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Amina Masood,1 Mohammed Yousuf Karim2 1Locum General Practitioner, The Cambridge Practice, Aldershot, UK; 2Immunology Laboratory, Department of Pathology, Sidra Medicine, Doha, QatarCorrespondence: Mohammed Yousuf Karim Department of Pathology, Sidra Medicine, Al Luqta St, Doha 26999, QatarTel +974 4003 2968Email mkarim@sidra.orgAbstract: Approximately 70% of all healthcare decisions affecting diagnosis and treatment involve the use of tests performed within pathology laboratories. The utilisation of diagnostic laboratory services continues to increase, with growth both in volume of tests requested, as well as in the breadth of test repertoire. Every year in the United Kingdom, approximately 1 billion tests are run in hospital laboratories, equivalent to 14 tests per person. Fifty million tests are requested in primary care. Accordingly, there is an inevitable increase in the number of unexpected laboratory results which clinicians review. This is an important, and potentially time-consuming, issue, which we considered to merit a more detailed discussion. Unexpected laboratory results may be critical or non-critical in nature. They may be absolutely genuine, reflecting a clinical change in the patient’s condition, a differential diagnosis not previously considered, or an additional test specifically added by the laboratory. However, such results may also occur due to a variety of different circumstances, including much more rarely laboratory error. As there is little published evidence or guidance available, herein we discuss aspects of the clinical approach for physicians after receiving an unexpected laboratory test result.Keywords: pathology, critical, non-critical, error, communication, diagnosis, assay

The antiphospholipid or Hughes syndrome is the association between antiphospholipid antibodies (aPL), venous and arterial thromboses and pregnancy morbidity. Antiphospholipid syndrome (APS) commonly coexists with autoimmune diseases usually systemic lupus erythematosus (SLE), when it is known as secondary APS. When present in isolation it is known as primary APS (PAPS). Although the kidney may be affected in APS, its involvement is perhaps not as well described as that of other organs. Thrombotic microangiopathy (TMA) affecting the kidney has been reported as a manifestation in both primary and secondary APS. This report describes hypertension related to underlying renal TMA as a presenting symptom of APS. [ABSTRACT FROM AUTHOR]

Unresponsive autoimmune haemolytic anaemia (AIHA) may require therapy with second-line drugs. There is no consensus that any one of these agents is more effective than another. Mycophenolatemofetil (MMF) is an immunosuppressive drug proven to be effective in reducing renal allograftrejectionas well as being used in autoimmune diseases including systemic lupus erythematosus (SLE). We describe its use in two patients who were treated with MMF for AIHA in the context of underlying SLE and antiphospholipid syndrome (APS). The patients showed a good response to treatment with MMF, suggesting a possible role in the treatment of AIHA. [ABSTRACT FROM AUTHOR]

Background: The global pandemic caused by SARS-CoV-2 has underlined the significance of strict genomic surveillance to track virus evolution and the possible emergence of new variants, particularly in densely populated countries like Bangladesh. This study outlines a strategic framework of genomic surveillance to track the evolution of the virus in Bangladesh between June 2021 and December 2022 through the National SARS-CoV-2 Variant Surveillance (NSVS) program involving collaboration across 4 major institutes and 13 hospitals nationwide., Methods: We aimed to capture the variants of SARS-CoV-2 throughout the country utilizing standardized procedures, modern sequencing technology, and stringent quality control, promoting data accuracy and the timely detection of new variants of concern. We sequenced over 2200 genomes, documenting the prevalence of the Delta variant initially, followed by the emergence of Omicron variants BA.1, BA.2, BA.5, and XBB, each affecting transmission rates and vaccine efficacy differently., Results: The clinical manifestations of the variants differed, with some symptoms occurring more frequently in Delta cases and vice versa. Vaccinated individuals were more affected by Omicron cases compared to Delta cases. These variants were responsible for two major COVID-19 waves in the country, each with significant clinical effects. Phylogenetic analyses placed the local SARS-CoV-2 variants within a global context, indicating the Delta variant likely entered from India and Omicron from Europe., Conclusion: This research highlights the significance of collaborative surveillance strategies for guiding public health choices and the critical role of genomic analysis in monitoring virus evolution, shaping targeted pandemic responses. Bangladesh's contributions significantly enhance global insight into COVID-19's genomic evolution., (© 2024 The Author(s). Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We report 18 coding-complete genome sequences of emerging SARS-CoV-2 Omicron sub-lineages JN.1, JN.1.4, and JN.1.11 from Bangladesh. Nasopharyngeal swab samples were obtained from individuals with COVID-19 symptoms between December 2023 and January 2024. Whole genome sequencing was performed following the ARTIC Network-based protocol using Oxford Nanopore Technology., Competing Interests: The authors declare no conflict of interest.

