Cross-sectional study evaluating the impact of SARS-CoV-2 variants on Long COVID outcomes in UK hospital survivors.

OBJECTIVES: COVID-19 studies report on hospital admission outcomes across SARS-CoV-2 waves of infection but knowledge of the impact of SARS-CoV-2 variants on the development of Long COVID in hospital survivors is limited. We sought to investigate Long COVID outcomes, aiming to compare outcomes in adult hospitalised survivors with known variants of concern during our first and second UK COVID-19 waves, prior to widespread vaccination. DESIGN: Prospective observational cross-sectional study. SETTING: Secondary care tertiary hospital in the UK. PARTICIPANTS: This study investigated Long COVID in 673 adults with laboratory-positive SARS-CoV-2 infection or clinically suspected COVID-19, 6 weeks after hospital discharge. We compared adults with wave 1 (wildtype variant, admitted from February to April 2020) and wave 2 patients (confirmed Alpha variant on viral sequencing (B.1.1.7), admitted from December 2020 to February 2021). OUTCOME MEASURES: Associations of Long COVID presence (one or more of 14 symptoms) and total number of Long COVID symptoms with SARS-CoV-2 variant were analysed using multiple logistic and Poisson regression, respectively. RESULTS: 322/400 (wave 1) and 248/273 (wave 2) patients completed follow-up. Predictors of increased total number of Long COVID symptoms included: pre-existing lung disease (adjusted count ratio (aCR)=1.26, 95% CI 1.07, 1.48) and more COVID-19 admission symptoms (aCR=1.07, 95% CI 1.02, 1.12). Weaker associations included increased length of inpatient stay (aCR=1.02, 95% CI 1.00, 1.03) and later review after discharge (aCR=1.00, 95% CI 1.00, 1.01). SARS-CoV-2 variant was not associated with Long COVID presence (OR=0.99, 95% CI 0.24, 4.20) or total number of symptoms (aCR=1.09, 95% CI 0.82, 1.44). CONCLUSIONS: Patients with chronic lung disease or greater COVID-19 admission symptoms have higher Long COVID risk. SARS-CoV-2 variant was not predictive of Long COVID though in wave 2 we identified fewer admission symptoms, improved clinical trajectory and outcomes. Addressing modifiable factors such as length of stay and timepoint of clinical review following discharge may enable clinicians to move from Long COVID risk stratification towards improving its outcome.

Evaluation of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Molecular Typing of Acinetobacter baumannii in Comparison with Orthogonal Methods.

Colonization and subsequent health care-associated infection (HCAI) with Acinetobacter baumannii are a concern for vulnerable patient groups within the hospital setting. Outbreaks involving multidrug-resistant strains are associated with increased patient morbidity and mortality and poorer overall outcomes. Reliable molecular typing methods can help to trace transmission routes and manage outbreaks. In addition to methods deployed by reference laboratories, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) may assist by making initial in-house judgments on strain relatedness. However, limited studies on method reproducibility exist for this application. We applied MALDI-TOF MS typing to A. baumannii isolates associated with a nosocomial outbreak and evaluated different methods for data analysis. In addition, we compared MALDI-TOF MS with whole-genome sequencing (WGS) and Fourier transform infrared spectroscopy (FTIR) as orthogonal methods to further explore their resolution for bacterial strain typing. A related subgroup of isolates consistently clustered separately from the main outbreak group by all investigated methods. This finding, combined with epidemiological data from the outbreak, indicates that these methods identified a separate transmission event unrelated to the main outbreak. However, the MALDI-TOF MS upstream approach introduced measurement variability impacting method reproducibility and limiting its reliability as a standalone typing method. Availability of in-house typing methods with well-characterized sources of measurement uncertainty could assist with rapid and dependable confirmation (or denial) of suspected transmission events. This work highlights some of the steps to be improved before such tools can be fully integrated into routine diagnostic service workflows for strain typing. IMPORTANCE Managing the transmission of antimicrobial resistance necessitates reliable methods for tracking outbreaks. We compared the performance of MALDI-TOF MS with orthogonal approaches for strain typing, including WGS and FTIR, for Acinetobacter baumannii isolates correlated with a health care-associated infection (HCAI) event. Combined with epidemiological data, all methods investigated identified a group of isolates that were temporally and spatially linked to the outbreak, yet potentially attributed to a separate transmission event. This may have implications for guiding infection control strategies during an outbreak. However, the technical reproducibility of MALDI-TOF MS needs to be improved for it to be employed as a standalone typing method, as different stages of the experimental workflow introduced bias influencing interpretation of biomarker peak data. Availability of in-house methods for strain typing of bacteria could improve infection control practices following increased reports of outbreaks of antimicrobial-resistant organisms during the COVID-19 pandemic, related to sessional usage of personal protective equipment (PPE).

