Risk factors and outcome of concurrent and sequential multiviral cytomegalovirus, Epstein-Barr virus, BK virus, adenovirus and other viral reactivations in transplantation.

PURPOSE OF REVIEW: Reactivation of viral infections occurs frequently in immunosuppressed populations, particularly in solid organ (SOT) or allogeneic haematopoietic cell (HCT) transplant patients. Concurrent and sequential multivirus infections are common, yet risk factors and outcomes remain unclear. This review aims to identify the patients vulnerable to multivirus infections and characterize the impact of increased viral burden to formulate prevention and treatment strategies. RECENT FINDINGS: Incidences of up to 89% in SOT and 36% in HCT have been reported for two viruses, and 32% in SOT and 28% in HCT for at least three viruses. Risk factors appear related to an increased burden of immunosuppression, with most viral coinfections occurring within 12 months of transplantation. Direct viral complications such as cytomegalovirus disease are more frequent in coinfected patients, with documented prolonged duration of viraemia, higher viral load and increased end-organ disease. Graft dysfunction, acute rejection and graft-vs.-host disease (GVHD) have also been associated. Increased mortality is reported in the HCT population. SUMMARY: Multivirus infections occur in a significant proportion of transplant patients and is linked to immunosuppressive burden. There is increasing evidence that this leads to worse graft and patient outcomes. Further prospective studies are required to further comprehensively characterise viral epidemiology, mechanisms and treatment strategies to ameliorate this risk.

Suboptimal COVID-19 vaccine uptake among hospitalised patients: an opportunity to improve vulnerable, hard-to-reach population vaccine rates.

BACKGROUND: COVID-19 vaccination represents a key preventative part of the Australian public health approach to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Hospital inpatients are frequently high risk for severe COVID-19 and death. Anecdotes of high-risk inpatients being unvaccinated and a lack of electronic medical record (EMR) visibility of COVID-19 vaccination status prompted the present study as these patients could represent a risk to themselves, staff, other patients and service provision. AIMS: To determine the uptake of COVID-19 vaccine among inpatients at an adult Australian tertiary public hospital and identify reasons for non-vaccination. METHODS: A point-prevalence study of patient-reported COVID-19 vaccine status was conducted on 26 October 2021 through an in-person interview with collection of demographic factors and reasons for non-vaccination. RESULTS: Of 368 (68% of inpatients) participants, 280 (76%) reported receiving at least one COVID-19 vaccine dose. Vaccination status was associated with older age, having received the flu vaccine, being born in Australia and not requiring an English-language interpreter. The majority (88%) of participants had at least one comorbid risk factor for severe COVID-19. Of the unvaccinated (n = 88), 67% were willing to be vaccinated with 54% of those indicating vaccination in hospital would be helpful and 42% requesting approval from their doctor. CONCLUSIONS: Vaccine uptake in our cohort is suboptimal. Existing public health programmes have failed to reach this high-risk, vulnerable population. Changes to the national vaccination strategy to include a parallel inhospital programme for all hospital encounters and target culturally and linguistically diverse individuals might improve uptake among this high-risk, hard-to-reach group of patients.

Feasibility of perflutren microsphere contrast transthoracic echocardiography in the visualization of ventricular endocardium during venovenous extracorporeal membrane oxygenation in a validated ovine model.

BACKGROUND: Transthoracic echocardiography (TTE) during extra corporeal membrane oxygenation (ECMO) is important but can be technically challenging. Contrast-specific TTE can improve imaging in suboptimal studies. These contrast microspheres are hydrodynamically labile structures. This study assessed the feasibility of contrast echocardiography (CE) during venovenous (VV) ECMO in a validated ovine model. METHOD: Twenty-four sheep were commenced on VV ECMO. Parasternal long-axis (Plax) and short-axis (Psax) views were obtained pre- and postcontrast while on VV ECMO. Endocardial definition scores (EDS) per segment were graded: 1 = good, 2 = suboptimal 3 = not seen. Endocardial border definition score index (EBDSI) was calculated for each view. Endocardial length (EL) in the Plax view for the left ventricle (LV) and right ventricle (RV) was measured. RESULTS: Summation EDS data for the LV and RV for unenhanced TTE (UE) versus CE TTE imaging: EDS 1 = 289 versus 346, EDS 2 = 38 versus 10, EDS 3 = 33 versus 4, respectively. Wilcoxon matched-pairs rank-sign tests showed a significant ranking difference (improvement) pre- and postcontrast for the LV (P < 0.0001), RV (P < 0.0001) and combined ventricular data (P < 0.0001). EBDSI for CE TTE was significantly lower than UE TTE for the LV (1.05 ± 0.17 vs. 1.22 ± 0.38, P = 0.0004) and RV (1.06 ± 0.22 vs. 1.42 ± 0.47, P = 0.0.0006) respectively. Visualized EL was significantly longer in CE versus UE for both the LV (58.6 ± 11.0 mm vs. 47.4 ± 11.7 mm, P < 0.0001) and the RV (52.3 ± 8.6 mm vs. 36.0 ± 13.1 mm, P < 0.0001), respectively. CONCLUSIONS: Despite exposure to destructive hydrodynamic forces, CE is a feasible technique in an ovine ECMO model. CE results in significantly improved EDS and increased EL.