Purpose: The interleukin-7 receptor (IL-7R) is primarily expressed on lymphoid cells and plays a crucial role in the development, proliferation, and survival of T cells. Autosomal recessive mutations that disrupt IL-7Rα chain expression give rise to a severe combined immunodeficiency (SCID), which is characterized by lymphopenia and a T - B + NK + phenotype. The objective here was to diagnose two siblings displaying the T - B + NK + SCID phenotype as initial clinical genetic testing did not detect any variants in known SCID genes., Methods: Whole genome sequencing (WGS) was utilized to identify potential variants causing the SCID phenotype. Splicing prediction tools were employed to assess the deleterious impact of the mutation. Polymerase Chain Reaction (PCR), Sanger sequencing, flow cytometry, and ELISA were then used to validate the pathogenicity of the detected mutation., Results: We discovered a novel homozygous synonymous mutation in the IL7R gene. Our functional studies indicate that this variant is pathogenic, causing exon 6, which encodes the transmembrane domain, to be preferentially spliced out., Conclusion: In this study, we identified a novel rare synonymous mutation causing a loss of IL-7Rα expression at the cellular membrane. This case demonstrates the value of reanalyzing genetic data based on the clinical phenotype and highlights the significance of functional studies in determining the pathogenicity of genetic variants., (© 2024. The Author(s).)

Background: Immunomodulatory processes exert steering functions throughout pregnancy. Detecting diversions from this physiologic immune clock may help identify pregnant women at risk for pregnancy-associated complications. We present results from a data-driven selection process to develop a targeted panel of mRNAs that may prove effective in detecting pregnancies diverting from the norm., Methods: Based on a de novo dataset from a resource-constrained setting and a dataset from a resource-rich area readily available in the public domain, whole blood gene expression profiles of uneventful pregnancies were captured at multiple time points during pregnancy. BloodGen3, a fixed blood transcriptional module repertoire, was employed to analyze and visualize gene expression patterns in the two datasets. Differentially expressed genes were identified by comparing their abundance to non-pregnant postpartum controls. The selection process for a targeted gene panel considered (i) transcript abundance in whole blood; (ii) degree of correlation with the BloodGen3 module; and (iii) pregnancy biology., Results: We identified 176 transcripts that were complemented with eight housekeeping genes. Changes in transcript abundance were seen in the early stages of pregnancy and similar patterns were observed in both datasets. Functional gene annotation suggested significant changes in the lymphoid, prostaglandin and inflammation-associated compartments, when compared to the postpartum controls., Conclusion: The gene panel presented here holds promise for the development of predictive, targeted, transcriptional profiling assays. Such assays might become useful for monitoring of pregnant women, specifically to detect potential adverse events early. Prospective validation of this targeted assay, in-depth investigation of functional annotations of differentially expressed genes, and assessment of common pregnancy-associated complications with the aim to identify these early in pregnancy to improve pregnancy outcomes are the next steps., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Brummaier, Rinchai, Toufiq, Karim, Habib, Utzinger, Paris, McGready, Marr, Kino, Terranegra, Al Khodor, Chaussabel and Syed Ahamed Kabeer.)

Asthma and obesity are two of the most common chronic conditions in children and adolescents. There is increasing evidence that sphingolipid metabolism is altered in childhood asthma and is linked to airway hyperreactivity. Dysregulated sphingolipid metabolism is also reported in obesity. However, the functional link between sphingolipid metabolism, asthma, and obesity is not completely understood. This paper describes the protocol of an ongoing study on sphingolipids that aims to examine the pathophysiology of sphingolipids in childhood asthma and obesity. In addition, this study aims to explore the novel biomarkers through a comprehensive multi-omics approach including genomics, genome-wide DNA methylation, RNA-Seq, microRNA (miRNA) profiling, lipidomics, metabolomics, and cytokine profiling. This is a cross-sectional study aiming to recruit 440 children from different groups: children with asthma and normal weight ( n = 100), asthma with overweight or obesity ( n = 100), overweight or obesity ( n = 100), normal weight ( n = 70), and siblings of asthmatic children with normal weight, overweight, or obesity ( n = 70). These participants will be recruited from the pediatric pulmonology, pediatric endocrinology, and general pediatric outpatient clinics at Sidra Medicine, Doha, Qatar. Information will be obtained from self-reported questionnaires on asthma, quality of life, food frequency (FFQ), and a 3-day food diary that are completed by the children and their parents. Clinical measurements will include anthropometry, blood pressure, biochemistry, bioelectrical impedance, and pulmonary function tests. Blood samples will be obtained for sphingolipid analysis, serine palmitoyltransferase (SPT) assay, whole-genome sequencing (WGS), genome-wide DNA methylation study, RNA-Seq, miRNA profiling, metabolomics, lipidomics, and cytokine analysis. Group comparisons of continuous outcome variables will be carried out by a one-way analysis of variance or the Kruskal-Wallis test using an appropriate pairwise multiple comparison test. The chi-squared test or a Fisher's exact test will be used to test the associations between categorical variables. Finally, multivariate analysis will be carried out to integrate the clinical data with multi-omics data. This study will help us to understand the role of dysregulated sphingolipid metabolism in obesity and asthma. In addition, the multi-omics data from the study will help to identify novel genetic and epigenetic signatures, inflammatory markers, and mechanistic pathways that link asthma and obesity in children. Furthermore, the integration of clinical and multi-omics data will help us to uncover the potential interactions between these diseases and to offer a new paradigm for the treatment of pediatric obesity-associated asthma.

