Search Results (68)

Background: Coronavirus disease 2019 (COVID-19) has led to the expansion of the spectrum of invasive fungal infections beyond traditional immunocompromised populations. Although COVID-19-associated pulmonary aspergillosis is increasingly being recognised, COVID-19-associated mucormycosis remains rare, particularly in non-endemic regions. Concurrent COVID-19-associated invasive tracheobronchial aspergillosis and pulmonary mucormycosis with histopathological confirmation is exceedingly uncommon and poses significant diagnostic and therapeutic challenges. Case presentation: We report the case of a 57-year-old female with myelodysplastic syndrome who underwent haploidentical allogeneic haematopoietic stem cell transplantation. During post-transplant recovery, she developed COVID-19 pneumonia, complicated by respiratory deterioration and radiological findings, including a reverse halo sign. Bronchoscopy revealed multiple whitish plaques in the right main bronchus. Despite negative serum and bronchoalveolar lavage fluid galactomannan assay results, cytopathological examination revealed septate hyphae and Aspergillus fumigatus was subsequently identified. Given the patient’s risk factors and clinical features, liposomal amphotericin B therapy was initiated. Subsequent surgical resection and histopathological analysis confirmed the presence of Rhizopus microsporus. Following antifungal therapy and surgical intervention, the patient recovered and was discharged in stable condition. Conclusions: This case highlights the critical need for heightened clinical suspicion of combined invasive fungal infections in severely immunocompromised patients with COVID-19, even in non-endemic regions for mucormycosis. Early tissue-based diagnostic interventions and prompt initiation of optimal antifungal therapy are essential for obtaining ideal outcomes when co-infection is suspected. Full article

Invasive fungal disease (IFD) is a recognised and potentially life-threatening complication of chronic graft-versus-host disease (cGVHD) and its treatment. Invasive aspergillosis (IA), most often due to the species Aspergillus fumigatus, is the leading IFD in this setting. IA can occur during the early weeks following allogeneic haematopoietic stem cell transplantation (HSCT) coinciding with profound neutropenia, but increasingly, cases of IA occur after engraftment, coinciding with the occurrence of cGVHD. Immunomodulatory treatments of cGVHD can impair innate immune responses to inhaled Aspergillus conidia, increasing the risk of developing IA. Here, in a pilot study, we present an analysis of the phenotypic characteristics (phagocytic efficiency, fungal killing, and cytokine release) of circulating monocytes derived from patients with cGVHD compared to healthy volunteers. We found that there was no statistically significant difference in their ability to phagocytose A. fumigatus conidia, and while there was a trend in their reduced ability to kill conidia, this was not significant when compared to the ability of volunteers’ monocytes to do so. Although we could not demonstrate in this small cohort of patients with cGVHD that monocytes may be a factor in the increased susceptibility to IA, further investigation of larger numbers of study subjects is warranted so that in vitro biomarkers may be developed for immune responses to Aspergillus in patients with cGVHD. Full article

Background: Haematological malignancies and their treatment regimens often lead to various complications that impair patients’ physical functioning. This study aimed to assess the level of physical activity and exercise capacity in patients with haematological malignancies who were qualified for haematopoietic stem cell transplantation (HSCT). Methods: A prospective, single-centre study was conducted on patients with haematological malignancies qualified for HSCT (study group, n = 103) and a cohort of healthy volunteers (reference group, n = 100). The assessment protocol included the International Physical Activity Questionnaire (IPAQ) and the 6-Minute Walk Test (6MWT). Results: The median age was 57 years in the study group and 56 years in the reference group. In the IPAQ assessment, at least 50% of the study group reported no engagement in moderate or intense physical activity. In the 6MWT, the study group demonstrated a significantly shorter walking distance compared to the reference group (p < 0.0001). Factors such as group membership (study vs. reference group), age, gender, and body mass index (BMI) were found to have a significant impact on 6MWT performance. No significant differences were observed in IPAQ or 6MWT results among subgroups within the study group when categorized by diagnosis. Conclusions: Patients with haematological malignancies who qualified for HSCT often show physical activity levels below recommended standards, which can negatively impact their ability to endure physical exertion. Insufficient activity prior to transplantation may contribute to reduced exercise capacity. Therefore, prehabilitation programmes aimed at improving physical activity and structured exercise should be an integral part of their care. Full article

