Pathogenesis and Control of Chronic and Emerging Infections

We analysed 9,030 variant-specific RT-PCR tests performed on SARS-CoV-2-positive samples collected in France between 31 May and 21 June 2021. This analysis revealed rapid growth of the Delta variant in three of the 13 metropolitan French regions and estimated a +79% (95% confidence interval: 52-110%) transmission advantage compared with the Alpha variant. The next weeks will prove decisive and the magnitude of the estimated transmission advantages of the Delta variant could represent a major challenge for public health authorities.

International audience

People on HIV treatment with undetectable virus cannot transmit HIV sexually (Undetectable = Untransmittable, U = U). However, the science of treatment-as-prevention (TasP) may not be widely understood by people with and without HIV who could benefit from this information. We systematically reviewed the global literature on knowledge and attitudes related to TasP and interventions providing TasP or U = U information. We included studies of providers, patients, and communities from all regions of the world, published 2008-2020. We screened 885 papers and abstracts and identified 72 for inclusion. Studies in high-income settings reported high awareness of TasP but gaps in knowledge about the likelihood of transmission with undetectable HIV. Greater knowledge was associated with more positive attitudes towards TasP. Extant literature shows low awareness of TasP in Africa where 2 in 3 people with HIV live. The emerging evidence on interventions delivering information on TasP suggests beneficial impacts on knowledge, stigma, HIV testing, and viral suppression.Review was pre-registered at PROSPERO: CRD42020153725.

According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying ∼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10-6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB.

The rate of mother-to-child transmission (MTCT) of HIV from breastfeeding is increasing relative to other causes of MTCT. Early effective preconception and antenatal antiretroviral therapy (ART) reduces intrauterine and intrapartum MTCT, whereas maternal post-partum HIV acquisition, untreated maternal HIV, and suboptimal postnatal maternal ART adherence increase the risk of MTCT through breastfeeding. Although the absolute number of cases of MTCT acquired through breastfeeding is decreasing, the rate of decrease is less than the decrease in intrauterine and intrapartum MTCT. Unless current strategies are universally applied, they might not be sufficient to eliminate MTCT due to breastfeeding. Urgent action is needed to evaluate and implement additional preventive biomedical strategies in high HIV prevalence and incidence settings to eliminate MTCT from breastfeeding. Preventive strategies include: pre-exposure prophylaxis in breastfeeding women who have an increased risk of acquiring HIV; postnatal reinforcement strategies, such as maternal retesting for HIV, maternal care reinforcement, and prophylaxis in infants exposed to HIV via breastmilk; and active (vaccine) or passive immunoprophylaxis with long-acting broadly neutralising antibodies.

Among CD4+ T-cells, T helper 17 (Th17) cells play a sentinel role in the defense against bacterial/fungal pathogens at mucosal barriers. However, Th17 cells are also highly susceptible to HIV-1 infection and are rapidly depleted from gut mucosal sites, causing an imbalance of the Th17/Treg ratio and impairing cytokines production. Consequently, damage to the gut mucosal barrier leads to an enhanced microbial translocation and systemic inflammation, a hallmark of HIV-1 disease progression. Th17 cells' expression of mucosal homing receptors (CCR6 and α4β7), as well as HIV receptors and co-receptors (CD4, α4β7, CCR5, and CXCR4), contributes to susceptibility to HIV infection. The up-regulation of numerous intracellular factors facilitating HIV production, alongside the downregulation of factors inhibiting HIV, helps to explain the frequency of HIV DNA within Th17 cells. Th17 cells harbor long-lived viral reservoirs in people living with HIV (PLWH) receiving antiretroviral therapy (ART). Moreover, cell longevity and the proliferation of a fraction of Th17 CD4 T cells allow HIV reservoirs to be maintained in ART patients.

Various neurological symptoms have been associated to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection including headache, fever, anosmia, ageusia, but also, encephalitis, Guillain-Barre syndrome and ischemic stroke. Responsible for the current coronavirus disease (COVID-19) pandemic, SARS-CoV-2 may access and affect the central nervous system (CNS) by several pathways such as axonal retrograde transport or through interaction with the blood-brain barrier (BBB) or blood-cerebrospinal fluid (CSF) barrier. Here, we explored the molecular and cellular effects of direct SARS-CoV-2 infection of human BBB cells. We observed low replication of SARS-CoV-2 that was accompanied by very moderate inflammatory response. Using a human in vitro BBB model, we also described low replication levels without strong inflammatory response or modulation of endothelium integrity. Finally, using serum samples from COVID-19 patients, we highlighted strong concentrations of pro-inflammatory factors that did not perturb BBB integrity after short term exposure. Altogether, our results show that the main mechanism of brain access following SARS-CoV-2 infection does not seem to be directed by brain infection through endothelial cells.