Antimicrobial stewardship in solid organ transplant-Opportunities in the National Health Service.

BACKGROUND: Antimicrobial stewardship (AMS) is an intervention, which ensures the appropriateness of antimicrobial use to avoid in part the rising problem of antimicrobial resistance and negative effects of inappropriate antimicrobial use. In the solid organ transplant (SOT) population, which is prone to a particularly high risk of infection resulting from immunosuppression and anatomical issues with each type of SOT, the need for good stewardship has never been more important. This article looks at current AMS practice in SOT units in the United Kingdom and how things could be improved in the future. METHODS: The current practice of AMS alongside national antimicrobial resistance rates were reviewed using national mandatory reporting data. The background to the current practice and policies in place in the National Health Service (NHS) were also reviewed and possibilities for future approaches explored. RESULTS: AMS is a requirement within all NHS hospitals in the United Kingdom as per government policy. Mandatory reporting of specific bloodstream infections (BSIs) and antimicrobial consumption alongside financial incentives has been the approach nationwide. Gram-negative resistance rates in BSIs have been increasing prior to the COVID-19 pandemic. Little SOT-specific data on antimicrobial resistance exists, and the general approach to AMS in SOT units has generally modeled the national approach. CONCLUSION: Although there is a good, standardized approach to AMS in the NHS, there is a need for SOT-specific AMS approaches to be developed in the United Kingdom. More data is required on antimicrobial resistance rates, and studies are needed to investigate optimal antimicrobial prophylaxis regimens for each solid organ group. Tools to aid AMS efforts and novel treatment options for complex multiresistant infection must also be explored amongst transplant centers.

Bacterascites confers poor patient prognosis beyond MELD prediction.

Spontaneous bacterial peritonitis (SBP) is a well-recognized clinical entity with a poor prognosis. In comparison, the prevalence, microbiological flora, and prognostic significance of bacterascites (BA) (the presence of organism on culture but ascitic PMN <250 cells/mm³) is largely unknown. We, therefore, assessed the prognosis and predictors of outcome in patients with BA in comparison with those with SBP. Ascitic fluid cultures from consecutive patients with cirrhosis from 2008 to 2018 were reviewed retrospectively, and patients with SBP and BA were identified. Baseline demographic, laboratory, and microbiological data were collated and analyzed as prognostic indicators, and clinical outcomes were recorded. Patients were censored at the time of LT, death, or last follow-up. For this study 176 and 213 cases of SBP and BA, respectively, were identified and included. Patients with SBP had significantly higher Model for End-Stage Liver Disease (MELD) ( p =<0.01), peripheral blood WCC ( p < 0.01), and higher rates of Enterobacteriaceae ( p < 0.01) and multi-drug resistant pathogens ( p < 0.01). Survival at 1 and 3 months was lower in patients with SBP ( p < 0.01) when compared with BA but at 6 months and beyond, no significant difference remained. After the exclusion of deaths within 30 days of presentation, survival between SBP and BA was equivocal at all time points. Mortality was substantially higher across all MELD groupings for both SBP and BA when compared with the predicted mortality calculated by the MELD score alone. BA has a negative impact on patient survival above that predicted by the MELD score. It has similar impact to SBP on patient survival beyond 1 month suggesting it should be seen as a poor prognostic marker and prompt consideration of LT where appropriate. Further studies evaluating the role of secondary prophylaxis in this group are required.

