Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral ...antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4 %) and three in the voriconazole group (6 %). The percentage of patients with adverse events potentially related to clinical drugs were 14 % in the voriconazole group, 12 % in the itraconazole group, and 8 % in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT.
Despite similarities relevant age- and gender-specific issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly ...underreported in the past but has a significant impact on the patients' health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT.
Objectives
Development of novel antiretrovirals aims at reducing long‐term toxicities. Tenofovir disoproxil fumarate (TDF) has been associated with potential nephrotoxicity. The aim of our study was ...to assess the impact of switching from TDF to tenofovir alafenamide (TAF) on functional nephropathy and lipid parameters in a real‐life setting.
Methods
We retrospectively analysed data from 347 HIV‐infected patients switching from a TDF‐ to a TAF‐containing regimen between April and December 2016. Sociodemographic, clinical and laboratory data were collected at TDF‐to‐TAF switch, and at 3 and 6 months thereafter. Proteinuria and albuminuria were classified according to Kidney Diseases Improving Global Outcomes (KDIGO) guidelines.
Results
At time of switch, moderately and severely increased proteinuria was detected in 32% and 8% of patients, respectively; however, urine dipstick analysis was negative in 84% and 42%, respectively. Moderately and severely increased albuminuria was found in 17% and 3% of patients, respectively. In patients with a urinary protein‐to‐creatinine ratio (UPCR) ≥ 150 mg/g, the mean value declined from 416 mg/g at baseline to 272 mg/g (P < 0.001) and 242 mg/g (P < 0.001) after 3 and 6 months, respectively. Patients with an albumin‐to‐creatinine ratio (UACR) ≥ 30 mg/g showed no significant decrease of albuminuria. Mean total cholesterol increased from 187 mg/dL at baseline to 202 (P < 0.001) and 208 mg/dL (P < 0.001) at 3 and 6 months, respectively, and mean low‐density lipoprotein (LDL) cholesterol increased from 114 mg/dL at baseline to 124 (P < 0.001) and 128 mg/dL (P < 0.001), respectively. As mean high‐density lipoprotein (HDL) cholesterol increased from 50 mg/dL at baseline to 54 (P < 0.001) and 57 mg/dL (P < 0.001) at 3 and 6 months, respectively, the LDL:HDL ratio remained stable.
Conclusions
In an aging HIV‐infected cohort, proteinuria and albuminuria were common findings and were underdiagnosed via urine dipstick. Our real‐life data suggest that laboratory markers of moderately/severely increased proteinuria improved after TDF‐to‐TAF‐switch. Lipid profiles were not aggravated. Long‐term follow‐up is needed to determine the clinical benefit of the TDF‐to‐TAF switch.
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αβ T- and B-cell-depleted allografts from ...haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαβ and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/μL, >200 CD19+ cells/μL and >200 CD56+ cells/μL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/μL), for CD3+4+ at day +30 (58 vs 11 cells/μL) and for CD56+ at day +14 (622 vs 27 cells/μL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received alpha beta T- and B-cell-depleted ...allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCR alpha beta and anti-CD19 Abs and immunomagnetic microbeads. The gamma delta T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/ mu L, >200 CD19+ cells/ mu L and >200 CD56+ cells/ mu L for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/ mu L), for CD3+4+ at day +30 (58 vs 11 cells/ mu L) and for CD56+ at day +14 (622 vs 27 cells/ mu L). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Pediatric patients with hemato-oncological malignancies and neutropenia resulting from chemotherapy have a high risk of acquiring invasive fungal infections. Oral antifungal prophylaxis with azoles, ...such as fluconazole or itraconazole, is preferentially used in pediatric patients after chemotherapy. During this retrospective analysis, posaconazole was administered based on favorable results from studies in adult patients with neutropenia and after allogeneic hematopoietic stem cell transplantation. Retrospectively, safety, feasibility, and initial data on the efficacy of posaconazole were compared to fluconazole and itraconazole in pediatric and adolescent patients during neutropenia. Ninety-three pediatric patients with hemato-oncological malignancies with a median age of 12 years (range 9 months to 17.7 years) that had prolonged neutropenia (>5 days) after chemotherapy or due to their underlying disease, and who received fluconazole, itraconazole, or posaconazole as antifungal prophylaxis, were analyzed in this retrospective single-center survey. The incidence of invasive fungal infections in pediatric patients was low under each of the azoles. One case of proven aspergillosis occurred in each group. In addition, there were a few cases of possible invasive fungal infection under fluconazole (
n
= 1) and itraconazole (
n
= 2). However, no such cases were observed under posaconazole. The rates of potentially clinical drug-related adverse events were higher in the fluconazole (
n
= 4) and itraconazole (
n
= 5) groups compared to patients receiving posaconazole (
n
= 3). Posaconazole, fluconazole, and itraconazole are comparably effective in preventing invasive fungal infections in pediatric patients. Defining dose recommendations in these patients requires larger studies.
