Aspergillus nodules: Natural history and the effect of antifungals.

BACKGROUND: Aspergillus nodules are classified as a subset of chronic pulmonary aspergillosis. The optimal management approach is not known as their natural evolution following biopsy, the rate of progression to chronic cavitary pulmonary aspergillosis (CCPA) and the effect of antifungal treatment have not been described. OBJECTIVES: To describe the clinical course of patients diagnosed with Aspergillus nodules and the effect of antifungal treatment. PATIENTS/METHODS: We present a series of 23 patients with histologically confirmed Aspergillus nodules and describe serial imaging, antifungal treatment and progression to other diagnoses. RESULTS: Thirteen patients were diagnosed after a CT-guided biopsy and 10 after surgical resection. Among those who had CT-guided biopsy, 8 did not receive antifungal treatment; the nodule was stable or smaller in all cases on subsequent CT scan after a mean of 15.5 months. However, one patient developed squamous cell carcinoma after 16 months and another developed CCPA after 7 months. Among the 5 patients who received antifungals for at least 4 weeks, the nodule was smaller in 1 and stable in 4. One patient developed CCPA 3 years after the biopsy. No patient who had a surgical resection subsequently had a CCPA diagnosis. CONCLUSION: Most Aspergillus nodules remained stable or improved following biopsy, irrespective of the effect of antifungals. However, CCPA can develop occasionally in patients with Aspergillus nodules and ongoing radiological follow-up may be warranted when the nodule is not resected.

FDA Public Workshop Summary-Addressing Challenges in Inhaled Antifungal Drug Development.

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On September 25, 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.

Predictive factors for treatment response and mortality in chronic pulmonary aspergillosis.

OBJECTIVES: Chronic pulmonary aspergillosis (CPA) is associated with significant mortality, and suboptimal antifungal treatment response. We describe predictive factors for treatment response and survival. METHODS: We retrospectively analysed clinical, serological and radiological parameters at baseline and following antifungal treatment in patients with CPA and correlated with clinical and radiological response and survival. RESULTS: Fifty-nine patients were included with a mean age of 61 years. Thirty (51%) had a diagnosis of COPD. On clinical assessment at 6 months, 21 (36%) had clinically improved, 20 (34%) were clinically stable and 15 (25%) had deteriorated. Radiological improvement was observed in 30 (53%), stability in 11 (19%) and deterioration in 16 (28%). Only a lower C-reactive protein (CRP) at baseline was associated with a favourable clinical-radiological response. On univariate analysis, lower CRP, higher albumin, lower Aspergillus IgG and use of inhaled steroids were associated with lower mortality. An overall favourable response at 6 months was associated with lower mortality. CONCLUSION: Inflammatory markers and Aspergillus IgG were predictors of mortality in CPA. This suggests that mortality in CPA is driven mainly by the chronic fungal infection itself rather than the underlying disease, therefore early optimised treatment of CPA may lead to improved outcomes.

Micafungin may be safely administered as outpatient parenteral antimicrobial therapy for chronic pulmonary aspergillosis.

BACKGROUND: Intravenous micafungin has been reported as a treatment alternative in patients with chronic pulmonary aspergillosis (CPA) where long-term oral triazole therapy is unfeasible. OBJECTIVES: We evaluated the safety and efficacy of micafungin administered via the outpatient parenteral antimicrobial therapy (OPAT) service for the treatment of CPA. METHODS: We included all CPA patients who received micafungin via OPAT between April 2016 and March 2018. Data on adverse events and line-related complications, and Quality of Life (QoL) scores at the start of micafungin course and 3 months later were extracted. Improvements in QoL were defined as an improvement of ≥4 points in at least one modality (symptom, impact, activity, total) in the St George's QoL score. A stable QoL score was defined as a change in score of <4 points in either direction whilst deterioration was defined as an increase of ≥4 points. RESULTS: There were 20 OPAT episodes involving 18 patients with a median duration of micafungin therapy of 21 (range: 4-248) days. Improvement or stability in the symptoms, activity, impact and total score was seen in 14 (78%), 12 (67%), 9 (50%) and 9 (50%) of the patients, respectively. However, half of the patients reported deterioration in the impact domain and total scores. By self-assessment, patients who categorised themselves as "poor" were comparable at the start of OPAT and at 3 months (43% vs 50%, McNemar's P = 0.7). Adverse events attributable to micafungin were recorded in 3 (14.3%) episodes. CONCLUSIONS: Micafungin may be safely administered via an OPAT service. Micafungin therapy was associated with an improvement or stability in QoL scores in at least 50% of the patients across the four domains.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.

