Pattern, Incidence, and Outcomes of Invasive Fungal Infections after Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis

Background: The prevalence of opportunistic invasive fungal infections (IFIs) following allogeneic hematopoietic cell transplantation (allo-HCT) is a significant concern due to prolonged immunosuppression. Despite advancements in anti-fungal prophylaxis and diagnostics, these infections continue to pose a substantial challenge, impacting post-transplant recovery and survival. This systematic review and meta-analysis aimed to understand the incidence of fungal infections, predominant fungal species, and their effects on overall survival and mortality in patients undergoing allo-HCT.

Methods: Eligible articles were retrieved from Embase, Cochrane Library, Clinicaltrials.gov, and PubMed databases per PRISMA using search terms related to “Fungal Infections” and “allogeneic hematopoietic stem cell transplant.” A total of 983 articles were screened for eligibility. After primary and secondary screening, 31 articles were included reporting patients with fungal infections post-allo-HCT. Patient and transplant characteristics were reported descriptively. Outcomes were extracted and combined for pooled rates with associated 95% confidence intervals (CI) using the inverse variance method with the random-effects model.

Results: A total of 72,314 patients were included, of which 60.2% (n=42,499) were males. The median age was 45 years (range: 0.1-82), and the median follow-up duration was 23 months (range: 8-898). All patients received allo-HCT, and the graft source was peripheral blood stem cells (n=42,537, 66.4%), bone marrow (28.4%, n=18,217), and cord blood (5.2%, n=3,326). The type of donor was matched sibling donors (64%, n=11,040), matched unrelated donors (21.7%, n=3,739), cord blood (17.3%, n=3,326), haploidentical (3.7%, n=651), and mismatched unrelated donors (2.6%, n=450). The underlying diagnoses were acute myeloid leukemia and myelodysplastic syndrome (73.8%, n=24,625), acute lymphoblastic leukemia (4%, n=1,336), chronic myeloid leukemia (6%, n=2,042), non-Hodgkin or Hodgkin lymphoma (4.8%,n=1,610), aplastic anemia (3.6%, n=1,215), chronic lymphocytic leukemia (1.5%, n=489), multiple myeloma (0.5%, n=180), and unknown (5.6%, n=1,852). The conditioning regimen was myeloablative in 55% (n=36,179) and non-myeloablative or reduced intensity in 45% (n=29,682) of recipients. The graft versus host disease (GVHD) prophylaxis used were cyclosporine (21%, n=659), tacrolimus (2.2%, n=69, 2.2%), methotrexate (23%, n=724), mycophenolate mofetil (22%, n=69), anti-thymoglobulin (22.8%, n=716), and others (8.8%, n=276). The incidence of GVHD was 23.8% (n=17,203) of the patients who were diagnosed with graft vs host disease, of which 91% (n=15,630) had acute GVHD (grade II-IV: 94%, grade III-IV: 6%). Chronic GVHD incidence was 9% (n=1,573, limited: 49%, extensive: 51%). The anti-fungal prophylaxis used was azoles (60%, n=3,839), amphotericin-B (30%, n=1,878), and echinocandins (10%, n=667). The incidence of proven, probable, or possible invasive fungal infections was 3.6% (n=2,623) sub-grouped as 75.4% (n=1,362) aspergillosis, 7.7% (n=140) candidiasis, and 17% (n=305) other fungal infections. The pooled cumulative incidence was 7% at one year (95% CI: 2%-17%, I2=92%). The pooled 1-year overall survival (OS) in IFI patients was 32% (95% CI: 24%-42%, I2=70%). The pooled overall mortality due to IFIs was 44% (95% CI: 16%-76%, I2=96%).

Conclusion: The incidence of invasive fungal infections in patients after allogeneic HSCT is at 7%, with a high mortality and poor overall survival of 32% at one year. Aspergillosis was the most common invasive fungal infection. Further research is needed to explore associations and draw a definitive conclusion. These findings have significant implications for patient outcomes and highlight the need for further research to improve survival rates in this patient population.