Comparative assessment of viral dynamic models for SARS-CoV-2 for pharmacodynamic assessment in early treatment trials.

Pharmacometric analyses of time series viral load data may detect drug effects with greater power than approaches using single time points. Because SARS-CoV-2 viral load rapidly rises and then falls, viral dynamic models have been used. We compared different modelling approaches when analysing Phase II-type viral dynamic data. Using two SARS-CoV-2 datasets of viral load starting within 7 days of symptoms, we fitted the slope-intercept exponential decay (SI), reduced target cell limited (rTCL), target cell limited (TCL) and TCL with eclipse phase (TCLE) models using nlmixr. Model performance was assessed via Bayesian information criterion (BIC), visual predictive checks (VPCs), goodness-of-fit plots, and parameter precision. The most complex (TCLE) model had the highest BIC for both datasets. The estimated viral decline rate was similar for all models except the TCL model for dataset A with a higher rate (median [range] day-1 : dataset A; 0.63 [0.56-1.84]; dataset B: 0.81 [0.74-0.85]). Our findings suggest simple models should be considered during pharmacodynamic model development.

What is the optimal antimicrobial prophylaxis to prevent postoperative infectious complications after liver transplantation? A systematic review of the literature and expert panel recommendations.

BACKGROUND: Antimicrobial prophylaxis is well-accepted in the liver transplant (LT) setting. Nevertheless, optimal regimens to prevent bacterial, viral, and fungal infections are not defined. OBJECTIVES: To identify the optimal antimicrobial prophylaxis to prevent post-LT bacterial, fungal, and cytomegalovirus (CMV) infections, to improve short-term outcomes, and to provide international expert panel recommendations. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. PROSPERO ID: CRD42021244976. RESULTS: Of 1853 studies screened, 34 were included for this review. Bacterial, CMV, and fungal antimicrobial prophylaxis were evaluated separately. Pneumocystis jiroveccii pneumonia (PJP) antimicrobial prophylaxis was analyzed separately from other fungal infections. Overall, eight randomized controlled trials, 21 comparative studies, and five observational noncomparative studies were included. CONCLUSIONS: Antimicrobial prophylaxis is recommended to prevent bacterial, CMV, and fungal infection to improve outcomes after LT. Universal antibiotic prophylaxis is recommended to prevent postoperative bacterial infections. The choice of antibiotics should be individualized and length of therapy should not exceed 24 hours (Quality of Evidence; Low | Grade of Recommendation; Strong). Both universal prophylaxis and preemptive therapy are strongly recommended for CMV prevention following LT. The choice of one or the other strategy will depend on individual program resources and experiences, as well as donor and recipient serostatus. (Quality of Evidence; Low | Grade of Recommendation; Strong). Antifungal prophylaxis is strongly recommended for LT recipients at high risk of developing invasive fungal infections. The drug of choice remains controversial. (Quality of Evidence; High | Grade of Recommendation; Strong). PJP prophylaxis is strongly recommended. Length of prophylaxis remains controversial. (Quality of Evidence; Very Low | Grade of Recommendation; Strong).

Chromobacterium violaceum causing disseminated soft tissue and pulmonary abscesses in a traveller returning from the Azores.

This case report describes a 30-year-old male patient presenting with Chromobacterium violaceum cutaneous lesions who develops a subsequent bacteraemia, complicated by soft tissue and pulmonary abscesses. C. violaceum disease is a rare infection that can manifest in a spectrum from cutaneous lesions to disseminated disease and sepsis, the latter associated with high mortality. Although in the available literature there is a recommendation for a prolonged antibiotic course, we describe effective management with a shorter course of antibiotics. This case highlights the importance of not only considering a diagnosis of C. violaceum if there has been a high risk and appropriate exposure, but to also consider the changing epidemiology of the organism due to certain geographical areas becoming warmer due to climate change.

Use of ß-D-glucan in diagnosis of suspected Pneumocystis jirovecii pneumonia in adults with HIV infection.