BACKGROUND: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS: In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS: Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION: Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING: Novartis Vaccines.

Diagnostic criteria and core outcome set development for necrotising otitis externa: the COSNOE Delphi consensus study.

OBJECTIVE: Evidence for necrotising otitis externa (NOE) diagnosis and management is limited, and outcome reporting is heterogeneous. International best practice guidelines were used to develop consensus diagnostic criteria and a core outcome set (COS). METHODS: The study was pre-registered on the Core Outcome Measures in Effectiveness Trials (COMET) database. Systematic literature review identified candidate items. Patient-centred items were identified via a qualitative study. Items and their definitions were refined by multidisciplinary stakeholders in a two-round Delphi exercise and subsequent consensus meeting. RESULTS: The final COS incorporates 36 items within 12 themes: Signs and symptoms; Pain; Advanced Disease Indicators; Complications; Survival; Antibiotic regimes and side effects; Patient comorbidities; Non-antibiotic treatments; Patient compliance; Duration and cessation of treatment; Relapse and readmission; Multidisciplinary team management.Consensus diagnostic criteria include 12 items within 6 themes: Signs and symptoms (oedema, otorrhoea, granulation); Pain (otalgia, nocturnal otalgia); Investigations (microbiology [does not have to be positive], histology [malignancy excluded], positive CT and MRI); Persistent symptoms despite local and/or systemic treatment for at least two weeks; At least one risk factor for impaired immune response; Indicators of advanced disease (not obligatory but mut be reported when present at diagnosis). Stakeholders were unanimous that there is no role for secondary, graded, or optional diagnostic items. The consensus meeting identified themes for future research. CONCLUSION: The adoption of consensus-defined diagnostic criteria and COS facilitates standardised research reporting and robust data synthesis. Inclusion of patient and professional perspectives ensures best practice stakeholder engagement.

Transient increase in atherosclerotic plaque macrophage content following Streptococcus pneumoniae pneumonia in ApoE-deficient mice.

Introduction: Despite epidemiological associations between community acquired pneumonia (CAP) and myocardial infarction, mechanisms that modify cardiovascular disease during CAP are not well defined. In particular, largely due to a lack of relevant experimental models, the effect of pneumonia on atherosclerotic plaques is unclear. We describe the development of a murine model of the commonest cause of CAP, Streptococcus pneumoniae pneumonia, on a background of established atherosclerosis. We go on to use our model to investigate the effects of pneumococcal pneumonia on atherosclerosis. Methods: C57BL/6J and ApoE-/- mice were fed a high fat diet to promote atherosclerotic plaque formation. Mice were then infected with a range of S. pneumoniae serotypes (1, 4 or 14) with the aim of establishing a model to study atherosclerotic plaque evolution after pneumonia and bacteremia. Laser capture microdissection of plaque macrophages enabled transcriptomic analysis. Results: Intratracheal instillation of S. pneumoniae in mice fed a cholate containing diet resulted in low survival rates following infection, suggestive of increased susceptibility to severe infection. Optimization steps resulted in a final model of male ApoE-/- mice fed a Western diet then infected by intranasal instillation of serotype 4 (TIGR4) S. pneumoniae followed by antibiotic administration. This protocol resulted in high rates of bacteremia (88.9%) and survival (88.5%). Pneumonia resulted in increased aortic sinus plaque macrophage content 2 weeks post pneumonia but not at 8 weeks, and no difference in plaque burden or other plaque vulnerability markers were found at either time point. Microarray and qPCR analysis of plaque macrophages identified downregulation of two E3 ubiquitin ligases, Huwe1 and Itch, following pneumonia. Treatment with atorvastatin failed to alter plaque macrophage content or other plaque features. Discussion: Without antibiotics, ApoE-/- mice fed a high fat diet were highly susceptible to mortality following S. pneumoniae infection. The major infection associated change in plaque morphology was an early increase in plaque macrophages. Our results also hint at a role for the ubiquitin proteasome system in the response to pneumococcal infection in the plaque microenvironment.

Ertapenem administered as outpatient parenteral antibiotic therapy for urinary tract infections caused by extended-spectrum-beta-lactamase-producing Gram-negative organisms.

