Pathology

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Efficacy of Gemcitabine-based chemotherapy in clear cell sarcoma of soft tissue.
(International Institute of Anticancer Research, 2020-12) Cojocaru, Elena; Thway, Khin; Fisher, Cyril; Messiou, Christina; Zaidi, Shane; Miah, Aisha B; Benson, Charlotte; Gennatas, Spyridon; Huang, Paul; Jones, Robin L; Cellular pathology; Medical and Dental; Fisher, Cyril
Background/aim: Clear cell sarcoma (CCS) is an aggressive sarcoma subtype, resistant to conventional anthracycline-based chemotherapy and radiation. The diagnosis is often challenging due to similarities with malignant melanoma. Patients and methods: We aimed to analyse the activity of gemcitabine-based chemotherapy in a cohort of patients with CCS treated at the Royal Marsden Hospital. Results: Five patients with metastatic CCS received gemcitabine as first- or second-line systemic therapy. The median time-to-progression was 10 weeks. The median number of cycles of gemcitabine-based therapy was 3 (range=2-7 cycles). Median overall survival in our cohort was 66 months from the initial diagnosis but in the metastatic setting, the overall survival was reduced to 28 months. Conclusion: Gemcitabine-based therapy has modest activity in CCS. There remains a significant unmet medical need for novel, effective therapies for this disease.
Extramedullary malignant melanotic schwannoma of the spine: Case report and an up to date systematic review of the literature.
(Wolters Kluwer, 2020-10-07) Solomou, Georgios; Dulanka Silva, Adikarige Haritha; Wong, Adrianna; Pohl, Ute; Tzerakis, Nikolaos; Pathology; Medical and Dental; Pohl, Ute
Background: Melanotic schwannoma is a rare variant of schwannoma. Extramedullary melanotic schwannoma originates in the vicinity of nerve roots mimicking other intervertebral disc disorders. Therefore, T1 and T2-weighted MRI sequences become an essential tool for diagnosis. Aside from case reports, no large studies exist to provide consensus on the signal intensities in T1 and T2-weighted MR imaging. Moreover, no clear evidence is available to delineate prognosis. Here, a case report is presented together with a subsequent systematic review of the literature regarding this rare entity. Case description: A 45-year old female presented with a one-year history of insidious onset of neck pain and paraesthesia. Magnetic resonance imaging confirmed an extramedullary lesion along the C6 nerve root with T1-weighted hyperintensity and T2-weighted hypointensity. Despite two surgical decompressions and adjuvant immunotherapy, the patient unfortunately passed away due to metastatic progression. Discussion: According to the systematic review conducted, in over half of the cases of extramedullary melanotic schwannoma, there is local reoccurrence and/or distal metastasis. Moreover, in 64.7% and 70.6% of the cases, the T1-weighted image of the lesion appears hyperintense and hypointense on a T2-weighted image, respectively. It is an aggressive variant of schwannoma, one of the most commonly observed extramedullary tumours presenting to neurosurgical practice. Conclusion: Our results highlight that specific T1 and T2-weighted imaging findings can provide valuable information, enabling early suspicion, influencing the surgical aims and strategy and the timely commencement of relevant immunotherapy. Considering the poor prognosis, early adjuvant therapy with other modalities should be considered.
Differential diagnosis of adipocytic differentiation in androgen-secreting mature ovarian teratoma with Leydig cell hyperplasia.
(Elsevier, 2021-05-08) Mpatsoulis, Diogenis; Nieto J, Joaquin; Lonsdale, Ray; Fisher, Cyril; Mazibrada, Jasenka; Cellular pathology; Medical and Dental; Fisher, Cyril
Mature cystic teratomas (dermoid cysts) of the ovary are very rarely associated with androgen production. The source of androgens in these cysts may be tumours such as Sertoli-Leydig cell tumour or Leydig cell hyperplasia. In this study, we present a case of virilisation in a postmenopausal female patient, where Leydig cell hyperplasia in a mature cystic teratoma was found to be responsible for the production of testosterone. In addition, extensive areas of lipomatous differentiation were identified. These areas showed significant alterations in adipocytic morphology, and differential diagnoses such as spindle cell lipoma (SCL) and atypical lipomatous tumour (ALT) were excluded after additional workup. Adipose tissue is traditionally described as an energy reservoir, but recently it has become clear that adipose tissue is a complex endocrine organ with additional metabolic roles in whole body homeostasis. Exuberant proliferation of lipomatous tissue in this teratoma raises the possibility of a synergistic role of Leydig cells and adipocytes in the development of hyperandrogenism.
