Parkkali T

Incidence and risk factors for invasive fungal infections in allogeneic BMT recipients

In order to analyze the incidence and risk factors for invasive fungal infection (IFI) after allogeneic BMT, 142 consecutive adult BMT recipients (131 sibling donors, 11 unrelated donors) transplanted in 1989–1993 were retrospectively analyzed. There were 21 cases with definite or probable IFI (incidence 15%) (Aspergillus, 15; Candida, four; Fusarium, one; Absidia, one). The median time to the diagnosis of IFI was 136 days after BMT (range 6–466 days). Only 14% of the IFIs were found during the neutropenic period post-BMT. Of the pretransplant characteristics, hematological disease (MDS vs other) (P = 0.001) and unrelated donor (P = 0.01) were risk factors for IFI. Acute GVHD grade III–IV (P = 0.03) and extensive chronic GVHD (P = 0.0002) were also found to be significant risk factors. Only three patients with IFI (14%) became long-term survivors. Invasive fungal infections tended to develop late after BMT, were usually caused by Aspergillus sp., and were strongly associated with GVHD and its treatment. Better prophylaxis and treatment of IFI are needed. More effective prophylaxis for GVHD might decrease the risk of IFI after allogeneic BMT.

Randomized Study of Early versus Late Immunization with Pneumococcal Conjugate Vaccine after Allogeneic Stem Cell Transplantation

BACKGROUND Invasive pneumococcal disease is a life-threatening complication after allogeneic stem cell transplantation, and at least 20% of cases occur within 1 year after transplantation. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has limited efficacy, especially during the first year after transplantation. The immune response to the conjugated vaccines is expected to be better than that to the polysaccharide vaccine, but the optimal timing of vaccination is not defined. Our objective was to show that a 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) was not inferior when first given 3 months after transplantation, compared with when first given 9 months after transplantation. METHODS We performed a multicenter, randomized, noninferiority study involving 158 patients from 13 European Group for Blood and Marrow Transplantation centers who were randomly allocated at approximately 100 days after myeloablative stem cell transplantation to receive a series of vaccinations (3 doses of PCV7 given 1 month apart) that was started immediately (i.e., 3 months after transplantation) or 6 months later (i.e., 9 months after transplantation). The primary evaluation criterion was the rate of response (antibody level, > or = 0.15 microg/mL for each of the 7 serotypes) at 1 month after the third dose of PCV7. The noninferiority margin was 20%. All patients were followed up for 24 months after transplantation or until death, whichever occurred first. RESULTS We found that the response rate was not lower after early vaccination (79% [45 of 57 patients]) than after late vaccination (82% [47 of 57 patients]) (difference, -3.5%; 90% confidence interval, -15.6 to 8.6; not significant). CONCLUSIONS We conclude that PCV7 vaccination at 3 months after stem cell transplantation is not inferior to PCV7 vaccination at 9 months after transplantation. Because invasive pneumococcal disease can occur early, we recommend starting the PCV7 vaccination series at 3 months after transplantation to ensure earlier protection against Streptococcus pneumoniae. However, the early vaccination may result in only short-lasting response and may not prime for a 23-valent pneumococcal polysaccharide vaccine boost as efficiently as the late vaccination.

Diagnostic aspects of invasive Aspergillus infections in allogeneic BMT recipients

To investigate diagnostic aspects of invasive aspergillosis (IA) in allogeneic BMT recipients, the charts of 22 consecutive patients with IA transplanted in 1989–1995 were reviewed. IA was diagnosed 69–466 days (median 131 days) post BMT. In 16 patients (73%), a definite or probable diagnosis of IA was made during life. Respiratory symptoms were the presenting feature in half of the patients followed by neurological symptoms (27%). Chest X-ray revealed single or multiple nodular lesions in 10 patients; cavitation was observed in five patients. Tissue biopsy was the most common method of diagnosis (nine patients: lungs 6, liver 1, subcutaneous tissue 1, brain 1). Five IA cases were detected by nine guided fine needle lung biopsies in eight patients and without complications. Bronchoalveolar lavage was performed in 14 patients with findings suggestive of invasive pulmonary aspergillosis in eight cases. Lungs were the most common organ affected (90%) followed by central nervous system (41%). The diagnosis of IA is still difficult, and a large number of patients have advanced infection at diagnosis. Methods for early diagnosis are needed. Patients with a clinical suspicion of IA should be treated vigorously with antifungal agents during the diagnostic work-up. Bone Marrow Transplantation (2000) 25, 867–871.