OBJECTIVES: Infections with extended-spectrum-beta-lactamase-producing organisms are an increasing public health concern. We reviewed the use of an outpatient parenteral antibiotic therapy (OPAT) programme to facilitate the early discharge from hospital of patients with ESBL-associated urinary tract infections. METHODS: A retrospective review of patients treated for urinary tract infections caused by ESBL-producing organisms through the OPAT programme at the Royal Hallamshire Hospital, Sheffield, UK over a 4 year period to January 2010 was conducted. Data on patient demographics, clinical presentation and laboratory results were collected. RESULTS: Twenty-four OPAT episodes involving 11 patients were identified. Six patients (54.5%) had an underlying urological abnormality on presentation to OPAT. All patients were treated with parenteral ertapenem. Two patients had multiple infections treated by OPAT. The mean duration of the OPAT episodes was 9.9 days (range 3-42). A total of 238 inpatient bed days were avoided, with resultant cost savings. CONCLUSIONS: Ertapenem administration through OPAT may help to decrease the costs associated with ESBL infections by reducing the number of inpatient bed days required for their successful treatment.

Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium.

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions.

Clinical efficacy and cost-effectiveness of outpatient parenteral antibiotic therapy (OPAT): a UK perspective.

OBJECTIVES: Outpatient parenteral antibiotic therapy (OPAT) is an effective treatment strategy for a wide variety of infections as long as clinical risk is minimized by conforming to practice guidelines. However, its cost-effectiveness has not been established in the setting of the UK National Health Service. We examined the clinical efficacy and cost-effectiveness of an OPAT service based in a large UK teaching hospital, predominantly using the outpatient 'infusion centre' and patient/carer administration models of service delivery. PATIENTS AND METHODS: Data on clinical activity and outcomes were collected prospectively on 334 episodes of treatment administered by the Sheffield OPAT service between January 2006 and January 2008. Cost-effectiveness was calculated by comparing real costs of OPAT with estimated inpatient costs for these patient episodes incorporating two additional sensitivity analyses. RESULTS: Of the OPAT episodes, 87% resulted in cure or improvement on completion of intravenous therapy. The readmission rate was 6.3%, and patient satisfaction was high. OPAT cost 41% of equivalent inpatient costs for an Infectious Diseases Unit, 47% of equivalent inpatient costs using national average costs and 61% of inpatient costs using minimum inpatient costs for each diagnosis. CONCLUSIONS: Using this service model, OPAT is safe and clinically effective, with low rates of complications/readmissions and high levels of patient satisfaction. OPAT is cost-effective when compared with equivalent inpatient care in the UK healthcare setting.

Late-onset isavuconazole-induced liver injury.

Antifungal agents account for approximately 3% of Drug-Induced Liver Injury (DILI) cases. Isavuconazole is a novel triazole, and experience with long-term use of it is lacking. We report a case of late-onset DILI occurring after 11 months of isavuconazole therapy in a 55-year old man of Angolan descent on long-term antifungal therapy for the management of chronic pulmonary aspergillosis complicating previously treated pulmonary tuberculosis. The DILI could be described as idiosyncratic as it was not associated with high isavuconazole serum levels and his liver function tests returned to normal following treatment discontinuation.

A phase III observer-blind randomized, controlled study to evaluate the immune response and the correlation with nasopharyngeal carriage after immunization of university students with a quadrivalent meningococcal ACWY glycoconjugate or serogroup B meningococcal vaccine.

BACKGROUND: University students have high rates of pharyngeal carriage of Neisseria meningitidis. Interruption of carriage acquisition is an important mechanism of vaccines for inducing herd protection. 4CMenB and MenACWY-CRM vaccines have been shown to be immunogenic against meningococcal serogroups B and ACWY respectively in younger age groups, and also to elicit a modest impact on meningococcal carriage in vaccinated students. However, vaccine responses in university students and the impact of serum bactericidal antibody (SBA) titers on meningococcal carriage are undetermined. METHODS: Immunogenicity of two 4CMenB doses or one MenACWY-CRM dose was measured in university students at Months 2, 4, 6 and 12 post-first vaccination. Immunogenicity of one MenACWY-CRM dose in students with previous meningococcal serogroup C conjugate vaccination was also assessed. Immune responses were measured with an SBA assay using human complement (hSBA) against three reference strains for serogroup B and against one strain for each for serogroups C and Y. Correlations between hSBA titers and meningococcal carriage were analyzed. RESULTS: All subjects demonstrated robust functional antibody responses to both vaccines at Month 2 and a high proportion maintained protective hSBA titers up to Month 12. At baseline, carriage of disease-associated serogroup B strains and serogroups C and Y were higher in subjects with already-protective hSBA titers. Post-vaccination, while both 4CMenB and MenACWY-CRM elicited robust immunogenicity in students, significant correlations between post-vaccination hSBA titers and carriage of disease-associated serogroups were not observed. CONCLUSIONS: 4CMenB and MenACWY-CRM were both highly immunogenic. There was no correlation between carriage and post-vaccination hSBA titers.

