SUMMARY: MicroRNAs (miRNAs) are conserved, short, non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They have been implicated in the pathogenesis of cancer and neurological, cardiovascular, and autoimmune diseases. Several recent studies have suggested that miRNAs are key players in regulating the differentiation, maturation, and activation of immune cells, thereby influencing the host immune response to infection. The resultant upregulation or downregulation of miRNAs from infection influences the protein expression of genes responsible for the immune response and can determine the risk of disease progression. Recently, miRNAs have been explored as diagnostic biomarkers and therapeutic targets in various infectious diseases. This review summarizes our current understanding of the role of miRNAs during viral, fungal, bacterial, and parasitic infections from a clinical perspective, including critical functional mechanisms and implications for their potential use as biomarkers and therapeutic targets.

In allogeneic stem cell transplant (Allo-SCT) recipients, the cell-mediated and humoral immunogenicity of the 3-dose SARS-CoV-2 vaccination schedule has not been investigated in prospective studies. In a prospective cohort, we recruited 122 Allo-SCT recipients since August 2021, when Ontario began offering a 3-dose vaccine schedule for Allo-SCT recipients. We determined humoral and cell-mediated immunity and adverse effects of the 3-dose SARS-COV-2 vaccination schedule in Allo-SCT recipients. In immunogenicity analysis (n = 95), the median (interquartile range [IQR]) antibody titer against the receptor-binding domain (RBD) of the spike (S) protein after the third dose (10,358.0 U/mL [IQR = 673.9-31,753.0]) was significantly higher than that after the first (10.2 U/mL [IQR = 0.6-37.0]) and the second doses (125.6 U/mL [IQR = 2.8-1251.0]) (P < .0001). The haploidentical donor status was an independent risk factor (adjusted odds ratio = 7.67, 95% confidence interval [CI], 1.86-31.60) for suboptimal antibody response (anti-RBD < 100 U/mL). S-specific CD4⁺ and CD8⁺ T-cell responses were measured in a subset of Allo-SCT recipients (n = 20) by flow cytometry. Most developed antigen-specific CD4⁺ (55%-80%) and CD8⁺ T-cells (80%) after 2 doses of vaccine. Frequencies of CD4⁺ polyfunctional (P = .020) and IL-2 monofunctional (P = .013) T-cells significantly increased after the third dose. Twenty-three episodes (23/301 doses [7.6%]) of new-onset or worsening pre-existing graft-versus-host disease (GVHD) occurred, including 4 episodes after the third dose. We observed 4 relapses (3.27%). Seven patients developed SARS-CoV-2 infection despite vaccination, although none required hospitalization. In conclusion, the 3-dose SARS-CoV-2 vaccine schedule provided immunity associated with a low risk of GVHD and other adverse effects. This prospective cohort showed that the third dose of SARS-CoV-2 vaccine in allogeneic stem cell transplant recipients promoted better humoral and cellar immune responses than after the initial series without increasing the risk of GVHD or severe adverse effects.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multi-center 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in eight cases (13%). 12-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotics usage (adjusted odds ratio [aOR], 4.74; p=0.03) and history of pneumonia (aOR, 48.7; p=0.01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; p=0.01), systemic antibiotics usage (aOR, 5.03; p=0.04), and anti-mold prophylaxis (aOR, 11.9; p=0.02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ration [aHR], 86.9; p<0.001), ICU stay (aHR, 3.67; p=0.02), disseminated IA (aHR, 8.98; p<0.001), and dialysis (aHR, 2.93; p=0.001) were identified as independent risk factors associated with 12-week all-cause mortality; while recent receipt of tacrolimus (aHR, 0.11; p=0.001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted anti-mold prophylactic and appropriate treatment strategies against IA.

