Tezepelumab for refractory eosinophilic granulomatosis with polyangiitis-related asthma.

Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA.

Severe asthma care trajectories: the French RAMSES cohort.

Background: The French RAMSES study is an observational prospective multicentre real-life cohort including severe asthmatic subjects. The objective of the study was to compare the characteristics of patients, in terms of phenotype and asthma care trajectories, between those managed by tertiary referral centres (TRCs) or secondary care centres (SCCs). Methods: Patients were prospectively recruited and enrolled for a 5-year follow-up. Patients' characteristics were analysed at inclusion and compared between TRCs and SCCs. Results: 52 centres (24 TRCs and 28 SCCs) included 2046 patients: 1502 (73.4%) were included by a TRC and 544 (26.6%) by a SCC. Patients were mainly women (62%), 53±15 years old, 67% with Asthma Control Test <20; at inclusion, 14% received oral corticosteroids (OCS) and 66% biologics. Compared with the SCC group, the TRC group had more frequent comorbidities and lower blood eosinophil counts (262 versus 340 mm-3; p=0.0036). OCS and biologics use did not differ between groups, but patients in the TRC group benefited more frequently from an educational programme (26% versus 18%; p=0.0008) and received more frequently two or more sequential lines of biologics (33% versus 24%; p=0.0105). In-depth investigations were more frequently performed in the TRC group (allergy tests: 74% versus 62%; p<0.0001; exhaled nitric oxide fraction: 56% versus 21%; p<0.0001; induced sputum: 6% versus 3%; p=0.0390). Conclusions: Phenotypes and care trajectories differed in the RAMSES cohort between SCCs and TRCs, probably related to different levels of asthma severity and differences in medical resources and practices among centres. This highlights the need for standardisation of severe asthma care.

Trend in respiratory viruses' activity in the COVID-19 area.

OBJECTIVES: SARS-CoV-2 has impacted the detection of seasonal respiratory viruses. We retrospectively assessed the trend in the detection of 10 viruses in the COVID-19 area in 2 hospitals located in the Paris area. METHODS: All patients positive for a respiratory virus in two hospitals from September 2016 to August 2021 were retrospectively included. The rate of RT-PCR positive for each virus was calculated for the 2020-2021 season and the 2019-2020 season in comparison to a baseline of 3 seasons, i.e. 2016-2017, 2017-2018, and 2018-2019. RESULTS: Overall, 7,835 patients were tested positive from September 2016 to August 2021. The detection of respiratory virus dramatically falls on week-11 of 2020, as the number of RT-PCR performed. Then, 3 trends were identified: a) almost a disappearance for influenza; b) a 10-weeks delay in the seasonal outbreak for RSV; c) a persistence of circulation with variable activity for other viruses. In comparison to a baseline of three seasons (2016-2019), the rate of positive patients was lower during the 2020-2021 season for coronavirus (4.51% vs. 1.26%, P < 0.0001), adenovirus (1.93% vs. 1.34%, P = 0.14), bocavirus (0.58% vs. 0.11%, P = 0.08), and enterovirus (0.28% vs. 0.0%, P = 0.12). In contrast, the rate of hMPV-positive (1.92% vs. 2.83%, P = 0.03) and hPIV-positive (2.17% vs. 2.99%, P = 0.06) patients increased. CONCLUSIONS: The fall in the number of respiratory viruses detected might be related to the lower number of tests performed and the implementation of non pharmaceutical intervention (NPI). Then, all viruses except influenza are detected, probably as a consequence of high adherence to influenza vaccines. Despite, a lower number of tests being performed, the rate of hMPV-positive and hPIV-positive patients increased suggesting an active circulation of these viruses. Altogether, these findings suggest a persistent circulation of common respiratory viruses all over the COVID-19 era.

Temporal dynamics of RSV shedding and genetic diversity in adults during the COVID-19 pandemic in a French hospital, early 2021.