Background: Allergic disorders are the consequence of IgE sensitization to allergens. Population studies have shown that certain human leukocyte antigen (HLA) alleles are associated with increased or decreased risk of developing allergy., Objective: We aimed to characterize the relationship between HLA class II allelic diversity and IgE sensitization in an understudied Arab population., Methods: We explored associations between IgE sensitization to 7 allergen mixes and mesquite (comprising 41 food or aeroallergens) and 45 common classical HLA class II alleles in a well-defined cohort of 797 individuals representing the general adult population of Qatari nationals and long-term residents. To do so, we performed HLA calling from whole genome sequencing data at 2-field resolution using 2 independent algorithms. We then applied 3 different regression models to assess either each allergen mix independently, in the context of IgE sensitization to other allergens tested, or polysensitization., Results: More than half (n = 447) of the study participants showed IgE sensitization to at least 1 allergen, most of them (n = 400) to aeroallergens (Phadiatop). We identified statistically significant negative and positive associations with 24 HLA class II alleles. These have been reported to confer risk or protection from variety of diseases; however, only a few have previously been associated with allergy in other populations., Conclusions: Our study reveals several new risk and protective genetic markers for allergen-specific IgE sensitization. This is a first and essential step toward a better understanding of the origins of allergic diseases in this understudied population., (© 2023 The Author(s).)

Background: Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins., Objective: We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency., Methods: We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays., Results: We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). A third individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact., Conclusions: Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic spontaneous urticaria (CSU) can be extremely debilitating to the patient and challenging for the treating clinician. The National Institute of Health and Clinical Excellence (NICE) in the United Kingdom (UK) recommendation of omalizumab for patients who fail to respond to high-dose anti-histamines has improved treatment options and quality of life. However, there is still lack of clear guidelines for treatment of patients resistant to standard and anti-IgE therapies., Methods: We discuss the therapeutic strategies employed among nine extremely resistant CSU cases and the heterogeneity between guidelines from different societies., Results: Patients with anti-histamine-resistant urticaria either remained on omalizumab or started on immunosuppressive drugs (dapsone or ciclosporin) when they stopped responding to omalizumab. We used clinical assessment, skin biopsies (when available) and previous published reports to consider dapsone (for predominantly neutrophilic infiltration), or ciclosporin at doses between 2 and 4 mg/kg/day. One patient with ciclosporin-resistant urticaria responded to mycophenolate mofetil. Two patients remain on long-term omalizumab due to its relative safety and efficacy including 1 patient with underlying antibody deficiency where omalizumab was preferred over risks of using immunosuppressive medications., Conclusions: These case studies bring to light the real-world difficulties in managing patients with resistant CSU and the need for generating the evidence base on alternative therapeutic options such as synergistic use of biologics and immunosuppressive drugs., (© The Author(s) 2022.)

Purpose: Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls., Methods: The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing., Results: The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient's whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens., Conclusion: Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells., (© 2021. The Author(s).)

To describe the clinical features, epidemiology, autoantibody status, HLA haplotypes and genetic mechanisms of type 1 diabetes mellitus (T1DM). Patients (0-18 years) with diabetes were recruited. Clinical data was collected, autoantibodies and c-peptide were measured. Whole Genome Sequencing was performed. Genomic data analysis was compared with the known genes linked with T1DM and HLA alleles were studied. 1096 patients had one or more antibody positivity. The incidence of T1DM in 2020 was 38.05 per 100,000 children and prevalence was 249.73. GADA was the most common autoantibody followed by IAA. Variants in GSTCD, SKAP2, SLC9B1, BANK1 were most prevalent. An association of HLA haplotypes DQA1*03:01:01G (OR = 2.46, p value = 0.011) and DQB1*03:02:01G (OR = 2.43, p value = 0.022) was identified. The incidence of T1DM in Qatar is the fourth highest in the world, IA2 autoantibody was the most specific with some patients only having ZnT8 or IA2 autoantibodies thus underlining the necessity of profiling all 4 autoantibodies. The genes associated with T1DM in the Arab population were different from those that are common in the Caucasian population. HLA-DQ was enriched in the Qatari patients suggesting that it can be considered a major risk factor at an early age., (© 2021. The Author(s).)

