Raphael H. Levey

Use of Cytomegalovirus Immune Globulin to Prevent Cytomegalovirus Disease in Renal-Transplant Recipients

We undertook a prospective randomized trial to examine whether an intravenous cytomegalovirus (CMV) immune globulin would prevent primary CMV disease in renal-transplant recipients. Fifty-nine CMV-seronegative patients who received kidneys from donors who had antibodies against CMV were assigned to receive either intravenous CMV immune globulin or no treatment. The immune globulin was administered in multiple doses over the first four months after transplantation. The incidence of virologically confirmed CMV-associated syndromes was reduced from 60 percent in controls to 21 percent in recipients of CMV immune globulin (P less than 0.01). Fungal or parasitic superinfections were not seen in globulin recipients but occurred in 20 percent of controls (P = 0.05). Only 4 percent of globulin recipients had marked leukopenia (reflecting serious CMV disease), as compared with 37 percent of the controls (P less than 0.01). There was a concomitant but not statistically significant reduction in the incidence of CMV pneumonia (17 percent of controls as compared with 4 percent of globulin recipients). A significant reduction in serious CMV-associated disease was observed even when patients were stratified according to therapy for transplant rejection (P = 0.04). We observed no effect of immune globulin on rates of viral isolation or seroconversion, suggesting that treated patients often harbored the virus but that clinically evident disease was much less likely to develop in them. We conclude that CMV immune globulin provides effective prophylaxis in renal-transplant recipients at risk for primary CMV disease.

Complete Correction of the Wiskott-Aldrich Syndrome by Allogeneic Bone-Marrow Transplantation

Two patients with the Wiskott-Aldrich syndrome had complete donor lymphoid and hematopoietic engraftment after successful allogeneic bone-marrow transplantation. One patient had had only a temporary donor T-lymphocyte graft after a previous transplantation, for which he had been prepared with cytarabine and cyclophosphamide; the patients own T lymphocytes returned six months later. A repeat transplant, for which the patient was prepared with anti-human thymocyte serum, total-body irradiation and procarbazine, resulted in complete donor engraftment. The second patient underwent a successful transplantation after similar preparation, except that procarbazine was omitted. At 11 and five months after transplantation both had normal hematopoiesis and no evidence of graft-versus-host disease. This treatment of the Wiskott-Aldrich syndrome may be a model for the correction of other genetically determined immune and hematologic bone-marrow disorders.

The medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia

The treatment of acute leukemia in childhood has been increasingly successful. Infectious complications are the major cause of morbidity and mortality among these patients receiving aggressive chemotherapy. In particular, neutropenic enterocolitis or typhlitis has had a reported mortality of 50% to 100%. The authors reviewed a series of 77 previously untreated patients with acute myelogenous leukemia begun on treatment from March 1976 to June of 1984 to better define the characteristics of typhlitis and its optimum management. Twenty‐five patients had episodes of typhlitis, characterized by fever, abdominal pain, and tenderness, occurring during periods of neutropenia. Ten of these patients had watery diarrhea as a major additional symptom, and nine patients had a significant episode of gastrointestinal bleeding. In seven instances, blood culture results were positive, all for intestinal flora. The episodes of typhlitis occurred most frequently during the induction therapy (19 patients). Five patients experienced typhlitis during maintenance therapy, and one patient had acute appendicitis. Two patients had typhlitis during their reinduction therapy, and of note, one had had abdominal symptoms during her initial induction. All patients were treated initially with broad‐spectrum antibiotics and bowel rest. Four criteria have been used for surgical intervention: (1) persistent gastrointestinal bleeding after resolution of neutropenia and thrombocytopenia and correction of clotting abnormalities; (2) evidence of free intraperitoneal perforation; (3) clinical deterioration requiring support with vasopressors, or large volumes of fluid, suggesting uncontrolled sepsis; and (4) development of symptoms of an intra‐abdominal process, in the absence of neutropenia, which would normally require surgery. Using these criteria, five patients required surgical intervention for typhlitis or its sequelae and one for acute appendicitis. There was one perioperative death resulting from miliary tuberculosis. Among the 21 patients managed medically, there was 1 death resulting from typhlitis in a patient in whom surgery was deferred because of her multiple failures to enter remission.

Neuroblastoma: the Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children's Hospital experience.

The treatment results for 118 patients with neuroblastoma seen at the Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Childrens Hospital from 1970 to 1980 were analyzed. Patients were treated with a combination of surgery, radiation therapy, and chemotherapy depending on stage and age. Disease-free survival was excellent in all patient groups except those over one year of age with stage IV disease, a group for which currently available therapy cures only a small proportion of patients. Patients with stage III disease and older patients with stage II disease did extremely well (survival of 81% and 89%, respectively) and may have benefited from intensive treatment with all three modalities. Survival for infants (under one year) with stage IV neuroblastoma (90%) has clearly improved with intensive combination chemotherapy. With combination approaches and newer, more effective systemic regimens, a real impact on survival appears to have been made in the last decade. Better approaches will be necessary to cure more than an occasional older patient with stage IV disease.