OBJECTIVES: An elevated serum (1-3)-ß-D-glucan (BDG) concentration has high sensitivity for a diagnosis of Pneumocystis pneumonia (PCP) in people with HIV (PWH). At the current manufacturer-recommended positive threshold of 80 pg/mL (Fungitell), specificity for PCP is variable and other diagnostic tests are required. We evaluated the utility of serum BDG for diagnosis of suspected PCP in PWH at three inner-London hospitals to determine BDG concentrations for diagnosis and exclusion of PCP. METHODS: From clinical case records, we abstracted demographic and clinical information and categorised patients as having confirmed or probable PCP, or an alternative diagnosis. We calculated sensitivity, specificity and positive predictive value (PPV) of serum BDG concentrations >400 pg/mL and negative predictive value (NPV) of BDG <80 pg/mL. RESULTS: 76 patients were included; 29 had laboratory-confirmed PCP, 17 had probable PCP and 30 had an alternative diagnosis. Serum BDG >400 pg/mL had a sensitivity of 83%, specificity of 97% and PPV 97% for diagnosis of PCP; BDG <80 pg/mL had 100% NPV for exclusion of PCP. CONCLUSIONS: In PWH with suspected PCP, BDG <80 pg/mL excludes a diagnosis of PCP, whereas BDG concentrations >400 pg/mL effectively confirm the diagnosis. Values 80-400 pg/mL should prompt additional diagnostic tests.

Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting.

OBJECTIVES: This systematic review focuses on the use of the in vitro hollow fibre infection model (HFIM) for microbial culture. We summarize the direction of the field to date and propose best-practice principles for reporting of the applications. METHODS: Searches in six databases (MEDLINE®, EMBASE®, PubMed®, BIOSIS®, SCOPUS® and Cochrane®) up to January 2020 identified 129 studies meeting our inclusion criteria. Two reviewers independently assessed and extracted data from each publication. The quality of reporting of microbiological and technical parameters was analysed. RESULTS: Forty-seven out of 129 (36.4%) studies did not report the minimum pharmacokinetic parameters required in order to replicate the pharmacokinetic profile of HFIM experiments. Fifty-three out of 129 (41.1%) publications did not report the medium used in the HFIM. The overwhelming majority of publications did not perform any technical repeats [107/129 (82.9%)] or biological repeats [97/129 (75.2%)]. CONCLUSIONS: This review demonstrates that most publications provide insufficient data to allow for results to be evaluated, thus impairing the reproducibility of HFIM experiments. Therefore, there is a clear need for the development of laboratory standardization and improved reporting of HFIM experiments.

Management of bacterial and fungal infections in cirrhosis: The MDRO challenge.

Bacterial infections are frequent in cirrhotic patients with acute decompensation or acute-on-chronic liver failure and can complicate the clinical course. Delayed diagnosis and inappropriate empirical treatments are associated with poor prognosis and increased mortality. Fungal infections are much less frequent, usually nosocomial and associated with extremely high short-term mortality. Early diagnosis and adequate empirical treatment of infections is therefore key in the management of these patients. In recent decades, antibiotic resistance has become a major worldwide problem in patients with cirrhosis, warranting a more complex approach to antibiotic treatment that includes the use of broad-spectrum antibiotics, new administration strategies, novel drugs and de-escalation policies. Herein, we review epidemiological changes, the main types of multidrug-resistant organisms, mechanisms of resistance, new rapid diagnostic tools and currently available therapeutic options for bacterial and fungal infections in cirrhosis.

Exclusion of bacterial co-infection in COVID-19 using baseline inflammatory markers and their response to antibiotics.