Effects of transfusing older red blood cells and platelets on obstetric patient outcomes: A retrospective cohort study.

OBJECTIVE: To investigate associations between transfusion of blood products close to the end of shelf-life and clinical outcomes in obstetric inpatients. METHODS: Mortality and morbidity were compared in patients transfused exclusively with red blood cells (RBC) stored for less than 21 days (fresh) versus RBC stored for 35 days or longer (old), and platelets (PLT) stored for 3 days or fewer (fresh) versus 4 days or longer (old) in Queensland, Australia from 2007 to 2013. Multivariable models were used to examine associations between these groups of blood products and clinical end points. RESULTS: There were 3371 patients who received RBC and 280 patients who received PLT of the eligible storage durations. Patients transfused with old RBC received fewer transfusions (2.7 ± 1.8 vs. 2.3 ± 1.0 units; P < 0.001). However, a higher rate of single-unit transfusions was also seen in those patients who exclusively received old RBC (252 [9.3%] vs. 92 [13.7%]; P = 0.003). Comparison of fresh vs. old blood products revealed no differences in the quantities of transfused RBC (9.5 ± 5.9 vs. 9.1 ± 5.2 units; P = 0.680) or PLT (1.5 ± 0.8 vs. 1.4 ± 1.1 units; P = 0.301) as well as the length of hospital stay for RBC (3 [2-5] vs. 3 [2-5] days; P = 0.124) or PLT (5 [4-8] vs. 6 [4-9] days; P = 0.120). CONCLUSION: Transfusing exclusively older RBC or PLT was not associated with increased morbidity or mortality.

Dietary Inulin to Improve SARS-CoV-2 Vaccine Response in Kidney Transplant Recipients: The RIVASTIM-Inulin Randomised Controlled Trial.

Kidney transplant recipients are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard two-dose vaccination schedules are typically inadequate to generate protective immunity. Gut dysbiosis, which is common among kidney transplant recipients and known to effect systemic immunity, may be a contributing factor to a lack of vaccine immunogenicity in this at-risk cohort. The gut microbiota modulates vaccine responses, with the production of immunomodulatory short-chain fatty acids by bacteria such as Bifidobacterium associated with heightened vaccine responses in both observational and experimental studies. As SCFA-producing populations in the gut microbiota are enhanced by diets rich in non-digestible fibre, dietary supplementation with prebiotic fibre emerges as a potential adjuvant strategy to correct dysbiosis and improve vaccine-induced immunity. In a randomised, double-bind, placebo-controlled trial of 72 kidney transplant recipients, we found dietary supplementation with prebiotic inulin for 4 weeks before and after a third SARS-CoV2 mRNA vaccine to be feasible, tolerable, and safe. Inulin supplementation resulted in an increase in gut Bifidobacterium, as determined by 16S RNA sequencing, but did not increase in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third vaccination. Dietary fibre supplementation is a feasible strategy with the potential to enhance vaccine-induced immunity and warrants further investigation.

Immunoglobulin replacement in hematological malignancies: a focus on evidence, alternatives, dosing strategy, and cessation rule.