Background/Objectives: Haematopoietic stem cell transplantation (HCT) induces profound immunosuppression, significantly increasing susceptibility to severe infections. This review examines vaccinations’ necessity, timing, and efficacy post-HCT to reduce infection-related morbidity and mortality. It aims to provide a structured protocol aligned with international and national recommendations. Methods: A systematic review of current guidelines and studies was conducted to assess vaccination strategies in HCT recipients. The analysis included the timing of vaccine administration, factors influencing efficacy, and contraindications. Recommendations for pre- and post-transplant vaccination schedules were synthesised, specifically for graft-versus-host disease (GVHD), immunosuppressive therapy, and hypogammaglobulinemia. Results: Vaccination is essential as specific immunity is often lost after HCT. Inactivated vaccines are recommended to commence three months post-transplant, including influenza, COVID-19, and pneumococcal vaccines. Live attenuated vaccines remain contraindicated for at least two years post-transplant and in patients with ongoing GVHD or immunosuppressive therapy. Factors such as GVHD and immunosuppressive treatments significantly impact vaccine timing and efficacy. The review also underscores the importance of pre-transplant vaccinations and ensuring that patients’ close contacts are adequately immunised to reduce transmission risks. Conclusions: Implementing a structured vaccination protocol post-HCT is critical to improving patient outcomes. Timely and effective vaccination strategies can mitigate infection risks while addressing individual patient factors such as GVHD and immunosuppression. This review highlights the need for tailored vaccination approaches to optimize immune reconstitution in HCT recipients. Full article

Background: Acute Kidney Injury (AKI) is a condition that affects a significant proportion of acutely unwell patients and is associated with a high mortality rate. Patients undergoing haemopoietic stem cell transplantation (HSCT) are in an extremely high group for AKI. Identifying a biomarker or panel of markers that can reliably identify at-risk individuals undergoing HSCT can potentially impact management and outcomes. Early identification of AKI can reduce its severity and improve prognosis. We evaluated the urinary Liver type fatty acid binding protein (L-FABP), a tubular stress and injury biomarker both as an ELISA and a point of care (POC) assay for AKI detection in HSCT. Methods: 85 patients that had undergone autologous and allogenic HSCT (35 and 50, respectively) had urinary L-FABP (uL-FABP) measured by means of a quantitative ELISA and a semi-quantitative POC at baseline, day 0 and 7 post-transplantation. Serum creatinine (SCr) was also measured at the same time. Patients were followed up for 30 days for the occurrence of AKI and up to 18 months for mortality. The sensitivity and specificity of uL-FABP as an AKI biomarker were evaluated and compared to the performance of sCr using ROC curve analysis and logistic regression. Results: 39% of participants developed AKI within 1 month of their transplantation. The incidence of AKI was higher in the allogenic group than in the autologous HTSC group (57% vs. 26%, p = 0.008) with the median time to AKI being 25 [range 9-30] days. This group was younger (median age 59 vs. 63, p < 0.001) with a lower percentage of multiple myeloma as the primary diagnosis (6% vs. 88%, p < 0.001). The median time to AKI diagnosis was 25 [range 9–30] days. uL-FABP (mcg/gCr) at baseline, day of transplant and on the 7th day post-transplant were 1.61, 5.39 and 10.27, respectively, for the allogenic group and 0.58, 4.36 and 5.14 for the autologous group. Both SCr and uL-FABP levels rose from baseline to day 7 post-transplantation, while the AUC for predicting AKI for baseline, day 0 and day 7 post-transplant was 0.54, 0.59 and 0.62 for SCr and for 0.49, 0.43 and 0.49 uL-FABP, respectively. Univariate logistic regression showed the risk of AKI to be increased in patients with allogenic HSCT (p = 0.004, 95%CI [0.1; 0.65]) and in those with impaired renal function at baseline (p = 0.01, 95%CI [0.02, 0.54]). The risk of AKI was also significantly associated with SCr levels on day 7 post-transplant (p = 0.03, 95%CI [1; 1.03]). Multivariate logistic regression showed the type of HSCT to be the strongest predictor of AKI at all time points, while SCr levels at days 0 and 7 also correlated with increased risk in the model that included uL-FABP levels at the corresponding time points. The POC device for uL-FABP measurement correlated with ELISA (p < 0.001, Spearman ‘correlation’ = 0.54) Conclusions: The urinary biomarker uL-FABP did not demonstrate an independent predictive value in the detection of AKI at all stages. The most powerful risk predictor of AKI in this setting appears to be allograft recipients and baseline renal impairment, highlighting the importance of clinical risk stratification. Urinary L-FAPB as a POC biomarker was comparable to ELISA, which provides an opportunity for simple and rapid testing. However, the utility of LFABP in AKI is unclear and needs further exploration. Whether screening through rapid testing of uL-FABP can prevent or reduce AKI severity is unknown and merits further studies. Full article