Langerhans cell histiocytosis (LCH) is a clonal histiocytic disorder with recurrent mutations of
BRAF
and
MAP2K1
, but data on the impact of genetic features on progression and long-term sequelae are ...sparse. Cases of pediatric LCH with long-term follow-up from our institution were analyzed for mutations in
BRAF
V600
and
MAP2K1
exons 2 and 3 by immunostaining with mutation-specific VE1 antibody, as well as allele-specific PCR and sequencing, respectively. Clinical and follow-up data were obtained from our files and a questionnaire sent to all former patients. Sixteen of 37 (43%) evaluable cases showed
BRAF
V600E
, one case a
BRAF
V600D
and eleven (30%) a
MAP2K1
mutation. Nine cases were unmutated for both genes. All cases with risk organ involvement showed either
BRAF
V600
or
MAP2K1
mutation. Patients with
BRAF
V600
mutation excluding Hashimoto-Pritzker cases had a significantly higher risk for relapses (
p
= 0.02). Long-term sequelae were present in 19/46 (41%) patients (median follow-up 12.5 years, range 1.0 to 30.8) with a trend for higher rates in mutated cases (mutated = 9/17, 53% versus non-
BRAF
V600
/
MAP2K1
mutated = 2/7, 29%). In addition, 8/9 cases with skin involvement including all Hashimoto-Pritzker cases (
n
= 3) were positive for
BRAF
V600E
. Infants below 2 years more frequently had
BRAF
V600
mutations (
p
= 0.013). Despite favorable prognosis, pediatric LCH shows a high frequency of relapses and long-term medical sequelae.
Objectives
While idiopathic pulmonary arterial hypertension (PAH) is a rare disease, it is seen more frequently in patients with HIV infection. The aim of this study was to evaluate the prevalence of ...pulmonary hypertension (PH) in patients with HIV infection by echocardiographic screening.
Methods
Echocardiography and N‐terminal of the prohormone brain natriuretic peptide measurement were used to examine the prevalence of PH prospectively in HIV‐positive patients (n = 374) during routine follow‐up visits for HIV disease.
Results
In echocardiographic screening, PH was detected in a total of 23 of 374 HIV‐infected patients (6.1%). Of these, three patients (13%) presented with symptoms of dyspnoea and fatigue, and diagnosis of PAH was confirmed by right heart catheterization. Patients with systolic pulmonary artery pressure (sPAP) > 30 mmHg were more likely to be female, to have a history of injecting drug use and to originate from high‐prevalence countries (HPCs).
Conclusions
Echocardiographic screening detected PH in a substantial proportion of HIV‐positive patients. Female gender, a history of injecting drug use and HPC origin were associated with a higher prevalence of HIV‐associated PH. The relevance and long‐term outcome of these findings need to be validated in follow‐up studies, which are ongoing.
HLA-B*57 affects the course of HIV infection. Under antiretroviral therapy, its effects cannot be explained by outstandingly efficient T cell responses alone but may also involve cells of innate ...immunity. Studying
in vitro
stimulation with Pam3CSK4,
E. coli
LPS-B5 and CpG-ODN-2216, we observed greater induction of IL-6/IL-1beta double-positive CD14
+
CD16
++
monocytes as well as IFN-gamma-positive cytotoxic CD56
high
CD16
neg
NK cells in HLA-B*57- versus HLA-B*44-positive HIV patients, while TNF-alpha induction remained unchanged. Differences were not seen in the other monocyte and NK cell subsets or in HLA-matched healthy controls. Our findings show that, in virally suppressed HIV infection, HLA-B*57 is associated with enhanced responsiveness of inflammatory innate immune cells to TLR ligands, possibly contributing to increased vulnerability in sepsis.
Key messages
• HLA-B*57 is a host factor affecting clinical outcomes of HIV infection.
• HLA-B*57 modifies inflammatory subsets of NK cells and monocytes in HIV infection.
• In HLA-B*57-positive HIV patients TLR agonists induce enhanced IL-6/IL-1beta in monocytes.
• NK cells from HLA-B*57 HIV patients release more IFN-gamma upon TLR costimulation.
• HLA-B*57 is linked to enhanced inflammatory responsiveness to TLR ligands.
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