International audience

OBJECTIVE: The aim of the study was to understand the experiences of advanced practice nurses (APNs) in the UK during the 2020 COVID-19 pandemic, particularly in relation to safety, shortages and retention. DESIGN: A cross-sectional, mixed-methods survey. SETTING: APNs in any UK setting. PARTICIPANTS: The survey was sent to an existing UK-wide cohort of APNs. 124 APNs responded (51%). RESULTS: UK-based APNs in this study reported shortages of staff (51%) and personal protective equipment (PPE) (68%) during the first 3 months of the coronavirus outbreak. Almost half (47%) had considered leaving their job over the same 3 months. Despite difficulties, there were reports of positive changes to working practice that have enhanced care. CONCLUSION: UK APNs report COVID-19-related shortages in staff and equipment across primary and secondary care and all regions of the UK. Shortages of PPE during a pandemic are known to be a factor in the development of mental health sequelae as well as a risk factor for increased turnover and retention issues. Half of APNs surveyed were considering a change in job. The UK risks a further crisis in staff morale and retention if this is not acknowledged and addressed. APNs also expressed concern about patients not receiving routine care as many specialties closed or reduced working during the crisis. However, there were also many examples of good practice, positive changes and innovation.

Summary Since the beginning of the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) the gastrointestinal (GI) tract has emerged as an important organ influencing the propensity to and potentially the severity of the related COVID‐19 disease. However, the contribution of the SARS‐CoV‐2 intestinal infection on COVID‐19 pathogenesis remains to be clarified. In this exploratory study, we highlighted a possible link between alterations in the composition of the gut microbiota and the levels of SARS‐CoV‐2 RNA in the gastrointestinal tract, which could be more important than the presence of SARS‐CoV‐2 in the respiratory tract, COVID‐19 severity and GI symptoms. As established by metaproteomics, altered molecular functions in the microbiota profiles of high SARS‐CoV‐2 RNA level faeces highlight mechanisms such as inflammation‐induced enterocyte damage, increased intestinal permeability and activation of immune response that may contribute to vicious cycles. Uncovering the role of this gut microbiota dysbiosis could drive the investigation of alternative therapeutic strategies to favour the clearance of the virus and potentially mitigate the effect of the SARS‐CoV‐2 infection.

Leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1, CD305) belongs to the family of immune-inhibitory receptors and is widely expressed on hematopoietic mature cells, particularly on immune cells. Four different types of ligands of LAIR1 have been described, including collagens, suggesting a potential immune-regulatory function on the extracellular matrix. By modulating cytokine secretion and cellular functions, LAIR1 displays distinct patterns of expression among NK cell and T/B lymphocyte subsets during their differentiation and cellular activation and plays a major negative immunoregulatory role. Beyond its implications in physiology, the activity of LAIR1 can be inappropriately involved in various autoimmune or inflammatory disorders and has been implicated in cancer physiopathology, including hematological neoplasms. Its action as an inhibitory receptor can result in the dysregulation of immune cellular responses and in immune escape within the tumor microenvironment. Furthermore, when expressed by tumor cells, LAIR1 can modulate their proliferation or invasion properties, with contradictory pro- or anti-tumoral effects depending on tumor type. In this review, we will focus on its role in normal physiological conditions, as well as during pathological situations, including hematological malignancies. We will also discuss potential therapeutic strategies targeting LAIR1 for the treatment of various autoimmune diseases and cancer settings.

BackgroundWest Nile virus (WNV) and Usutu virus (USUV), two closely related flaviviruses, mainly follow an enzootic cycle involving mosquitoes and birds, but also infect humans and other mammals. Since 2010, their epidemiological situation may have shifted from irregular epidemics to endemicity in several European regions; this requires confirmation, as it could have implications for risk assessment and surveillance strategies.AimTo explore the seroprevalence in animals and humans and potential endemicity of WNV and USUV in Southern France, given a long history of WNV outbreaks and the only severe human USUV case in France in this region.MethodsWe evaluated the prevalence of WNV and USUV in a repeated cross-sectional study by serological and molecular analyses of human, dog, horse, bird and mosquito samples in the Camargue area, including the city of Montpellier, between 2016 and 2020.ResultsWe observed the active transmission of both viruses and higher USUV prevalence in humans, dogs, birds and mosquitoes, while WNV prevalence was higher in horses. In 500 human samples, 15 were positive for USUV and 6 for WNV. Genetic data showed that the same lineages, WNV lineage 1a and USUV lineage Africa 3, were found in mosquitoes in 2015, 2018 and 2020.ConclusionThese findings support existing literature suggesting endemisation in the study region and contribute to a better understanding of USUV and WNV circulation in Southern France. Our study underlines the importance of a One Health approach for the surveillance of these viruses.

