Richard B. Pollard

Effect of Human Leukocyte Interferon on Hepatitis B Virus Infection in Patients with Chronic Active Hepatitis

Four patients with chronic hepatitis B infection and chronic active hepatitis were treated with human leukocyte interferon. Three of them had consistently elevated levels of circulating Dane-particle markers, including Dane-particle-associated DNA polymerase activity, hepatitis B core antigen and Dane-particle-associated DNA. Parenteral interferon administration at a dosage between 6.0 X 10(3) and 17 X 10(4) U per kilogram per day was associated with a rapid and reproducible fall in all Dane-particle markers in the three patients. The suppressive effect was transient when the interferon was given for 10 days or less but appeared to be more permanent when administration was prolonged for a month or more. In addition, long-term interferon therapy was associated with a marked fall in hepatitis B surface antigen in two of three patients and a disappearance of e antigen in two of two patients. Interferon may be useful in limiting carrier infectivity or eradicating chronic infection.

Increased pulmonary superinfections in cardiac transplant patients undergoing primary cytomegalovirus infection

CYTOMEGALOVIRUS infection is extremely common after renal transplantation, with evidence of infection in as many as 90 per cent1 to 96 per cent2 of patients. Although many recipients excrete the vi...

Cytomegalovirus Retinitis in Immunosuppressed Hosts: II. Ocular Manifestations

We observed the course of cytomegalovirus (CMV) retinitis in 21 eyes of 14 immunosuppressed patients. In two patients, other organisms, specifically Toxoplasma and Candida, also appeared to be causing retinal disease simultaneously. Post-mortem examination was done on 10 eyes from seven patients. At initial presentation, the retinitis was often asymptomatic and diagnosed during routine examination. The ophthalmoscopic picture was characteristic of cytomegalovirus; the early lesion was a small opaque, white granular area of retinal necrosis that spread in a centrifugal, brush-fire-like manner over 1 to 8 months. Vessel sheating and hemorrhages appeared as the disease progressed. In two patients new foci of retinitis developed remote from the original lesion. Four weeks to 4 months (average, 10 weeks) elapsed from the most extensive disease to total resolution. Resolution of active disease left a subtle retinal scar, and final visual acuity was reduced in one half the eyes. Repeated ophthalmoscopic examinations can aid in early diagnosis of CMV retinitis and in ascertaining which persons are most at risk for visual loss.

Cellular Immunity and Herpesvirus Infections in Cardiac-Transplant Patients

We observed severe infection with herpes simplex virus in cardiac-transplant patients despite their high serum antibody levels to this virus. Therefore, we sought to correlate clinical susceptibility to two herpesvirus (simplex and zoster) infections with specific cellular immunity, assessed by the transformation and interferon responses of peripheral blood mononuclear cells to heat-inactivated antigens. Transformation and interferon response to herps simplex virus was maximally depressed immediately after transplantation, the time when severe and prolonged infection with herps simplex virus occurred. Six months to six years after transplantation, both clinical susceptibility and cellular immunity to herpes simplex virus were normal. Herpes zoster infections were more frequent than normal at all times after cardiac transplantation; depressed or absent cellular responses to the varicella zoster virus paralleled that susceptibility. In these patients the risk of severe herpesvirus infections correlated with depressed cellular immune responses to the specific viral agent involved.

Cytomegalovirus retinitis in immunosuppressed hosts. I. Natural history and effects of treatment with adenine arabinoside

Cytomegalovirus (CMV) retinitis presents with typical ophthalmologic appearance in patients with underlying immunosuppressive conditions. Fourteen patients with this disorder were diagnosed by culture of cytomegalovirus from urine or throat specimens, elevated complement fixation titers to cytomegalovirus, and characteristic funduscopic appearance. Ten of 11 had decreased CMV-specific cell-mediated immune responses. Three of seven who received no specific therapy improved after decreasing dosages of immunosuppressive drugs. Seven patients with progressive disease despite minimal immunosuppressive therapy were treated with adenine arabinoside at doses from 1 to 20 mg/kg of body weight per day. Daily dosages of 20 mg/kg . d in five patients were associated with decreased inflammatory activity and improvement of retinal lesions and quantitative decreases in urinary virus excretion. Adenine arabinoside administration was associated with significant gastrointestinal, hematologic, and neurologic side effects. Adenine arabinoside may have some beneficial effect on selected patients with progressive CMV retinitis.

Cellular and Humoral Immunity in the Pathogenesis of Recurrent Herpes Viral Infections in Patients with Lymphoma