Discovered cancers at postmortem donor examination: A starting point for quality improvement of donor assessment.
(W.B. Saunders, 2021-02-20) Girolami, Ilaria; Neil, Desley; Segev, Dorry Lidor; Furian, Lucrezia; Zaza, Gianluigi; Boggi, Ugo; Gambaro, Giovanni; De Feo, Tullia; Casartelli-Liviero, Marilena; Cardillo, Massimo; Lombardini, Letizia; Zampicinini, Laura; D'Errico, Antonietta; Eccher, Albino; Cellular Pathology; Medical and Dental; Neil, Desley
Background: clinical and imaging investigations allow a detailed assessment of an organ donor, but a quota of cancer still elude detection. Complete autopsy of donors is even less frequently performed, due to economic issues and increasing availability of high-quality imaging. The aim of this study is to gather evidence from the literature on donor malignancy discovered at autopsy following organ donation and to discuss the utility and limitations of autopsy practice in the field of transplantation. Methods: A systematic search according to PRISMA guidelines was carried out in Pubmed and Embase databases until September 2020 to select articles with reporting of cancer discovered in a donor at postmortem examination. Cancer discover in not-transplant setting were excluded. A descriptive synthesis was provided. Results: Of 7388 articles after duplicates removal, 56 were included. Fifty-one studies reported on complete autopsy, while 5 dealt only with limited autopsy (prostate and central nervous system). The number of autopsies ranged between 1 and 246 with a total of 823 autopsies performed. The most frequent cancer discovered at autopsy was lymphoma (n = 13, 15%), followed by renal cell carcinoma (RCC) (n = 11, 13%), non-small cell lung cancer (NSCLC) (n = 10, 11%), melanoma (n = 10, 11%), choriocarcinoma (n = 6, 7%) and glioblastoma (GBM) (n = 6, 7%). Conclusions: Lymphoma and melanoma are still difficult-to-detect cancers both during donor investigation and at procurement, whilst prostate cancer and choriocarcinoma are almost always easily detected nowadays thank to blood markers and clinical examination. There have been improvements with time in pre-donation detection procedures which are now working well, particularly when complete imaging investigations are performed, given that detection rate of CT/MRI is high and accurate. Autopsy can play a role to help to establish the correct donor management pathways in case of cancer discover. Furthermore, it helps to better understand which cancers are still eluding detection and consequently to refine guidelines' assessment procedures.
Microscopic changes in the multifidus muscle in people with low back pain associated with lumbar disc herniation.
(Nature Publishing Group, 2024-12-30) Purushotham, Shilpa; Hodson, Nathan; Greig, Carolyn; Gardner, Adrian; Falla, Deborah
Lumbar disc herniation (LDH) is a common degenerative condition causing low back pain (LBP) due to nerve compression. Previous studies show conflicting findings regarding the multifidus (MF) muscle's microscopic changes in LDH patients. So, this study aimed to compare the affected MF to the adjacent MF on the ipsilateral and contralateral sides in LDH patients and examined correlations with clinical features of LBP. Four muscle biopsies were collected from each of 30 surgical participants. Immunohistochemistry was performed on tissue sections and imaged with an epifluorescence microscope. Data was analysed using a two-way ANOVA for muscle fibre cross-sectional area, perimeter, diameter, and composition, while pathological fibres were analysed using a one-way ANOVA. Pearson's correlation was employed to examine MF microscopy associations with clinical features. Results revealed no significant differences between the affected MF and MF from other sites, though significantly more pathological fibres were present in the affected MF (p < 0.05). A weak but significant negative correlation was found between type I fibres and LBP clinical features, though no such correlations were observed for type IIA fibres. In conclusion, LDH primarily impacts the pathological status of the MF rather than fibre phenotype or size, and severity of clinical features is associated with the size of type I fibres.
Severe conflict-associated wound infections complicated by the discovery of carbapenemase-coproducing Pseudomonas aeruginosa in Ukraine.
(Elsevier Ltd., 2024-12-06) Pallett, Scott J C; Morkowska, Anna; Woolley, Stephen D; O'Shea, Matthew K; Moore, Luke S P; Moshynets, Olena; Pathology; Medical and Dental; O'Shea, Matthew
No abstract available.
Longitudinal genomic surveillance of a UK intensive care unit shows a lack of patient colonisation by multi-drug-resistant Gram-negative bacterial pathogens.
