Publications
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Eke AC, Olagunju A, Momper J, et al., 2021, Optimizing pharmacology studies in pregnant and lactating women using lessons from HIV: a consensus statement., Clinical Pharmacology and Therapeutics, Vol: 110, Pages: 36-48, ISSN: 0009-9236
Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The IMPAACT network and the WHO-convened Paediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to: define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low- and middle-income countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy PK/PD studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end-points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical.
Rosadas de Oliveira C, Woo T, Haddow J, et al., 2021, Anti-HTLV-1/2 IgG antibodies in the breastmilk of seropositive mothers, Microorganisms, Vol: 9, Pages: 1-8, ISSN: 2076-2607
Background: HTLV-1/2 mother-to-child transmission (MTCT) is an important route for the maintenance of HTLV-1/2 within populations and disproportionally contributes to the burden of HTLV-1-associated diseases. Avoidance of breastfeeding is the safest recommendation to prevent MTCT. Due to the benefits of breastfeeding, alternative methods that would allow seropositive mothers to breastfeed their babies are needed. There is limited knowledge about HTLV-1/2 infection and breastmilk. Methods: Paired blood and milk samples collected from HTLV-1/2 seropositive mothers were tested for HTLV-1 proviral load (PVL) quantification and for the detection of anti-HTLV-1/2 IgG. Results: All breastmilk samples had detectable anti-HTLV-1/2 IgG. HTLV-1/2 proviral DNA was detected in all samples except for one. HTLV-1 PVL and IgG binding ratio (BR) was similar in milk and plasma. However, antibody titer was significantly higher in blood (Median (95%CI): Milk:128 (32–512); Plasma:131,584 (16,000–131,584), p < 0.05). There was a strong correlation between HTLV-1 PVL, anti-HTLV-1/2 IgG BR, and titer when comparing milk and blood. PVL did not correlate with antibody BR nor titer in blood or milk. Conclusions: Anti-HTLV-1/2 IgG are present in milk in the same proportion as blood but in lower quantity. PVL in milk correlates with blood.
Meng B, Kemp SA, Papa G, et al., 2021, Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7, CELL REPORTS, Vol: 35, ISSN: 2211-1247
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- Citations: 249
Volz E, Mishra S, Chand M, et al., 2021, Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England, Nature, Vol: 593, Pages: 266-269, ISSN: 0028-0836
The SARS-CoV-2 lineage B.1.1.7, designated a Variant of Concern 202012/01 (VOC) by Public Health England1, originated in the UK in late Summer to early Autumn 20202. Whole genome SARS-CoV-2 sequence data collected from community-based diagnostic testing shows an unprecedentedly rapid expansion of the B.1.1.7 lineage during Autumn 2020, suggesting a selective advantage. We find that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S-gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that the VOC has higher transmissibility than non-VOC lineages, even if the VOC has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with a larger share of under 20 year olds among reported VOC than non-VOC cases. Time-varying reproduction numbers for the VOC and cocirculating lineages were estimated using SGTF and genomic data. The best supported models did not indicate a substantial difference in VOC transmissibility among different age groups. There is a consensus among all analyses that the VOC has a substantial transmission advantage with a 50% to 100% higher reproduction number.
Collier DA, De Marco A, Ferreira IATM, et al., 2021, Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies, NATURE, Vol: 593, Pages: 136-+, ISSN: 0028-0836
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- Citations: 39
Rosa A, Pye VE, Graham C, et al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, Science Advances, Vol: 7, Pages: 1-14, ISSN: 2375-2548
The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.
