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Fungi are opportunists: They particularly require a defect of immunity to cause severe or disseminated disease. While often secondary to an apparent iatrogenic cause, fungal diseases do occur in the absence of one, albeit infrequently. These rare cases may be due to an underlying genetic immunodeficiency that can present variably in age of onset, severity, or other infections, and in the absence of a family history of disease. They may also be due to anti-cytokine autoantibodies. This review provides a background on how human genetics or autoantibodies underlie cases of susceptibility to severe or disseminated fungal disease. Subsequently, the lessons learned from these inborn errors of immunity marked by fungal disease (IEI-FD) provide a framework to begin to mechanistically decipher fungal syndromes, potentially paving the way for precision therapy of the mycoses., (© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Rationale: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair., Objective: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis., Methods: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms., Results: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms., Conclusion: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections., (© 2024. The Author(s).)

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2., (© 2024 Bastard et al.)

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c -statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c -statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Life-threatening "breakthrough" cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/β, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes., Competing Interests: Disclosure SJ has received support for conferences, speaker, advisory boards, trials, data and safety monitoring boards, and projects with CSL Behring, Takeda, Swedish Orphan Biovitrum, Biotest, Binding Site, Grifols, BPL, Octapharma, LFB, Pharming, GSK, Weatherden, Zarodex, Sanofi, and UCB Pharma. SG has received research funding from Miltenyi Biotec, Takeda, Celgene, Amgen, Sanofi, Johnson and Johnson, and Actinium and is on the advisory boards for: Kite Pharmaceuticals, Celgene, Sanofi, Novartis, Johnson and Johnson, Amgen, Takeda, Jazz Pharmaceuticals, Actinium Pharmaceuticals and CSL Behring. TK has received support (never on a personal account) for conferences, speaker bureaus, advisory boards, trials, data and safety monitoring boards, and projects with Sanofi, Takeda, BMS, Johnson & Johnson, MSD, Novartis, Gilead, Octapharma and CSL Behring. HML has received consultancy fees and support for advisory boards from CSL Behring and Actinium Pharmaceuticals; is a member of the data safety and monitoring boards for BMS, BioSight, and Celgene; is a consultant, promotional speaker, and a member of the advisory boards for Jazz Pharmaceuticals and Seattle Genetics; is a promotional speaker for AstraZeneca; has received consultancy fees and has stock options with Partner Therapeutics; and has received consultancy fees from Pluristem. SM has received support for an advisory board and speaker bureaus with CSL Behring. GAP has received grants from Merck and Takeda and received support for advisory boards, data and safety monitoring boards, consultancy, speaker projects with Symbio, Merck, MSD, Allovir, Vera, Amplyx, Pfizer, Takeda, Cidara, Octapharma, Astellas and CSL Behring. RR has received support for advisory boards, data and safety monitoring boards, and speaker bureaus with Janssen Cilag, BMS, Celgene, Takeda, CSL Behring and Octapharma. DCV has received salary support from Fonds de Recherche du Québec - Santé Senior Clinician-Scientist scholar program; clinical trial support from CSL Behring, Cidara Therapeutics, Moderna, and Janssen; has received honoraria for advisory board consultations or speaker presentations from Astra Zeneca, GSK, Merck Canada, CSL Behring, Moderna, Novartis Canada, and UCB Biosciences GmbH; and has a patent application pending (Electronic Filing System ID: 40101099) and a report of invention submitted to McGill University (Track code: D2021-0043). JRW has received support for advisory boards and data and safety monitoring boards from CSL Behring, Cidara, Merck, Celgene, Ansun, and Takeda and royalties from UptoDate., (Copyright © 2023. Published by Elsevier Inc.)

Background: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves., Methods: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic., Results: During the Omicron wave, 28-day mortality was significantly lower in vaccinated ( n = 19/237) than unvaccinated hospitalized patients ( n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15-0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24-0.59; and 0.42, 95% CI 0.26-0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43-1.51) and had less organ dysfunction than in the first 2 waves., Interpretation: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave., Competing Interests: Competing interests: Keith Walley reports receiving a Canadian Institutes of Health Research (CIHR) Foundation grant, paid to the University of British Columbia. Dr. Walley has also participated on data safety monitoring boards (unpaid) for Northern Therapeutics and the Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome (CIRCA-19) trial. Allison McGeer reports receiving grants from Sanofi, Merck and Pfizer (paid to institution), as well as payment or honoraria from AstraZeneca, Merck, Biogen and Moderna. Dr. McGeer has also received travel support from Moderna and has participated on a data safety monitoring or advisory board for Pfizer, GlaxoSmithKline, Moderna, Medicago, Janssen, AstraZeneca, Novavax and Sanofi., (© 2023 CMA Impact Inc. or its licensors.)

