Berit Lönnqvist

RESULTS OF DIFFERENT STRATEGIES FOR REDUCING CYTOMEGALOVIRUS-ASSOCIATED MORTALITY IN ALLOGENEIC STEM CELL TRANSPLANT RECIPIENTS

BACKGROUND Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to identify each strategys contribution. METHODS Risk factors for CMV disease, death in CMV disease and transplant-related mortality were analyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants. RESULTS The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corresponding probabilities for seronegative patients with seropositive donors, seropositive patients with seronegative donors, and seropositive patients with seropositive donors were 5.4%, 13.7%, and 11.7%, respectively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seronegative reduced the risk for CMV disease, CMV-associated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched family donor transplants had increased risks for CMV disease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymerase chain reaction for CMV DNA were analyzed separately to assess whether addition of another CMV preventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influence. CONCLUSIONS Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.

CYTOMEGALOVIRUS INFECTION ASSOCIATED WITH AND PRECEDING CHRONIC GRAFT-VERSUS-HOST DISEASE

Of 68 consecutive allogeneic bone marrow transplant patients, 53 survived more than three months after transplantation. Twenty-two (42%) developed chronic graft-versus-host disease (GVHD). Chronic GVHD was more common among patients who had previously experienced cytomegalovirus (CMV) infection (20/36, 56%) than among those without signs of active CMV infection (2/17, 12%) (P<0.01). The CMV infections preceded the development of chronic GVHD by a median of 128 days (range 23–322 days). Children below 14 years of age who had had CMV infection developed chronic GVHD as often as older patients (8/14 vs. 12/22). CMV infection may pave the way for chronic GVHD.

Disturbances in dental development after total body irradiation in bone marrow transplant recipients

The dental status of 16 children who had been treated with bone marrow transplantation (BMT) for serious bone marrow diseases was followed for up to 6 years. Several types of disturbances in dental development were observed in children who had been conditioned with total body irradiation (TBI) at 10 Gy before BMT. Thus, impaired root development that caused short V-shaped roots was found in all patients, a complete failure of root development and premature apical closure were found in five patients, enamel hypoplasia was observed in four patients, and microdontia was observed in three patients conditioned with TBI. Patients younger than 6 years of age at BMT exhibited the most severe and extensive dental aberrations. The TBI at 10 Gy appeared to be the major cause of the disturbances found.

Low incidence of acute graft-versus-host disease, using unrelated HLA-A-, HLA-B-, and HLA-DR-compatible donors and conditioning, including anti-T-cell antibodies.

BACKGROUND Using unrelated bone marrow, there is an increased risk of graft-versus-host disease (GVHD). METHODS HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow was given to 132 patients. The diagnoses included chronic myeloid leukemia (n=43), acute lymphoblastic leukemia (n=29), acute myeloid leukemia (n=27), myelodysplastic syndrome (n=4), lymphoma (n=3), myeloma (n=1), myelofibrosis (n=1), severe aplastic anemia (n=12), and metabolic disorders (n=12). The median age was 25 years (range 1-55 years). HLA class I was typed serologically, and class II was typed by polymerase chain reaction using sequence-specific primer pairs. Immunosuppression consisted of antithymocyte globulin or OKT3 for 5 days before transplantation and methotrexate combined with cyclosporine. RESULTS Engraftment was seen in 127 of 132 patients (96%). Bacteremia occurred in 47%, cytomegalovirus (CMV) infection in 49%, and CMV disease in 8%. The cumulative incidences of acute GVHD > or = grade II and of chronic GVHD were 23% and 50%, respectively. The 5-year transplant-related mortality rate was 39%. The overall 5-year patient survival rate was 49%; in patients with metabolic disorders and severe aplastic anemia, it was 61% and 48%, respectively. The disease-free survival rate was 47% in patients with hematological malignancies in first remission or first chronic phase and 38% in patients with more advanced disease (P=0.04). Acute GVHD was associated with early engraftment of white blood count (P=0.02). Poor outcome in multivariate analysis was associated with acute myeloid leukemia (P=0.01) and CMV disease (P=0.04). CONCLUSION Using HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow and immunosuppression with antithymocyte globulin, methotrexate, and cyclosporine, the probability of GVHD was low and survival was favorable.

DECREASED INCIDENCE OF VIRIDANS STREPTOCOCCAL SEPTICAEMIA IN ALLOGENEIC BONE MARROW TRANSPLANT RECIPIENTS AFTER THE INTRODUCTION OF ACYCLOVIR

SIR,-Dr Cohen and his colleagues (Dec 24/31, p 1452) and Dr Henslee and colleagues (Feb 18, p 393) have reported on streptococcal septicaemia in bone marrow transplant (BMT) recipients. Cohen et al suggested that Hickman catheters or oral ulcerations, caused by conditioning treatment, could provide entry points for infection by viridans streptococci. Henslee et al discussed the risk of contaminating the marrow during manipulation. We suggest that oral herpes simplex virus ulceration may be another entry point for septicaemia caused by viridans streptococci that normally reside in the mouth. From the start ofour BMT programme in leukaemia in 1980 until April, 1982, septicaemia by viridans streptococci was observed during the neutropenic phase (neutrophil count <0’ 5 x z/1) after transplantation in 8 out of 30 consecutive leukaemic patients receiving marrow from HLA-identical siblings. In May, 1982, a randomised double-blind trial of acyclovir versus placebo was started. Furthermore, from this date active diagnosis of herpes . simplex virus infections resulted in a prompt treatment with acyclovir. From May, 1982, until March, 1984, none of 30 patients have experienced viridans streptococcal septicaemia (p<0-01). The incidence of septicaemia caused by other microorganisms during the neutropenic period was 6/30 in each patient group. In March, 1982, a randomised trial comparing prophylaxis for graft-versus-host disease with cyclosporin or methotrexate was also started at our centre. This is mentioned because cyclosporin may be associated with less mucosal inflammation than methotrexate. No viridans streptococcal septicaemia has been observed, not even in the patients treated with methotrexate, since the introduction of acyclovir. There were essentially no other differences between patients transplanted before or after May, 1982, in respect clinical status, conditioning, mouth care, or antimicrobial therapy. We believe that the major reason for the decreased incidence of viridans streptococcal septicaemia was more active treatment of oral herpes simplex infections by acyclovir.