Background: The number of fatal pedestrian injuries in the United States has steadily increased over the past decade. Multiple factors likely contribute to this trend, but the growth of pedestrians distracted by mobile devices is widely hypothesized to play a major role. Existing strategies to reduce distracted pedestrian behavior are few and mostly ineffective. The present study evaluated StreetBit, a mostly-passive primary prevention program to reduce distracted pedestrian behavior by alerting distracted pedestrians directly on their smartphone when they approach an intersection, reminding them to attend to traffic as they crossed., Methods: 385 individuals who regularly crossed a target street corner at an urban university downloaded StreetBit on their phones and participated in a crossover design study whereby the app was inactive for 3 weeks (baseline behavior phase), actively provided alerts for 3 weeks (intervention phase), and then was inactive again for 4 weeks (post-intervention phase). User distraction while crossing the intersection was collected electronically for a total of 34,923 street-crossing events throughout the 10-week study., Results: In crude (unadjusted) models, participant distraction was similar across all phases of the research; this result was maintained after adjusting for potential covariates as well as after conducting a sensitivity analysis limited to data from only week 3 of each study intervention phase. In a model stratified by phone/warning type and baseline distraction rates, Android phone users who received a warning that blocked the full screen and had a high baseline distraction rate (≥75% distracted crossings) had a 64% decreased odds of distraction during the alert phase (OR 0.36, 95% CI 0.25-0.51) and a 52% decreased odds of distraction during the post-intervention phase (OR 0.48, 95% CI 0.25-0.94). Users reported positive impressions about the StreetBit app in a post-intervention survey., Discussion: StreetBit, an innovative app designed to prevent distracted pedestrian behavior through a mostly-passive primary prevention strategy relying on intrusive reminders, proved effective among smartphone users who received a warning blocking the full screen and who were frequently distracted at baseline, but not among other users. The results appear to reflect the confluence of two influencing factors. First, due to software development limitations, visually-distracted Android users received a highly intrusive app warning that blocked their smartphone screen whereas iOS users received a less intrusive banner notification blocking a small upper portion of the screen. Second, most users were curious to see if the app was functioning properly, creating artificially-inflated estimates of distraction as users purposefully watched their phones when crossing. Thus, our results indicate promise for StreetBit as an effective intervention and warrant continued software development and empirical testing., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Transcriptome profiling approaches have been widely used to investigate the mechanisms underlying psoriasis pathogenesis. Most researchers have measured changes in transcript abundance in skin biopsies; relatively few have examined transcriptome changes in the blood. Although less relevant to the study of psoriasis pathogenesis, blood transcriptome profiles can be readily compared across various diseases. Here, we used a pre-established set of 382 transcriptional modules as a common framework to compare changes in blood transcript abundance in two independent public psoriasis datasets. We then compared the resulting "transcriptional fingerprints" to those obtained for a reference set of 16 pathological or physiological states. The perturbations in blood transcript abundance in psoriasis were relatively subtle compared to the changes we observed in other autoimmune and auto-inflammatory diseases. However, we did observe a consistent pattern of changes for a set of modules associated with neutrophil activation and inflammation; interestingly, this pattern resembled that observed in patients with Kawasaki disease. This similarity between the blood-transcriptome signatures in psoriasis and Kawasaki disease suggests that the immune mechanisms driving their pathogenesis might be partially shared., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Rawat, Rinchai, Toufiq, Marr, Kino, Garand, Tatari-Calderone, Kabeer, Krishnamoorthy, Bedognetti, Karim, Sastry and Chaussabel.)

This is a series of 4 cases (3 therapeutic failure and 1 early relapse) in adult patients treated with allergen immunotherapy (AIT) for allergic rhinitis (AR) in our immunotherapy clinic, which treats 110 new patients per year. AIT includes both subcutaneous and sublingual routes. The current national/international AIT recommendations and the literature have been searched to identify guidance for the optimal management of therapeutic failure of AIT in AR. There is scant information available to support clinicians when treatment failure and/or intolerable side effects occur. The importance is highlighted for developing the guidance and evidence base for the benefit of this patient subgroup. The potential strategies that clinicians have proposed are discussed in this article, though it is acknowledged that these are mostly not evidence-based., (© The Author(s) 2020.)

The majority of medical students and many physicians find basic science immunology confusing and the teaching of immunology to be uninteresting. Physicians undergoing training in a range of disciplines treat patients with immunological disease, including allergy/immunology and rheumatology. It is essential for senior medical students and physicians to understand the pathology of immune diseases and the pharmacology of immune interventions. In order to optimize this learning, underlying concepts of basic immunology need to be revised, or sometimes learned for the first time. Teachers may need to overcome baseline attitudinal negativity. Medical students and postgraduates are more able to relate to basic immunology if approached through a clinical route. Case presentations and case-based discussions are a familiar format for medical students and physicians, though typically utilized to enhance understanding of clinical presentation, investigation, and treatment. Hence, they may be more receptive to "difficult" immunology concepts when presented in a familiar teaching framework. Although there is data supporting case-based learning for basic immunology in medical students, there is little data in physicians. Extrapolating from the medical student literature, I devised a program of clinical cases for physicians whereby understanding the immunopathological basis of the condition and/or its immunological treatment was employed as a platform to appreciate the basic science immunology in more depth. A variety of cases were selected to illustrate different immunological topics. The sessions were small group and highly interactive in nature. As this programme has only recently been introduced, formal evaluation has yet to be concluded., (Copyright © 2020 Karim.)

