killing

Eosinophils (EOSs) are implicated in damaging host tissues in diseases such as asthma and eosinophilic gastroenteritis. In the present study, we assessed the cytotoxicity of human EOSs from peripheral blood of patients with eosinophilia and from peritoneal fluid of patients undergoing continuous peritoneal dialysis and compared them to normal neutrophils. Cytotoxicity was measured by the release of 51chromium from cultured tumor cells and chicken erythrocytes. Both EOSs and neutrophils were separated on discontinuous Percoll gradients with greater than 95% purity. The granulocytes were activated by preincubation in an ice bath with phorbol myristate acetate and washed before incubation with the target cells. The EOSs lysed significantly more tumor cells (K562, Raji, and CEM lines) in an 18-hour assay than did neutrophils, and no significant difference was found between the peritoneal and blood EOSs. The EOSs were also much more efficient than neutrophils in lysing chicken erythrocytes when they were activated by granulocyte-macrophage colony-stimulating factor instead of phorbol myristate acetate. Cytolysis by EOSs is mediated by both oxidative and nonoxidative mechanisms, as indicated by experiments with cells from patients with chronic granulomatous disease. Thus, EOSs are much more cytotoxic than neutrophils and potentially much more damaging to patients with eosinophilia.

Lipid tolerance in children receiving long-term parenteral nutrition: A biochemical and immunologic study

The effect of intravenously administered lipids (intralipid) on immunologic function, complement, and coagulation was prospectively studied over 1 year in 15 children. The mean age of the children was 52.4 +/- 37.9 months; they had received total parenteral nutrition for an average of 3 years. Immunoglobulins (IgA, IgM, IgG), coagulation studies (platelets, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrinogen degradation products, factor V) and components of complement (C3, C4, and CH100) were analyzed. Activation of monocytes by opsonized zymosan was measured by chemiluminescence and compared with that of normal control subjects. The clinically stable children had normal monocyte activation and normal complement levels. The PT and PTT values were significantly increased but improved with increased intralipid dose; other coagulation factors were normal. Acutely sick children, however, had decreased fat tolerance with significantly increased serum triglyceride levels and PT and PTT values; their monocyte activation and complement factors remained normal. These data indicate that the dose of intralipid should be lowered during acute illnesses; we suggest close monitoring of PT and PTT values and of serum triglyceride and cholesterol levels to avoid the fat overload syndrome.

Interleukin-15 enhances cytotoxicity, receptor expression, and expansion of neonatal natural killer cells in long-term culture.

ABSTRACT Newborn infants have a higher susceptibility to various pathogens due to developmental defects in their host defense system, including deficient natural killer (NK) cell function. In this study, the effects of interleukin-15 (IL-15) on neonatal NK cells was examined for up to 12 weeks in culture. The cytotoxicity of fresh neonatal mononuclear cells (MNC) as assayed by K562 cell killing is initially much less than that of adult MNC but increases more than eightfold after 2 weeks of culture with IL-15 to a level equivalent to that of adult cells. This high level of cytotoxicity was maintained for up to 12 weeks. In antibody-dependent cellular cytotoxicity (ADCC) assays using CEM cells coated with human immunodeficiency virus gp120 antigen, IL-15 greatly increased ADCC lysis by MNC from cord blood. IL-15 increased expression of the CD16+ CD56+ NK markers of cord MNC fivefold after 5 weeks of incubation. Cultures of neonatal MNC with IL-15 for up to 10 weeks resulted in a unique population of CD3− CD8+ CD56+ cells (more than 60%), which are not present in fresh cord MNC. These results show that IL-15 can stimulate neonatal NK cells and sustain their function for several weeks, which has implications for the clinical use of IL-15.

