Stewardship: it's going viral.

Introduction: Historically, antimicrobial stewardship (AMS) has considered the judicious use of antibiotics. AMS is widely adopted across Europe and the US; recently antifungal AMS is gaining momentum but antiviral AMS has been little described. Here we describe the introduction of AMS virology reviews at University Hospitals Birmingham (UHBFT); a novel concept and an opportunity to broaden the beneficial aspects of AMS to virology, termed anti-viral stewardship (AVS). Method: In June 2022, a UK supply issue with aciclovir injection (ACV IV) was announced. In order to review and preserve parenteral ACV for those in greatest need, UHBFT pharmacist and virologists implemented a specialist review for patients prescribed more than 48 hours of treatment. This review initially lasted 10 weeks and data was collected on the advice offered, whether it was accepted, and time required completing the review. Results: AVS rounds halved IV ACV consumption, compared to pre or post intervention levels, with more than half of patients advised to stop or switch to oral therapy. Diagnostics and sampling guidance was offered in one quarter of reviews, whilst the remaining interventions were more stewardship focused. In almost all cases stewardship advice was readily accepted by clinical teams. Due to positive feedback from clinicians and its effective management of supply, the anti-viral stewardship (AVS) programme was re-introduced in June 2023. Conclusions: Antiviral AMS rounds provide an opportunity to optimise sampling, diagnosis and improve patient management. Introduction of regular AVS at UHBFT are now well established and plan to be implemented in other hospitals.

Recent treatment advances and practical management of hepatitis D virus.

Hepatitis D virus (HDV), also referred to as hepatitis delta virus, is the smallest virus capable of causing human disease. It is unable to replicate on its own and can only propagate in the presence of hepatitis B virus (HBV). Infection with both HBV and HDV frequently results in more severe disease than HBV alone, with higher instances of cirrhosis, liver failure and hepatocellular carcinoma (HCC). Thus, there is a need for effective treatment for HDV; however, currently approved treatment options are very limited both in terms of their efficacy and availability. This makes the management of HDV a challenge for physicians. In this review, we look at the background, diagnosis and treatment of HDV, informed by our hospital data, to set out the optimal management of HDV; we also explore novel treatment options for this disease.

Monkeypox: An old foe, with new challenges.

At first glance, a multi-country outbreak of monkeypox in 2022 seems unusual. However, the re-emergence and expansion of this viral disease beyond its endemicity in West and Central Africa had previously been predicted as a possible consequence of a decline in population immunity following smallpox eradication. Since the 13th of May 2022, cases of monkeypox have been reported in at least 28 WHO member states from within 4 regions (the Americans, European, Eastern Mediterranean and Western Pacific regions). This summary describes the multi-country outbreak to date, with an emphasis on patient demographics, common symptoms and signs, clinical management (including infection prevention measures) and clinical outcomes of the cases in the United Kingdom, which has so far reported the largest number of laboratory confirmed cases. The future implications of this outbreak, including preventative measures to curb the current outbreak, prevent future outbreaks and the likelihood of the disease becoming endemic in the UK are also discussed.

Are the Patterns of Cytomegalovirus Viral Load Seen After Solid Organ Transplantation Affected by Circadian Rhythm?

BACKGROUND: Cytomegalovirus (CMV) is an important opportunistic pathogen after transplantation. Some virological variation in transplant recipients is explained by donor and recipient CMV serostatus, but not all. Circadian variability of herpesviruses has been described, so we investigated the effect of time of day of transplantation on posttransplant CMV viremia. METHODS: We performed a retrospective analysis of 1517 patients receiving liver or kidney allografts at a single center from 2002 to 2018. All patients were given preemptive therapy with CMV viremia monitoring after transplantation. Circulatory arrest and reperfusion time of donor organ were categorized into 4 periods. Patients were divided into serostatus groups based on previous CMV infection in donor and recipient. CMV viremia parameters were compared between time categories for each group. Factor analysis of mixed data was used to interrogate this complex data set. RESULTS: Live-donor transplant recipients were less likely to develop viremia than recipients of deceased-donor organs (48% vs 61%; P < .001). After controlling for this, there was no evidence of time of day of transplantation affecting CMV parameters in any serostatus group, by logistic regression or factor analysis of mixed data. DISCUSSION: We found no evidence for a circadian effect of transplantation on CMV viremia, but these novel results warrant confirmation by other centers.