Background: Infections with multidrug-resistant organisms (MDRO) pose a serious threat to patients with dysregulated immunity such as in hemophagocytic lymphohistiocytosis (HLH), but such infections have rarely been comprehensively characterized. Here, we present a fatal case of HLH secondary to cytomegalovirus (CMV) infection complicated by both anti-viral drug resistance and sepsis from multiple MDROs including pandrug-resistant superbug bacteria., Case Presentation: A previously healthy, six-year-old boy presented with a 45-day history of fever prior to a diagnosis of hemophagocytic lymphohistiocytosis and hemorrhagic colitis, both associated with CMV. On hospital admission, the patient was found to be colonized with multiple, multidrug-resistant (MDR) bacteria including vancomycin-resistant enterococci (VRE) and carbapenamase-producing organisms (CPO). He eventually developed respiratory, urine and bloodstream infections with highly drug-resistant, including pandrug-resistant bacteria, which could not be controlled by antibiotic treatment. Antiviral therapy also failed to contain his CMV infection and the patient succumbed to overwhelming bacterial and viral infection. Whole genome sequencing (WGS) of the MDR bacteria and metagenomic analysis of his blood sample revealed an unusual accumulation of a wide range of antimicrobial resistance mechanisms in a single patient, including antiviral resistance to ganciclovir, and resistance mechanisms to all currently available antibiotics., Conclusions: The case highlights both the risk of acquiring MDR superbugs and the severity of these infections in HLH patients.

Background: Multiplex bead assays, also known as addressable laser bead immunoassays (ALBIA) or Luminex® technology, have provided an alternative to enzyme-linked immunoassay, which is still the most widely utilized routine immunoassay for detection of specific autoantibodies. Our laboratory adopted the ALBIA technology early into its routine service., Methods: We report the performance and utility of measurement of three different autoantibody types tested using the FIDIS (BMD, Marne La Vallee, France) ALBIA system. The analytes discussed are thyroid antibodies (thyroglobulin [TG], thyroid peroxidase [TPO]), anti-neutrophil cytoplasmic antibodies (ANCA), and ribonucleo-protein (RNP) antibodies., Results: In single antibody analysis, TPO antibody testing was superior to TG antibody in identifying patients with Graves' disease and Hashimoto's thyroiditis. However, testing only TPO antibody would result in missing 8.6% of Graves' and 11.9% of Hashimoto's thyroiditis patients, hence demonstrating an advantage for the multiplex TG plus TPO assay. With respect to ANCA, the FIDIS ALBIA produced an overall similar level of performance to our comparator method, the Phadia fluorescent enzyme linked immunoassay. Sensitivity of the ALBIA for RNP antibodies was low in comparison to countercurrent immunoelectrophoresis, but performance was improved by altering the cutoff value for the assay., Conclusions: ALBIA technology has many potential advantages in the routine laboratory, but as with any new assay, evaluation must be thorough and ongoing to ensure satisfactory clinical performance is obtained. Both false positive and false negative results have been reported in ALBIA studies. It may be necessary to re-evaluate assay performance and cutoff and consider further clinical correlation.

Background: Hypogammaglobulinemia is a complication of B-cell targeting therapies (BCTT), used in vasculitis, rheumatoid arthritis and systemic lupus erythematosus (SLE). Since autoimmune diseases are associated with underlying and induced immune abnormalities, several societies recommend assessing immune function before and during rituximab treatment. In SLE, polyclonal hypergammaglobulinemia is the typical alteration of gammaglobulins, though hypogammaglobulinemia has also been reported., Methods: This is a cross-sectional study describing immunoglobulin levels measured as part of routine care in patients with lupus nephritis, a group with multiple factors contributing to immunoglobulin abnormalities, including immune dysregulation, immunosuppression and nephrotic syndrome., Results: Polyclonal hypergammaglobulinemia occurred in 15/83 (18.1%) patients. In contrast, low levels of immunoglobulins were found as follows: selective IgA deficiency 2/83 (2.4%), reduced IgG levels 7/83 (8.4%), reduced IgM 14/83 (16.9%). Only 1 patient required immunoglobulin replacement., Conclusions: Immunoglobulin abnormalities are frequently found in lupus nephritis, ranging from polyclonal hypergammaglobulinemia to hypogammglobulinemia. Consequently, immunoglobulin levels should be assessed prior to commencing BCTT., Competing Interests: Competing interestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

B-cell targeted therapies (BCTT) are now widely used in autoimmune rheumatic diseases, including SLE, antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. Early studies suggested that rituximab did not influence serum immunoglobulins. However, subsequently, with increased patient numbers, longer follow-up duration and many patients having received multiple BCTT courses, multiple subsequent studies have identified hypogammaglobulinaemia as a potential side effect. Patients developing hypogammaglobulinaemia appear to fit into two principal categories: the majority who develop transient, often mild reduction in immunoglobulins without increased infection and a much smaller but clinically significant group with a more sustained antibody deficiency, who display increased risk of infection. Monitoring immunoglobulin levels represents an opportunity for the early detection of hypogammaglobulinaemia, and the prevention of avoidable morbidity. In the two major studies, approximately 4%-5% of BCTT-treated patients required immunoglobulin replacement due to recurrent infections in the context of hypogammaglobulinaemia. Despite this, monitoring of immunoglobulins is suboptimal, and there remains a lack of awareness of hypogammaglobulinaemia as an important side effect., Competing Interests: Competing interests: DJ has received research grants from Roche/Genentech. From August 2017 to February 2018, SW was a Clinical Research Fellow supported by an unrestricted grant from Roche Products (UK) to undertake a Systematic Literature Review on hypogammaglobulinaemia after B-cell targeted therapies. MYK, CM and DJ were co-applicants on that grant (grant number GDRC-FEB-001-2017).