Graham MS, Sudre CH, May A, et al., 2021, Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study, The Lancet Public Health, Vol: 6, Pages: e335-e345, ISSN: 2468-2667
BACKGROUND: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. METHODS: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. FINDINGS: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in repo
Pereira C, Harris B, Di Giovannantonio M, et al., 2021, Antibody response to SARS-CoV-2 infection is not associated with Post-COVID-19 Syndrome in healthcare workers, Journal of Infectious Diseases, Vol: 223, Pages: 1671-1676, ISSN: 0022-1899
It is currently unknown how Post-COVID-19 Syndrome (PCS) may affect those infected with SARS-CoV-2. This longitudinal study reports on healthcare staff who tested positive for SARS-CoV-2 between March-April 2020 and follows their antibody titres and symptomatology. Over half (n=21/38) had PCS at 7-8 months. There was no statistically significant difference between initial RT-PCR viral titres or serial antibody levels between those who did and did not develop PCS. This study highlights the relative commonality of PCS in healthcare workers and this should be considered in vaccination scheduling and workforce planning to allow adequate frontline staffing numbers.
Kemp SA, Collier DA, Datir RP, et al., 2021, SARS-CoV-2 evolution during treatment of chronic infection, NATURE, Vol: 592, Pages: 277-+, ISSN: 0028-0836
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- Citations: 417
Edhom KA, Lidman C, Granberg T, et al., 2021, Expanding the etiologic spectrum of spastic ataxia syndrome: chronic infection with human T lymphotropic virus type 1, Journal of NeuroVirology, Vol: 27, Pages: 345-347, ISSN: 1355-0284
Infection with human T cell lymphotropic virus type 1 (HTLV-1) is in most cases indolent; however, some patients develop adult T cell leukemia, associated with poor prognosis, or the highly disabling and incurable HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Verdonck et al. 2007; Cooper et al. 2009). HTLV-1 is an endemic infection in Southern Japan, Iran, South America, the Caribbean basin, West Africa, and among aborigines in Australia (Verdonck et al. 2007). There are no established biomarkers to predict complications in HTLV-1; however, the percentage of peripheral blood mononuclear cells (PBMCs) harboring the provirus, called proviral load (PVL), and beta-2 microglobulin (β2M) in serum are surrogate biomarkers. Associations with neurological syndromes other than HAM/TSP have been claimed, including neuropathy, motor neuron disease (Araujo et al. 2019), as well as cerebellar ataxia (Iwasaki 4,5,6,; Kira et al. 1993; Gracia et al. 1995; e-1 to e-6). In the majority of reported cases, ataxia occurred in Japanese patients with HAM/TSP (Iwasaki 1990; Iwanaga 1993; Kira et al. 1993; e1, e-2, e-4, e-6). Here, we present an Iranian HTLV-1 positive patient with a cerebellar syndrome, elevated β2M in serum, and elevated neopterin and CXCL10 in cerebrospinal fluid (CSF).
Wolf S, Haddow J, Greiller C, et al., 2021, Quantification of T cell clonality in Human T cell leukaemia virus type-1 carriers can detect the development of Adult T cell Leukaemia early, Blood Cancer Journal, Vol: 11, Pages: 1-11, ISSN: 2044-5385
Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells which are infected with Human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL could be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+CCR4+CD26-T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n=38) and patients with ATL (n=30). In a third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n=106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n=14) had higher lymphocyte counts and PVLs, and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p=0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease.
Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, et al., 2021, Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19, Science Immunology, Vol: 6, Pages: 1-17, ISSN: 2470-9468
While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.
Rosadas C, Caterino-de-Araujo A, Taylor GP, 2021, Specificity of HTLV screening tests and its impact on health care program costs: The perspective of antenatal screening in Brazil, Revista da Sociedade Brasileira de Medicina Tropical, Vol: 54, ISSN: 0037-8682
INTRODUCTION: Brazil ranks first in the number of HTLV-1/-2-infected individuals worldwide. The high morbidity and mortality of HTLV-1-associated diseases, especially following infection in infancy, requires strong action to reduce vertical transmission. METHODS: To facilitate the appraisal of the implementation of the HTLV antenatal screening program by the Brazilian Ministry of Health, we determined the costs in distinct scenarios according to HTLV seroprevalence, specificity of the screening test, and type of confirmatory test. RESULTS: HTLV antenatal screening would cost R$ 55,777,012-R$ 77,082,123/year. Screening assays with high specificity reduce the need and cost of confirmatory assays by up to 25%. CONCLUSIONS: Careful selection of the screening assay is required to optimize the program.