Wiskott-Aldrich syndrome is an X-linked recessive primary immune-deficiency disorder very rarely reported from black African children. A 12-year old boy with recurrent sinopulmonary and diarrheal infections, eczema, thrombocytopenia, and low platelet volume was found by whole genome sequencing to harbor a predicted pathogenic c.1205dupC (p.Pro403Alafs*92) variant of a mutation in the WAS gene - confirming the diagnosis. This case report summarizes his presentation and management and provides a useful summary of the diagnosis and the responsible novel genetic mutation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In medical mycology, the main context of disease is iatrogenic-based disease. However, historically, and occasionally, even today, fungal diseases affect humans with no obvious risk factors, sometimes in a spectacular fashion. The field of "inborn errors of immunity" (IEI) has deduced at least some of these previously enigmatic cases; accordingly, the discovery of single-gene disorders with penetrant clinical effects and their immunologic dissection have provided a framework with which to understand some of the key pathways mediating human susceptibility to mycoses. By extension, they have also enabled the identification of naturally occurring auto-antibodies to cytokines that phenocopy such susceptibility. This review provides a comprehensive update of IEI and autoantibodies that inherently predispose humans to various fungal diseases.

The SARS-CoV-2 pandemic highlighted the need for rapid, collaborative, and population-centric research to define health impact, develop health care policies and establish reliable diagnostic and surveillance tests. Critical for these objectives were in-depth clinical data collected in standardized fashion and large numbers of various types of human samples prior and post-viral encounter. As the pandemic evolved with the emergence of new variants of concern (VOCs), access to samples and data from infected and vaccinated individuals were needed to monitor immune durability, the possibility of increased transmissibility and virulence, and vaccine protection against new and emerging VOCs. Therefore, essential to the pandemic response is a strong laboratory and data research component, supported by effective biobanking and data sharing. Critically important to the speed of the research response is the rapid access to biobanked samples. To address critical challenges brought to light by the pandemic, the Coronavirus Variants Rapid Response Network (CoVaRR-Net), funded by the Canadian Institutes of Health Research, was established to coordinate research efforts to provide rapid evidence-based responses to emerging VOCs. The purpose of this paper is to introduce the CoVaRR-Net Biobank and define its contribution to pandemic preparedness., (© Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada), 2022.)

Inborn errors of immunity are a heterogeneous group of genetically determined disorders that compromise the immune system, predisposing patients to infections, autoinflammatory/autoimmunity syndromes, atopy/allergies, lymphoproliferative disorders, and/or malignancies. An emerging manifestation is susceptibility to fungal disease, caused by yeasts or moulds, in a superficial or invasive fashion. In this review, we describe recent advances in the field of inborn errors of immunity associated with increased susceptibility to fungal disease.

Secondary immunodeficiency (SID) in patients with B-cell hematological malignancies is a common condition that presents with recurrent infection. SID is due to both the inherent immune defects due to the malignancy, as well as secondary to cancer therapies, many of which have B-cell depleting properties. The early diagnosis of SID and the optimization of intervention strategies are key to delivering the most effective cancer treatments and reducing infection-related morbidity and mortality. This review discusses current practice, recommendations, and challenges for SID diagnosis, based on the evaluation of clinical history and laboratory assessments, and the effectiveness of specific vaccines and immunoglobulin replacement therapy in reducing the frequency and recurrence of infections in patients with SID, and the healthcare system-associated costs., Competing Interests: Conflict of interest statement NS has received research funding from Celgene/BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, and Nektar; and reports advisory role for GSK, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite, Karyopharm, and Oncopeptides. SSM reports speaker’s bureau for Genentech, GSK, Regeneron, AstraZeneca, and CSL Behring. DCV has received clinical trial support from CSL Behring, Cidara Therapeutics, and Janssen Pharmaceuticals; has received honoraria for advisory board consultations or speaker presentations from Merck Canada, CSL Behring, Novartis Canada, and UCB Biosciences GmbH; and has a patent application pending (Electronic Filing System ID: 40101099) and a report of invention submitted to McGill University (Track code: D2021–0043)., (Copyright © 2022. Published by Elsevier B.V.)