United Kingdom and Republic of Ireland renal physicians' experiences of patients undergoing renal transplants abroad: a questionnaire-based cross-sectional survey.

BACKGROUND: Due to ongoing poor availability of organs, increasingly patients from developed countries are reported to be travelling abroad for renal transplants. We aimed to assess the extent and characteristics of this trend across the UK and Republic of Ireland. METHODS: A questionnaire-based cross-sectional survey; 397 renal consultants from 33 hospitals with renal units across the UK and the Republic of Ireland were contacted through email and 62 replied (16%). RESULTS: Fifty-seven out of 62 (93%) renal consultants managed transplant patients, and of these 36/57 (63%) had managed at least one patient who had undergone a transplant abroad. The most popular reason reported for doing this was being on the UK or Republic of Ireland transplant list but seeking a shorter wait. Respondents reported commencement by overseas doctors of appropriate routine post-transplant prophylaxis with the following medications in all cases they had encountered as follows: co-trimoxazole 12%, isoniazid 3%, anti-fungals 0%, and Cytomegalovirus prophylaxis or treatment 0%. Fourty-four percent of renal consultants reported having some prior warning of a patient undergoing a renal transplant abroad. CONCLUSIONS: Renal transplant tourism has become widely established in the UK and the Republic of Ireland, and care for these patients is often suboptimal. Furthermore, the opportunity exists for pre-transplant counselling.

Mechanistic links between acute respiratory tract infections and acute coronary syndromes.

Cardiovascular disease has emerged as the leading cause of mortality worldwide. Acute coronary syndromes occur as a result of thrombotic complications at the site of atherosclerotic plaques, often following rupture of the fibrous cap of vulnerable plaques. A growing body of evidence from clinical and experimental studies suggests that acute respiratory tract infections can act as a trigger for acute coronary syndromes. The mechanism underlying this association has yet to be established. We explore the mechanistic links between acute respiratory tract infection and acute coronary syndromes, with a particular focus on the host response to infection and its potential interaction with pathogenic processes involved in atherosclerosis and atherosclerotic plaque rupture. The prothrombotic and haemodynamic effects of acute respiratory infection are also discussed. We review mechanistic studies as well as clinical trial data to investigate potential links between acute coronary syndromes and acute respiratory infection. Understanding the link between acute respiratory infections and acute coronary syndromes should help improve the outcome of acute coronary syndromes.

Over-the-counter kaolin and morphine: two hazards in one.

A 56-year-old woman, who was admitted with hypokalaemia, hypertension and metabolic alkalosis, was found to be dependent on kaolin and morphine, a common agent used for the treatment of diarrhoea. This case report highlights the problems of an over-the-counter (OTC) medicine such as kaolin and morphine when it can be purchased in large quantities.

Quality of malaria information provided on Internet travel operator websites.

BACKGROUND: Over the past 20 years, there has been a steady growth in the number of reported cases of malaria in the UK. With increasing Internet flight sales over recent years, online travel operator websites may be the only place many travellers could conceivably receive pre-travel malaria prevention advice. METHODS: 29 Travel operator websites which allow for online flight purchases to malarious areas from the UK, identified using a Google(®) web search and the website of the International Air Transport Association, were assessed for the existence, accuracy and accessibility of malaria prevention advice available through internal and external website links. RESULTS: Eight (28%) websites provided malaria prevention information on their own pages. Five (17%) websites contained country specific malaria information relevant to the requested destination, including variation of malaria risk within that country and accurate destination specific chemoprophylaxis advice. No malaria information was available, either on internal or external links, on 8 (28%) websites. On average, it took 2.4 additional mouse clicks to access malaria information during the online flight booking process. Six of the 29 websites (21%) allowed for access to information with only 1 click. CONCLUSIONS: Malaria prevention information on online travel operator websites is most often absent or inadequate. Even on websites where such information is of good quality, it can be difficult to access. The travel industry should introduce and enforce guidelines for the malaria information provided by online travel operators.

Anticonvulsant hypersensitivity syndrome presenting as aseptic meningitis.

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, potentially life-threatening drug reaction which usually occurs after exposure to aromatic antiepileptics. AHS secondary to non-aromatic antiepileptics is even more rare and there are only few case reports of AHS presenting as aseptic meningitis. We present the case of a 48-year-old patient who presented with meningism within 3 weeks of adding lamotrigine for control of her juvenile myoclonic epilepsy. When lamotrigine was restarted 2 weeks later she developed similar but more severe symptoms which resolved on stopping lamotrigine. Our patient was subsequently rendered seizure free on levetiracetam which has not so far been linked with this syndrome. It is important to be aware of this life-threatening complication associated with the use of antiepileptics.