How and when to use CSF to investigate neonates and children with possible central nervous system infection.

A child presented to the emergency department with fever, reduced consciousness, irritability and reduced oral intake. Infective meningitis and encephalitis were within the differential diagnoses. Is a lumbar puncture (LP) indicated and, if so, what is the optimal timing of LP? Will antimicrobial pretreatment affect the cerebrospinal fluid (CSF) results? How can clinicians optimise diagnostic stewardship to benefit individual patients and society at large? Interpretation of rapidly available CSF biochemical tests (protein, glucose and lactate levels) and microscopy can provide a prompt insight into the infective aetiology and inform treatment and further diagnostic testing strategies. Diagnosis of an aetiological pathogen in a patient presenting with central nervous system (CNS) infection has clinical, infection control and public health implications. A plethora of tests are available to enable CSF analysis in patients with possible CNS infection. We aimed to summarise current evidence and guidance to ensure the best possible use of the diagnostics available.

An experience using historical hepatitis C data to Re-Engage: Possibilities and pitfalls during the COVID-19 pandemic.

OBJECTIVES: Public Health England (PHE) aims meet the WHO target to eliminate hepatitis C as a public health concern by 2030. One aspect of this strategy is to use historical surveillance data of anti-HCV positive patients identified by PHE to re-engage with offers of PCR testing and treatment if RNA-positive. Operational Delivery Networks (ODN), who deliver Hepatitis C treatment across 22 regions in England, are responsible for enacting this initiative. This study aims to evaluate the effectiveness of using this data with regional PCR results to re-engage HCV-infected persons in the West Midlands region of England. STUDY DESIGN: A longitudinal prospective study using historical surveillance data. METHODS: A dataset of historical anti-HCV positive antibody patients provided to the ODN by PHE was cross-referenced with HCV RNA data from 01/01/1996 to 01/01/2019 from five laboratories across the West Midlands. Letters were sent to the general practitioner and to the patients who were HCV RNA positive to invite them for repeat testing and treatment to achieve cure. RESULTS: From a dataset of 4540 anti-HCV antibody results, 31.7% (n=1440) had a PCR result: 48.1% (n=693) were PCR positive for HCV RNA. 693 letters were sent to GPs with responses from 14.2% (n=99). By May 2021, only 212 patient letters were sent (due to significant interruption by the COVID-19 pandemic) and 11.3% (n=24) replied, 17 presented for PCR testing and 4 were found to be viraemic. To date, one patient has achieved cure and three have completed treatment awaiting confirmation of cure. CONCLUSION: The use of historical anti-HCV antibody results can be used to successfully re-engage people into testing and treatment for hepatitis C, albeit with modest gains.

S-Variant SARS-CoV-2 Lineage B1.1.7 Is Associated With Significantly Higher Viral Load in Samples Tested by TaqPath Polymerase Chain Reaction.

A SARS-CoV-2 variant B1.1.7 containing mutation Δ69/70 has spread rapidly in the United Kingdom and shows an identifiable profile in ThermoFisher TaqPath RT-qPCR, S gene target failure (SGTF). We analyzed recent test data for trends and significance. Linked cycle threshold (Ct) values for respiratory samples showed that a low Ct for ORF1ab and N were clearly associated with SGTF. Significantly more SGTF samples had higher inferred viral loads between 1×107 and 1×108. Our conclusion is that patients whose samples exhibit the SGTF profile are more likely to have high viral loads, which may explain higher infectivity and rapidity of spread.

Are all blood-based postal sampling kits the same? A comparative service evaluation of the performance of dried blood spot and mini tube sample collection systems for postal HIV and syphilis testing.