Acquired hypogammaglobulinemia or secondary immunodeficiency (SID) occurs commonly in hematological malignancies with increasing incidence and complexity in the era of modern therapies. Despite current practice of immunoglobulin replacement (IgRT) in SID, the evidence is lacking, especially for newer treatments. We discuss the current evidence for IgRT in various disease groups including issues, such as actual or ideal body weight (IBW)-based dosing, length of treatment, antibiotic prophylaxis, and vaccination. Incidence of SID with newer treatment is lacking. While there is a trend toward decreased respiratory infections and hospitalizations with IgRT, this is not consistent across all disease course or treatment groups. Dosing and indications for cessation of IgRT are also inadequately characterized. Further randomized controlled trials (RCTs) and observational studies are required to assess the optimal indications, timing, and duration of IgRT to improve the efficacy, safety, and cost-effectiveness. Assessment of alternative and adjunctive therapies, such as vaccination and antibiotic prophylaxis could also improve the outcomes and costs.

Examining the Characteristics of Colchicine-Induced Myelosuppression in Clinical Cases: A Systematic Review.

OBJECTIVE: The use of colchicine has been associated with varying degrees of myelosuppression. Despite expanded use in cardiovascular and inflammatory conditions, there remains clinician concern because of potential myelosuppressive side effects. A systematic review was conducted to explore the reported myelosuppressive events of colchicine. METHODS: A systematic review was conducted using the MeSH terms ("colchicine") AND ("myelosuppression," "bone*," "marrow," "suppression," "aplasia," "leukopenia/leucopenia," "lymphopenia," "neutropenia") on September 1, 2020, and was updated on November 30, 2021. The search was conducted in PubMed, ScienceDirect, Scopus, Embase, and Cochrane Library. The search included references published from 1978 to 2020 and was limited to English-language observational studies (ie, case reports, case series, case control studies, and cohort studies) or trial data. RESULTS: In total, 3233 articles were screened, with 30 studies of 47 patients with myelosuppression from colchicine identified. Most patients with myelosuppression had comorbidities, including renal impairment (21/47, 44.7%). Out of 47 patients, 15 (31.9%) and 13 (27.7%) were reported to be concurrently taking cytochrome P450 3A4 (CYP3A4) inhibitors and P-glycoprotein (P-gp) efflux transporter inhibitors, respectively. Patients with renal impairment accounted for the majority of overall patients taking these CYP3A4 and P-gp inhibitors (8/15, 53.3%, and 8/13, 61.5%, respectively). Out of 21 patients with renal impairment, 13 had worsening cytopenia during colchicine use. The presentations ranged from moderate anemia (grade 2) to severe thrombocytopenia, neutropenia, and leukopenia (grade 4). CONCLUSION: Colchicine has few reports of myelosuppression. The majority of patients with myelosuppression had preexisting renal impairment or concomitant CYP3A4 or P-gp inhibitor use. Caution should be taken in this subset of patients with increased monitoring.

Predicting infections in patients with haematological malignancies treated with chimeric antigen receptor T-cell therapies: A systematic scoping review and narrative synthesis.

BACKGROUND: Chimeric antigen receptor T cells (CAR-T cells) are increasingly used to treat haematological malignancies. Strategies for preventing infections in CAR-T-treated patients rely on expert opinions and consensus guidelines. OBJECTIVES: This scoping review aimed to identify risk factors for infections in CAR-T-treated patients with haematological malignancies. DATA SOURCES: A literature search utilized MEDLINE, EMBASE and Cochrane to identify relevant studies from conception until 30 September 2022. STUDY ELIGIBILITY CRITERIA: Trials and observational studies were eligible. PARTICIPANTS: Studies required ≥10 patients treated for haematological malignancy to report infection events (as defined by the study), and either (a) a descriptive, univariate or multivariate analysis of the relationship between infections event and a risk factors for infections, or (b) diagnostic performance of a biochemical/immunological marker in CAR-T-treated patients with infection. METHODS: A scoping review was conducted in accordance with PRISMA guidelines. DATA SOURCES: A literature search utilised MEDLINE, EMBASE and Cochrane to identify relevant studies from conception until September 30, 2022. Eligibility/Participants/Intervention: Trials and observational studies were eligible. Studies required ≥ 10 patients treated for haematological malignancy, to report infection events (as defined by the study), and either A) a descriptive, univariate or multivariate analysis of the relationship between infections event and a risk-factors for infections, or B) diagnostic performance of a biochemical/immunological marker in CAR-T treated patients with infection. ASSESSMENT OF RISK OF BIAS: Bias assessment was undertaken according to Joanna Brigg's Institute criteria for observational studies. METHODS OF DATA SYNTHESIS: Data were synthesized descriptively because of the heterogeneity of reporting. RESULTS: A total of 1522 patients across 15 studies were identified. All-cause infections across haematological malignancies were associated with lines of prior therapy, steroid administration, immune-effector cell-associated neurotoxicity and treatment-emergent neutropenia. Procalcitonin, C-reactive protein and cytokine profiles did not reliably predict infections. Predictors of viral, bacterial and fungal infections were poorly canvassed. DISCUSSION: Meta-analysis of the current literature is not possible because of significant heterogeneity in definitions of infections and risk factors, and small, underpowered cohort studies. Radical revision of how we approach reporting infections for novel therapies is required to promptly identify infection signals and associated risks in patients receiving novel therapies. Prior therapies, neutropenia, steroid administration and immune-effector cell-associated neurotoxicity remain the most associated with infections in CAR-T-treated patients.