Severe haematological diseases and lymphoid malignancies require bone marrow (BM)-suppressive treatments. Knowledge regarding the impact of BM-suppressive treatments on children’s memory T cells is very limited. Memory T cells play a crucial role in defending against herpesviruses, which is particularly relevant in paediatric cancer care. We studied 53 children in total; 34 with cancer and 2 with severe haematological disorders, with some receiving BM-suppressive treatment with or without allogeneic–haematopoietic stem cell transplantation (allo-HSCT), alongside 17 healthy controls. We focused on peripheral blood proportions of memory T-cell subsets using flow cytometry and analysed cytokine-secreting T cells with a four-parameter FluoroSpot assay in response to T-cell mitogen and varicella zoster virus (VZV) peptides. Patients on BM-suppressive treatment showed increased clusters of differentiation (CD)4⁺ and CD8⁺ effector memory (TEM)/terminally differentiated effector (TEFF) T cells compared to the healthy controls. They also exhibited, amongst other things, when compared to the healthy controls, a reduced total number of cytokine-secreting cells, by means of interferon (IFN)-γ, interleukin (IL)-17A, IL-10, and IL-22, following mitogen activation. A diminished IFN-γ response among the children with BM-suppressive treatment was observed upon VZV-peptide stimulation, compared to the healthy children. Collectively, the findings herein indicate that the children who are undergoing or have finished BM-suppressive treatment display qualitative differences in their T-cell memory compartment, potentially increasing their susceptibility to severe viral infections and impacting their immunotherapy, which relies on the functional ability of autologous T cells. Full article

Both scleroderma and immunoglobulin G4-related disease (IgG4-RD) are systemic fibro-inflammatory diseases characterised by lymphoplasmacytic infiltrates. IgG4-RD and systemic sclerosis (SSc) may share common pathophysiological mechanisms, but no examples of co-occurrence of the diseases have been found. Autologous haematopoietic stem cell transplantation (AHSCT) is implemented in selected rapidly progressive SSc with a high risk of organ failure. However, existing guidelines are based on clinical trials that do not represent the entire patient population and exclude critically ill patients with no therapeutic alternatives. Examples of AHSCT in IgG4-RD are absent. We report the case of a 44-year-old female patient with overlapping progressive diffuse SSc and sinonasal IgG4-RD. After 11 years of ineffective SSc treatment, AHSCT was performed. The 63-month follow-up showed a regression of SSc symptoms. AHSCT was not intended as treatment in the case of IgG4RD, although the first symptoms of the disease developed before transplantation. The sinus lesions progressed after AHSCT and remained indolent only after surgical treatment (bilateral ethmoidectomy, sphenoidotomy, intranasal buccal antrostomy), which allowed histopathological confirmation of IgG4-RD. Full article