Loss of protective immunity to polio, diphtheria and Haemophilus influenzae type b after allogeneic bone marrow transplantation

Immunity to poliovirus, diphtheria and Haemophilus influenzae type b (Hib) was studied in 16 adult recipients of a bone marrow transplant from an HLA‐identical sibling donor in order to evaluate the need for revaccinations. T‐cell depletion was not done in any case. The donors and patients were studied before bone marrow transplantation (BMT) and the patients 1, 3, 6, and 12 months later. Prior to the BMT 10 of 11 patients were immune (titre ≥ 4) to all vaccine poliovirus types by a standard microneutralization assay. At 12 months after BMT only two of seven patients were immune to all vaccine types, and none had immunity against an antigenically altered poliovirus type 3 strain Finland. The geometric means of antibody titres against poliovirus types 1, 2, and 3 strain Saukett and strain Finland declined gradually after 1 month postgrafting, being 4.4, 5.4, 3.3, and 1.3 respectively at 12 months after BMT. At 1 year 6 of 11 patients had immunity against diphtheria by a toxin neutralization method, but the antitoxin geometric mean level had decreased to a barely protective level, 0.01 IU/ml. The geometric mean Hib antibody concentration decreased during the first 6 months after BMT and thereafter increased slightly. A significant proportion of BMT recipients lose their protection against polio, diphtheria and Hib, and revaccinations are necessary.

Immune response to the 23-valent polysaccharide pneumococcal vaccine after the 7-valent conjugate vaccine in allogeneic stem cell transplant recipients : Results from the EBMT IDWP01 trial

The current recommendations for active immunization after stem cell transplant (SCT) include 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7) from 3 months after transplant, followed by a 23-valent polysaccharide pneumococcal vaccine (PPV23). However, until now, the immune response to PPV23 after PCV7 has not been assessed after SCT. In the EBMT IDWP01 trial, 101 patients received 1 dose of PPV23 at 12 or 18 months, both after 3 doses of PCV7. The efficacy of PPV23 was assessed 1 month later and at 24 months after transplant by the pneumococcal serotype 1 and 5 antibody levels. Serotype 1 and 5 are not included in PCV7. Although the geometric mean concentrations were significantly higher 1 month after PPV23, for both antigens, the response rates (> or =0.15 microg/mL), in the range of 68-94%, were not different between groups independent of the assessment date. One PPV23 dose after 3 PCV7 doses, already known to increase the response to PCV7, also extends the serotype coverage given 12 or 18 months after transplant.

A randomized comparison between early and late vaccination with tetanus toxoid vaccine after allogeneic BMT

Forty-five adult HLA-matched sibling BMT recipients were randomized to receive tetanus toxoid (TT) vaccine at 6, 8 and 14 months (early group, n = 23) or at 18, 20 and 26 months after BMT (late group, n = 22). At 6 months after BMT, prior to the first vaccination, 90% of the early group patients had a protective tetanus antibody concentration of ⩾0.1 HU/ml (passive haemagglutination test) but only 70% of the late group patients did so at 18 months after BMT. The antibody responses 1 month after each of the three TT vaccine doses were similar in the two vaccination groups, except that after the first dose, four-fold responses occurred more frequently in the late group. All vaccinated patients achieved the protective antibody concentration of ⩾0.1 HU/ml. In the late group the recipient antibody responses after the first and second vaccine doses correlated with the donor anti-TT level. A tetanus vaccination schedule consisting of three vaccine doses is equally immunogenic when started at 6 or 18 months after BMT. Donor immunity against tetanus may influence recipient responses to TT vaccination.

Randomized comparison of early and late vaccination with inactivated poliovirus vaccine after allogeneic BMT.

Forty-five adult HLA-matched sibling BMT recipients were randomized to receive inactivated poliovirus vaccine (IPV) at 6, 8 and 14 months (early group, n = 23) or at 18, 20 and 26 months after BMT (late group, n = 22). Ninety-five percent of the early group patients had protective antibody titres of ⩾4 to poliovirus type 1 (PV1), poliovirus type 2 (PV2) and poliovirus type 3 (PV3) by a microneutralization assay prior to the first vaccination, at 6 months after BMT. The corresponding proportion for the late group patients was only 67% at 18 months. The antibody responses 1 month after each of the three IPV doses were similar in the two vaccination groups, except that four-fold responses occurred more frequently after the first dose to PV2 and PV3 in the late group. All patients had a protective antibody titre to all poliovirus serotypes 1 and 22 months after the third vaccine dose, except one patient in the early group who lacked antibodies to PV3 at 22 months. Acute GVHD accelerated the decrease of poliovirus antibody titres prior to vaccination but had no influence on vaccination response. Chronic GVHD neither influenced the patient’s ability to retain poliovirus antibodies prior to vaccination nor impaired responses to vaccinations. A vaccination schedule consisting of three IPV doses was equally immunogenic when started at 6 or 18 months after allogeneic BMT.