Infections in haematology patients treated with CAR-T therapies: A systematic review and meta-analysis.

A registered (PROSPERO - CRD42022346462) systematic review and meta-analysis was conducted of all-grade infections amongst adult patients receiving CAR-T therapy for haematological malignancy. Meta-analysis of pooled incidence, using random effects model, was conducted. Cochran's Q test examined heterogeneity. 2678 patients across 33 studies were included in the primary outcome. Forty-percent of patients (95% CI: 0.33 - 0.48) experienced an infection of any grade. Twenty-five percent of infection events (95% CI: 0.16 - 0.34) were severe. Late infections were as common as early infections (IRR = 0.86, 95% CI: 0.38 - 1.98). All-grade infections, bacterial and viral infections were highest in myeloma patients at 57%, 37% and 28% respectively. Patients with NHL more commonly experienced late infections. Pooled rate of invasive candidiasis/yeast infections was 2% in studies utilizing anti-yeast prophylaxis. This review identified a high rate of all-grade infections, moderate rate of severe infections, and myeloma as a high-risk haematological group.

COVID-19 infection among patients with cancer in Australia from 2020 to 2022: a national multicentre cohort study.

Background: The global COVID-19 pandemic disproportionately affected certain populations and its management differed between countries. This national study describes characteristics and outcomes of COVID-19 in patients with cancer in Australia. Methods: We performed a multicentre cohort study of patients with cancer and COVID-19 from March 2020 to April 2022. Data were analysed to determine varying characteristics between cancer types and changes in outcomes over time. Multivariable analysis was performed to determine risk factors associated with oxygen requirement. Findings: 620 patients with cancer from 15 hospitals had confirmed COVID-19. There were 314/620 (50.6%) male patients, median age 63.5 years (IQR 50-72) and majority had solid organ tumours (392/620, 63.2%). The rate of COVID-19 vaccination (≥1 dose) was 73.4% (455/620). Time from symptom onset to diagnosis was median 1 day (IQR 0-3), patients with haematological malignancy had a longer duration of test positivity. Over the study period, there was a significant decline in COVID-19 severity. Risk factors associated with oxygen requirement included male sex (OR 2.34, 95% CI 1.30-4.20, p = 0.004), age (OR 1.03, 95% CI 1.01-1.06, p = 0.005); not receiving early outpatient therapy (OR 2.78, 95% CI 1.41-5.50, p = 0.003). Diagnosis during the omicron wave was associated with lower odds of oxygen requirement (OR 0.24, 95% CI 0.13-0.43, p < 0.0001). Interpretation: Outcomes from COVID-19 in patients with cancer in Australia over the pandemic have improved, potentially related to changing viral strain and outpatient therapies. Funding: This study was supported by research funding from MSD.

The aetiology and clinical characteristics of cryptococcal infections in Far North Queensland, tropical Australia.

Cryptococcal infections are an important cause of morbidity and mortality in tropical Australia. This retrospective audit was conducted to characterise the aetiology, temporospatial epidemiology, and clinical course of 49 cryptococcal infections in Far North Queensland between 1 January 1999 and 31 December 2019. Cryptococcus gattii was identified in 15/32 (47%) in whom it was possible to speciate the organism. Among these 15 patients, 13 (87%) had a rural residential address, 10 (67%) were Indigenous Australians and 11 (73%) presented during the May-November dry season. When compared to the 17 patients with Cryptococcus neoformans infection, patients with C. gattii were less likely to be immunocompromised (0/15 versus 8/17 (47%), p = 0.003). Neurosurgery was necessary in 5/15 C. gattii cases and 3/17 (18%) C. neoformans cases (p = 0.42). Outcomes were generally good with 42/49 (86%) cases-and 14/15 (93%) with C. gattii infection-surviving to hospital discharge. These positive outcomes are likely to be explained by the development of standardised treatment guidelines during the study period, low rates of comorbidity in the patients with C. gattii infection and access to liposomal amphotericin and neurosurgical support in the well-resourced Australian healthcare system.