Background: Monkeypox, a viral zoonotic disease, is causing a global outbreak outside of endemic areas., Objective: To characterize the outbreak of monkeypox in Montréal, the first large outbreak in North America., Design: Epidemiologic and laboratory surveillance data and a phylogenomic analysis were used to describe and place the outbreak in a global context., Setting: Montréal, Canada., Patients: Probable or confirmed cases of monkeypox., Measurements: Epidemiologic, clinical, and demographic data were aggregated. Whole-genome sequencing and phylogenetic analysis were performed for a set of outbreak sequences. The public health response and its evolution are described., Results: Up to 18 October 2022, a total of 402 cases of monkeypox were reported mostly among men who have sex with men (MSM), most of which were suspected to be acquired through sexual contact. All monkeypox genomes nested within the B.1 lineage. Montréal Public Health worked closely with the affected communities to control the outbreak, becoming the first jurisdiction to offer 1 dose of the Modified Vaccinia Ankara-Bavarian Nordic vaccine as preexposure prophylaxis (PrEP) to those at risk in early June 2022. Two peaks of cases were seen in early June and July (43 and 44 cases per week, respectively) followed by a decline toward near resolution of the outbreak in October. Reasons for the biphasic peak are not fully elucidated but may represent the tempo of vaccination and/or several factors related to transmission dynamics and case ascertainment., Limitations: Clinical data are self-reported. Limited divergence among sequences limited genomic epidemiologic conclusions., Conclusion: A large outbreak of monkeypox occurred in Montréal, primarily among MSM. Successful control of the outbreak rested on early and sustained engagement with the affected communities and rapid offer of PrEP vaccination to at-risk persons., Primary Funding Source: None.

Purpose of Review: This review provides readers with examples of refractory infections due to inborn errors of immunity, highlighting how they may be successfully treated by deducing and targeting the underlying immunodeficiency., Recent Findings: The use of host-directed immunotherapy to treat infectious disease in inborn errors of immunity is currently limited but growing. Different strategies include depleting the cellular reservoir for pathogens with restricted cell-tropism; augmenting the diminished effector response; and restoring molecular equipoise. The immunotherapies illustrated are existing drugs that have been re-purposed and rationally used, depending on the molecular or cellular impact of the mutation. As more biologic response modifiers and molecular targeted therapies are developed for other indications, they open the avenues for their use in inborn errors of immunity. Conversely, as more molecular pathways underlying defective immune responses and refractory infections are elucidated, they lend themselves to tractability with these emerging therapies., Summary: Infections that fail appropriate antimicrobial therapy are a harbinger of underlying inborn errors of immunity. Dissecting the mechanism by which the immune system fails provides opportunities to target the host response and make it succeed., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1β-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

As the SARS-CoV-2 pandemic evolves, vaccine evaluation needs to include consideration of both durability and cross-reactivity. This report expands on previously reported results from a Phase 1 trial of an AS03-adjuvanted, plant-based coronavirus-like particle (CoVLP) displaying the spike (S) glycoprotein of the ancestral SARS-CoV-2 virus in healthy adults (NCT04450004). Humoral and cellular responses against the ancestral strain were evaluated 6 months post-second dose (D201) as secondary outcomes. Independent of dose, all vaccinated individuals retain binding antibodies, and ~95% retain neutralizing antibodies (NAb). Interferon gamma and interleukin-4 responses remain detectable in ~94% and ~92% of vaccinees respectively. In post-hoc analyses, variant-specific (Alpha, Beta, Delta, Gamma and Omicron) NAb were assessed at D42 and D201. Using a live virus neutralization assay, broad cross-reactivity is detectable against all variants at D42. At D201, cross-reactive antibodies are detectable in almost all participants against Alpha, Gamma and Delta variants (94%) and the Beta variant (83%) and in a smaller proportion against Omicron (44%). Results are similar with the pseudovirion assay. These data suggest that two doses of 3.75 µg CoVLP+AS03 elicit a durable and cross-reactive response that persists for at least 6 months post-vaccination., (© 2022. The Author(s).)

The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and to fight variants. We report herein a pre-specified interim analysis of the phase 2 portion of a Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate, produced in plants that displays the SARS-CoV-2 spike glycoprotein, adjuvanted with AS03 (NCT04636697). A total of 753 participants were recruited between 25th November 2020 and 24th March 2021 into three groups: Healthy Adults (18-64 years: N = 306), Older Adults (≥65 years: N = 282) and Adults with Comorbidities (≥18 years: N = 165) and randomized 5:1 to receive two intramuscular doses of either vaccine (3.75 µg CoVLP/dose+AS03) or placebo, 21 days apart. This report presents safety, tolerability and immunogenicity data up to 6 months post-vaccination. The immune outcomes presented include neutralizing antibody (NAb) titres as measured by pseudovirion assay at days 21 and 42 as well as neutralizing antibody cross-reactivity to several variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron (BA.1), up to 201 days post-immunization. Cellular (IFN-γ and IL-4 ELISpot) response data in day 21 and 42 peripheral blood are also presented. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults and the reactogenicity was higher after the second dose. CoVLP+AS03 induced seroconversion in >35% of participants in each group after the first dose and in ~98% of participants, 21 days after the second dose. In all cohorts, 21-days after the second dose, NAb levels in sera against the vaccine strain were ~10-times those in a panel of convalescent sera. Cross-reactivity to Alpha, Beta and Delta variants was generally retained to day 201 (>80%) while cross-reactivity to the Gamma variant was reduced but still substantial at day 201 (73%). Cross-reactivity to the Omicron variant fell from 72% at day 42 to 20% at day 201. Almost all participants in all groups (>88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after the second dose. These data demonstrated that CoVLP+AS03 is well-tolerated and highly immunogenic, generating a durable (at least 6 months) immune response against different VOCs, in adults ≥18 years of age, with and without comorbidities., (© 2022. The Author(s).)

