Long-term interferon alpha maintenance therapy for chronic hepatitis C infection in a patient with common variable immune deficiency.

A 46-year-old woman with common variable immune deficiency acquired acute non-A, non-B hepatitis from contaminated intravenous gamma globulin in 1983. For 6 years she had fluctuating elevations of her serum aminotransferase levels. In 1990 her serum was documented to be hepatitis C virusribonucleic acid positive by polymerase chain reaction, and her liver biopsy revealed chronic hepatitis with early cirrhosis (Knodell score, 15 points). Hepatitis C virus genotyping indicated that she had been infected with the type 3 genotype. She subsequently underwent treatment with interferon alpha (IFN-alpha) for 1 year and experienced biochemical, virologic, and histologic (Knodell score, 9) suppression. She was continued on maintenance therapy for an additional 7 years, with sustained biochemical and virologic suppression. During the sixth year of therapy, complications of portal hypertension were noted with mild ascites and eventually bleeding esophageal varices. This case report documents a favorable biochemical, virologic, and histologic response to IFN-alpha therapy in this setting; supports the notion that the natural progression of hepatitis C virus infection may be more aggressive in patients with common variable immune deficiency; and, although complications of portal hypertension eventually occurred, the suppressive maintenance IFN therapy may have delayed their onset. The future establishment of the long-term effects of IFN therapy on important clinical outcomes is necessary to understand better its therapeutic benefit in chronic hepatitis C infection.

CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency.

Common variable immunodeficiency (CVI) is characterized by hypogammaglobulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma cells. We hypothesized that T-cell dysfunction resulting in abnormal contact-mediated B-cell activation may play a prominent role in the failure of CVI B cells to produce specific antibody. We have previously shown that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evaluated, indicating that CVI B cells respond to signals delivered via CD40. Here we report that CD40 ligand (gp39) mRNA expression by activated lymphocytes from CVI patients (n = 31) as a group was significantly depressed (P < 0.0001) compared with normal controls (n = 32). gp39 mRNA expression by activated lymphocytes from 13 CVI patients fell below the normal control range. T-cell surface expression of functional gp39 protein was correspondingly low in those patients with gp39 mRNA levels below normal control range and normal in patients with gp39 mRNA levels within normal control range. In CVI patients as a group, gp39 mRNA levels correlated with IL-2 mRNA levels (P < 0.002, r = 0.6) and production (P < 0.001, r = 0.7) but not with gene expression or production of other lymphokines evaluated, suggesting an as-yet-undetermined association between gp39 and IL-2 gene regulation. Of the 13 patients whose activated T cells exhibited gp39 mRNA expression below the normal control range, 2 had normal T-cell-derived lymphokine production, whereas the remaining 11 exhibited broader T-cell dysfunction, resulting in IL-2 deficiency, and in some patients deficient production of other lymphokines as well, reflecting a heterogeneity in the underlying mechanisms leading to depressed gp39 expression in these patients. The observation that both gene and surface expression of gp39 by activated T cells is depressed in a subgroup of CVI patients suggests that inefficient signaling via CD40 may be responsible, in part, for failure of B-cell differentiation in these patients.

Intravenous immunoglobulin therapy for active, extensive, and medically refractory idiopathic ulcerative or Crohn's colitis.

To determine whether intravenous immunoglobulin produces demonstrable clinical improvement in patients with refractory idiopathic inflammatory bowel disease, a pilot, open-label, nonrandomized, safety and therapeutic efficacy study was carried out at a tertiary care referral medical center. Twelve consecutive patients with refractory idiopathic colitis (nine ulcerative colitis, three Crohn's colitis) who were reluctant to receive immunosuppressive therapy or have surgical intervention were referred by physicians not participating as investigators in this study. Eleven patients were symptomatic for at least 6 months, with endoscopically moderate or severe mucosal inflammation despite medical therapy, including systemic corticosteroids in all cases, and one patient was dependent on oral prednisone to remain in clinical remission. Ten patients had extensive colitis, six of whom had pancolitis and four of whom had colitis extending to the hepatic flexure or transverse colon. Nine patients required hospitalization for treatment of colitis. Intravenous immunoglobulin was administered in one or two induction phases (2 g/kg over 2 or 5 days), followed by a maintenance phase (200-500 mg/kg every 2 wk for 12 or 24 wk). Tapering of systemic corticosteroid therapy was attempted, whereas other medications for idiopathic colitis were continued. Treatment response was assessed clinically and by colonoscopy with multiple biopsies whenever possible. Immunoglobulin therapy was well-tolerated and did not produce any biochemical abnormalities. In six patients who completed the treatment protocol, mean reductions +/- SE were achieved in subjective symptoms as quantified by a colitis activity score, 13.3 +/- 1.2 to 4.7 +/- 0.9 (p less than 0.001), and daily mg dose of prednisone, 41.7 +/- 8.0 to 1.9 +/- 1.2 (p less than 0.001). For all 12 patients, statistically significant reductions were achieved in the colitis activity score and daily prednisone dose. Of five patients who completed the treatment protocol and improved clinically, four underwent post-treatment colonoscopic and biopsy evaluations and had unequivocal reductions in the intensity of colonic mucosal inflammation. Three patients who had objective improvement with intravenous immunoglobulin experienced relapses of colitis after discontinuation of this therapy. Six patients did not complete the treatment protocol, two of whom required surgical intervention and four of whom withdrew to undergo colectomy electively. Intravenous immunoglobulin may be beneficial in subsets of patients with idiopathic colitis. The results of our pilot study justify the undertaking of a prospective, randomized controlled trial to determine the efficacy of intravenous immunoglobulin in carefully defined subsets of patients with idiopathic inflammatory bowel disease.