Abstract The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non‐Langerhans cell histiocytosis (‐LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAF V600E . Most BRAF WT samples were analyzed by next‐generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim‐Chester disease, 21 Rosai‐Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAF V600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non‐ BRAF V600E ‐mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 ( n = 44), BRAF exon 12 deletions ( n = 26), and duplications ( n = 8), other BRAF V600 codon mutation ( n = 4), and non‐MAP‐kinase pathway genes ( n = 5). Wild‐type sequences were identified in 17.1% of samples. BRAF V600E was the only variant significantly correlated with critical presentations: organ‐risk involvement and neurodegeneration. MAP‐kinase pathway mutations were identified in seven RDD (mostly MAP2K1 ) and three JXG samples, but most samples were wild‐type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAF G469R mutation. Rarely, we identified mutations unrelated to MAP‐kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.

BACKGROUND: Usutu virus (USUV) is an emerging neurotropic arthropod-borne virus recently involved in massive die offs of wild birds predominantly reported in Europe. Although primarily asymptomatic or presenting mild clinical signs, humans infected by USUV can develop neuroinvasive pathologies (including encephalitis and meningoencephalitis). Similar to other flaviviruses, such as West Nile virus, USUV is capable of reaching the central nervous system. However, the neuropathogenesis of USUV is still poorly understood, and the virulence of the specific USUV lineages is currently unknown. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages circulating at the same time and in the same location. METHODS: The aim of this work was to determine the neurovirulence of isolates from the six main lineages circulating in Europe using mouse model and several neuronal cell lines (neurons, microglia, pericytes, brain endothelial cells, astrocytes, and in vitro Blood-Brain Barrier model). RESULTS: Our results indicate that all strains are neurotropic but have different virulence profiles. The Europe 2 strain, previously described as being involved in several clinical cases, induced the shortest survival time and highest mortality in vivo and appeared to be more virulent and persistent in microglial, astrocytes, and brain endothelial cells, while also inducing an atypical cytopathic effect. Moreover, an amino acid substitution (D3425E) was specifically identified in the RNA-dependent RNA polymerase domain of the NS5 protein of this lineage. CONCLUSIONS: Altogether, these data show a broad neurotropism for USUV in the central nervous system with lineage-dependent virulence. Our results will help to better understand the biological and epidemiological diversity of USUV infection.

To gain access to the brain, a so-called immune-privileged organ due to its physical separation from the blood stream, pathogens and particularly viruses have been selected throughout evolution for their use of specific mechanisms. They can enter the central nervous system through direct infection of nerves or cerebral barriers or through cell-mediated transport. Indeed, peripheral lymphoid and myeloid immune cells can interact with the blood-brain and the blood-cerebrospinal fluid barriers and allow viral brain access using the "Trojan horse" mechanism. Among immune cells, at the frontier between innate and adaptive immune responses, dendritic cells (DCs) can be pathogen carriers, regulate or exacerbate antiviral responses and neuroinflammation, and therefore be involved in viral transmission and spread. In this review, we highlight an important contribution of DCs in the development and the consequences of viral brain infections.

Among emerging arthropod-borne viruses (arbovirus), West Nile virus (WNV) is a flavivirus that can be associated with severe neuroinvasive infections in humans. In 2018, the European WNV epidemic resulted in over 2000 cases, representing the most important arboviral epidemic in the European continent. Characterization of inflammation and neuronal biomarkers released during WNV infection, especially in the context of neuronal impairments, could provide insight into the development of predictive tools that could be beneficial for patient outcomes. We first analyzed the inflammatory signature in the serum of WNV-infected mice and found increased concentrations of several inflammatory cytokines. We next analyzed serum and cerebrospinal-fluid (CSF) samples from a cohort of patients infected by WNV between 2018 and 2019 in Hungary to quantify a large panel of inflammatory cytokines and neurological factors. We found higher levels of inflammatory cytokines (e.g., IL4, IL6, and IL10) and neuronal factors (e.g., BDNF, GFAP, MIF, TDP-43) in the sera of WNV-infected patients with neuroinvasive disease. Furthermore, the serum inflammatory profile of these patients persisted for several weeks after initial infection, potentially leading to long-term sequelae and having a deleterious effect on brain neurovasculature. This work suggests that early signs of increased serum concentrations of inflammatory cytokines and neuronal factors could be a signature underlying the development of severe neurological impairments. Biomarkers could play an important role in patient monitoring to improve care and prevent undesirable outcomes.