86 patients with lymphoma were evaluated prospectively for clinical and laboratory evidence of recurrent varicella-zoster, herpes simplex, and cytomegalovirus infections during the first 16 mo of treatment. Cellular immunity to the viral antigens was measured by in vitro lymphocyte transformation and interferon production. Antibody titers and nonspecific measures of cellular immunity, including T-cell quantitation and transformation to phytohemagglutinin, were also assessed. The patients treated with radiation and chemotherapy had the highest incidence of reactivation of each of the viruses (15-19%). Greater susceptibility to herpes viral reactivation in these patients correlated with suppression of cell-mediated immunity to the specific virus. In individual patients, suppression of cellular immunity to the specific herpes viral antigen preceded each episode of reactivation, but recurrent infection did not occur in all patients with diminished specific lymphocyte transformation. Absence of the response appears to be a necessary but not a sufficient condition for the recrudescence of latent infection. Better preservation of cellular immunity to herpes simplex antigen during treatment was associated with infrequent reactivation of herpes simplex. In 25 patients with acute herpes zoster, uncomplicated recovery from the infection was accompanied by the development of lymphocyte transformation and interferon production to varicella-zoster antigen. Quantitation of T-cell numbers and phytohemagglutinin transformation did not correlate with the presence of viral cellular immunity in treated patients. Responses returned while T-cell numbers were low, and the recovery of phytohemagglutinin transformation often preceded recovery of the responses to viral antigens. Although some patients had deficiencies in viral cellular immunity at diagnosis, the duration of the suppression of specific antiviral responses resulting from treatment appears to be the most important factor predisposing to the recurrence of herpes infections in lymphoma patients.

Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination.

In an uncontrolled trial, 29 patients with chronic hepatitis B virus infection were treated with 93 courses of adenine arabinoside at doses ranging from 2.5 to 15 mg/kg per day. Most patients were treated concomitantly with human leukocyte interferon. Significant, but transient, neurotoxicity was seen with adenine arabinoside therapy in 44% of all courses. Manifestations of toxicity were mainly neurological and ranged from pain syndromes to tremors and, rarely, seizures. Suppression of numbers of lymphocytes was also noted. All effects were reversible with time. The extent of toxicity was dependent upon the dosage of adenine arabinoside. Treatment with interferon appeared to potentiate the occurrence of toxicity with adenine arabinoside. Arabinofuranosylhypoxanthine serum levels increased in a dose-dependent manner and tended to accumulate in interferon-treated hepatitis patients during a course of therapy. Elevated blood levels and drug accumulation were associated with toxicity in a significant fashion. Human leukocyte interferon was administered to 38 patients in 113 separate courses. Interferon side effects were rapidly reversible upon cessation of therapy. These included initial fever, myalgias, and hair loss as well as suppression of granulocytes, platelets, and lymphocytes in the blood.

Specific cell-mediated immunity and infections with herpes viruses in cardiac transplant recipients

Immune responses and infections with herpes viruses were studied prospectively in 36 cardiac transplant recipients. Specific lymphocyte transformation and interferon production in response to viral antigens, viral culture results, antibody levels, responses to phytohemagglutinin, and T-cell numbers were determined. Responses to phytohemagglutinin and T-cell numbers were depressed for six to 12 weeks. Cytomegalovirus infection occurred in 100 percent of seropositive patients and in 62 percent of seronegative patients. Primary infection was more frequently symptomatic. Heart implantation from a seropositive patient wwas significantly correlated with subsequent infection in seronegative patients. Depression of transformation in response to cytomegalovirus correlated with prolonged shedding. Herpes simplex infection occurred in 95 percent of seropositive patients but decreased after 12 weeks. Asymptomatic shedding was rare, and primary infection did not occur. Return of transformation in response to herpes simplex was associated with decreased infection. Herpes zoster occurred in 22 percent during the first year, and transformation responses to varicella-zoster returned thereafter. Depression of interferon production in response to viruses did not correlate with infection as well as did lymphocyte transformation.

Short-course human leukocyte interferon in treatment of herpes zoster in patients with cancer

Because of encouraging results when human leukocyte interferon was given for 5 to 7 days to treat early localized herpes zoster in patients with cancer, a small placebo-controlled, randomized, double-blind trial was set up involving only 48 h of therapy. In this trial, there was no effect on acute pain or disease progression in the primary dermatome. However, a modest but significant effect was noted in that distal cutaneous spread was diminished in the treated patients compared with the controls and the treated patients had diminished severity and duration of postherpetic neuralgia. No evidence of impairment in varicella-zoster-specific lymphocyte transformation was observed in interferon-treated patients.

Effects of Interferon and Adenine Arabinoside Treatment of Hepatitis B Virus Infection on Cellular Immune Responses

Fifteen patients with chronic hepatitis B were treated with adenine arabinoside (Ara-A) or human leukocyte interferon (HLI). Cellular immune response to hepatitis B virus surface antigen and antigens prepared from herpes simplex virus, varicella zoster virus, and cytomegalovirus was measured by a lymphocyte blast transformation assay and an assay for interferon production. Measurements were made before, during, and after antiviral treatment. Unlike patients convalescing from acute hepatitis B, only 2 of 15 patients with chronic hepatitis B had significant blast transformation to hepatitis B surface antigen. One such response occurred during the pretreatment period of HLI therapy, and the other was in a patient undergoing low-dose (<105 U/kg per day) HLI therapy. Mononuclear cell cultures were tested for interferon production in the presence of hepatitis B surface antigen. Cells from only 1 of 15 patients produced detectable levels of interferon. In contrast, all of these patients had normal cellular immune responses to herpesvirus antigens. Transformation responses to herpes antigens decreased three- to fivefold after patients were treated with >105 U of HLI per kg per day. Antiviral therapy with <105 U of HLI per kg per day or Ara-A did not produce a detectable depression of transformation response. Ara-A produced marked lymphocytopenia and a marked lymphocyte fragility after 5 or more days of therapy. In vitro Ara-A was toxic to lymphocytes at concentrations as low as 0.5 μg/ml. These changes in lymphocyte parameters may affect the outcome of antiviral therapy.