The seasonality of infections in tropical Far North Queensland, Australia: A 21-year retrospective evaluation of the seasonal patterns of six endemic pathogens.

An understanding of the seasonality of infections informs public health strategies and assists clinicians in their management of patients with undifferentiated illness. The seasonality of infections is driven by a variety of environmental and human factors; however, the role of individual climatic factors has garnered much attention. This study utilises Poisson regression models to assess the seasonality of six important infections in tropical Australia and their association with climatic factors and severe weather events over a 21-year period. Melioidosis and leptospirosis showed marked wet season predominance, while more cases of rickettsial disease and cryptococcosis were seen in cooler, drier months. Staphylococcus aureus infections were not seasonal, while influenza demonstrated inter-seasonality. The climate did not significantly change during the 21 years of the study period, but the incidence of melioidosis and rickettsial disease increased considerably, highlighting the primacy of other factors-including societal inequality, and the impact of urban expansion-in the incidence of these infections. While anthropogenic climate change poses a threat to the region-and may influence the burden of these infections in the future-this study highlights the fact that, even for seasonal diseases, other factors presently have a greater effect on disease incidence. Public health strategies must also target these broader drivers of infection if they are to be effective.

Rapamycin and inulin for booster vaccine response stimulation (RIVASTIM)-rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients.

Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed. METHODS: RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4-6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch. DISCUSSION: Immunosuppression modification strategies may improve immunological vaccine response. We hypothesise that substituting the mTOR inhibitor sirolimus for mycophenolate in a triple drug regimen will enhance humoral and cell-mediated responses to COVID vaccination for kidney transplant recipients. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12621001412820. Registered on 20 October 2021; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382891&isReview=true.

Primary aortoduodenal fistula and chronic Q fever infection.

We report a case of chronic Q fever presenting with catastrophic bleeding from an infected abdominal aortic aneurysm causing a primary aortoduodenal fistula in an 80-year-old retired farmer. This presentation is rarely reported in literature and only through case reports. Early diagnosis and definitive surgery were critical to a successful outcome. Serological diagnosis of Q fever was initiated on the patient's past exposure to animal reservoirs. Complicating the case was ongoing gastrointestinal bleeding postsurgery, with multiple endoscopies undertaken before a culprit remnant fistula was found. This case highlights the value in considering Coxiella burnetii as an underlying cause in patients with known risk factors presenting with primary aortoduodenal fistulas. Though rare, it represents a readily treatable cause.

Efforts to Attenuate the Spread of Infection (EASI): a prospective, observational multicentre survey of ultrasound equipment in Australian emergency departments and intensive care units.

BACKGROUND AND OBJECTIVES: Ultrasound is a common and necessary part of acute care medicine, but may present an infection risk to patients secondary to transfer of infectious agents between patients. Our primary objective was to detect blood contamination on ultrasound equipment in emergency departments (EDs) and intensive care units. Secondary objectives included detection of microbial contamination and determination of factors associated with contamination. DESIGN AND SETTING: We tested ultrasound equipment used in five EDs and five ICUs for blood and microbial contamination, and collated and analysed contamination data using tables and multiple logistic regression. MAIN OUTCOME MEASURES AND RESULTS: We performed 109 tests for blood and 131 tests for microbial contamination, with 61% of samples testing positive for blood contamination (95% CI, 52%-71%) and 48% testing positive for microbiological contamination (95% CI, 40%-57%). Transducer leads and transducers had high blood contamination (88% and 57%, respectively) and microbiological contamination (62% and 46%, respectively). Equipment from ICUs was less likely to test positive (odds ratio, 0.55; 95% CI, 0.37-0.79). Only 51% of blood-contaminated samples were visibly stained, and visible staining was not associated with microbiological contamination (57%; P=1). CONCLUSION: Our results show significant contamination of ultrasound equipment, and that visual inspection of equipment is neither sufficient nor reliable in excluding contamination. Ultrasound equipment is a possible factor in the transmission of infectious diseases in EDs and ICUs. Guidelines must be formulated, disseminated and rapidly adopted to ensure the safety of the most acutely ill patients exposed to ultrasound procedures in acute care settings.