Moshe M, Daunt A, Flower B, et al., 2021, SARS-CoV-2 lateral flow assays for possible use in national covid-19 seroprevalence surveys (REACT2): diagnostic accuracy study, BMJ: British Medical Journal, Vol: 372, Pages: 1-8, ISSN: 0959-535X
Objective: To evaluate the performance of new lateral flow immunoassays (LFIAs) suitable for use in a national COVID-19 seroprevalence programme (REACT2).Design: Laboratory sensitivity and specificity analyses were performed for seven LFIAs on a minimum of 200 sera from individuals with confirmed SARS-CoV-2 infection, and 500 pre-pandemic sera respectively. Three LFIAs were found to have a laboratory sensitivity superior to the finger-prick sensitivity of the LFIA currently used in REACT2 seroprevalence studies (84%). These LFIAs were then further evaluated through finger-prick testing on participants with confirmed previous SARS-CoV-2 infection. Two LFIAs (Surescreen, Panbio) were evaluated in clinics in June-July, 2020, and a third LFIA (AbC-19) in September, 2020. A Spike protein enzyme-linked immunoassay (S-ELISA) and hybrid double antigen binding assay (DABA) were used as laboratory reference standards.Setting: Laboratory analyses were performed at Imperial College, London and University facilities in London, UK. Research clinics for finger-prick sampling were run in two affiliated NHS trusts.Participants: Sensitivity analysis on sera were performed on 320 stored samples from previous participants in the REACT2 programme with confirmed previous SARS-CoV-2 infection. Specificity analysis was performed using 1000 pre-pandemic sera. 100 new participants with confirmed previous SARS-CoV-2 infection attended study clinics for finger-prick testing.Main outcome measures: The accuracy of LFIAs in detecting IgG antibodies to SARS-CoV-2 in comparison to two in-house ELISAs.Results: The sensitivity of seven new LFIAs using sera varied between 69% and 100% (vs S-ELISA/hybrid DABA). Specificity using sera varied between 99.6% and 100%. Sensitivity on finger-prick testing for Panbio, Surescreen and AbC-19 was 77% (CI 61.4 to 88.2), 86% (CI 72.7 to 94.8) and 69% (CI 53.8 to 81.3) respectively vs S-ELISA/hybrid DABA. Sensitivity for sera from matched clinical samples performe
Einsiedel L, Chiong F, Jersmann H, et al., 2021, Correction to: Human T-cell leukaemia virus type 1 associated pulmonary disease: clinical and pathological features of an under-recognised complication of HTLV-1 infection, Retrovirology, Vol: 18, Pages: 1-1, ISSN: 1742-4690
Short C-E, Brown R, Quinlan R, et al., 2021, Lactobacillus-depleted vaginal microbiota in pregnant women living with HIV-1 infection are associated with increased local inflammation and preterm birth, Frontiers in Cellular and Infection Microbiology, Vol: 10, ISSN: 2235-2988
Background: Pregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.Methods: Prospective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.Findings: There was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.Interpretation: There is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.
