Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial.

BACKGROUND: Real-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data. METHODS AND FINDINGS: In this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18-30 years, 2.1% for age 31-45 years, 1.8% for age 46-55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting. CONCLUSIONS: We observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions.

Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Optimization of a Human Bacille Calmette-Guérin Challenge Model: A Tool to Evaluate Antimycobacterial Immunity.

BACKGROUND: There is an urgent need for an improved tuberculosis vaccine. The lack of a validated correlate of protection slows progress in achieving this goal. A human mycobacterial challenge model, using bacille Calmette-Guérin (BCG) as a surrogate for a Mycobacterium tuberculosis challenge, would facilitate vaccine selection for field efficacy testing. Optimization of this model is required. METHODS: Healthy BCG-naive adults were assigned to receive intradermal standard-dose BCG SSI (group A), standard-dose BCG TICE (group B), high-dose BCG SSI (group C), and high-dose BCG TICE (group D). Two weeks after BCG challenge, skin biopsy of the challenge site was performed. BCG mycobacterial load was quantified by solid culture and quantitative polymerase chain reaction. RESULTS: BCG was well tolerated, and reactogenicity was similar between groups, regardless of strain and dose. There was significantly greater recovery of BCG from the high-dose challenge groups, compared with standard-dose challenge. BCG strain did not significantly affect BCG recovery. CONCLUSIONS: BCG challenge dose affects sensitivity of this model. We have selected high-dose BCG SSI to take forward in future challenge studies. Assessment of candidate tuberculosis vaccine effectiveness with this optimized model could contribute to vaccine selection for efficacy trials. CLINICAL TRIALS REGISTRATION: NCT02088892.

Sensitivity of C-Tb: a novel RD-1-specific skin test for the diagnosis of tuberculosis infection.

C-Tb, a novel Mycobacterium tuberculosis and 6-kDa early secretory antigenic target/10-kDa culture filtrate protein (ESAT-6/CFP-10)-specific skin test, has high specificity in bacille Calmette-Guerin-vaccinated healthy controls. However, the sensitivity of C-Tb has hitherto not been determined. The objective was to determine the sensitivity of C-Tb in patients with active tuberculosis (TB) in comparison with the tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT).C-Tb and TST were randomly administered in a double-blinded fashion to one or the other forearm in 253 patients with active TB with or without HIV co-infection. QFT-GIT testing was performed prior to skin testing.Using a receiver operating characteristic curve-derived cut-point of 5 mm, C-Tb sensitivity was similar to QFT-GIT (73.9 (95% CI 67.8-79.3) versus 75.1 (95% CI 69.3-80.2)), and similar in HIV-infected and HIV-uninfected patients (76.7 (95% CI 69.0-83.3) versus 69.5 (95% CI 59.2-78.5)). However, sensitivity was significantly diminished in HIV-infected patients with CD4 counts <100 cells·mm(-3). C-Tb and QFT-GIT combined had significantly higher sensitivity than C-Tb alone (p<0.0001). C-Tb was safe with no significant adverse events. The 5 mm cut-point corresponded to that found in the previously published specificity study (TESEC-04).C-Tb has similar sensitivity compared with QFT-GIT for the diagnosis of M. tuberculosis infection. Sensitivity was reduced only in HIV-infected patients with severe immunosuppression. Further studies in different settings are required to validate the proposed 5 mm cut-point.

Sputum induction to aid diagnosis of smear-negative or sputum-scarce tuberculosis in adults in HIV-endemic settings.

Sputum induction can aid tuberculosis (TB) diagnosis, but adult data from HIV-endemic environments are limited, and it is unclear how performance varies depending on the clinical context (in-patient versus outpatient), HIV status and whether patients are smear-negative or sputum-scarce. 696 adults with suspected smear-negative or sputum-scarce TB from Cape Town (South Africa) were referred for routine sputum induction. Liquid culture for Mycobacterium tuberculosis served as the reference standard. 82% (573 out of 696) of patients provided a specimen ≥1 mL, 83% (231 out of 278) of which were of adequate quality. 15% (96 out of 652) of sputum induction specimens were culture-positive, and this yield was higher among inpatients versus outpatients (17% (71 out of 408) versus 10% (25 out of 244), p=0.01) and HIV-infected versus uninfected patients (17% (51 out of 294) versus 9% (16 out of 173), p=0.02), but similar for CD4 (>200 versus ≤200 cells·µL(-1)) and patient (smear-negative versus sputum-scarce) subcategories. Overall sensitivity (95% CI) of smear-microscopy was 49% (39-59%), higher among in-patients versus outpatients (55% (43-67%) versus 32% (14-50%), p=0.05), but unaffected by HIV co-infection, CD4 count or patient type. 29% (203 out of 696) of patients commenced anti-TB treatment and sputum induction offered microbiological confirmation and susceptibility testing in only 47% (96 out of 203). Under programmatic conditions in an HIV-endemic environment although the yield of culture was approximately two-fold higher amongst HIV-infected patients and inpatients, a fifth of all patients were unable to provide a specimen following sputum induction. Same-day microbiological diagnosis was only possible in ~50% of patients.

Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study.

BACKGROUND: Tuberculous pericarditis (TBP) is associated with high morbidity and mortality, and is an important treatable cause of heart failure in developing countries. Tuberculous aetiology of pericarditis is difficult to diagnose promptly. The utility of the new quantitative PCR test (Xpert MTB/RIF) for the diagnosis of TBP is unknown. This study sought to evaluate the diagnostic accuracy of the Xpert MTB/RIF test compared to pericardial adenosine deaminase (ADA) and unstimulated interferon-gamma (uIFNγ) in suspected TBP. METHODS: From October 2009 through September 2012, 151 consecutive patients with suspected TBP were enrolled at a single centre in Cape Town, South Africa. Mycobacterium tuberculosis culture and/or pericardial histology served as the reference standard for definite TBP. Receiver-operating-characteristic curve analysis was used for selection of ADA and uIFNγ cut-points. RESULTS: Of the participants, 49% (74/151) were classified as definite TBP, 33% (50/151) as probable TBP and 18% (27/151) as non TBP. A total of 105 (74%) participants were human immunodeficiency virus (HIV) positive. Xpert-MTB/RIF had a sensitivity and specificity (95% confidence interval (CI)) of 63.8% (52.4% to 75.1%) and 100% (85.6% to 100%), respectively. Concentration of pericardial fluid by centrifugation and using standard sample processing did not improve Xpert MTB/RIF accuracy. ADA (≥35 IU/L) and uIFNγ (≥44 pg/ml) both had a sensitivity of 95.7% (88.1% to 98.5%) and a negative likelihood ratio of 0.05 (0.02 to 0.10). However, the specificity and positive likelihood ratio of uIFNγ was higher than ADA (96.3% (81.7% to 99.3%) and 25.8 (3.6 to 183.4) versus 84% (65.4% to 93.6%) and 6.0 (3.7 to 9.8); P = 0.03) at an estimated background prevalence of TB of 30%. The sensitivity and negative predictive value of both uIFNγ and ADA were higher than Xpert-MT/RIF (P < 0.001). CONCLUSIONS: uIFNγ offers superior accuracy for the diagnosis of microbiologically confirmed TBP compared to the ADA assay and the Xpert MTB/RIF test.

The identification of tuberculosis biomarkers in human urine samples.

We aimed to determine whether shotgun proteomic approaches could be used to identify tuberculosis (TB)-specific biomarkers in the urine of well-characterised patients with active TB versus no TB. Patients with suspected TB (n=63) were classified as: definite TB (Mycobacterium tuberculosis positive culture, n=21); presumed latent-TB infection (LTBI) (M. tuberculosis negative culture, no radiological features of active TB, a positive QuantiFERON-TB Gold In-Tube (QFT-IT) test and a positive T-SPOT.TB test, n=24); and presumed non-TB/non-LTBI (M. tuberculosis negative culture, no radiological features of active TB, a negative QFT-IT test and a negative T-SPOT.TB test, n=18). Urine proteins, in the range of 3-50 kDa, were collected, separated by a one-dimensional SDS-PAGE gel and digested using trypsin, after which high-performance liquid chromatography-tandem mass spectrometry was used to identify the urinary proteome. 10 mycobacterial proteins were observed exclusively in the urine of definite TB patients, while six mycobacterial proteins were found exclusively in the urine of presumed LTBI patients. In addition, a gene ontology enrichment analysis identified a panel of 20 human proteins that were significant discriminators (p<0.05) for TB disease compared to no TB disease. Furthermore, seven common human proteins were differentially over- or under-expressed in the TB versus the non-TB group. These biomarkers hold promise for the development of new point-of-care diagnostics for TB.