OBJECTIVES: We comparatively evaluated two HIV and syphilis blood sampling kits (dried blood spot (DBS) and mini tube (MT)) as part of an online STI postal sampling service that included tests for chlamydia and gonorrhoea. We aimed to see how the blood collection systems compared regarding sample return rates and result rates. Additionally, we aimed to observe differences in false-positive results and describe a request-to-result ratio (RRR)-the required number of kit requests needed to obtain one successful result. METHODS: We reviewed data from an online postal STI kit requesting service for a client transitioning from MT to DBS blood collection systems. We described service user baseline characteristics and compared kit requests, kit and blood sample return rates, and the successful resulting rates for HIV and syphilis for MT and DBS. Pearson's χ2 and Fisher's exact test were used to determine statistical differences, and statistical formulae were applied to produce CIs for differences in proportions. RESULTS: 5670 STI postal kit requests from a Midlands region were reviewed from 6 September 2016-2 January 2019 (1515 MT and 4155 DBS). Baseline characteristics between the two groups were comparable (68.0% female, 74.0% white British and 87.5% heterosexual, median age 26 years). Successful processing rates for DBS were 94.6% and 54.4% for MT (p<0.001) with a percentage difference of 40.2% (95% CI 36.9% to 43.4%). The RRR for MT was 2.9 cf. 1.6 for DBS. False-positive results for MT samples were 5.2% (HIV) and 0.4% (syphilis), and those for DBS were 0.4% (HIV) and 0.0% (syphilis). CONCLUSIONS: This comparative analysis demonstrated the superior successful processing rates for postal DBS collection systems compared with MT. Reasons for this included insufficient volumes, high false-positive rates and degradation of blood quality in MT samples. A postal sampling service using DBS to screen for HIV, syphilis and other blood-borne viruses could be a viable alternative.

Cytomegalovirus viral load parameters associated with earlier initiation of pre-emptive therapy after solid organ transplantation.

BACKGROUND: Human cytomegalovirus (HCMV) can be managed by monitoring HCMV DNA in the blood and giving valganciclovir when viral load exceeds a defined value. We hypothesised that such pre-emptive therapy should occur earlier than the standard 3000 genomes/ml (2520 IU/ml) when a seropositive donor transmitted virus to a seronegative recipient (D+R-) following solid organ transplantation (SOT). METHODS: Our local protocol was changed so that D+R- SOT patients commenced valganciclovir once the viral load exceeded 200 genomes/ml; 168 IU/ml (new protocol). The decision point remained at 3000 genomes/ml (old protocol) for the other two patient subgroups (D+R+, D-R+). Virological outcomes were assessed three years later, when 74 D+R- patients treated under the old protocol could be compared with 67 treated afterwards. The primary outcomes were changes in peak viral load, duration of viraemia and duration of treatment in the D+R- group. The secondary outcome was the proportion of D+R- patients who developed subsequent viraemia episodes. FINDINGS: In the D+R- patients, the median values of peak viral load (30,774 to 11,135 genomes/ml, p<0.0215) were significantly reduced on the new protocol compared to the old, but the duration of viraemia and duration of treatment were not. Early treatment increased subsequent episodes of viraemia from 33/58 (57%) to 36/49 (73%) of patients (p< 0.0743) with a significant increase (p = 0.0072) in those episodes that required treatment (16/58; 27% versus 26/49; 53%). Median peak viral load increased significantly (2,103 to 3,934 genomes/ml, p<0.0249) in the D+R+ but not in the D-R+ patient subgroups. There was no change in duration of viraemia or duration of treatment for any patient subgroup. INTERPRETATION: Pre-emptive therapy initiated at the first sign of viraemia post-transplant significantly reduced the peak viral load but increased later episodes of viraemia, consistent with the hypothesis of reduced antigenic stimulation of the immune system.

Dried blood spot and mini-tube blood sample collection kits for postal HIV testing services: a comparative review of successes in a real-world setting.