Long-term results of the APO protocol (vincristine, doxorubicin [adriamycin], and prednisone) for treatment of mediastinal lymphoblastic lymphoma.

Twenty-one patients with biopsy-proven mediastinal lymphoblastic lymphoma were treated with the APO protocol (vincristine, doxorubicin, and prednisone). Treatment consisted of two years of therapy with a modified doxorubicin-containing acute lymphoblastic leukemia regimen with preventive cranial irradiation and intrathecal methotrexate. The median age in the group was 13 years (range, 2.5-22 years). Complete remission was obtained in 20 of 21 patients. Three patients required mediastinal irradiation for successful remission induction. Six patients have subsequently relapsed: two in the central nervous system, one in the central nervous system and testicle, one in the testicle, one in the pleura, and one in the abdomen. The median follow-up is six years (range, 16 months to 9.5 years) and a Kaplan-Meier estimate of disease-free survival at three years is 58% +/- 23% (2 SE).

ESTABLISHMENT OF IMMUNOLOGICAL COMPETENCE IN A CHILD WITH CONGENITAL THYMIC APLASIA BY A GRAFT OF FETAL THYMUS

Abstract Fetal thymus tissue was implanted into a 21-month-old patient with congenital aplasia of the thymus gland (DiGeorges syndrome). Clinical and immunological studies carried out for 16 months thereafter revealed prompt and long-lasting improvement in previously defective cellular immune functions including dermal sensitivity to monilia antigen and dinitrofluorobenzene, skin allograft rejection, and the responses of peripheral blood leucocytes in vitro to phytohaemagglutenin and to monilia antigen. It is suggested that implanting fetal thymus tissues into patients with DiGeorges syndrome offers at present the best hope of improving their deficient cellular immune function.

Improved prognosis for infants with stage IV neuroblastoma.

From 1970 to 1982 11 infants with Evans stage IV neuroblastoma who were 11 months of age or less at diagnosis were treated. All but one were treated with intensive multiagent chemotherapy; eight had attempted surgical resection; only one received radiotherapy to the primary tumor. Ten of the 11 infants remain free of disease from 2 1/2 to 13 years (median, four years). Multiagent chemotherapy has clearly improved the outcome for infants with stage IV neuroblastoma.

Bone-marrow transplantation in severe combined immunodeficiency syndrome

Summary Six sibling-to-patient allogeneic bone-marrow transplantations were carried out in three infants with the combined immunodeficiency syndrome. There was HL-A identity between two donor-recipient pair combinations and no detectable antigenic disparity in the third pair. Each recipient received at least one stem-cell enriched marrow which had been fractionated on a discontinuous albumin gradient in an attempt to avoid graft-versus-host disease. This technique prevented secondary disease but resulted in equipment with humoral immunity only in one patient. Cellular immunity was not restored either by this technique or by the implantation of fetal thymus. One patient, in whom gradient marrow failed, was restored to full cellular and humoral immunocompetence by the infusion of whole, unfractionated marrow.

Warts in a Pediatric Renal Transplant Population

18 of 49 pediatric renal transplant recipients, all of whom were on continual steroid and immunosuppressive treatment, were found to have warts. Although all 18 patients received treatment for this problem, only 5 had the warts successfully eradicated. The frequency of warts among transplant patients is three times that of the general childhood population and twice that of a group of nephrotic pediatric patients who received immunosuppressive therapy. We propose that drug-induced suppression of cell-mediated, and to a lesser extent, humoral immunity, may predispose people to develop warts.

Studies on the isolation of lymphocytes active in cell-mediated immune responses: II. Identification and recovery of an immunocompetent subpopulation of mouse thymocytes

Abstract Suspensions of mouse thymocytes were separated into subpopulations of cells by centrifugation on discontinuous bovine serum albumin (BSA) gradients. Nine bands or fractions of cells localized at the interfaces of the ten different concentrations of albumin used. The fractions were numbered from 1 through 9, beginning with least dense harvested at the 17/19% interface and thereafter counted sequentially to the most dense. Fraction 5 comprised at least 50% of the cell population while fractions 1–4 constituted approximately 20% of which 15–18% were in fraction 4. Each fraction was then evaluated individually to assess its reactivity. Five parameters of responsiveness were used: 1. Incorporation of tritiated thymidine in tissue culture and in vivo ; 2. Response to stimulation with the mitogen phytohemagglutinin ; 3. Homing or migratory potential to peripheral lymph nodes; 4. Ability to provoke a significant graft-versus-host reaction; and 5. Sensitivity to heterologous antilymphocyte serum. Fractions 2, 3 and 4 each possessed at least one of these attributes of thymus derived small lymphocytes, although others were lacking. Fraction 5 was inert in all systems tested. The striking depletion of bands 2–4 by ALS was reversible by the injection of marrow precursor cells obtained by differential centrifugation of syngenic marrow. Marrow cells from fractions 6–10 of marrow gradients did not replenish the depleted thymus. In whole organ perfusion culture fractions 2–4 were found to egress from the gland while the bulk of cells remained behind. It was concluded that there is a small active immunocompetent population of thymocytes within the thymus which undergoes sequential maturation and/or modulation, so that some surface changes may be necessary for circulation but not for competence.