Kerry Atkinson

Varicella-zoster virus infection after marrow transplantation for aplastic anemia or leukemia

SUMMARY Nearly one-half of marrow transplant recipients who survive at least 6 months develop varicella-zoster virus (VZV) infection. Of 92 cases studied, 82 occurred within the first 12 months after transplant. Only one patient had recurrent infection. Seventy-seven patients had herpes zoster, 22 with subsequent cutaneous dissemination, and 15 had varicella. The overall mortality rate was 8%, and all deaths occurred within 9 months of transplant. Twenty-six of 32 patients studied had significant rises in VZV antibody during recovery. Among patients with acute leukemia, those with syngeneic transplants had a significantly lower incidence of VZV infection than those with allogeneic transplants. Incidence was slightly, but not significantly, decreased among patients with aplastic anemia. In contrast to other infections, the incidence of VZV infection was not influenced by graftversus-host disease or predicted by the results of dinitrochlorobenzene skin testing.

Cyclosporin A and methotrexate in canine marrow transplantation: engraftment, graft-versus-host disease, and induction of intolerance.

We examined the effect of methotrexate (MTX) and cyclosporin A (Cy A) on engraftment, graft-versus-host disease (GVHD), and the induction of tolerance in dogs prepared for marrow transplantation by 9 Gy of total body irradiation and grafted with bone marrow and buffy coat cells. Nineteen dogs were given grafts from DLA-identical littermates followed by immunosuppression with Cy A for 25 or 100 days. All had sustained engraftment, and 12 became healthy long-term chimeras. Sixty dogs were given grafts from DLA-nonidentical unrelated donors. Among nine given MTX only post-grafting, one rejected the graft and eight died with GVHD. Among 18 dogs given Cy A only postgrafting, eight failed to achieve engraftment, seven died of various causes, and three died with GVHD. Thirty-four dogs were given both MTX and Cy A in various regimens postgrafting. The only long-term survivors were 4 of 10 dogs given MTX on days 1, 3, 6, and 11 and Cy A from days 0 through 100. Two have chronic GVHD. We conclude that Cy A can induce graft-host tolerance across minor, but not major, histocompatibility differences. The combination of MTX early after transplantation with Cy A prevents failure of engraftment of histoincompatible marrow and some recipients become long-term survivors.

Recovery of in vivo cellular immunity after human marrow grafting: influence of time postgrafting and acute graft-versus-host disease

Three hundred thirty-two marrow graft recipients and 241 healthy marrow donors were studied by skin testing with recall and neoantigens. Two hundred thirty patients with leukemia and seventy-eight patients with aplastic anemia received allogeneic HLA-identical sibling marrow. Twenty-four patients with leukemia received syngeneic marrow. The conditioning regimen prior to marrow infusion consisted of 120 mg/kg cyclophosphamide and 9.2–15.75 Gy total-body irradiation (leukemia) or 200 mg/kg cyclophosphamide (aplastic anemia). The patients were skin-tested with the neoantigens dinitrochlorobenzene (DNCB)4, keyhole limpet hemocyanin, and a battery of five recall antigens around 100, 150, 365, 730, 1095, 1460, and 1825 days after grafting. A binary logistic regression analysis was used to investigate the factors thought to influence immunocompetence. At 3 months postgrafting, the proportion of patients positive to DNCB was equal to that of normal marrow donors, but thereafter it was lower until 2 years. The proportion of patients positive to keyhole limpet hemocyanin was lower than normal regardless of the time after grafting. The proportion of patients positive to recall antigens was lower than that of normal marrow donors until 4 years after grafting. Patients with a history of acute graft-versus-host disease had the lowest probability of a positive reaction to recall antigens. None of the other factors was significantly associated with an increased or reduced level of response.

6. Analysis of late infections in 89 long-term survivors of bone marrow transplantation

Eighty-nine patients with aplastic anaemia or acute leukaemia treated by either syngeneic (13 patients) or allogeneic (76 patients) marrow transplantation who had survived for more than 6 mth were surveyed to determine the incidence of late infections. Most patients (72%) had either no or very few late infections and only a minority (28%) had 3 or more infections. Eight patients (9%) died from infection. Bacterial infections of lung, respiratory tract, skin and blood represented more than half of the 152 infections encountered. Gram-positive cocci represented one-third of the documented infecting organisms. Varicella-zoster (VZ) infections were seen in 22% of all patients. Each affected patient had only a single episode of VZ infection. Fungal infections and interstitial pneumonia were uncommon. By the use of a proportional hazards regression model we attempted to identify clinical and immunological factors predictive of and predisposing to late infections. Only 2 factors were significantly associated with late non-VZ infections; chronic graft-versus-host disease (C-GVHD) and inability to respond to cutaneous dinitrochlorobenzene (DNCB). Other factors analysed, e.g. underlying disease, conditioning regimen, type of transplant, age and sex, did not not show significant associations. In contrast, VZ infections were not associated with C-GVHD. Negative DNCB skin test reactivity appeared to be the only factor correlating with VZ infections. The recurrent (and occasionally fatal) infections seen in a minority of long-term survivors after syngeneic and allogeneic marrow transplantation are most likely the result of immunologic deficits—as indicated by the failure to respond to DNCB—which in turn are most often associated with C-GVHD.