Objectives: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases., Methods: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology., Results: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82-100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy., Conclusion: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Consensus guidelines are not available for the use of immunoglobulin replacement therapy (IGRT) in patients developing iatrogenic secondary antibody deficiency following B-cell targeted therapy (BCTT) in autoimmune rheumatic disease., Objectives: To evaluate the role of IGRT to manage hypogammaglobulinemia following BCTT in autoimmune rheumatic disease (AIRD)., Methods: Using an agreed search string we performed a systematic literature search on Medline with Pubmed as vendor. We limited the search to English language papers with abstracts published over the last 10 years. Abstracts were screened for original data regarding hypogammaglobulinemia following BCTT and the use of IGRT for hypogammaglobulinemia following BCTT. We also searched current recommendations from national/international organisations including British Society for Rheumatology, UK Department of Health, American College of Rheumatology, and American Academy of Asthma, Allergy and Immunology., Results: 222 abstracts were identified. Eight papers had original relevant data that met our search criteria. These studies were largely retrospective cohort studies with small patient numbers receiving IGRT. The literature highlights the induction of a sustained antibody deficiency, risk factors for hypogammaglobulinemia after BCTT including low baseline serum IgG levels, how to monitor patients for the development of hypogammaglobulinemia and the limited evidence available on intervention thresholds for commencing IGRT., Conclusion: The benefit of BCTT needs to be balanced against the risk of inducing a sustained secondary antibody deficiency. Consensus guidelines would be useful to enable appropriate assessment prior to and following BCTT in preventing and diagnosing hypogammaglobulinemia. Definitions for symptomatic hypogammaglobulinemia, intervention thresholds and treatment targets for IGRT, and its cost-effectiveness are required., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: Current non-invasive methods of assessing disease activity in systemic lupus erythematosus (SLE) are of limited sensitivity and specificity. Testing includes acute phase markers, autoantibodies and complement levels. Although measurements of dsDNA antibodies and complement C3/C4 levels are routine, they remain of limited value. Improved blood and urine markers may help in early detection of flare, distinction between flare and chronic damage, and monitoring response to therapy., Methods: A total of 87 patients with SLE were tested for the following cytokines in serum and urine: monocyte chemoattractant protein 1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), soluble tumour necrosis factor receptor 1 (sTNF-R1), interferon-inducible protein 10 (IP-10), monocyte inhibitory protein 1α (MIP-1α) and vascular endothelial growth factor (VEGF). Patients attending the Lupus Unit at St Thomas' Hospital, London, UK were divided into active lupus nephritis (LN), inactive LN and non-renal SLE groups based on their renal pathology and SLE disease activity index (SLEDAI). Cytokine testing was performed using the FIDIS multiplex bead assay., Results: The mean level of serum sTNF-R1 was higher in the active LN group compared with both inactive LN and non-renal SLE groups ( p < 0.001). For urine measurements there were significant differences between active LN and non-renal SLE for VEGF ( p = 0.016), after statistical correction for multiple testing. Both urinary and serum sTNF-R1 and IP-10 levels correlated with SLEDAI scores ( p < 0.001), while serum VEGF correlated weakly with SLEDAI ( p = 0.025). The optimum combination for differentiating active from inactive LN patients was serum VEGF, sTNF-R1, MCP-1 and glomerular filtration rate plus urinary sTNF-R1 and protein-creatinine ratio., Conclusion: These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for VEGF in the urine. This study has confirmed the ability of the multiplex bead technique to detect cytokines in a good analytical range, including very low and high levels, in both serum and urine. Combining serum and urine markers provided additional sensitivity in distinguishing active from inactive LN.

Purpose: To investigate the safety of trivalent seasonal influenza vaccine (TIVc) (Optaflu ® ), the first cell culture seasonal trivalent influenza vaccine available in Europe., Methods: Codes and unstructured text in adult electronic healthcare records (The Health Improvement Network) were searched for a TIVc brand name or batch number and possible outcomes within a 3 month pre- to 6 month post-TIVc exposure study period (2012-2015). The outcomes were severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis (optic and brachial), vasculitis, inflammatory bowel disease, and thrombocytopenia. Risk periods were defined based on biologically plausible time frame postvaccination when an outcome caused by the vaccine might be expected to occur. Possible outcomes were adjudicated against outcome specific case definitions and a date of onset assigned by using electronic and other medical records. Observed (risk period) to expected (outside risk and preexposure periods) rate ratios, postexposure incidence, and plots of time from exposure to outcome were reported., Results: Sixteen of 1011 events from 4578 exposures fulfilled a primary case definition and had a date of onset during the study period. Three were in observed time. The observed-to-expected rate ratios were (3.3, 95% CI 0.3, 31.7) for convulsions and (1.5, 95% CI 0.2, 14.9) for thrombocytopenia with 1 outcome each in observed time. There was 1 incident inflammatory bowel disease in observed, but none in expected, time., Conclusion: The small sample size restricts interpretation; however, no hypothesis of an increased risk of a study outcome was generated. Adjudication of events against case definitions to reduce misclassification of onset and outcomes allowed use of precise risk periods. KEY POINTS This observational study did not generate a hypothesis of an association between the first cell-culture seasonal influenza vaccination available in the European Union and any of the study outcomes (severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis [optic and brachial], vasculitis, inflammatory bowel disease [IBD], and thrombocytopenia). The small sample size limits interpretation of the results. The review of each possible outcome identified from electronic healthcare records against case definitions was included to minimize misclassification of time and outcomes and allow the use of precise risk-periods in an observed-to-expected within cohort analysis. Plots of time from exposure to outcome were included to assess the risk windows., (Copyright © 2017 John Wiley & Sons, Ltd.)