Variants of severe acute respiratory syndrome coronavirus 2 raise concerns regarding the control of coronavirus disease epidemics. We analyzed 40,000 specific reverse transcription PCR tests performed on positive samples during January 26-February 16, 2021, in France. We found high transmission advantage of variants and more advanced spread than anticipated.

BACKGROUND: The humoral immune response following COVID-19 vaccination in nursing home residents is poorly known. A longitudinal study compared levels of IgG antibodies against the spike protein (S-RBD IgG) (S-RDB protein IgG) after one and two BNT162b2/Pfizer jabs in residents with and without prior COVID-19. METHODS: In 22 French nursing homes, COVID-19 was diagnosed with real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2. Blood S-RDB-protein IgG and nucleocapsid (N) IgG protein (N-protein IgG) were measured 21-24 days after the first jab (1,004 residents) and 6 weeks after the second (820 residents). RESULTS: In 735 residents without prior COVID-19, 41.7% remained seronegative for S-RDB-protein IgG after the first jab vs. 2.1% of the 270 RT-PCR-positive residents (p < 0.001). After the second jab, 3% of the 586 residents without prior COVID-19 remained seronegative. However, 26.5% had low S-RDB-protein IgG levels (50-1050 UA/ml) vs. 6.4% of the 222 residents with prior COVID-19. Residents with an older infection (first wave), or with N-protein IgG at the time of vaccination, had the highest S-RDB-protein IgG levels. Residents with a prior COVID-19 infection had higher S-RDB-protein IgG levels after one jab than those without after two jabs. INTERPRETATION: A single vaccine jab is sufficient to reach a high humoral immune response in residents with prior COVID-19. Most residents without prior COVID-19 are seropositive for S-RDB-protein IgG after the second jab, but around 30% have low levels. Whether residents with no or low post-vaccine S-RDB protein IgG are at higher risk of symptomatic COVID-19 requires further analysis.

In the area of mood profiling, six distinct profiles are reported in the literature, termed the iceberg, inverse iceberg, inverse Everest, shark fin, surface, and submerged profiles. We investigated if the prevalence of the six mood profiles varied by sex, age, and education among a large heterogeneous sample. The Brunel Mood Scale (BRUMS) was completed via the In The Mood website by 15,692 participants. A seeded k-means cluster analysis was used to confirm the six profiles, and discriminant function analysis was used to validate cluster classifications. Significant variations in the prevalence of mood profiles by sex, age, and education status were confirmed. For example, females more frequently reported negative mood profiles than males, and older and more highly educated participants had a higher prevalence of the iceberg profile than their younger and lesser educated counterparts. Findings suggest that refinement of the existing tables of normative data for the BRUMS should be considered.

Abstract The implementation of rapid diagnostic tests (RDTs) may enhance the efficiency of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) testing, as RDTs are widely accessible and easy to use. The aim of this study was to evaluate the performance of a diagnosis strategy based on a combination of antigen and immunoglobulin M (IgM) or immunoglobulin G (IgG) serological RDTs. Plasma and nasopharyngeal samples were collected between 14 March and 11 April 2020 at hospital admission from 45 patients with reverse transcription polymerase chain reaction (RT‐PCR) confirmed COVID‐19 and 20 negative controls. SARS‐CoV‐2 antigen (Ag) was assessed in nasopharyngeal swabs using the Coris Respi‐Strip. For IgM/IgG detection, SureScreen Diagnostics and Szybio Biotech RDTs were used in addition to laboratory assays (Abbott Alinity i SARS‐CoV‐2 IgG and Theradiag COVID‐19 IgM enzyme‐linked immunosorbent assay). Using the Ag RDT, 13 out of 45 (29.0%) specimens tested positive, the sensitivity was 87.0% for cycle threshold ( C t ) values ≤25% and 0% for C t values greater than 25. IgG detection was associated with high C t values and the amount of time after the onset of symptoms. The profile of isolated IgM on RDTs was more frequently observed during the first and second week after the onset of symptoms. The combination of Ag and IgM/IgG RDTs enabled the detection of up to 84.0% of COVID‐19 confirmed cases at hospital admission. Antigen and antibody‐based RDTs showed suboptimal performances when used alone. However when used in combination, they are able to identify most COVID‐19 patients admitted in an emergency department.