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are susceptible to severe COVID-19 outcomes. Most guidelines recommend a fourth dose (i.e., booster) COVID-19 vaccine to reduce the infection risk, and observational studies are required to determine the immunogenicity and safety of the booster dose in this population. The primary outcome was to determine the quantitative anti-receptor binding domain (RBD) antibody titers after the fourth dose of the COVID-19 vaccine. The secondary outcomes included adverse effects and all-cause mortality. In this single-group prospective cohort, we included allogeneic HSCT patients aged ≥18 who received the fourth dose of COVID-19 mRNA vaccine between December 15, 2021, and August 2, 2022. We excluded patients with a history of COVID-19 diagnosis and those who received IVIG within 21 days of antibody testing or rituximab within six months before cohort entry. We used regression models to determine the contributing factors significantly associated with post-4^th-dose anti-RBD titer. Sixty-seven patients [median (IQR) age: 59.5 (53.5-65.5) years, 33 male (61%)] received the fourth dose of vaccine, and 54 were included in the anti-RBD titer analysis. The median anti-RBD titer, 4-6 weeks after the third and fourth doses, were significantly different [13,350 (2,618 - 34,740) U/ml and 44,500 (11,163 - 84,330) U/ml, respectively, p < 0.0001]. In univariate analysis, the post-third-dose anti-RBD titer (β: 0.70; CI95%: 0.54 to 0.87, p<0.001), and treatment with mycophenolate compounds (β: -1.05; CI95%: -1.97 to -1.12, p=0.03) significantly predicted the antibody response to the 4^th dose. In multivariate analysis, the inverse association between treatment with mycophenolate compounds and the post-fourth-dose anti-RBD antibody titer was not significant (β: -0.57; CI95%: -1.32 to 0.19, p=0.14), while the significant association between the anti-RBD titres following the third and fourth doses did not considerably change (β: 0.66; CI95%: 0.47 to 0.86, p<0.001). The most frequent adverse event was vaccination site soreness (44%), followed by fatigue (16%), myalgia (4%) and headache (2%). No recipient experienced new or worsening pre-existing graft-versus-host disease (GvHD) within 40 days of vaccination, and no patient died. Six patients (11%) developed breakthrough SARS-CoV-2 infections not associated with hospitalization or severe outcomes. The fourth dose of the COVID-19 vaccine appears to be highly immunogenic and safe in allogeneic HSCT patients. Further studies are needed to determine the neutralizing antibody titers against SARS-CoV-2 subvariants and the effectiveness and immunogenicity of bivalent vaccines in allogeneic stem cell transplant recipients.

Background: Screening for latent tuberculosis infection (LTBI) in patients with hematological malignancy is recommended because of their increased risk of tuberculosis (TB). We assessed the utility of tuberculin skin test (TST) screening in patients with acute leukemia and subsequent outcomes of LTBI treatment. Methods: We retrospectively evaluated patients ≥16 years of age with acute leukemia from 2013–2014 with a TST planted and read prior to the initiation of antineoplastic chemotherapy treatment. Demographics, clinical information and treatment outcomes of LTBI therapy were compared between patients with positive TST (≥10 mm induration) and negative TST. Results: A total of 389 patients with acute leukemia were included in the cohort. Of them, 37/389 (9.5%) had a positive TST. Only 3.4% (8/235) of individuals originating from North and South America as well as the Caribbean were TST positive, while 21% (20/95) of individuals from Asia were TST positive. Diagnostic imaging findings consistent with prior tuberculosis infection were higher in TST positive patients compared to TST negative ones (29.7% versus 9.4%, p < 0.0001). Furthermore, 31/38 patients (81.6%) who were TST positive received LTBI therapy, which was well tolerated. There was no significant difference in overall survival among those who received LTBI therapy compared to those who did not. No patients developed active TB. Conclusions: Universal screening with TST may be of low yield in individuals with acute leukemia unless patients originate from a TB endemic country. When therapy for LTBI is prescribed, patients with acute leukemia do not experience drug-induced liver toxicity and are likely to complete the intended duration of therapy, thus preventing the development of active tuberculosis.