Comment on: Proposal for a new diagnostic classification of photodistributed Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap (SJS/TEN), collectively referred to SJS/TEN, form a spectrum of severe life-threatening adverse drug reactions whose pathomechanism is not fully understood. The article "Photodistributed Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Proposal for a New Diagnostic Classification" by McKinley et. al., discusses a distinct distribution of epidermal necrosis in SJS/TEN, attributable to preceding exposure to ultraviolet radiation (UVR), and relative sparing of photo-protected areas. After reviewing numerous cases within the Immune-mediated Adverse drug Reactions in African HIV endemic setting Register and Biorepository (IMARI-SA) at the University of Cape Town with a similar clinical pattern as those published by McKinley et. al., we propose that the relative sparing of some areas giving an impression of photo-distribution is due to localised increase in skin pressure that reduces the blood supply in that area below a critical threshold. A dip in blood supply below this critical threshold quantitively limited T lymphocytes and cytokines that drive SJS/TEN to reach and damage the skin.

Risk Factors for COVID-19 and Respiratory Tract Infections during the Coronavirus Pandemic.

(1) Background: Some individuals are more susceptible to developing respiratory tract infections (RTIs) or coronavirus disease (COVID-19) than others. The aim of this work was to identify risk factors for symptomatic RTIs including COVID-19 and symptomatic COVID-19 during the coronavirus pandemic by using infection incidence, participant baseline, and regional COVID-19 burden data. (2) Methods: Data from a prospective study of 1000 frontline healthcare workers randomized to Bacillus Calmette-Guérin vaccination or placebo, and followed for one year, was analyzed. Parametric time-to-event analysis was performed to identify the risk factors associated with (a) non-specific symptomatic respiratory tract infections including COVID-19 (RTIs+COVID-19) and (b) symptomatic RTIs confirmed as COVID-19 using a polymerase chain reaction or antigen test (COVID-19). (3) Results: Job description of doctor or nurse (median hazard ratio [HR] 1.541 and 95% confidence interval [CI] 1.299-1.822), the reported COVID-19 burden (median HR 1.361 and 95% CI 1.260-1.469 for 1.4 COVID-19 cases per 10,000 capita), or a BMI > 30 kg/m2 (median HR 1.238 and 95% CI 1.132-1.336 for BMI of 35.4 kg/m2) increased the probability of RTIs+COVID-19, while positive SARS-CoV-2 serology at enrollment (median HR 0.583 and 95% CI 0.449-0.764) had the opposite effect. The reported COVID-19 burden (median HR 2.372 and 95% CI 2.116-2.662 for 1.4 COVID-19 cases per 10,000 capita) and a job description of doctor or nurse (median HR 1.679 and 95% CI 1.253-2.256) increased the probability of developing COVID-19, while smoking (median HR 0.428 and 95% CI 0.284-0.648) and positive SARS-CoV-2 serology at enrollment (median HR 0.076 and 95% CI 0.026-0.212) decreased it. (4) Conclusions: Nurses and doctors with obesity had the highest probability of developing RTIs including COVID-19. Non-smoking nurses and doctors had the highest probability of developing COVID-19 specifically. The reported COVID-19 burden increased the event probability, while positive SARS-CoV-2 IgG serology at enrollment decreased the probability of RTIs including COVID-19, and COVID-19 specifically.

Additional Roles Reimbursement Scheme commissioning 2020-2023: associations with patient experience and QOF.

BACKGROUND: The Additional Roles Reimbursement Scheme (ARRS) was introduced by NHS England in 2020 alongside Primary Care Networks (PCNs) with aims of increasing the workforce and improving patient outcomes. AIM: Describe the uptake of direct-patient care (DPC)-ARRS roles and its impact on patients' experiences. DESIGN AND SETTING: Ecological study using 2020-2023 PCN and Practice workforce data, registered patient characteristics, the General Practice Patient Survey, and the Quality and Outcomes Framework (QOF). METHODS: Descriptive statistics with associations examined using quantile and linear regression. RESULTS: By March 2023, 17,714 FTE DPC-ARRS roles were commissioned by 1,223 PCNs. PCNs with fewer constituent practices had more DPC-ARRS roles per population (p<0.001) as did PCNs with more FTE GPs per population (p=0.012). DPC-ARRS commissioning did not vary with age, proportion female or deprivation of practice populations. DPC-ARRS roles were associated with small increases in patient satisfaction (0.8 percentage points increase in patients satisfied per one DPC-ARRS FTE) and perceptions of access (0.7 percentage points increase in patients reporting 'good' experience of making an appointment per one DPC-ARRS FTE), but not with overall QOF achievement. CONCLUSIONS: The commissioning of DPC-ARRS roles was associated with small increases in patient satisfaction and perceptions of access, but not with QOF achievement. DPC-ARRS roles were employed in areas with more GPs rather than compensating for a shortage of doctors. Single practice PCNs commissioned more roles per registered population, which may be advantageous to single practice PCNs. Further evaluation of the scheme is warranted.