OBJECTIVES: This is a comparative review between using dried blood spot (DBS) and mini-tube (MT) HIV sampling kits as part of an online sexually transmitted infection (STI) postal testing service. England has recently seen increases in internet-based and postal (eHealth) STI services. Expanding accessibility and testing for patients, cost implications and narrowing the HIV undiagnosed margin are drivers for this. METHODS: In 2017, data were reviewed from an online postal STI kit requesting service at a time of transitioning from MT to DBS. We compared the STI postal kit and HIV blood sample return rates, and the successful processing/analysis rates of the DBS and MT kits. Descriptive statistics were applied to participant characteristics, with Pearson's χ2 or Fisher exact test used to demonstrate statistical differences. We also describe and calculate a 'request-to-result ratio' (RRR) for both kit types. The RRR is defined as the number of online kit requests required to produce one successfully analysed result. RESULTS: 550 STI postal kit requests from a North-West of England region were reviewed from 13 June 2017 to 22 September 2017 (275 MT, 275 DBS). Baseline characteristics between the two groups were comparable (63% woman, 90% white British and 86% heterosexual with a median age of 26 years). The successful processing rate for the DBS was 98.8% c.f. 55.7% for the MT (p<0.001). The RRR for MT was 2.96, c.f. 1.70 for DBS. There was a 5.4% false positive HIV rate in the MT c.f. none in the DBS. CONCLUSIONS: This comparative analysis suggests that in this community setting, the use of postal HIV DBS kits resulted in a significantly improved RRR compared with MT. The biggest factor was the large number of MT samples not analysed due to inadequate blood volumes. The unexpected level of false positive results in the MT samples needs confirming in larger studies.

Seroprevalence of maternal HIV, hepatitis B, and syphilis in a major maternity hospital in North Kordofan, Sudan.

Routine infectious diseases screening of Sudanese pregnant women has been patchy due to scarcity of healthcare resources and social stigma. We sought to determine the seroprevalence of HIV, hepatitis B, and syphilis among pregnant women attending antenatal care (ANC) at El Obeid Maternity Hospital in western Sudan. We also explored the association between these infections and a set of socio-demographic and maternal variables. Unlinked anonymous testing for HIV-1/2 antibodies, hepatitis B surface antigen, and Treponema pallidum antibodies was performed on residual blood samples collected during routine ANC (August 2016-March 2017). Seroprevalence of HIV was 1.13% (5/444; 95% CI 0.37-2.61%), hepatitis B 2.93% (13/444; 95% CI 1.57-4.95%), and syphilis 7.43% (33/444; 95% CI 5.17-10.28%). On bivariate analysis, there were no statistically significant associations between hepatitis B, syphilis, or a composite outcome including any of the three infections and age, stage of pregnancy, gravidity, parity, previous mode of delivery, history of blood transfusion, or husband polygamy. Urgent action is needed to scale up routine maternal screening for HIV, hepatitis B, and syphilis on an opt-out basis. Further research into the socio-demographic and behavioural determinants of these infections as well as their clinical outcomes is needed.

Correction: Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy.

[This corrects the article DOI: 10.1371/journal.pone.0163722.].

Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy.

BACKGROUND: To help decide when to start and when to stop pre-emptive therapy for cytomegalovirus infection, we conducted two open-label randomized controlled trials in renal, liver and bone marrow transplant recipients in a single centre where pre-emptive therapy is indicated if viraemia exceeds 3000 genomes/ml (2520 IU/ml) of whole blood. METHODS: Patients with two consecutive viraemia episodes each below 3000 genomes/ml were randomized to continue monitoring or to immediate treatment (Part A). A separate group of patients with viral load greater than 3000 genomes/ml was randomized to stop pre-emptive therapy when two consecutive levels less than 200 genomes/ml (168 IU/ml) or less than 3000 genomes/ml were obtained (Part B). For both parts, the primary endpoint was the occurrence of a separate episode of viraemia requiring treatment because it was greater than 3000 genomes/ml. RESULTS: In Part A, the primary endpoint was not significantly different between the two arms; 18/32 (56%) in the monitor arm had viraemia greater than 3000 genomes/ml compared to 10/27 (37%) in the immediate treatment arm (p = 0.193). However, the time to developing an episode of viraemia greater than 3000 genomes/ml was significantly delayed among those randomized to immediate treatment (p = 0.022). In Part B, the primary endpoint was not significantly different between the two arms; 19/55 (35%) in the less than 200 genomes/ml arm subsequently had viraemia greater than 3000 genomes/ml compared to 23/51 (45%) among those randomized to stop treatment in the less than 3000 genomes/ml arm (p = 0.322). However, the duration of antiviral treatment was significantly shorter (p = 0.0012) in those randomized to stop treatment when viraemia was less than 3000 genomes/ml. DISCUSSION: The results illustrate that patients have continuing risks for CMV infection with limited time available for intervention. We see no need to alter current rules for stopping or starting pre-emptive therapy.