Interactions of Neisseria gonorrhoeae with human neutrophils: effects of serum and gonococcal opacity on phagocyte killing and chemiluminescence.

Serum-sensitive strains of Neisseria gonorrhoeae were incubated with suspensions of normal or chronic granulomatous disease human neutrophils in the absence or presence of fresh or heat-inactivated human serum; phagocytosis, gonococcal viability, and chemiluminescence were measured. Nonpiliated opaque or transparent gonococci (colony types 3 and 4, respectively) were used for phagocytic bactericidal assays. In the presence of 2.0% fresh human serum, normal neutrophils killed >90% of types 3 and 4 gonococci by 135 min. Serum alone at this concentration was not bactericidal. In the absence of serum, type 4 gonococci were not killed, whereas type 3 gonococci were killed to the same degree as in the presence of serum. Interestingly, heat-inactivated normal serum slightly inhibited phagocytic killing of type 3 gonococci. Results almost identical to those above were obtained when 5% fresh human serum deficient in complement component 7 was substituted for 2% normal autologous serum. This indicated that the later components of complement were not involved in the observed results. To investigate the mechanisms responsible for the intracellular killing of the gonococci, we used neutrophils from patients with chronic granulomatous disease. These neutrophils are deficient in an activable NADPH oxidase and do not produce bactericidal oxygen products upon phagocytic stimulation. Neutrophils from two unrelated boys with chronic granulomatous disease killed type 3 and 4 gonococci to the same degree as did normal neutrophils. As with normal neutrophils, serum was needed for killing type 4 organisms. As expected, neutrophils from these patients showed absolutely no increased chemiluminescence in the presence of type 3 or 4 gonococci, with or without serum. The effects of serum on gonococcus-induced chemiluminescence by normal neutrophils was also investigated. For these studies, in addition to type 3 and 4 gonococci, we also used transparent colony types of lightly (type 1) and heavily (type 2) piliated organisms. Chemiluminescence induced by type 1, 2, or 3 gonococci (i.e., gonococci possessing either pili or opacity-associated proteins, but not both) was augmented only slightly by serum and then only at low ratios of gonococci to neutrophils. On the other hand, chemiluminescence induced by type 4 gonococci (i.e., gonococci possessing neither pili nor opacity-associated proteins) was substantially increased in the presence of serum. Stimulation of chemiluminescence by type 1, 2, 3, or 4 gonococci was dose dependent in the absence or presence of serum. Heat-killed type 3 gonococci induced chemiluminescence to the same degree as did viable organisms. Since the gonococci used in this research was strongly catalase positive, as are gonococci in general, and since it was killed by chronic granulomatous disease neutrophils, the results indicate that gonococci can be effectively killed within neutrophils, i.e., within phagolysosomes, by nonoxidative bactericidal mechanisms. Whereas type 3 gonococci were phagocytized and killed by neutrophils equally well with or without serum, serum was obligatory for phagocytic killing of type 4 gonococci, i.e., gonococci lacking opacity-associated proteins. In addition, either pili or opacity-associated proteins were apparently necessary for maximal stimulation of neutrophil chemiluminescence. The submaximal stimulation of chemiluminescence by gonococci lacking both pili and opacity-associated proteins, i.e., type 4 gonococci was augmented by low concentrations of nonimmune serum.