BACKGROUND: COVID-19 is infrequently complicated by bacterial co-infection, but antibiotic prescriptions are common. We used community-acquired pneumonia (CAP) as a benchmark to define the processes that occur in bacterial pulmonary infections, testing the hypothesis that baseline inflammatory markers and their response to antibiotic therapy could distinguish bacterial co-infection from COVID-19. METHODS: Retrospective cohort study of CAP (lobar consolidation on chest radiograph) and COVID-19 (PCR detection of SARS-CoV-2) patients admitted to Royal Free Hospital (RFH) and Barnet Hospital (BH), serving as independent discovery and validation cohorts. All CAP and >90% COVID-19 patients received antibiotics on hospital admission. RESULTS: We identified 106 CAP and 619 COVID-19 patients at RFH. Compared with COVID-19, CAP was characterized by elevated baseline white cell count (WCC) [median 12.48 (IQR 8.2-15.3) versus 6.78 (IQR 5.2-9.5) ×106 cells/mL, P < 0.0001], C-reactive protein (CRP) [median 133.5 (IQR 65-221) versus 86.0 (IQR 42-160) mg/L, P < 0.0001], and greater reduction in CRP 48-72 h into admission [median ΔCRP -33 (IQR -112 to +3.5) versus +14 (IQR -15.5 to +70.5) mg/L, P < 0.0001]. These observations were recapitulated in the independent validation cohort at BH (169 CAP and 181 COVID-19 patients). A multivariate logistic regression model incorporating WCC and ΔCRP discriminated CAP from COVID-19 with AUC 0.88 (95% CI 0.83-0.94). Baseline WCC >8.2 × 106 cells/mL or falling CRP identified 94% of CAP cases, and excluded bacterial co-infection in 46% of COVID-19 patients. CONCLUSIONS: We propose that in COVID-19, absence of both elevated baseline WCC and antibiotic-related decrease in CRP can exclude bacterial co-infection and facilitate antibiotic stewardship efforts.

Transmission of Hepatitis B Core Antibody and Galactomannan Enzyme Immunoassay Positivity via Immunoglobulin Products: A Comprehensive Analysis.

BACKGROUND: Therapeutic immunoglobulins are used as replacement or immunomodulatory therapy, but can transmit clinically important molecules. We investigated hepatitis B virus (HBV) antibodies and galactomannan enzyme immunoassay (GM-EIA) positivity. Detection of HBV core antibody may prompt antiviral prophylaxis when commencing therapy such as rituximab; a positive GM-EIA result prompts investigation or treatment for invasive fungal disease. METHODS: We performed a cross-sectional analysis of HBV serology in 80 patients established (>6 months) on immunoglobulin therapy; prospective analysis of HBV serology in 16 patients commencing intravenous immunoglobulin (IVIG); and pre- and post-infusion analysis of GM-EIA in 37 patients receiving IVIG. RESULTS: Pre-IVIG, 9 of 80 patients tested positive for HBV surface antibody and 1 of 80 tested equivocal for HBV core antibody. On IVIG, 79 of 79 tested positive for surface antibody, 37 of 80 tested positive for core antibody, and 10 of 80 tested equivocal for core antibody. There were significant differences by product, but among patients receiving products that appear to transmit core antibody, negative results correlated with lower surface antibody titers and longer time since infusion, suggesting a simple concentration effect. There was a progressive increase with each infusion in the percentage of patients testing positive for HBV core antibody among patients newly commencing IVIG. Some patients "seroreverted" to negative during therapy. Certain IVIG products tested positive for GM-EIA and there were rises in index values in corresponding patient samples from pre- to post-infusion. Overall, 5 of 37 patient samples pre-infusion and 15 of 37 samples post-infusion tested positive for GM-EIA. CONCLUSIONS: HBV antibodies and GM-EIA positivity are common in patients receiving IVIG and confound diagnostic results.

A method for the detection of antibiotic resistance markers in clinical strains of Escherichia coli using MALDI mass spectrometry.