Active screening and surveillance in the United Kingdom for Middle East respiratory syndrome coronavirus in returning travellers and pilgrims from the Middle East: a prospective descriptive study for the period 2013-2015.

BACKGROUND: Over 25000 pilgrims from the UK visit Saudi Arabia every year for the Umrah and Hajj pilgrimages. The recent outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) in South Korea and the continuing reports of MERS-CoV cases from Saudi Arabia highlight the need for active surveillance for MERS-CoV in returning pilgrims or travellers from the Middle East. Public Health England Birmingham Laboratory (PHEBL) is one of a few selected UK public health laboratories responsible for MERS-CoV screening in travellers returning to the UK from the Middle East who present to hospital with severe respiratory symptoms. The results of the PHEBL MERS-CoV screening and surveillance over the past 3 years is presented. METHODS: UK travellers/pilgrims who returned from the Middle East and presented to a hospital with respiratory symptoms were studied over the period February 1, 2013 to December 31, 2015. Patients with respiratory symptoms, who satisfied the Public Health England MERS-CoV case algorithm, were tested for MERS-CoV and other respiratory tract viruses on admission to hospital. RESULTS: Two hundred and two patients suspected of having MERS-CoV were tested. None of them had a laboratory-confirmed MERS-CoV infection. A viral aetiology was detected in half (50.3%) of the cases, with rhinoviruses, influenza A (H1N1 and H3N2), and influenza B being most frequent. Peak testing occurred following the annual Hajj season and in other periods of raised national awareness. CONCLUSIONS: Respiratory tract infections in travellers/pilgrims returning to the UK from the Middle East are mainly due to rhinoviruses, influenza A, and influenza B. Whilst MERS-CoV was not detected in the 202 patients studied, heightened awareness of the possibility of MERS-CoV and continuous proactive surveillance are essential to rapidly identify cases of MERS-CoV and other seasonal respiratory tract viruses such as avian influenza, in patients presenting to hospital. Early identification and isolation may prevent outbreaks in nosocomial settings.

Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial.

BACKGROUND: Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise. METHODS: We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260. FINDINGS: 67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12,537 (95% CI 6593-23,840) versus 86 (63-118) in recipients of placebo recipients; p<0.0001) and seropositive (118,395; 64,503-217,272) versus 24,682 (17,909-34,017); p<0.0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0.0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0.0480) and number of days of ganciclovir treatment (p=0.0287) were reduced in vaccine recipients. INTERPRETATION: Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients. FUNDING: National Institute of Allergy and Infectious Diseases, Grant R01AI051355 and Wellcome Trust, Grant 078332. SPONSOR: University College London (UCL).

Immunotherapy and vaccination after transplant: the present, the future.

Vaccination and adoptive immunotherapy for herpes virus infections has become an attractive option for the control of a virus family that negatively affects transplantation. In the future, enhanced ability to select antigen-specific T cells without significant in vitro manipulation should provide new opportunities for refining and enhancing adoptive immunotherapeutic approaches. This article focuses on advances in the area of vaccinology for some of these infections and in the use of adoptive immunotherapy. At present, many of these approaches in transplant recipients have focused on infections such as human cytomegalovirus, but the opportunity to use these examples as proof of concept for other infections is discussed.