Safety-netting advice documentation out-of-hours: a retrospective cohort from 2013 to 2020.

BACKGROUND: Providing safety-netting advice (SNA) in out-of-hours primary care is a recognised standard of safe care but it is not known how frequently this occurs in practice. AIM: Assess the frequency and type of SNA documented in out-of-hours primary care and explore factors associated with its presence. DESIGN AND SETTING: Retrospective cohort using the Birmingham Out-of-hours General Practice Research Database. METHOD: A stratified sample of 30 adult consultation records per month from July 2013 to February 2020 were assessed using a safety-netting coding tool. Associations were tested using linear and logistic regression. RESULTS: The overall frequency of SNA per consultation was 78.0%, increasing from 75.7% (2014) to 81.5% (2019). The proportion of specific SNA and the average number of symptoms patients were told to look out for increased with time. The most common symptom to look out for was if the patients' condition worsened followed by if their symptoms persisted, but only one in five consultations included a time-frame to reconsult for persistent symptoms. SNA was more frequently documented in face-to-face treatment-centre encounters compared to telephone-consultations (Odds Ratio [OR]=1.77, p=0.02), for possible infections (OR=1.53, p=0.006), and less frequently for mental (vs. physical) health consultations (OR=0.33, p=0.002) and where follow-up was planned (OR=0.34, p<0.001). CONCLUSION: The frequency of SNA documented in OOH was higher than previously reported during in-hours care. Over time, the frequency of SNA and proportion that contained specific advice increased, however this study highlights potential consultations where SNA could be improved, such as mental health and telephone consultations.

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema.

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

Determine TB-LAM lateral flow urine antigen assay for HIV-associated tuberculosis: recommendations on the design and reporting of clinical studies.

Detection of the Mycobacterium tuberculosis cell wall antigen lipoarabinomannan (LAM) in urine permits diagnoses of tuberculosis (TB) to be made in HIV-infected patients with advanced immunodeficiency. This can be achieved at the point-of-care within just 30 minutes using the Determine TB-LAM, which is a commercially available, lateral-flow urine 'strip test' assay. The assay has been shown to have useful diagnostic accuracy in patients enrolling in antiretroviral treatment services or in HIV-infected patients requiring admission to hospital medical wards in sub-Saharan Africa. Such patients have high mortality risk and have most to gain from rapid diagnosis of TB and immediate initiation of treatment. However, few studies using this assay have yet been reported and many questions remain concerning the correct use of the assay, interpretation of results, the role of the assay as an add-on test within existing diagnostic algorithms and the types of further studies needed. In this paper we address a series of questions with the aim of informing the design, conduct and interpretation of future studies. Specifically, we clarify which clinical populations are most likely to derive benefit from use of this assay and how patients enrolled in such studies might best be characterised. We describe the importance of employing a rigorous microbiological diagnostic reference standard in studies of diagnostic accuracy and discuss issues surrounding the specificity of the assay in different geographical areas and potential cross-reactivity with non-tuberculous mycobacteria and other organisms. We highlight the importance of careful procedures for urine collection and storage and the critical issue of how to read and interpret the test strips. Finally, we consider how the assay could be used in combination with other assays and outline the types of studies that are required to build the evidence base concerning its use.

Point-of-care diagnosis of tuberculosis: past, present and future.

Diagnosis represents only one aspect of tuberculosis (TB) control but is perhaps one of the most challenging. The drawbacks of current tools highlight several unmet needs in TB diagnosis, that is, necessity for accuracy, rapidity of diagnosis, affordability, simplicity and the ability to generate same-day results at point-of-care (POC). When a return visit is required to access test results, time to treatment is prolonged, and default rates are significant. However, a good diagnostic tool is also critically dependent on obtaining an adequate biological sample. Here, we review the accuracy and potential impact of established and newer potential POC diagnostic tests for TB, including smear microscopy, the Xpert MTB/RIF assay (Cepheid) and the Determine TB lipoarabinomannan antigen test (Alere). Novel experimental approaches and detection technologies for POC diagnosis of active TB, including nucleic acid amplification tests, detection of volatile organic compounds or metabolites, mass spectroscopy, microfluidics, surface-enhanced Raman spectroscopy, electrochemical approaches, and aptamers among others, are discussed. We also discuss future applications, including the potential POC diagnosis of drug-resistant TB and presumed latent TB infection. Challenges to the development and roll-out of POC tests for TB are also reviewed.