The syndrome of chronic mucocutaneous candidiasis with selective antibody deficiency

BACKGROUND Most patients with chronic mucocutaneous candidiasis (CMC) have a selective defect of cell-mediated immunity against Candida albicans (as demonstrated by cutaneous anergy and decreased lymphoproliferative responses to Candida antigen) and intact antibody responses. Many CMC patients also develop infections with other organisms, suggesting a more extensive immunologic defect. OBJECTIVES The aim of this study was to describe a patient with CMC and selective antibody deficiency and identify eight similar previously reported patients. DATA SOURCES Relevant articles in the English language derived from searching the MEDLINE database were used. RESULTS We describe an 18-year-old male patient who was identified with CMC as an infant and later developed immunoglobulin (Ig)G2, IgG4, and IgA deficiency at age 12 associated with poor antibody responses to vaccine antigens. We have identified eight other previously reported CMC patients with selective antibody deficiencies and bacterial infections. IgG2 deficiency was present in all nine patients, and was associated with IgG4 deficiency in 8 patients and IgA deficiency in 3 patients. Six patients had poor or absent antibody responses to pneumococcal polysaccharide vaccine, and all nine patients developed severe recurrent lung infections. CONCLUSIONS We suggest that these cases represent a distinct phenotype of CMC and should be studied for common histocompatibility leukocyte antigen types and molecular defects.

Immune thrombocytopenia after umbilical cord progenitor cell transplant: response to vincristine.

An 8-month-old male with X-linked lymphoproliferative disease underwent an unrelated, partially matched (with major mismatch at DR locus), cord blood stem cell transplant. Four months following the transplant, he developed immune thrombocytopenia with hemolytic anemia (Evans syndrome). He received multiple courses of intravenous immunoglobulin, anti-Rh D immunoglobulin, a pulse of high-dose corticosteroids and cyclosporine with some improvement of hemolytic anemia, but no improvement of the thrombocytopenia. Addition of vincristine, resulted in long-term resolution of thrombocytopenia and anemia. No major toxicity was observed during treatment. Vincristine should be considered as a treatment for refractory immune thrombocytopenia after hematopoietic stem cell transplantation.

Differences in infarct size with lidocaine as compared with bretylium tosylate in acute myocardial ischemia and reperfusion in pigs

Summary: The effects of the antiarrhythmic drugs lidocaine and bretylium tosylate on myocardial necrosis were studied in anesthetized pigs subjected to 60-min coronary occlusion followed by 3-h reperfusion. Group A (n = 7) received lidocaine (average dose × SD = 1,828 × 515 mg) before and during coronary occlusion and after reperfusion; the other series (group B, n = 7) received bretylium tosylate (3,457 × 1,323 mg). Infarct size was 16.3 × 14.7% in the lidocaine group as compared with 68.6 × 12.6% (p < 0.01) in the bretylium group. In vitro release of superoxide anion from porcine granulocytes was studied using the lucigenin-dependent chemiluminescence technique. Lidocaine significantly reduced the peak chemiluminescence response to zymosan from 3.34 × 0.44 without lidocaine to 2.23 × 0.46 (p < 0.01) and 1.06 × 0.17 mV (p < 0.001), with lidocaine concentrations of 20 and 200 μg/ml, respectively. Bretylium had no effect on the chemiluminescence response. Adherence of porcine granulocytes to plastic was also reduced from 332 × 32 cells/mm2 (no lidocaine) to 247 × 35 and 206 × 26 cells/mm2 with lidocaine concentrations of 20 and 200 μg/ml, respectively (p < 0.001). Bretylium had no significant effect. Eight additional bretylium-treated pigs received either rabbit antiporcine granulocyte serum (group C, n = 4) to reduce circulating granulocytes or nonimmune serum (group D, n = 4). Infarct size in the granulocyte-depleted pigs was 26.6 × 5.6% as compared with 51.4 × 5.5% in pigs that received nonimmune serum (p < 0.01). Smaller infarct size with lidocaine as compared with bretylium tosylate therapy is associated with decreased adherence of granulocytes to vascular endothelium in the ischemic myocardium and inhibition of superoxide anion release.