Kalil RS, Vasconcellos I, Rosadas C, et al., 2021, Association between high proviral load, cognitive impairment, and white matter brain lesions in HTLV-1-infected individuals, Journal of NeuroVirology, Pages: 1-10, ISSN: 1355-0284
The association between high proviral load (PVL) in peripheral blood mononuclear cells (PBMC), cognitive disturbance and white matter brain lesions in HTLV-1-infected individuals is still undefined. A cross-sectional study included 62 participants: 22 asymptomatic carriers (mean age 43.4 ± 13.1 years old), 22 patients with HTLV-1-associated myelopathy (HAM/TSP) (mean age 51.5 ± 8.7 years old), and 18 uninfected controls (mean age 52.3 ± 11.1 years old). All individuals fulfilled the following criteria: between 18 and 65 years of age, more than 4 years of formal education, and completed neuropsychological evaluation and HTLV-1 serology. Infected individuals underwent brain conventional magnetic resonance imaging and PVL quantitative PCR (qPCR). Statistical analysis was adjusted in the models by age and education. Cognitive deficit was observed in all groups. Patients with HAM/TSP showed higher neurocognitive deviation in attention and motor skills, higher frequency (84%) of brain white matter lesions, and higher PVL median (range) 8.45 (0.5–71.4) copies/100 PBMC. Brain white matter lesion was associated with verbal memory deficit in HTLV-1-infected individuals (HAM/TSP and asymptomatic carriers) (p = 0.026). In addition, there was a correlation between higher PVL and neurocognitive dysfunction score (processing speed of visuomotor information and visuoconstructive praxis) in HTLV-1-infected patients. The study demonstrates an association between HTLV-1 infection, neurocognitive disorder, and white matter brain lesions on MRI as well as a correlation with higher HTLV-1 PVL, suggesting that the central nervous system involvement by HTLV-1 is not restricted to the spinal cord but involves the whole neuro-axis. HTLV-1-infected individuals should be tested for cognitive impairment.
Motedayen Aval L, Boullier M, Lyall H, et al., 2021, Adult T cell leukaemia/lymphoma (ATL) in pregnancy: a UK case series, EJHaem, Vol: 2, Pages: 131-135, ISSN: 2688-6146
Introduction: Chronic infection with human T-cell lymphotropic virus type-1 (HTLV-1) may result in aggressive adult T-cell leukaemia/lymphoma (ATL) in 4-6% carriers. The majority of this risk arises in carriers infected during infancy, and so each infant has ∼25% lifetime risk. Other risk factors include a family history of ATL. Antenatal HTLV-1 screening is not undertaken in the UK. Methods: Here we describe four cases of ATL diagnosed during pregnancy and describe strategies to minimise HTLV-1 transmission to neonates. Results/conclusion: These cases highlight undiagnosed HTLV-1 in pregnancy which allows ongoing mother to child vertical transmission and risk of future ATL. We recommend the UK National Screening Committee incorporate HTLV-1 serology into antenatal screening.
Pillay TD, Kondratiuk A, Davies M, et al., 2021, THE INDUCTION OF EARLY, DYNAMIC AIRWAY MUCOSAL AND SYSTEMIC IMMUNE RESPONSES FOLLOWING RECENT SARS-COV-2 HOUSEHOLD EXPOSURE, Publisher: BMJ PUBLISHING GROUP, Pages: A225-A226, ISSN: 0040-6376
Rosa A, Pye VE, Graham C, et al., 2021, SARS-CoV-2 recruits a haem metabolite to evade antibody immunity., medRxiv
The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.
Harris BHL, Zuhair M, Di Giovannantonio M, et al., 2021, Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in a rehabilitation facility: evolution of the presence of nasopharyngeal SARS-CoV-2 and serological antibody responses., Journal of Infectious Diseases, Vol: 223, Pages: 192-196, ISSN: 0022-1899
At the start of the UK coronavirus disease 2019 epidemic, this rare point prevalence study revealed that one-third of patients (15 of 45) in a London inpatient rehabilitation unit were found to be infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but asymptomatic. We report on 8 patients in detail, including their clinical stability, the evolution of their nasopharyngeal viral reverse-transcription polymerase chain reaction (RT-PCR) burden, and their antibody levels over time, revealing the infection dynamics by RT-PCR and serology during the acute phase. Notably, a novel serological test for antibodies against the receptor binding domain of SARS-CoV-2 showed that 100% of our asymptomatic cohort remained seropositive 3-6 weeks after diagnosis.