Allogeneic haematopoietic stem cell transplantation (HSCT) leads to the establishment of graft-versus-leukaemia (GVL) immunity, but in many cases also results in the development of graft-versus-host disease (GVHD). This study aimed to determine if P2X7 antagonism using Brilliant Blue G (BBG) could improve the beneficial effects of post-transplant cyclophosphamide (PTCy) in a humanised mouse model of GVHD, without comprising GVL immunity. NOD.Cg-Prkdc^scid Il2rg^tm1Wjl (NSG) mice were injected with human peripheral blood mononuclear cells (PBMCs) (Day 0), then with cyclophosphamide (33 mg/kg) on Days 3 and 4, and with BBG (50 mg/kg) (or saline) on Days 0–10. PTCy with BBG reduced clinical GVHD development like that of PTCy alone. However, histological analysis revealed that the combined treatment reduced liver GVHD to a greater extent than PTCy alone. Flow cytometric analyses revealed that this reduction in liver GVHD by PTCy with BBG corresponded to an increase in human splenic CD39⁺ Tregs and a decrease in human serum interferon-γ concentrations. In additional experiments, humanised NSG mice, following combined treatment, were injected with human THP-1 acute myeloid leukaemia cells on Day 14. Flow cytometric analyses of liver CD33⁺ THP-1 cells showed that PTCy with BBG did not mitigate GVL immunity. In summary, PTCy combined with BBG can reduce GVHD without compromising GVL immunity. Future studies investigating P2X7 antagonism in combination with PTCy may lead to the development of novel treatments that more effectively reduce GVHD in allogeneic HSCT patients without promoting leukaemia relapse. Full article

The use of human leukocyte antigen (HLA)–haploidentical haematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PTCY), which markedly reduces the risk of graft-versus-host disease, has rapidly increased worldwide, even in children. It was initially developed for post-transplant relapse or non-remission at transplant for patients with high-risk haematologic malignancies. However, this strategy is currently used more frequently for standard-risk, transplant-eligible paediatric haematological malignancies. It has recently been recognised in adults that the transplant outcomes after PTCY-based HLA–haploidentical HSCT are comparable with those achieved after HLA-matched HSCT. Therefore, even in children, parental donors who are HLA–haploidentical donors and cord blood are currently considered the next donor candidates when an HLA-matched related or unrelated donor is unavailable. This review addresses the current status of the use of haplo-HSCT with PTCY for paediatric haematologic malignancies and future directions for donor selection (sex, age, ABO blood type, and HLA disparity), donor source, the dose of infused CD34⁺ cells, optimal conditioning, the concomitant graft-versus-host disease prophylaxis other than PTCY, and the pharmacokinetic study of CY and CY metabolites. These aspects present key solutions for further improvements in the outcomes of haplo-HSCT with PTCY for paediatric haematological malignancies. Full article

Haematopoietic stem cell transplantation (HSCT) is a curative approach for blood cancers, yet its efficacy is undermined by a range of acute and chronic complications. In light of mounting evidence to suggest that these complications are linked to a dysbiotic gut microbiome, we aimed to evaluate the feasibility of faecal microbiota transplantation (FMT) delivered during the acute phase after HSCT. Of note, this trial opted for FMT prepared using the individual’s own stool (autologous FMT) to mitigate the risks of disease transmission from a donor stool. Adults (>18 years) with multiple myeloma were recruited from a single centre. The stool was collected prior to starting first line therapy. Patients who progressed to HSCT were offered FMT via 3 × retention enemas before day +5 (HSCT = day 0). The feasibility was determined by the recruitment rate, number and volume of enemas administered, and the retention time. Longitudinally collected stool samples were also collected to explore the influence of auto-FMT using 16S rRNA gene sequencing. n = 4 (2F:2M) participants received auto-FMT in 12 months. Participants received an average of 2.25 (1–3) enemas 43.67 (25–50) mL total, retained for an average of 60.78 (10–145) min. No adverse events (AEs) attributed to the FMT were identified. Although the minimum requirements were met for the volume and retention of auto-FMT, the recruitment was significantly impacted by the logistical challenges of the pretherapy stool collection. This ultimately undermined the feasibility of this trial and suggests that third party (donor) FMT should be prioritised. Full article

Inborn errors of immunity (IEIs) are a heterogeneous group of diverse clinical and genetic phenotypes that have an estimated combined prevalence as high as 1/1000. Increased risk of frequent, severe, or opportunistic infections is a common feature of IEIs, but there are also diverse immune-mediated, non-infective complications that are associated with significant morbidity and mortality. As patient survival increases, these are becoming more apparent within the liver. Hepatic involvement of IEIs may not only manifest as infections, but also nodular regenerative hyperplasia, granulomatous disease, autoimmune hepatitis and malignancy. As therapeutic options for patients are expanding, with both pharmaceutical treatments as well as haematopoietic stem cell transplant (HSCT), iatrogenic liver injury is increasingly common and important to identify. This review article summarises the spectrum of hepatic complications seen in IEIs, and highlights the challenges of management within this patient cohort, where immunosuppression is poorly tolerated. Early recognition and prompt diagnosis of potential hepatic complications is therefore crucial in ensuring potentially reversible causes are treated, but significant uncertainty remains regarding best practice for many features of immune dysregulation with limited high-quality evidence. Full article

Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic possibilities of MF are expanding, it is critical to identify patients predisposed to early ruxolitinib monotherapy failure and worse outcomes. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 patients included in the “RUX-MF” retrospective study. Overall, 172 patients were alive on ruxolitinib after ≥5 years (long-term ruxolitinib, LTR), 115 patients were alive but off ruxolitinib after ≥5 yrs (short-term RUX, STR), and 123 patients died while on ruxolitinib after <5 yrs (early death on ruxolitinib, EDR). The cumulative incidence of the blast phase was similar in LTR and STR patients (p = 0.08). Overall survival (OS) was significantly longer in LTR pts (p = 0.002). In multivariate analysis, PLT < 100 × 10⁹/L, Hb < 10 g/dL, primary MF, absence of spleen response at 3 months and ruxolitinib starting dose <10 mg BID were associated with higher probability of STR. Assigning one point to each significant variable, a prognostic model for STR (STR-PM) was built, and three groups were identified: low (score 0–1), intermediate (score 2), and high risk (score ≥ 3). The STR-PM may identify patients at higher risk of failure with ruxolitinib monotherapy who should be considered for alternative frontline strategies. Full article

Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus. Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970’s. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD. Full article

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in the phagocytic function of the innate immune system owing to mutations in genes encoding the five subunits of the nicotinamide adenine dinucleotide phosphatase (NADPH) oxidase enzyme complex. This review aimed to provide a comprehensive approach to the pathogens associated with chronic granulomatous disease (CGD) and its management. Patients with CGD, often children, have recurrent life-threatening infections and may develop infectious or inflammatory complications. The most common microorganisms observed in the patients with CGD are Staphylococcus aureus, Aspergillus spp., Candida spp., Nocardia spp., Burkholderia spp., Serratia spp., and Salmonella spp. Antibacterial prophylaxis with trimethoprim-sulfamethoxazole, antifungal prophylaxis usually with itraconazole, and interferon gamma immunotherapy have been successfully used in reducing infection in CGD. Haematopoietic stem cell transplantation (HCT) have been successfully proven to be the treatment of choice in patients with CGD. Full article

Graft-versus-host disease (GVHD) is a T cell-mediated inflammatory disorder that arises from allogeneic haematopoietic stem cell transplantation and is often fatal. The P2X7 receptor is an extracellular adenosine 5′-triphosphate-gated cation channel expressed on immune cells. Blockade of this receptor with small molecule inhibitors impairs GVHD in a humanised mouse model. A species-specific blocking monoclonal antibody (mAb) (clone L4) for human P2X7 is available, affording the opportunity to determine whether donor (human) P2X7 contributes to the development of GVHD in humanised mice. Using flow cytometric assays of human RPMI 8266 and murine J774 cells, this study confirmed that this mAb bound and impaired human P2X7. Furthermore, this mAb prevented the loss of human regulatory T cells (hTregs) and natural killer (hNK) T cells in vitro. NOD-scid IL2Rγ^null mice were injected with 10 × 10⁶ human peripheral blood mononuclear cells (Day 0) and an anti-hP2X7 or control mAb (100 μg i.p. per mouse, Days 0, 2, 4, 6, and 8). The anti-hP2X7 mAb increased hTregs and hNK cells at Day 21. Moreover, anti-hP2X7 mAb-treatment reduced clinical and histological GVHD in the liver and lung compared to the control treatment at disease endpoint. hTregs, hNK, and hNK T cell proportions were increased, and human T helper 17 cell proportions were decreased at endpoint. These studies indicate that blockade of human (donor) P2X7 reduces GVHD development in humanised mice, providing the first direct evidence of a role for donor P2X7 in GVHD. Full article