(Microbiology Society, 2024-11-10) Snaith, Ann E; Moran, Robert A; Hall, Rebecca J; Casey, Anna; Ratcliffe, Liz; van Schaik, Willem; Whitehouse, Tony; McNally, Alan; University of Birmingham; University Hospitals Birmingham NHS Foundation Trust; Pathology; Research & Development; Critical Care; Healthcare Scientists; Medical and Dental; Casey, Anna; Ratcliffe, Liz; Whitehouse, Tony
Vulnerable patients in an intensive care unit (ICU) setting are at high risk of infection from bacteria including gut-colonising Escherichia coli and Klebsiella species. Complex ICU procedures often depend on successful antimicrobial treatment, underscoring the importance of understanding the extent of patient colonisation by multi-drug-resistant organisms (MDROs) in large UK ICUs. Previous work on ICUs globally uncovered high rates of colonisation by transmission of MDROs, but the situation in UK ICUs is less understood. Here, we investigated the diversity and antibiotic resistance gene (ARG) carriage of bacteria present in one of the largest UK ICUs at the Queen Elizabeth Hospital Birmingham (QEHB), focusing primarily on E. coli as both a widespread commensal and a globally disseminated multi-drug-resistant pathogen. Samples were taken during highly restrictive coronavirus disease 2019 (COVID-19) control measures from May to December 2021. Whole-genome and metagenomic sequencing were used to detect and report strain-level colonisation of patients, focusing on E. coli sequence types (STs), their colonisation dynamics and antimicrobial resistance gene carriage. We found a lack of multi-drug resistance (MDR) in the QEHB. Only one carbapenemase-producing organism was isolated, a Citrobacter carrying bla KPC-2. There was no evidence supporting the spread of this strain, and there was little evidence overall of nosocomial acquisition or circulation of colonising E. coli. Whilst 22 different E. coli STs were identified, only 1 strain of the pandemic ST131 lineage was isolated. This ST131 strain was non-MDR and was found to be a clade A strain, associated with low levels of antibiotic resistance. Overall, the QEHB ICU had very low levels of pandemic or MDR strains, a result that may be influenced in part by the strict COVID-19 control measures in place at the time. Employing some of these infection prevention and control measures where reasonable in all ICUs might therefore assist in maintaining low levels of nosocomial MDR.
Will we need water in the hospitals of the future? The role of water vs waterless systems - case for vs case against.
(W.B. Saunders, 2024-07-31) Garvey, M I; Holden, E; University Hospitals Birmingham NHS Foundation Trust; Infection Control; Pathology; Medical and Dental; Garvey, Mark; Holden, Elisabeth
No abstract available
Recommendations for assessing commutability of a replacement batch of a secondary calibrator certified reference material
(Elsevier, 2024-12-16) Deprez, Liesbet; Johansen, Jesper V; Keller, Thomas; Budd, Jeffrey; Greenberg, Neil; Weykamp, Cas; Sandberg, Sverre; Panteghini, Mauro; Ceriotti, Ferruccio; Barczak, Elizabeth; Rej, Robert; Fauskanger, Pernille Kjeilen; MacKenzie, Finlay; Camara, Johanna E; Lyle, Alicia N; Miller, W Greg; Delatour, Vincent; European Commission; Radiometer Medical ApS; ACOMED Statistic; Jeff Budd Consulting; Neil Greenberg Consulting; Queen Beatrix Hospital; Haraldsplass Deaconess Hospital; Haukeland University Hospital; University of Bergen; Nicolaus Copernicus University; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Siemens Healthineers; University at Albany; University Hospitals Birmingham NHS Foundation Trust; National Institute of Standards and Technology; Centers for Disease Control and Prevention; Virginia Commonwealth University; Laboratoire national de métrologie et d'essais; Research and Development; Healthcare Scientists; MacKenzie, Finlay
Commutable secondary certified reference materials (CRMs) play an essential role in the calibration hierarchy of many in-vitro diagnostic measurement procedures used in the medical laboratory. Therefore, sustainable availability of these CRMs is crucial to guarantee the long-term equivalence of results obtained for the clinical samples. The IFCC Working Group on Commutability in Metrological Traceability (WG-CMT) has published several recommendations for assessing the commutability of secondary calibrator CRMs. Performing a full commutability study according to these recommendations may present significant demands on the resources of CRM producers. This report provides recommendations for performing commutability equivalence assessments between existing CRMs of proven commutability and replacement batches of those CRMs. The approach evaluates the relationship of measurement results obtained with the relevant measurement procedures for the replacement batch versus the existing CRM batch. If this relationship is the same, the commutability properties of the replacement batch are considered equivalent to those of the existing CRM batch. Since the existing batch has a suitable commutability, the commutability of the replacement batch is also declared fit for purpose. Because this commutability equivalence assessment involves certain risks, a small number of representative clinical samples are included as safeguards. There are several prerequisites for performing the commutability equivalence assessment and producers of secondary CRMs will probably need to implement improvements before using this approach. However, once the improvements are implemented, the commutability equivalence assessment approach will significantly reduce the resources needed to maintain the supply of CRMs.