Central nervous system aspergillosis in allogeneic stem cell transplant recipients

Summary:Invasive aspergillosis (IA) is relatively common in allogeneic stem cell transplant (SCT) recipients. Although lungs are the most common site, central nervous system (CNS) involvement is also observed in this setting. We have retrospectively studied 14 cases of CNS aspergillosis found in a cohort of 455 allogeneic SCT recipients (incidence 3%). All patients, except one, had experienced acute graft-versus-host disease treated with high-dose methylprednisolone, and eight patients (57%) had also received ATG. The median time to the diagnosis of CNS aspergillosis was 124 days (range 49–347 days) from SCT. Pulmonary aspergillosis had been diagnosed earlier in four patients (29%). The most common initial symptoms of CNS aspergillosis were convulsions, hemiparesis, and mental alteration. Neuroradiological studies revealed single (two patients) or multiple (seven patients) focal lesions of 0.2–9 cm in diameter. Despite clinical suspicion in many patients, a confirmed diagnosis of CNS aspergillosis was made during life in only one patient. A total of 12 patients (86%) received amphotericin B. Despite therapy, all patients died 0–27 days (median seven days) after the initial CNS symptoms. CNS aspergillosis is not uncommon in allogeneic SCT recipients. Clinical manifestations are usually dramatic and progress quickly. Earlier and more effective treatment of IA is needed to prevent dissemination of infection into the CNS.

Tetravalent meningococcal polysaccharide vaccine is immunogenic in adult allogeneic BMT recipients

Forty-four adult BMT recipients transplanted from an HLA-identical sibling donor were randomized to receive meningococcal polysaccharide (Men PS) vaccine either 8 (early group; 22 patients) or 20 (late group; 22 patients) months after BMT. The geometric mean concentrations (GMC) of antibodies to serogroup A Neisseria meningitidis (Men A) and serogroup C Neisseria meningitidis (Men C), determined by an EIA method, decreased during the first 6 months after BMT but remained at a stable level thereafter. Before vaccination the GMCs of anti-Men A were 1.53 μg/ml and 1.61 μg/ml, but 1 month after vaccination they were significantly higher, 3.46 μg/ml and 6.39 μg/ml, in the early and late groups. The GMCs of anti-Men C increased from 0.37 μg/ml and 0.44 μg/ml before vaccination to 3.31 μg/ml and 4.62 μg/ml at 1 month after vaccination in the early and late groups, respectively. By 6 months after vaccination the GMCs of Men antibodies had decreased to levels of about 50% of those measured at 1 month after vaccination. Two-fold responses to Men A PS were seen in 52% and 74% and to Men C PS in 76% and 89% of the BMT recipients in the early and late groups, respectively. Chronic GVHD had no influence on the vaccination response. In the present study, Men PS vaccine induced good and equal antibody responses to Men A and Men C PSs in allogeneic BMT recipients regardless of timing after BMT. Vaccination against Neisseria meningitidis should be considered, especially in the event of travelling or military service ⩾8 months after BMT. Bone Marrow Transplantation (2001) 27, 79–84.

Candidaemia in allogeneic stem cell transplant recipients: low risk without fluconazole prophylaxis

Summary:Invasive fungal infections (IFI) are common in allogeneic SCT recipients. We have reviewed our experience of IFI with special reference to candidaemia in 685 adult patients transplanted in 1983–2002. The donor was a matched sibling in 505 patients and an unrelated donor in 180 patients. A BM graft was used in 561 patients and a PB graft in 124 patients. Fluconazole prophylaxis was not used during the study period. Definite or probable IFI was observed in 60 patients (8.7%) with a dominance of Aspergillus infections (46 patients, incidence 6.7%). Candidaemia was found only in nine patients (1.3%). The causative agents were Candida albicans (n=8), C. krusei (n=2), and C. glabrata (n=1); in two patients, two causative agents were found. The median time to the diagnosis of candidaemia was 53 days (range 6–249 days) post transplant. Seven patients were neutropaenic at diagnosis, and four patients had experienced acute GVHD. All patients received antifungal therapy, but only one patient was cured. According to this study, candidaemia was a rare event in allogeneic SCT recipients. Thus, systematic prophylaxis against Candida infections might not be indicated. The prognosis of established infections is still poor due to comorbid conditions, notably GVHD.