Human respiratory syncytial virus (RSV) is responsible of lower respiratory tract infections which may be severe in infants, elderly and immunocompromised adults. Europe and North-American countries have observed a massive reduction of RSV incidence during the 2020-2021 winter season. Using a systematic RSV detection coupled to SARS-CoV-2 for all adult patients admitted at the Foch hospital (Suresnes, France) between January and March 2021 (n = 11,324), only eight RSV infections in patients with prolonged RNA shedding were diagnosed. RSV whole-genome sequencing revealed that six and two patients were infected by RSV groups A and B, respectively. RSV carriage lasted from 7 to at least 30 days disregarding of RSV lineage. The most prolonged RSV shedding was observed in an asymptomatic patient. We detected novel patient-specific non-synonymous mutations in the G glycoprotein gene, including a double identical mutation in the repeated region for one patient. No additional mutation occurred in the RSV genome over the course of infection in the four patients tested for. In conclusion, our results suggest that the temporal shift in the RSV epidemic is not likely to be explained by the emergence of a high frequency, unreported variant. Moreover, prolonged RSV carriages in asymptomatic patients could play a role in virus spread.

Benralizumab for eosinophilic granulomatosis with polyangiitis: a retrospective, multicentre, cohort study.

BACKGROUND: Interleukin-5 (IL-5) inhibitors represent novel therapies for eosinophilic granulomatosis with polyangiitis (EGPA). This study assessed the effectiveness and safety of the IL-5 receptor inhibitor benralizumab in a European cohort of patients with EGPA. METHODS: This retrospective cohort study included patients with EGPA from 28 European referral centres of the European EGPA Study Group across six countries (Italy, France, UK, Russia, Spain, and Switzerland) who received benralizumab as any line of treatment between Jan 1, 2019, and Sep 30, 2022. We assessed the rates of complete response, defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] of 0) and a prednisone dose of up to 4 mg/day, in contrast to partial response, defined as a BVAS of 0 and a prednisone dose greater than 4 mg/day. Active disease manifestations, pulmonary function, variation in glucocorticoid dose, and safety outcomes were also assessed over a 12-month follow-up. FINDINGS: 121 patients with relapsing-refractory EGPA treated with benralizumab at the dose approved for eosinophilic asthma were included (64 [53%] women and 57 [47%] men; median age at the time of beginning benralizumab treatment 54·1 years [IQR 44·2-62·2]). Complete response was reported in 15 (12·4%, 95% CI 7·1-19·6) of 121 patients at month 3, 25 (28·7%, 19·5-39·4) of 87 patients at month 6, and 32 (46·4%, 34·3-58·8) of 69 patients at month 12; partial response was observed in an additional 43 (35·5%, 27·0-44·8) patients at month 3, 23 (26·4%, 17·6-37·0) at month 6, and 13 (18·8%, 10·4-30·1) at month 12. BVAS dropped from 3·0 (IQR 2·0-8·0) at baseline to 0·0 (0·0-2·0) at months 3 and 6, and to 0·0 (0·0-1·0) at month 12. The proportion of patients with systemic manifestations, active peripheral neurological disease, ear, nose, and throat involvement, and pulmonary involvement decreased, with an improvement in lung function tests. Six patients relapsed after having a complete response. The oral prednisone (or equivalent) dose decreased from 10·0 mg/day (5·0-12·5) at baseline to 5·0 mg/day (3·6-8·5) at month 3 (p<0·01), to 5·0 mg/day (2·5-6·3) at month 6, and to 2·5 mg/day (0·0-5·0) at month 12 (p<0·0001). 19 (16%) of 121 patients had adverse events and 16 (13%) discontinued benralizumab. INTERPRETATION: These data suggest that benralizumab could be an effective treatment for EGPA in real-life clinical practice. Further clinical trials are required to confirm the efficacy of benralizumab in patients with a higher baseline disease activity. FUNDING: None.

Venous thrombosis and predictors of relapse in eosinophil-related diseases.