Harris BHL, Zuhair M, di Giovannantonio M, et al., 2021, Asymptomatic COVID-19 in a rehabilitation facility: evolution of the presence of nasopharyngeal SARS-CoV-2 and serological antibody responses, The Journal of Infectious Diseases, Vol: 223, Pages: 192-196, ISSN: 0022-1899
At the start of the UK COVID-19 epidemic, this rare point prevalence study reveals ⅓ of patients in a London inpatient rehabilitation unit were found to be infected with SARS-CoV 2, but asymptomatic (n=15/45). We report on eight patients in detail, including their clinical stability, the evolution of their nasopharyngeal viral RT-PCR burden and their antibody levels over time revealing the infection dynamics by RT-PCR and serology during the acute phase. Notably, a novel serological test for antibodies against the receptor binding domain of SARS40 CoV-2 (anti-RBD) showed 100% of our asymptomatic cohort remained seropositive between 3 to 6 weeks post-diagnosis.
Volz E, Hill V, McCrone J, et al., 2021, Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity, Cell, Vol: 184, Pages: 64-75.e11, ISSN: 0092-8674
In February 2020 a substitution at the interface between SARS-CoV-2 Spike protein subunits, Spike D614G, was observed in public databases. The Spike 614G variant subsequently increased in frequency in many locations throughout the world. Global patterns of dispersal of Spike 614G are suggestive of a selective advantage of this variant, however the origin of Spike 614G is associated with early colonization events in Europe and subsequent radiations to the rest of the world. Increasing frequency of 614G may therefore be due to a random founder effect. We investigate the hypothesis for positive selection of Spike 614G at the level of an individual country, the United Kingdom, using more than 25,000 whole genome SARS-CoV-2 sequences collected by COVID-19 Genomics UK Consortium. Using phylogenetic analysis, we identify Spike 614G and 614D clades with unique origins in the UK and from these we extrapolate and compare growth rates of co-circulating transmission clusters. We find that Spike 614G clusters are introduced in the UK later on average than 614D clusters and grow to larger size after adjusting for time of introduction. Phylodynamic analysis does not show a significant increase in growth rates for clusters with the 614G variant, but population genetic modelling indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We also investigate the potential influence of Spike 614D versus G on virulence by matching a subset of records to clinical data on patient outcomes. We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality, but younger patients have slightly increased odds of 614G carriage. Despite the availability of a very large data set, well represented by both Spike 614 variants, not all approaches showed a conclusive signal of higher transmission rate for 614G, but significant differences in growth, size, and composition of these lineages indicate a need
Einsiedel L, Chiong F, Jersmann H, et al., 2021, Human T-cell leukaemia virus type 1 associated pulmonary disease: clinical and pathological features of an under-recognised complication of HTLV-1 infection, Retrovirology, Vol: 18, ISSN: 1742-4690
The lung is one of several organs that can be affected by HTLV-1 mediated inflammation. Pulmonary inflammation associated with HTLV-1 infection involves the interstitium, airways and alveoli, resulting in several clinical entities including interstitial pneumonias, bronchiolitis and alveolitis, depending on which structures are most affected. Augmentation of the inflammatory effects of HTLV-1 infected lymphocytes by recruitment of other inflammatory cells in a positive feedback loop is likely to underlie the pathogenesis of HTLV-1 associated pulmonary disease, as has been proposed for HTLV-1 associated myelopathy. In contrast to the conclusions of early case series, HTLV-1 associated pulmonary disease can be associated with significant parenchymal damage, which may progress to bronchiectasis where this involves the airways. Based on our current understanding of HTLV-1 associated pulmonary disease, diagnostic criteria are proposed.