Matrix-assisted laser-desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) is one of the most widely used mass spectrometry based approaches for bacterial identification and classification. The relatively simple sample preparation requirements and the speed of analysis which can usually be completed within a few minutes have resulted in the adoption and assimilation of MALDI-TOF MS into the routine diagnostic workflow of Clinical microbiology laboratories worldwide. This study describes the facilitation of bacterial discrimination based on antibiotic resistance markers through the implementation of MALDI-TOF MS. The periplasmic compartment of whole bacterial cells contains several proteins which confer antibiotic resistance in the Enterobacteriaceae. In order to reduce the complexity of the sample to be analysed via MALDI-TOF MS, the periplasm was extracted and subjected to in solution tryptic digestion followed by nano-LC separation. This method, established that peptide sequence biomarkers from several classes of antibiotic resistance proteins could be predicted using protein/peptide database tools such as Mascot. Biomarkers for a CTX-M-1 group extended spectrum ß-lactamase, CMY-2 an Amp-C ß-lactamase, VIM a metallo-ß-lactamase, TEM a ß-lactamase and KanR an aminoglycoside modifying enzyme were detected. This allowed for discrimination at a species level and at an almost identical strain level where the only difference between strains was the carriage of a modified antibiotic resistance carrying plasmid. This method also was able to detect some of these biomarkers in clinical strains where multiple resistance mechanisms were present.

The mental and physical health difficulties of children held within a British immigration detention center: a pilot study.

OBJECTIVE: The present study aimed to assess the mental and physical health of children held within a British immigration detention center. METHOD: A total of 24 detained children (aged 3 months to 17 years) were assessed with their parents or carer after being referred by a registered legal charity. Thirteen were seen by a pediatrician alone, 4 by a psychologist alone, and 7 by both professions using semi-structured clinical interviews. The psychologist also used standardized self-report questionnaires to measure psychopathology. RESULTS: During the psychological assessment of 11 children, 8 met criteria for psychiatric "caseness" on the Strengths and Difficulties Questionnaire. All 11 reported symptoms of depression and anxiety. Sleep problems, somatic complaints, poor appetite, emotional symptoms, and behavioral difficulties were common. Symptoms of global distress were also reported by all 9 parents. According to pediatric assessment 8 out of 20 children had lost weight. Six had missed health appointments and 2 were taken to hospital. Nutritional, developmental, educational, and child protection concerns were raised. CONCLUSIONS: Detained children were found to be experiencing mental and physical health difficulties of recent onset, which appeared to be related to the detention experience. These findings support previous Australian studies demonstrating that detention is not in the best interest of the child. It suggests that current UK policies regarding the detention of children for purposes of immigration control should be re-examined. Further research in the area is required. PRACTICE IMPLICATIONS: Although high levels of mental and physical health problems, as well as child protection concerns were detected, detained families had very limited access to appropriate assessment, support or treatment. The traumatic experience of detention itself also has implications for the sizeable proportion of psychologically distressed children who are eventually released from detention and expected to successfully reintegrate into British society; while those children who are deported are returned with increased vulnerability to future stressors.

Emergency drug availability on general paediatric units.

Following an incident where intravenous lorazepam was not available on a general paediatric ward we undertook a national survey of emergency drug availability on general paediatric units in the United Kingdom. Drugs chosen were those recommended in the Advanced Paediatric Life Support manual and the British National Formulary for the management of the most common paediatric emergencies. Twelve drugs were chosen covering emergencies in the following systems: cardiovascular (adrenaline (epinephrine), atropine and adenosine); neurological (flumazenil, lorazepam, paraldehyde, phenytoin and mannitol); metabolic (Hypostop Gel and glucagon); analgesia related (naloxone); and respiratory (aminophylline). A thirteenth drug, intravenous salbutamol was included in a reminder letter sent to non-responding units. Questionnaires were sent to 274 units. Replies were received from 242 (88.3%), of whom 20 did not have a general paediatric ward, leaving 222 units (81.0%). Drug availability varied for the different drugs: adrenaline (available on 100% of units), atropine (98.2%), naloxone (96.4%), phenytoin (95.9%), aminophylline (93.2%), paraldehyde (92.3%), mannitol (87.8%), lorazepam (86.9%), glucagon (86.5%), Hypostop Gel (80.6%), adenosine (72.1%) and flumazenil (66.7%). Six of the drugs were classified as first line agents (adrenaline, atropine, adenosine, lorazepam, paraldehyde and aminophylline). Over one in 10 units did not stock two or more of these first line drugs. Consideration needs to be given to the compiling of a consensus based list of drugs that ought to be stocked on all general paediatric units.