Eosinophils have widespread procoagulant effects. Eosinophilic cardiovascular toxicity mostly consists of endomyocardial damage or eosinophilic vasculitis, while reported cases of venous thrombosis (VT) are scarce. We aimed to report on the clinical features and treatment outcomes of patients with unexplained VT and eosinophilia, and to identify predictors of relapse. This retrospective, multicenter, observational study included patients aged over 15 years with VT, concomitant blood eosinophilia ≥ 1G/L and without any other moderate-to-strong contributing factors for VT. Fifty-four patients were included. VT was the initial manifestation of eosinophil-related disease in 29 (54%) patients and included pulmonary embolism (52%), deep venous thrombosis (37%), hepatic (11%) and portal vein (9%) thromboses. The median [IQR] absolute eosinophil count at VT onset was 3.3G/L [1.6-7.4]. Underlying eosinophil-related diseases included FIP1L1-PDGFRA-associated chronic myeloid neoplasm (n = 4), Eosinophilic Granulomatosis with Polyangiitis (n = 9), lymphocytic (n = 1) and idiopathic (n = 29) variants of hypereosinophilic syndrome. After a median [IQR] follow-up of 24 [10-62] months, 7 (13%) patients had a recurrence of VT. In multivariate analysis, persistent eosinophilia was the sole variable associated with a shorter time to VT relapse (HR 7.48; CI95% [1.94-29.47]; p = 0.015). Long-term normalization of eosinophil count could prevent the recurrence of VT in a subset of patients with unexplained VT and eosinophilia ≥ 1G/L.

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis.

BACKGROUND: High levels of serum interleukin-6 (IL-6) correlate with disease severity in COVID-19. We hypothesized that tocilizumab (a recombinant humanized anti-IL-6 receptor) could improve outcomes in selected patients with severe worsening COVID-19 pneumonia and high inflammatory parameters. METHODS: The TOCICOVID study included a prospective cohort of patients aged 16-80 years with severe (requiring > 6 L/min of oxygen therapy to obtain Sp02 > 94%) rapidly deteriorating (increase by ≥ 3 L/min of oxygen flow within the previous 12 h) COVID-19 pneumonia with ≥ 5 days of symptoms and C-reactive protein levels > 40 mg/L. They entered a compassionate use program of treatment with intravenous tocilizumab (8 mg/kg with a maximum of 800 mg per infusion; and if needed a second infusion 24 to 72 h later). A control group was retrospectively selected with the same inclusion criteria. Outcomes were assessed at D28 using inverse probability of treatment weighted (IPTW) methodology. RESULTS: Among the 96 patients included (81% male, mean (SD) age: 60 (12.5) years), underlying conditions, baseline disease severity, and concomitant medications were broadly similar between the tocilizumab (n = 49) and the control (n = 47) groups. In the IPTW analysis, treatment with tocilizumab was associated with a reduced need for overall ventilatory support (49 vs. 89%, wHR: 0.39 [0.25-0.56]; p < 0.001). Albeit lacking statistical significance, there was a substantial trend towards a reduction of mechanical ventilation (31% vs. 45%; wHR: 0.58 [0.36-0.94]; p = 0.026). However, tocilizumab did not improve overall survival (wHR = 0.68 [0.31-1.748], p = 0.338). Among the 85 (89%) patients still alive at D28, patients treated with tocilizumab had a higher rate of oxygen withdrawal (82% vs. 73.5%, wHR = 1.66 [1.17-2.37], p = 0.005), with a shorter delay before being weaned of oxygen therapy (mean 11 vs. 16 days; p < 0.001). At D28, the rate of patients discharged from hospital was higher in the tocilizumab group (70% vs. 40%, wHR = 1.82 [1.22-2.75]; p = 0.003). The levels of CRP and fibrinogen post therapy (p < 0.001 for both variables) were significantly lower in the tocilizumab group (interaction test, mixed model). Rates of neutropenia (35% vs. 0%; p < 0.001) were higher in the tocilizumab group, yet rates of infections (22% vs. 38%, p = 0.089) including ventilator-acquired pneumonia (8% vs. 26%, p = 0.022) were higher in the control group. CONCLUSION: These data could be helpful for the design of future trials aiming to counter COVID-19-induced inflammation, especially before patients require admission to the intensive care unit.

Extensive DVT and Pulmonary Embolism Leading to the Diagnosis of Coronavirus Disease 2019 in the Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia.

There is growing evidence that coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. To date, all patients reported with venous thromboembolic disease and COVID-19 have shown evidence of viral pneumonia. Here, we report the case of a 31-year-old patient with unexplained extensive DVT and bilateral pulmonary embolism in the absence of COVID-19 pneumonia, leading to the diagnosis of otherwise asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the context of the COVID-19 pandemic, given the high rates of otherwise asymptomatic patients, testing for SARS-CoV-2 should be performed in all patients with unexplained VTE occurring in COVID-19-endemic areas, even in the absence of other disease manifestations suggestive of SARS-CoV-2 infection.