Bollen P, Freriksen J, Konopnicki D, et al., 2021, The Effect of Pregnancy on the Pharmacokinetics of Total and Unbound Dolutegravir and Its Main Metabolite in Women Living With Human Immunodeficiency Virus, CLINICAL INFECTIOUS DISEASES, Vol: 72, Pages: 121-127, ISSN: 1058-4838
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Gibani MM, Toumazou C, Sohbati M, et al., 2020, Assessing a novel, lab-free, point-of-care test for SARS-CoV-2 (CovidNudge): a diagnostic accuracy study., The Lancet Microbe, Vol: 1, Pages: e300-e307, ISSN: 2666-5247
Background: Access to rapid diagnosis is key to the control and management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory RT-PCR testing is the current standard of care but usually requires a centralised laboratory and significant infrastructure. We describe our diagnostic accuracy assessment of a novel, rapid point-of-care real time RT-PCR CovidNudge test, which requires no laboratory handling or sample pre-processing. Methods: Between April and May, 2020, we obtained two nasopharyngeal swab samples from individuals in three hospitals in London and Oxford (UK). Samples were collected from three groups: self-referred health-care workers with suspected COVID-19; patients attending emergency departments with suspected COVID-19; and hospital inpatient admissions with or without suspected COVID-19. For the CovidNudge test, nasopharyngeal swabs were inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as sample adequacy control. Swab samples were tested in parallel using the CovidNudge platform, and with standard laboratory RT-PCR using swabs in viral transport medium for processing in a central laboratory. The primary analysis was to compare the sensitivity and specificity of the point-of-care CovidNudge test with laboratory-based testing. Findings: We obtained 386 paired samples: 280 (73%) from self-referred health-care workers, 15 (4%) from patients in the emergency department, and 91 (23%) hospital inpatient admissions. Of the 386 paired samples, 67 tested positive on the CovidNudge point-of-care platform and 71 with standard laboratory RT-PCR. The overall sensitivity of the point-of-care test compared with laboratory-based testing was 94% (95% CI 86-98) with an overall specificity of 100% (99-100). The sensitivity of the test varied
Khan M, Tosswill J, Haddow J, et al., 2020, Virological and immunological evaluation of individuals with spontaneous persistent viral control without ART, Publisher: WILEY, Pages: 12-12, ISSN: 1464-2662
Rosadas C, Assone T, Yamashita M, et al., 2020, Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life, PLoS Neglected Tropical Diseases, Vol: 14, ISSN: 1935-2727
BACKGROUND: HTLV-1 is a neglected sexually transmitted infection despite being the cause of disabling neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is no treatment for this infection and public health policies are essential to reduce its transmission. However, there are no data to support adequate cost-effective analysis in this field. The aim of this study was to obtain health state utility values for individuals with HAM/TSP and HTLV-1 asymptomatic carriers (AC). The impact of both states on quality of life (QoL) is described and compared to other diseases. METHODS: A cross-sectional observational study of 141 individuals infected with HTLV-1 (79 with HAM/TSP and 62 AC) from three Brazilian states (Rio de Janeiro, São Paulo and Alagoas) and from the United Kingdom. Participants completed a validated general health questionnaire (EQ-5D, Euroqol) from which country specific health state utility values are generated. Clinical and epidemiological data were collated. PRINCIPAL FINDINGS: Health state utility value for HAM/TSP was 0.2991. QoL for 130 reported clinical conditions ranges from 0.35 to 0.847. 12% reported their quality of life as worse as death. Low QoL was associated with severity rather than duration of disease with a moderate inverse correlation between QoL and Osame's Motor Disability Score (-0.4933) Patients who are wheelchair dependent had lowest QoL whilst those still walking unaided had the highest. AC also reported impaired QoL (0.7121) compared to general population. CONCLUSION: HTLV-1 and its associated neurological disease has a marked impact on QoL. This study provides robust data to support the development of cost-utility analysis of interventions for HTLV-1.