Pre-analytical stability of haematinics, lactate dehydrogenase and phosphate in whole blood at room temperature up to 24 h, and refrigerated serum stability of lactate dehydrogenase, folate and vitamin B12 up to 72 h using the CRESS checklist
(Walter De Gruyter, 2024-12-02) Williams, Robert; Jankute, Monika; Ifrahim, Rizwan; Cordle, Jane; Hepburn, Sophie; University Hospitals of North Midlands NHS Trust; University Hospitals Birmingham NHS Foundation Trust; East Suffolk and North Essex NHS Foundation Trust; Raigmore Hospital; Pathology; Healthcare Scientists; Jankute, Monika
Objectives: There is a lack of analyte stability data in whole blood (WB). The aim of this study was to determine the allowable delay in WB processing for lactate dehydrogenase (LDH), folate, vitamin B12, iron and phosphate measurement. The stability of LDH, folate and vitamin B12 was also assessed in stored serum at clinically relevant time points. Methods: Blood was taken from n=10 volunteers into Sarstedt serum gel tubes. We assessed stability in WB at room temperature up to 24 h, and stability in refrigerated serum up to 72 h. Mean percentage deviation at each time point was compared to criteria for minimum allowable bias. Results: Results produced from one individual were removed due to discordant results, leaving n=9 specimens at each time point. Stability of folate and phosphate was variable in WB across 24 h, but was deemed to be clinically acceptable. LDH was unstable in WB, iron was stable for at least 12 h, and vitamin B12 and ferritin were acceptable for up to 24 h. Serum LDH, folate and vitamin B12 all demonstrated acceptable stability in refrigerated serum stored for up to 72 h. Conclusions: Blood should ideally be centrifuged within 7 h for phosphate, LDH and folate, and 12 h for iron. However, for phosphate, folate and iron, there is likely to be little clinical impact if serum separation is delayed up to 24 h. Further research is needed to assess LDH stability in WB at 0-12 h, but changes are minimal at 12 h. All other analytes assessed showed acceptable stability across the time-points tested.
Round cells in diagnostic semen analysis: a guide for laboratories and clinicians
(Frontiers Media SA, 2022-02-02) Long, S; Kenworthy, S; University Hospitals Birmingham NHS Foundation Trust
Round cells in seminal fluid are defined as either leucocytes or immature germ cells. Laboratories undertaking semen analysis often report these combined as a concentration, with no further review, comment or direction for clinician action or review. Although numerous publications discuss the possible clinical relevance of these cells (particularly leucocytes) in infertility, the methods employed to differentiate them are often beyond the scope of most diagnostic laboratories. This paper aims to support healthcare scientists in understanding the clinical significance of round cells and aid their identification, differentiation and interpretation. This will support the quality of care the patient receives and direct clinicians to further considerations that may be appropriate for their patient and should consequently reduce indiscriminate and unnecessary use of antibiotics.
Is there an association between daylight hours and serum testosterone levels in men?
