James G. Gallagher

Cytomegalovirus Immune Plasma in Bone Marrow Transplant Recipients

The effects of passive immunization on cytomegalovirus infection and interstitial pneumonia in marrow transplants were evaluated in a randomized, controlled trial. Twenty-four patients received cytomegalovirus immune plasma before and after transplantation, and 24 patients were controls. Although the incidence of cytomegalovirus infection was similar in the control and plasma groups, symptomatic infection (12 of 24 versus five of 24, p = 0.07) and interstitial pneumonia (11 of 24 versus five of 24, p = 0.12) occurred less frequently in the group receiving plasma. Cytomegalovirus infection occurred in 11 of 13 recipients of leukocyte transfusions and in 16 of 35 patients not given leukocyte transfusions (p = 0.02). Among patients not given leukocyte transfusions, the incidence of cytomegalovirus infection was similar in the control and plasma groups, but symptomatic infection (eight of 18 versus one of 17, p = 0.03) and interstitial pneumonia (nine of 18 versus one of 17, p = 0.01) were significantly less in the group receiving plasma. These results suggest that passive immunization modifies cytomegalovirus infection in humans and prevents interstitial pneumonia in marrow transplants especially when leukocyte transfusions are not used.

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.

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.

Prolonged Herpes-Zoster Infection Associated with Immunosuppressive Therapy

Unusually prolonged zoster was observed in four patients, two with cardiac transplants, one with acute lymphocytic leukemia, and one with diffuse histiocytic lymphoma. Lesions increased in number and persisted for 5 to 24 weeks before beginning to resolve. Specific cellular-immune responsiveness to varicella-zoster virus was markedly depressed during these infections. Absolute numbers of T lymphocytes were also very low. Reducing immunosuppressive therapy to increase immune responses appeared to initiate resolution of zoster lesions and halt dissemination. In one patient treatment with adenine arabinoside was also needed for resolution of disseminated zoster. This syndrome appears to be counterpart of the prolonged mucocutaneous herpes-simplex infection previously reported in immunosuppressed cardiac and renal transplant patients.

Human interferon alpha in malignant lymphoma and Hodgkin's disease. Results of the american cancer society trial

Forty‐nine patients with non‐Hodgkins lymphoma or Hodgkins disease were entered into a multi‐institutional phase II trial to evaluate the antitumor activity of human interferon alpha, prepared from buffy coats. Interferon alpha was administered intramuscularly in doses of 1 × 106 u, 3 × 106 u or 9 × 106 u daily for 30 days. Objective partial responses were seen in 3 of 18 patients with nodular lymphoma, all at the 9 × 106 u dose. Interferon alpha was not observed to be of therapeutic benefit in the other subtypes of non‐Hodgkins lymphoma or Hodgkins disease. The major toxicities consisted of fatigue, fever, myalgias and weight loss. Serum interferon levels obtained 3 to 4 hours after injection varied widely, even among patients treated at the same dose level. Despite the relatively low doses of interferon used and the brief period of administration, this study extends the earlier observations of the antitumor effect of interferon in nodular lymphoma. These results are discussed in relation to the cumulative experience in human lymphoma using alpha interferons induced in human leukocytes and those produced in bacteria by recombinant DNA techniques.

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.

Recombinant interferon alpha-2a for treatment of herpes zoster in immunosuppressed patients with cancer

PURPOSE Acyclovir and high doses of intramuscular leukocyte interferon have been shown to prevent dissemination of herpes zoster in cancer patients with localized herpes zoster. With the availability of recombinant interferon, we decided to conduct a multicenter, placebo-controlled, double-blind trial of intramuscular recombinant interferon alpha-2a to assess its efficacy and safety in the treatment of localized herpes zoster in immunosuppressed patients with cancer. PATIENTS AND METHODS Immunosuppressed cancer patients with localized herpes zoster were randomly assigned to receive placebo, 36 X 10(6) units of recombinant interferon alpha-2a per day, or 68 X 10(6) units of recombinant interferon alpha-2a per day. Due to frequent adverse effects, the 68 X 10(6) unit dose of interferon was discontinued prior to conclusion of the trial. RESULTS Dissemination of herpes zoster occurred in 14 of the 24 patients (58 percent) who received placebo but in only four of 24 recipients (17 percent) of 36 X 10(6) units of interferon per day (p = 0.003). Adverse effects (fever, chills, headaches, gastrointestinal irritability, fatigue, and myalgias) were more common or severe in interferon-treated patients. CONCLUSION These results suggest that interferon modifies the severity of herpes zoster in immunosuppressed patients with cancer but is associated with frequent side effects.

Infections With Cytomegalovirus in Adults and the Natural History and Treatment of Cytomegalovirus Retinitis

Cytomegalovirus infections occur in the majority of all populations examined and once acquired remain in a latent state throughout the lifespan of the individual infected. Immunosuppressed individuals, particularly transplant recipients have increased severity of primary infections due to this agent and not infrequently reactivate the latent infection. Disseminated infections occur with resultant mortality in patients with underlying diseases, especially bone marrow transplant recipients. Retinitis due to CMV has been reported in over 30 patients and occurs in immunosuppressed patients. Fourteen cases of retinitis were seen at one institution and seven were treated with systemically administered adenine arabinoside. A dosage of 20 mg/kg was associated with improvement in retinitis and a decrease in quantitative shedding of CMV in the urine. Improvement was observed in several cases following lowering of immunosuppression without antiviral therapy. Significant side effects, mainly hematologic and gastrointestinal were observed at the dosages required. Certain patients with progressive retinitis due to CMV may respond to therapy with adenine arabinoside, but require frequent monitoring for side effects before and after such treatments.