Management of systemic vasculitis has been revolutionised over the last decade with the introduction of targeted biological agents. With an increase in both the prevalence and the recognition of vasculitis as well as the high cost of these agents, it is important to ensure their most optimal utilisation. The goals of vasculitis therapy include the induction and maintenance of remissions, preventing relapses, reducing the toxicity of therapy with the aim of reducing morbidity and mortality as well as improving the quality of life of those afflicted. This review focuses on the recent advances in the diagnosis, surveillance and treatment of these conditions., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

We experimentally study quasi-two-dimensional dilute granular flow around intruders whose shape, size, and relative impact speed are systematically varied. Direct measurement of the flow field reveals that three in-principle independent measurements of the nonuniformity of the flow field are in fact all linearly related: (1) granular temperature, (2) flow-field divergence, and (3) shear-strain rate. The shock front is defined as the local maxima in each of these measurements. The shape of the shock front is well described by an inverted catenary and is driven by the formation of a dynamic arch during steady flow. We find universality in the functional form of the shock front within the range of experimental values probed. Changing the intruder size, concavity, and impact speed only results in a scaling and shifting of the shock front. We independently measure the horizontal lift force on the intruder and find that it can be understood as a result of the interplay between the shock profile and the intruder shape.

Drug allergy is defined as an adverse drug reaction with an established immunological mechanism. The National Institute for Health and Care Excellence published clinical guidelines on drug allergy in 2014 and quality standards in 2015. The intention of this article is to highlight indications for referral to specialists for management of drug allergy. Accurate diagnosis of drug allergy is critical of course for patient safety, but also for better use of the drugs that we have available and to reduce unnecessary avoidance of drugs. However, there are significant limitations in terms of resource availability and also in terms of testing. There is a careful balance here in that drug allergy is very common and clearly there is neither indication nor sufficient resource in the NHS for all patients with drug allergy to be reviewed by a specialist. It is, therefore, important to highlight to general physicians and physicians of other specialties, those patients who do require referral for specialist review., (© Royal College of Physicians 2016. All rights reserved.)

Low serum immunoglobulin E (IgE) (<2 kU/L) found during allergy investigations may be a marker for other immunodeficiency states, in particular common variable immunodeficiency. The latter is characterised by recurrent infections, mainly respiratory, resulting in structural lung damage making early diagnosis important. We looked through 4013 samples retrospectively over a 12-month period to identify samples with IgE<2 kU/L. We identified 74/4013 (1.84%) with serum IgE levels<2 kU/L. Only 20 samples had serum immunoglobulin quantification and serum electrophoresis requested. Three of these samples were from the same patient, 10/18 (56%) had one or more classes of immunoglobulin above/below reference range for age and two of these had new diagnosis of immunodeficiency. Serum IgE<2 kU/L can be a marker for hypogammaglobulinaemia or common variable immunodeficiency. As early diagnosis is important to reduce morbidity and mortality, very low serum IgE should trigger further investigation—that is, serum protein electrophoresis and immunoglobulin quantification.

The Janssen effect is a unique property of confined granular materials experiencing gravitational compaction in which the pressure at the bottom saturates with an increasing filling height due to frictional interactions with side walls. In this Letter, we replace gravitational compaction with frictional compaction. We study friction-compacted 2D granular materials confined within fixed boundaries on a horizontal conveyor belt. We find that even with high-friction side walls the Janssen effect completely vanishes. Our results demonstrate that gravity-compacted granular systems are inherently different from friction-compacted systems in at least one important way: vibrations induced by sliding friction with the driving surface relax away tangential forces on the walls. Remarkably, we find that the Janssen effect can be recovered by replacing the straight side walls with a sawtooth pattern. The mechanical force introduced by varying the sawtooth angle θ can be viewed as equivalent to a tunable friction force. By construction, this mechanical friction force cannot be relaxed away by vibrations in the system.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by abnormal autoantibody production and clearance. This immunological background has been suggested to play a role in the susceptibility of SLE patients to infection. Moreover, drugs (most of them immunosuppressive or immunomodulating agents) used in the treatment of moderate and severe lupus give rise to a tendency for infections, including opportunistic ones. Infections may mimic the exacerbations of SLE, leading to confusion over the diagnosis and appropriate treatment. Despite increased awareness of this problem, infections remain a major source of morbidity and mortality in SLE. There are various strategies which can be applied to try and reduce the risk of infection in SLE patients. Options include vaccinations, antibiotic/antiviral prophylaxis and intravenous immunoglobulins., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Cytokines play an important role in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. This is currently a very active area of research. Of particular interest is the use of cytokines as biomarkers of disease activity in SLE and lupus nephritis. Can cytokine measurements assist in early detection of renal flare in known lupus nephritis? Can such measurements be used to distinguish between flare and chronic damage? Or help to confirm renal remission? Could they be used to help assess the required duration of immunosuppression and reduce the need for invasive renal biopsy? This review discusses limitations of current laboratory methods in monitoring SLE, how measurements of cytokines may contribute in relation to following disease activity and summarizes what is known about cytokines as biomarkers in SLE and lupus nephritis.