(Taylor and Francis Group, 2024-10-13) Livingston, Mark; Heald, Adrian H; Hackett, Geoffrey; Ramachandran, Harishnath; Ramachandran, Sudarshan; Black Country Pathology Services; The University of Wolverhampton; Manchester University; Salford Royal Hospital; Aston University; University of East Anglia; University Hospitals Birmingham NHS Foundation Trust; University Hospitals of North Midlands; Keele University; Staffordshire University; Brunel University London; Black Country Pathology Service; Pathology; Medical and Dental; Livingston, Mark; Ramachandran, Sudarshan
Background: Studies assessing variability of serum testosterone levels associated with seasonal environmental factors have been contradictory. Design: We assessed associations between the seasons and changes (δ) in seasonality indices and male serum total testosterone (δTT) variability. Patients and measurements: Data were collected in 144 men with paired serum TT samples (126 non-fasting/18 fasting) analysed at Walsall Manor Hospital, UK (52.3 degrees North). Seasonal factors (ambient temperature within 15 min of sampling, humidity, precipitation, duration of daylight on the day of sampling, monthly average ambient temperature, and precipitation) were obtained from local weather-station archives. Sign-rank test determined inter-sample differences between TT and seasonality indices. Linear regression analyses studied associations between δTT and δ seasonal indices in the total cohort and subgroups (stratified by medians of age, TT and men with paired non-fasting samples). Sign-rank determined whether serum TT differed between the seasons. Results: Median inter-sample interval was 63 days. No significant inter-sample differences were evident regarding serum TT levels and seasonality indices. No associations were noted between δTT and δ seasonality indices in the total cohort and subgroups stratified by age and TT. Interestingly, δ ambient temperature (p = 0.012) and daylight duration (p = 0.032) were inversely associated with δTT in the 126 men in the non-fasting group (dependent variable). Only a small degree of the variability in the δTT was accounted by the above-mentioned independent variables. The seasons did not appear to influence serum TT values. Conclusions: No relation was shown between seasonality and serum TT in the total cohort, thus possibly eliminating a confounding variable that could affect laboratory and clinical practice. It may be that seasonal variation in length of day is too modest at this latitude to demonstrate significant associations, hence our findings are latitude specific. We suggest that further data analysis to address this question in areas with greater seasonal variation would be appropriate.
The growth of faecal microbiota transplantation in the UK: time for a registry?
(Elsevier, 2022-02) Inglis, David; Quraishi, Mohammed Nabil; Green, Christopher; Iqbal, Tariq; Pathology; GI Medicine; Medical and Dental; Green, Christopher; Iqbal, Tariq
No abstract available.
Standardising the biochemical confirmation of adult male hypogonadism : a joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine
(Wiley, 2023-07-01) Jayasena, Channa N; de Silva, Nipun L; O'Reilly, Michael W; MacKenzie, Finlay; Marrington, Rachel; Jones, Hugh; Livingston, Mark; Downie, Paul; Hackett, Geoff; Ramachandran, Sud; Tomlinson, Jeremy; David, Janine; Boot, Christopher; Patel, Mayur; Tarling, Julie; Wu, Fredrick; Quinton, Richard; Imperial College; Royal College of Surgeons in Ireland (RCSI); University Hospitals Birmingham NHS Foundation Trust; Walsall Healthcare NHS Trust et al.; Black Country Pathology Service; Research and Development; Pathology; Medical and Dental; Livingston, Mark; MacKenzie, Finlay; Ramachandran, Sud
Background: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain. Design: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. Results: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. Conclusions: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.
pQEB1: a hospital outbreak plasmid lineage carrying blaKPC-2 .
(Microbiology Society, 2024-09-02) Moran, Robert A; Behruznia, Mahboobeh; Holden, Elisabeth; Garvey, Mark I; McNally, Alan; Pathology; Infection Control; Healthcare Scientists; Holden, Elisabeth; Garvey, Mark
While conducting genomic surveillance of carbapenemase-producing Enterobacteriaceae (CPE) from patient colonisation and clinical infections at Birmingham's Queen Elizabeth Hospital (QE), we identified an N-type plasmid lineage, pQEB1, carrying several antibiotic resistance genes, including the carbapenemase gene bla KPC-2. The pQEB1 lineage is concerning due to its conferral of multidrug resistance, its host range and apparent transmissibility, and its potential for acquiring further resistance genes. Representatives of pQEB1 were found in three sequence types (STs) of Citrobacter freundii, two STs of Enterobacter cloacae, and three species of Klebsiella. Hosts of pQEB1 were isolated from 11 different patients who stayed in various wards throughout the hospital complex over a 13 month period from January 2023 to February 2024. At present, the only representatives of the pQEB1 lineage in GenBank were carried by an Enterobacter hormaechei isolated from a blood sample at the QE in 2016 and a Klebsiella pneumoniae isolated from a urine sample at University Hospitals Coventry and Warwickshire (UHCW) in May 2023. The UHCW patient had been treated at the QE. Long-read whole-genome sequencing was performed on Oxford Nanopore R10.4.1 flow cells, facilitating comparison of complete plasmid sequences. We identified structural variants of pQEB1 and defined the molecular events responsible for them. These have included IS26-mediated inversions and acquisitions of multiple insertion sequences and transposons, including carriers of mercury or arsenic resistance genes. We found that a particular inversion variant of pQEB1 was strongly associated with the QE Liver speciality after appearing in November 2023, but was found in different specialities and wards in January/February 2024. That variant has so far been seen in five different bacterial hosts from six patients, consistent with recent and ongoing inter-host and inter-patient transmission of pQEB1 in this hospital setting.