Value of diagnostic vaccination in diagnosis of humoral inborn errors of immunity.

Inborn errors of immunity (IEIs) or primary immunodeficiency diseases, are disorders caused by genetic defects affecting immune function. Clinically, IEI presents mainly as recurrent or severe infections, immune dysregulation (autoimmunity or autoinflammatory disorders), and lymphoproliferation with or without dysmorphic features. Humoral IEIs are the largest subgroup of IEI, with a wide spectrum of quantitative and qualitative antibody defects. These disorders are normally diagnosed based on immunological evaluation; diagnostic vaccination is part of this evaluation. This review examines the importance and relevance of diagnostic vaccination in the diagnosis of humoral IEIs and different technologies which can be utilised in diagnosis.

Skin infiltrating T-cell profile of drug reaction with eosinophilia and systemic symptoms (DRESS) reactions among HIV-infected patients.

Introduction: Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) is more common in persons living with HIV (PLHIV), and first-line anti-TB drugs (FLTDs) and cotrimoxazole are the commonest offending drugs. Limited data is available on the skin infiltrating T-cell profile among DRESS patients with systemic CD4 T-cell depletion associated with HIV. Materials and methods: HIV cases with validated DRESS phenotypes (possible, probable, or definite) and confirmed reactions to either one or multiple FLTDs and/or cotrimoxazole were chosen (n = 14). These cases were matched against controls of HIV-negative patients who developed DRESS (n = 5). Immunohistochemistry assays were carried out with the following antibodies: CD3, CD4, CD8, CD45RO and FoxP3. Positive cells were normalized to the number of CD3+ cells present. Results: Skin infiltrating T-cells were mainly found in the dermis. Dermal and epidermal CD4+ T-cells (and CD4+/CD8+ ratios) were lower in HIV-positive vs. negative DRESS; p < 0.001 and p = 0.004, respectively; without correlation to whole blood CD4 cell counts. In contrast, no difference in dermal CD4+FoxP3+ T-cells was found in HIV-positive vs. negative DRESS, median (IQR) CD4+FoxP3+ T-cells: [10 (0-30) cells/mm2 vs. 4 (3-8) cells/mm2, p = 0.325]. HIV-positive DRESS patients reacting to more than one drug had no difference in CD8+ T-cell infiltrates, but higher epidermal and dermal CD4+FoxP3+ T-cell infiltrates compared to single drug reactors. Conclusion: DRESS, irrespective of HIV status, was associated with an increased skin infiltration of CD8+ T-cells, while CD4+ T-cells were lower in HIV-positive DRESS compared to HIV-negative DRESS skin. While inter-individual variation was high, the frequency of dermal CD4+FoxP3+ T-cells was higher in HIV-positive DRESS cases reacting to more than one drug. Further research is warranted to understand the clinical impact of these changes.

Presentation and management of insect bites in out-of-hours primary care: a descriptive study.

OBJECTIVES: To describe the population presenting to out-of-hours primary care with insect bites, establish their clinical management and the factors associated with antibiotic prescribing. DESIGN: An observational study using routinely collected data from a large out-of-hours database (BORD, Birmingham Out-of-hours general practice Research Database). SETTING: A large out-of-hour primary care provider in the Midlands region of England. PARTICIPANTS: All patients presenting with insect bites between July 2013 and February 2020 were included comprising 5774 encounters. OUTCOME MEASURES: This cohort was described, and a random subcohort was created for more detailed analysis which established the clinical features of the presenting insect bites. Logistic regression was used to model variables associated with antibiotic prescribing. RESULTS: Of the 5641 encounters solely due to insect bites, 67.1% (95% CI 65.8% to 68.3%) were prescribed antibiotics. General practitioners were less likely to prescribe antibiotics than advanced nurse practitioners (60.5% vs 71.1%, p<0.001) and there was a decreasing trend in antibiotic prescribing as patient deprivation increased. Pain (OR 2.13, 95% CI 1.18 to 3.86), swelling (OR 2.88, 95% CI 1.52 to 5.46) and signs of spreading (OR 3.45, 95% CI 1.54 to 7.70) were associated with an increased frequency of antibiotic prescribing. Extrapolation of the findings give an estimated incidence of insect bite consultations in England of 1.5 million annually. CONCLUSION: Two-thirds of the patients presenting to out-of-hours primary care with insect bites receive antibiotics. While some predictors of prescribing have been found, more research is required to understand the optimal use of antibiotics for this common presentation.