Pregnancy represents a major challenge in the management of patients with systemic lupus erythematosus, with substantial risks to both mother and baby. Over the past 40 years there have been major improvements in outcomes. This partly relates to the discovery of the antiphospholipid syndrome, which has transformed management of lupus pregnancy, but also due to more effective drugs and better obstetric practice. Despite these advances, significant maternal and fetal morbidity may still occur in patients with lupus nephritis, and there remain ongoing challenges in order to improve outcomes further. In this article we focus on the challenges facing lupus nephritis patients considering pregnancy, and discuss how we approach practical management issues in relation to the current literature.

There have been significant advances in the treatment of SLE, which have produced major impacts on morbidity and in some cases mortality. The major drugs of the last three decades in treatment of SLE have been corticosteroids, AZA, MTX and cyclophosphamide. However, these drugs have considerable toxicities, and with the increasing knowledge of the immune system, and further understanding of SLE immunopathogenesis, many groups are seeking to identify and trial novel immunotherapeutic strategies. These have included therapies aimed at influencing particular immune cells (e.g. B cells) and molecules (e.g. costimulatory molecules, cytokines) which are thought to be important in disease pathogenesis. The advantage of such therapies is that efficacy may be achieved with lower toxicity, and without wide-ranging suppression of the immune system. Success has not always been achieved by specific design of immunotherapies for SLE, and the best recent example has been the use of B-cell depletion therapy, a concept derived from its successful use in RA. In this article, we discuss those immunotherapeutic strategies that have arrived as far as clinical trials in human subjects. In addition to these relatively specific immunotherapies, we also highlight the use of mycophenolate mofetil, an anti-proliferative immunosuppressant which has had good success over the last 10 yrs, with similar early efficacy to cyclophosphamide when used as induction therapy for lupus nephritis. Data are presented on more generalized immune strategies, such as the use of stem cell transplantation and intravenous immunoglobulin.

Objectives: Systemic lupus erythematosus (SLE) is typically associated with hypergammaglobulinaemia but has been described in the setting of hypogammaglobulinaemia as well. The purpose of this article is to describe various cases of SLE and hypogammaglobulinaemia, review the literature and present management strategies for hypogammaglobulinaemia in SLE., Methods: We describe five patients with SLE and antibody deficiency, and review the literature exploring the relationship between the two., Results: Various types of antibody deficiency syndromes, including common variable immunodeficiency (CVID), IgA deficiency, IgM deficiency, drug-induced hypogammaglobulinaemia and hypogammaglobulinaemia secondary to nephrotic syndrome can occur in SLE. Antibody deficiency states can be treated with antibiotics and replacement immunoglobulin therapy (particularly CVID) but sometimes close monitoring is all that is required., Conclusion: Measurement of immunoglobulin levels is useful in SLE to identify coexisting antibody deficiency and the later development of hypogammaglobulinaemia. This allows monitoring and appropriate treatment to be instituted.

Renal involvement is a serious clinical feature of systemic lupus erythematosus and can present at any stage of the disease. Although its treatment and outcome have improved, lupus nephritis is still a major contributor to morbidity. Autoantibodies, particularly those directed toward nuclear antigens, are a major feature of systemic lupus erythematosus. With respect to nephritis, there are several aspects of lupus autoantibodies that merit attention, including their use in diagnosis and monitoring, and their role in pathogenesis. Anti-dsDNA antibodies are well known, but other important autoantibodies include anti-C1q, antinucleosomal and antiactinin. There has also been interesting work on the relationship of antiphospholipid antibodies with renal disease.

Systemic lupus erythematous (SLE) and immunodeficiency are linked in various ways. For example, rare genetic complement deficiencies can pre-dispose to developing SLE, whilst some treatments for SLE can cause secondary immunodeficiencies. Various case reports describe SLE patients who have concomitant or later develop antibody deficiency, possibly related to immunosuppressive treatment, or possibly related to the lupus itself. Other components of the immune system, innate and adaptive may also be affected. Immunosuppressive treatment may also cause infections in the absence of defects on routine immunological testing. It is important for the clinician to be aware of the associations between SLE and immunodeficiency to ensure optimal investigation and management. This review focuses on aspects of humoral and cellular immunity, and their association with SLE.