Undifferentiated and dedifferentiated soft tissue neoplasms : immunohistochemical surrogates for differential diagnosis
(W.B. Saunders, 2021-09-29) Thway, Khin; Fisher, Cyril; Cellular Pathology; Medical and Dental; Fisher, Cyril
Undifferentiated soft tissue sarcomas (USTS) are described in the current World Health Organization Classification of Soft Tissue and Bone Tumours as those showing no identifiable line of differentiation when analyzed by presently available technologies. This is a markedly heterogeneous group, and the diagnosis of USTS remains one of exclusion. USTS can be divided into four morphologic subgroups: pleomorphic, spindle cell, round cell and epithelioid undifferentiated sarcomas, with this combined group accounting for up to 20% of all soft tissue sarcomas. As molecular advances enable the stratification of emerging genetic subsets within USTS, particularly within undifferentiated round cell sarcomas, other groups, particularly the category of undifferentiated pleomorphic sarcomas (UPS), still remain difficult to substratify and represent heterogeneous collections of neoplasms often representing the common morphologic endpoints of a variety of malignant tumors of various (mesenchymal and non-mesenchymal) lineages. However, recent molecular developments have also enabled the identification and correct classification of many tumors from various lines of differentiation that would previously have been bracketed under 'UPS'. This includes pleomorphic neoplasms and dedifferentiated neoplasms (the latter typically manifesting with an undifferentiated pleomorphic morphology) of mesenchymal (e.g. solitary fibrous tumor and gastrointestinal stromal tumor) and non-mesenchymal (e.g. melanoma and carcinoma) origin. The precise categorization of 'pleomorphic' or 'undifferentiated' neoplasms is critical for prognostication, as, for example, dedifferentiated liposarcoma typically behaves less aggressively than other pleomorphic sarcomas, and for management, including the potential for targeted therapies based on underlying recurrent molecular features. In this review we focus on undifferentiated and dedifferentiated pleomorphic and spindle cell neoplasms, summarizing their key genetic, morphologic and immunophenotypic features in the routine diagnostic setting, and the use of immunohistochemistry in their principal differential diagnosis, and highlight new developments and entities in the group of undifferentiated and dedifferentiated soft tissue sarcomas.
T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study
(Elsevier, 2021-11-09) Angyal, Adrienn; Longet, Stephanie; Moore, Shona C; Payne, Rebecca P; Harding, Adam; Tipton, Tom; Rongkard, Patpong; Ali, Mohammad; Hering, Luisa M; Meardon, Naomi; Austin, James; Brown, Rebecca; Skelly, Donal; Gillson, Natalie; Dobson, Sue L; Cross, Andrew; Sandhar, Gurjinder; Kilby, Jonathan A; Tyerman, Jessica K; Nicols, Alexander R; Spegarova, Jarmila S; Mehta, Hema; Hornsby, Hailey; Whitham, Rachel; Conlon, Christopher P; Jeffery, Katie; Goulder, Philip; Frater, John; Dold, Christina; Pace, Matthew; Ogbe, Ane; Brown, Helen; Ansari, M Azim; Adland, Emily; Brown, Anthony; Chand, Meera; Shields, Adrian; Matthews, Philippa C; Hopkins, Susan; Hall, Victoria; James, William; Rowland-Jones, Sarah L; Klenerman, Paul; Dunachie, Susanna; Richter, Alex; Duncan, Christopher J A; Barnes, Eleanor; Carroll, Miles; Turtle, Lance; de Silva, Thushan I; Pathology; Haematology; Medical and Dental; Shields, Adrian; Richter, Alex
Background: Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer-BioNTech) mRNA vaccine. Methods: We sampled health-care workers enrolled in the PITCH study across four hospital sites in the UK (Oxford, Liverpool, Newcastle, and Sheffield). All health-care workers aged 18 years or older consenting to participate in this prospective cohort study were included, with no exclusion criteria applied. Blood samples were collected where possible before vaccination and 28 (±7) days following one or two doses (given 3-4 weeks apart) of the BNT162b2 vaccine. Previous infection was determined by a documented SARS-CoV-2-positive RT-PCR result or the presence of positive anti-SARS-CoV-2 nucleocapsid antibodies. We measured spike-specific IgG antibodies and quantified T-cell responses by interferon-γ enzyme-linked immunospot assay in all participants where samples were available at the time of analysis, comparing SARS-CoV-2-naive individuals to those with previous infection. Findings: Between Dec 9, 2020, and Feb 9, 2021, 119 SARS-CoV-2-naive and 