Gibani M, Toumazou C, Sohbati M, et al., 2020, CovidNudge: diagnostic accuracy of a novel lab-free point-of-care diagnostic for SARS-CoV-2, Publisher: Cold Spring Harbor Laboratory
Background Access to rapid diagnosis is key to the control and management of SARS-CoV-2. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) testing usually requires a centralised laboratory and significant infrastructure. We describe the development and diagnostic accuracy assessment of a novel, rapid point-of-care RT-PCR test, the DnaNudge® platform CovidNudge test, which requires no laboratory handling or sample pre-processing.Methods Nasopharyngeal swabs are inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as positive control. Between April and May 2020, swab samples were tested in parallel using the CovidNudge direct-to-cartridge platform and standard laboratory RT-PCR using swabs in viral transport medium. Samples were collected from three groups: self-referred healthcare workers with suspected COVID-19 (Group 1, n=280/386; 73%); patients attending the emergency department with suspected COVID-19 (Group 2, n=15/386; 4%) and hospital inpatient admissions with or without suspected COVID-19 (Group 3, n=91/386; 23%).Results Of 386 paired samples tested across all groups, 67 tested positive on the CovidNudge platform and 71 with standard laboratory RT-PCR. The sensitivity of the test varied by group (Group 1 93% [84-98%], Group 2 100% [48-100%] and Group 3 100% [29-100%], giving an average sensitivity of 94.4% (95% confidence interval 86-98%) and an overall specificity of 100% (95%CI 99-100%; Group 1 100% [98-100%]; Group 2 100% [69-100%] and Group 3 100% [96-100%]). Point of care testing performance was comparable during a period of high (25%) and low (3%) background prevalence. Amplification of the viral nucleocapsid (n1, n2, n3) targets were most sensitive for detection of SARS-CoV2, with the assay able to detect 1×104 viral particles in
Flower B, Brown JC, Simmons B, et al., 2020, Clinical and laboratory evaluation of SARS-CoV-2 lateral flow assays for use in a national COVID-19 sero-prevalence survey, Thorax, Vol: 75, Pages: 1082-1088, ISSN: 0040-6376
BackgroundAccurate antibody tests are essential to monitor the SARS-CoV-2 pandemic. Lateral flow immunoassays (LFIAs) can deliver testing at scale. However, reported performance varies, and sensitivity analyses have generally been conducted on serum from hospitalised patients. For use in community testing, evaluation of finger-prick self-tests, in non-hospitalised individuals, is required.MethodsSensitivity analysis was conducted on 276 non-hospitalised participants. All had tested positive for SARS-CoV-2 by RT-PCR and were ≥21d from symptom-onset. In phase I we evaluated five LFIAs in clinic (with finger-prick) and laboratory (with blood and sera) in comparison to a) PCR-confirmed infection and b) presence of SARS-CoV-2 antibodies on two “in-house” ELISAs. Specificity analysis was performed on 500 pre-pandemic sera. In phase II, six additional LFIAs were assessed with serum.Findings95% (95%CI [92.2, 97.3]) of the infected cohort had detectable antibodies on at least one ELISA. LFIA sensitivity was variable, but significantly inferior to ELISA in 8/11 assessed. Of LFIAs assessed in both clinic and laboratory, finger-prick self-test sensitivity varied from 21%-92% vs PCR-confirmed cases and 22%-96% vs composite ELISA positives. Concordance between finger-prick and serum testing was at best moderate (kappa 0.56) and, at worst, slight (kappa 0.13). All LFIAs had high specificity (97.2% - 99.8%).InterpretationLFIA sensitivity and sample concordance is variable, highlighting the importance of evaluations in setting of intended use. This rigorous approach to LFIA evaluation identified a test with high specificity (98.6% (95%CI [97.1, 99.4])), moderate sensitivity (84.4% with fingerprick (95%CI [70.5, 93.5])), and moderate concordance, suitable for seroprevalence surveys.
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