Experience with a cooperative bone marrow transplantation program in Stockholm

Twenty-seven patients (age range from 1 to 55 years) were included in a cooperative bone marrow transplantation program in Stockholm. Of eight patients with severe aplastic anemia (SAA), two died following graft rejection and six (75%) are alive between 3 months and 4½ years after transplantation. Two patients with end stage leukemia died of septicemia and bleeding shortly after transplantation. Thirteen of 17 patients (76%) with acute leukemia in their first or second remission are alive 1 to 16 months after transplantation. Death was caused by septicemia in two patients, interstitial Candida pneumonitis in one and gastrointestinal bleeding in association with graft-versus-host disease in one. Among the leukemic patients all deaths occurred in subjects over 17 years of age and all 10 children are alive. No relapse has yet been seen. Successful bone marrow transplantations were carried out utilizing ordinary hospital resources only. This justifies the practice of performing transplantations in subjects with SAA and acute leukemia in remission even outside specially equipped and designed bone marrow transplantation units.

Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection.

The following findings were noted among 45 bone marrow transplant recipients. The patients without cytomegalovirus (CMV) infection or chronic graft-versus-host disease (GVHD) showed normal lymphocyte stimulation in vitro by concanavalin A (Con A) more than 3 months after transplantation, and normal stimulation by phytohemagglutinin (PHA), anti-β2-microglobulin (A-β2m) and protein A (SpA) after 6 months. In contrast, the patients who had CMV infection without chronic GVHD had Con A and SpA responses within the normal range after 12 months and reduced lymphocyte responses to PHA and A-β2m more than 12 months after transplantation. The patients with chronic GVHD had reduced responses to all of these four mitogens after more than 12 months. In comparison with other patients those who later developed chronic GVHD showed an increased mixed lymphocyte culture stimulation during the first 3 months that decreased between 6–12 months. Patients with chronic GVHD still had reduced IgA levels at 12 months after transplantation. Patients with CMV infection, but without chronic GVHD, had higher percentages of lymphocytes with surface membrane Ig than healthy controls during the first 3 months after transplantation. The data suggest that CMV infection, regardless of chronic GVHD, delays immunologic recovery after marrow transplantation.

Foscarnet for Treatment of Cytomegalovirus Infections in Bone Marrow Transplant Recipients

42 episodes of verified or clinically suspected cytomegalovirus (CMV) infection in 40 bone marrow transplant (BMT) recipients were treated with foscarnet (trisodium phosphonophormate hexahydrate). CMV infection was verified in 31/42 treatment episodes. Symptoms treated were pneumonia (n = 17), pancytopenia with or without fever (n = 12), enteritis (n = 5), fever (n = 4), encephalitis (n = 2), retinitis (n = 1) and hepatitis (n = 1). Foscarnet was given as a continuous intravenous infusion. Side-effects observed were increase in serum creatinine (38%), decrease in serum calcium (19%), increase in serum bilirubin (12%), decrease in hemoglobin concentration (7%), increase in serum calcium (5%), increase in serum transaminase (5%), hypophosphatemia (2%) and tremor (2%). CMV was eradicated from blood and/or urine in 11/25 (44%) of assessable treatment episodes with infection verified by isolation. Overall clinical improvements including eradication of CMV, afebrility and/or improvements in laboratory abnormalities were seen in 14/31 (45%) episodes of verified infection. All 15 patients with CMV interstitial pneumonia (CMV IP) died. We conclude that foscarnet is nephrotoxic but otherwise well tolerated with moderate clinical and virostatic effects on CMV infection. The effect on CMV IP is discouraging.

Variables predicting bacterial and fungal infections after allogeneic marrow engraftment.

Sixty-seven consecutive patients with a plastic anemia or leukemia who had been treated by allogeneic marrow transplantation and had survived for more than 1 month were surveyed in order to determine the incidence of nonviral infections occurring from 1 month to 3 years after transplantation. Twenty-eight of the 67 patients had one or more infections during this period. Around 20% suffered from pulmonary infections and 20% were classified as having a systemic infection. Ten patients died of bacterial or fungal infection, of whom 6 had graft-versus-host disease. In multivariate analyses acute graft-versus-host disease (P<0.0009), splenectomy (P<0.02), cytomegalovirus infection (P<0.05), and a low marrow cell dose (P<0.07) were correlated with nonviral infections.

TRANSFER OF IgA DEFICIENCY TO A BONE-MARROW-GRAFTED PATIENT WITH APLASTIC ANAEMIA

IgA deficiency developed in a 2-year-old boy with aplastic anaemia who received a bone-marrow graft from his HLA-identical, 6-year-old, IgA-deficient sister. Southern blot analysis revealed the presence of alpha-genes in both children, thus suggesting a defect of lymphocyte stem-cell differentiation as a cause of IgA deficiency. Tissue typing showed homozygosity of HLA A1, B8, DR3, the haplotype associated with IgA deficiency in healthy people. Despite normal serum levels of IgG subclasses in both donor and recipient, both children showed a relative lack of specific IgG2 anticarbohydrate antibodies. This suggests that their IgA deficiency is part of a more fundamental aberration of immunoglobulin class and subclass distribution.