145 previously infected health-care workers received one dose, and 25 SARS-CoV-2-naive health-care workers received two doses, of the BNT162b2 vaccine. In previously infected health-care workers, the median time from previous infection to vaccination was 268 days (IQR 232-285). At 28 days (IQR 27-33) after a single dose, the spike-specific T-cell response measured in fresh peripheral blood mononuclear cells (PBMCs) was higher in previously infected (n=76) than in infection-naive (n=45) health-care workers (median 284 [IQR 150-461] vs 55 [IQR 24-132] spot-forming units [SFUs] per 106 PBMCs; p<0·0001). With cryopreserved PBMCs, the T-cell response in previously infected individuals (n=52) after one vaccine dose was equivalent to that of infection-naive individuals (n=19) after receiving two vaccine doses (median 152 [IQR 119-275] vs 162 [104-258] SFUs/106 PBMCs; p=1·00). Anti-spike IgG antibody responses following a single dose in 142 previously infected health-care workers (median 270 373 [IQR 203 461-535 188] antibody units [AU] per mL) were higher than in 111 infection-naive health-care workers following one dose (35 001 [17 099-55 341] AU/mL; p<0·0001) and higher than in 25 infection-naive individuals given two doses (180 904 [108 221-242 467] AU/mL; p<0·0001). Interpretation: A single dose of the BNT162b2 vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with previous SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals, including against variants of concern. Future studies should determine the additional benefit of a second dose on the magnitude and durability of immune responses in individuals vaccinated following infection, alongside evaluation of the impact of extending the interval between vaccine doses. Funding: UK Department of Health and Social Care, and UK Coronavirus Immunology Consortium.
Variability in detection of SARS-CoV-2-specific antibody responses following mild infection: a prospective multicentre cross-sectional study, London, United Kingdom, 17 April to 17 July 2020
(European Centre for Disease Prevention and Control, 2022-01) Pallett, Scott Jc; Jones, Rachael; Abdulaal, Ahmed; Pallett, Mitchell A; Rayment, Michael; Patel, Aatish; Denny, Sarah J; Mughal, Nabeela; Khan, Maryam; Rosadas de Oliveira, Carolina; Pantelidis, Panagiotis; Randell, Paul; Toumazou, Christofer; O'Shea, Matthew K; Tedder, Richard; McClure, Myra O; Davies, Gary W; Moore, Luke Sp; Pathology; Medical and Dental; O'Shea, Matthew K
Introduction: Immunoassays targeting different SARS-CoV-2-specific antibodies are employed for seroprevalence studies. The degree of variability between immunoassays targeting anti-nucleocapsid (anti-NP; the majority) vs the potentially neutralising anti-spike antibodies (including anti-receptor-binding domain; anti-RBD), particularly in mild or asymptomatic disease, remains unclear. Aims: We aimed to explore variability in anti-NP and anti-RBD antibody detectability following mild symptomatic or asymptomatic SARS-CoV-2 infection and analyse antibody response for correlation with symptomatology. Methods: A multicentre prospective cross-sectional study was undertaken (April-July 2020). Paired serum samples were tested for anti-NP and anti-RBD IgG antibodies and reactivity expressed as binding ratios (BR). Multivariate linear regression was performed analysing age, sex, time since onset, symptomatology, anti-NP and anti-RBD antibody BR. Results: We included 906 adults. Antibody results (793/906; 87.5%; 95% confidence interval: 85.2-89.6) and BR strongly correlated (ρ = 0.75). PCR-confirmed cases were more frequently identified by anti-RBD (129/130) than anti-NP (123/130). Anti-RBD testing identified 83 of 325 (25.5%) cases otherwise reported as negative for anti-NP. Anti-NP presence (+1.75/unit increase; p < 0.001), fever (≥ 38°C; +1.81; p < 0.001) or anosmia (+1.91; p < 0.001) were significantly associated with increased anti-RBD BR. Age (p = 0.85), sex (p = 0.28) and cough (p = 0.35) were not. When time since symptom onset was considered, we did not observe a significant change in anti-RBD BR (p = 0.95) but did note decreasing anti-NP BR (p < 0.001). Conclusion: SARS-CoV-2 anti-RBD IgG showed significant correlation with anti-NP IgG for absolute seroconversion and BR. Higher BR were seen in symptomatic individuals, particularly those with fever. Inter-assay variability (12.5%) was evident and raises considerations for optimising seroprevalence testing strategies/studies.
Nonadherence in hypertension: how to develop and implement chemical adherence testing.