TLR-9 agonist and CD40-targeting vaccination induces HIV-1 envelope-specific B cells with a diversified immunoglobulin repertoire in humanized mice.

The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to efficiently transition from IgM B cells to IgG B cells. Here, we found that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mice. We further dissected hu-B cell responses directed against the HIV-1 Env protein elicited by targeting Env gp140 clade C to the CD40 receptor of antigen-presenting cells. The anti-CD40.Env gp140 vaccine was injected with CpG-B in a homologous prime/boost regimen or as a boost of a NYVAC-KC pox vector encoding Env gp140 clade C. Both regimens elicited Env-specific IgG-switched memory hu-B cells at a greater magnitude in hu-mice primed with NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific hu-B cells to express polyclonal IgG1 and IgG3 isotypes and a broad Ig VH/VL repertoire, with predominant VH3 family gene usage. These cells exhibited a higher rate of somatic hypermutation than the non-specific IgG+ hu-B-cell counterpart. Both vaccine regimens induced splenic GC-like structures containing hu-B and hu-Tfh-like cells expressing PD-1 and BCL-6. We confirmed in this model that circulating ICOS+ memory hu-Tfh cells correlated with the magnitude of gp140-specific B-cell responses. Finally, the NYVAC-KC heterologous prime led to a more diverse clonal expansion of specific hu-B cells. Thus, this study shows that CD40-targeted vaccination induces human IgG production in hu-mice and provides insights for the development of a CD40-targeting vaccine to prevent HIV-1 infection in humans.

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Aspergillus fumigatus Infection in Humans With STAT3-Deficiency Is Associated With Defective Interferon-Gamma and Th17 Responses.

In humans, loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3) gene is frequently associated with susceptibility to bacterial as well as fungal infections including aspergillosis, although its pathogenesis remains largely unknown. In the present study, we investigated the immune responses obtained after stimulation with Aspergillus fumigatus in STAT3-deficient patients. A. fumigatus conidial killing efficiencies of both monocytes and neutrophils isolated from whole blood samples of STAT3-deficient patients were not different compared to those of healthy controls. After stimulation with A. fumigatus conidia, lower concentrations of adaptive cytokines (IFN-γ, IL-17 and IL-22) were secreted by peripheral blood mononuclear cells from STAT3-deficient patients compared to those from healthy controls. Moreover, the frequency of IFN-γ and IL-17 producing CD4+ T cells was lower in STAT3-deficient patients vs. healthy controls. Among the STAT3-deficient patients, those with aspergillosis showed further lower secretion of IFN-γ upon stimulation of their PBMCs with A. fumigatus conidia compared to the patients without aspergillosis. Together, our study indicated that STAT3-deficiency leads to a defective adaptive immune response against A. fumigatus infection, particularly with a lower IFN-γ and IL-17 responses in those with aspergillosis, suggesting potential therapeutic benefit of recombinant IFN-γ in STAT3-deficient patients with aspergillosis.

Overexpression of GILZ in macrophages limits systemic inflammation while increasing bacterial clearance in sepsis in mice.

Studies support the beneficial effects of glucocorticoids (GCs) during septic shock, steering research toward the potential role of GC-induced proteins in controlling excessive inflammatory responses. GILZ is a glucocorticoid-induced protein involved in the anti-inflammatory effects of GCs. We investigated whether the overexpression of GILZ specifically limited to monocytes and macrophages (M/M) alone could control inflammation, thus improving the outcome of septic shock in animal models. We also monitored the expression of GILZ in M/M from septic mice and septic-shock patients. M/M from patients and septic mice displayed significantly lower expression of GILZ than those isolated from controls. Furthermore, transgenic mice (Tg-mice) experiencing sepsis, with increased expression of GILZ restricted to M/M, showed lower frequencies of inflammatory monocytes than their littermates and lower plasma levels of inflammatory cytokines. Tg-mice also had lower blood bacterial counts. We further established that the upregulation of GILZ in M/M enhanced their phagocytic capacity in in vivo assays. The increase of GILZ in M/M was also sufficient to improve the survival rates of septic mice. These results provide evidence for a central role of both GILZ and M/M in the pathophysiology of septic shock and a possible clue for the modulation of inflammation in this disease.