(Lippincott Williams & Wilkins, 2021-11-05) Lane, Dan; Lawson, Alexander; Burns, Angela; Azizi, Michel; Burnier, Michel; Jones, Donald J L; Kably, Benjamin; Khunti, Kamlesh; Kreutz, Reinhold; Patel, Prashanth; Persu, Alexandre; Spiering, Wilko; Toennes, Stefan W; Tomaszewski, Maciej; Williams, Bryan; Gupta, Pankaj; Dasgupta, Indranil; Pathology; Renal Medicine; Medical and Dental; Lawson, Alexander; Dasgupta, Indranil
Nonadherence to antihypertensive medication is common, especially in those with apparent treatment-resistant hypertension (true treatment-resistant hypertension requires exclusion of nonadherence), and its routine detection is supported by clinical guidelines. Chemical adherence testing is a reliable and valid method to detect adherence, yet methods are unstandardized and are not ubiquitous. This article describes the principles of chemical adherence testing for hypertensive patients and provides a set of recommendations for centers wishing to develop the test. We recommend testing should be done in either of two instances: (1) in those who have resistant hypertension or (2) in those on 2 antihypertensives who have a less than 10 mm Hg drop in systolic blood pressure on addition of the second antihypertensive medication. Furthermore, we recommend that verbal consent is secured before undertaking the test, and the results should be discussed with the patient. Based on medications prescribed in United Kingdom, European Union, and United States, we list top 20 to 24 drugs that cover >95% of hypertension prescriptions which may be included in the testing panel. Information required to identify these medications on mass spectrometry platforms is likewise provided. We discuss issues related to ethics, sample collection, transport, stability, urine versus blood samples, qualitative versus quantitative testing, pharmacokinetics, instrumentation, validation, quality assurance, and gaps in knowledge. We consider how to best present, interpret, and discuss chemical adherence test results with the patient. In summary, this guidance should help clinicians and their laboratories in the development of chemical adherence testing of prescribed antihypertensive drugs.
Multisystem screening reveals SARS-CoV-2 in neurons of the myenteric plexus and in megakaryocytes
(John Wiley & Sons, 2022-03-31) Gray-Rodriguez, Sandra; Jensen, Melanie P; Otero-Jimenez, Maria; Hanley, Brian; Swann, Olivia C; Ward, Patrick A; Salguero, Francisco J; Querido, Nadira; Farkas, Ildiko; Velentza-Almpani, Elisavet; Weir, Justin; Barclay, Wendy S; Carroll, Miles W; Jaunmuktane, Zane; Brandner, Sebastian; Pohl, Ute; Allinson, Kieren; Thom, Maria; Troakes, Claire; Al-Sarraj, Safa; Sastre, Magdalena; Gveric, Djordje; Gentleman, Steve; Roufosse, Candice; Osborn, Michael; Alegre-Abarrategui, Javier; Cellular Pathology; Medical and Dental; Pohl, Ute
SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness, although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, as well as frequent thrombotic events, are increasingly recognised. How this maps onto SARS-CoV-2 organ tropism at the histological level, however, remains unclear. Here, we perform a comprehensive validation of a monoclonal antibody against the SARS-CoV-2 nucleocapsid protein (NP) followed by systematic multisystem organ immunohistochemistry analysis of the viral cellular tropism in tissue from 36 patients, 16 postmortem cases and 16 biopsies with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 status from the peaks of the pandemic in 2020 and four pre-COVID postmortem controls. SARS-CoV-2 anti-NP staining in the postmortem cases revealed broad multiorgan involvement of the respiratory, digestive, haematopoietic, genitourinary and nervous systems, with a typical pattern of staining characterised by punctate paranuclear and apical cytoplasmic labelling. The average time from symptom onset to time of death was shorter in positively versus negatively stained postmortem cases (mean = 10.3 days versus mean = 20.3 days, p = 0.0416, with no cases showing definitive staining if the interval exceeded 15 days). One striking finding was the widespread presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE2 expression, the entry receptor for SARS-CoV-2, and one of the earliest affected cells in Parkinson's disease. In the bone marrow, we observed viral SARS-CoV-2 NP within megakaryocytes, key cells in platelet production and thrombus formation. In 15 tracheal biopsies performed in patients requiring ventilation, there was a near complete concordance between immunohistochemistry and PCR swab results. Going forward, our findings have relevance to correlating clinical symptoms with the organ tropism of SARS-CoV-2 in contemporary cases as well as providing insights into potential long-term complications of COVID-19.

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