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT., (© 2022 by The American Society of Hematology.)

Objectives: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components., Design: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup ( n = 46), recorded d -dimer ( n = 967), comparing males with females., Setting: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces., Patients: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included., Interventions: None., Measurements and Main Results: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation ( p = 0.006) and vasopressors ( p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females., Conclusions: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19., Competing Interests: Drs. Rocheleau’s, Cheng’s, Lee’s, Haljan’s, Vinh’s, Mann’s, Donohoe’s, and Russell’s institutions received funding from the Canadian Institutes for Health Research. Dr. Mohammed’s institution received funding from Genome Canada and Genome British Colombia. Dr. Goodlett disclosed that he is the founder of Pataigin LLC and Deurion LLC and that the University of Victoria Genome British Columbia Proteome Centre (for which he is a director) received funding from Genome Canada and Genome British Colombia. Dr. Burns disclosed that he is a consultant to JN Nova Pharma. Dr. Cheng’s institution received funding from McGill Interdisciplinary Initiative in Infection and Immunity; he received funding from GEn1E Lifesciences and NPlex Biosciences; he disclosed that he is the cofounder of Kanvas Biosciences and owns equity in the company; and he disclosed that he is a named coinventor on a pending patent entitled “Methods for assessing the severity and progression of SARS-CoV2 infections using cell-free DNA.” Dr. Slutsky received funding from Apeiron, GlaxoSmithKline, Baxter, Cellenkos, Diffusion, Edesa, Exvastat, Faron, and Novalung. Dr. Lee received funding from the Fonds de recherche du Quebec santé (FRQS). Dr. Haljan’s institution received funding from Michael Smith Foundation for Health Research and Surrey Hospital Foundation. Dr. Vinh’s institution received funding from the Jeffrey Modell Foundation and FRQS; he received funding from CSL Behring, Astra Zeneca, Moderna, Takeda, QU Biologics, Merck Canada, Novartis Canada, and the COVID Immunity Task Force (Public Health Agency of Canada); he disclosed he has patent applications pending (Encrypting File System Identification [EFS ID] 40101099; EFS ID 44321620). Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of proprotein convertase subtilisin/kexin type 9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock and a patent owned by Ferring for use of selepressin in septic shock; he is an inventor on these patents; he was a founder, director, and shareholder in Cyon Therapeutics and is a shareholder in Molecular You Corp; he reports receiving consulting fees in the last 3 years from: Asahi Kesai Pharmaceuticals of America (was developing recombinant thrombomodulin in sepsis), SIB Therapeutics LLC (developing a sepsis drug), and Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin); he is no longer actively consulting for the following: La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chaired the Data Safety Monitoring Board of a trial of angiotensin II from 2015 to 2017), PAR Pharma (sells prepared bags of vasopressin); and he reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Despite the availability of highly efficacious vaccines, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks effective drug treatment, which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a systems biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified messenger RNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill patients with COVID-19, leading us to identify tacrolimus, zotatifin, and nintedanib as three strong candidates for treatment of severely ill patients at the time of hospital admission.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Background: There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces., Methods: We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0-1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces., Results: A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24-0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27-0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26-0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29-0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1., Interpretation: Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes., Study Registration: ClinicalTrials.gov, no. NCT04510623., Competing Interests: Competing interests: James Russell reports an investigator-initiated grant from Grifols that was provided to and administered by the University of British Columbia (UBC). He reports patents owned by UBC that are related to the use of PCSK9 inhibitor(s) in sepsis and the use of vasopressin in septic shock, and a patent owned by Ferring Pharmaceuticals for use of selepressin in septic shock. He is an inventor on these patents. He was a founder, director and shareholder in Cyon Therapeutics and is a shareholder in Molecular You. He reports consulting fees from SIB Therapeutics (developing a sepsis drug) and Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). He is no longer actively consulting for any industry. He was a nonfunded science advisor and member of the Government of Canada COVID-19 Therapeutics Task Force (June 2020–December 2021) and a nonfunded member of the data and safety monitoring board of a trial of plasma in COVID-19 (PassITON) (2020–2021) sponsored by the National Institutes of Health. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N = 13) in comparison to controls (N = 10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N = 29; P < 0.001 for each), which was accompanied by decreased levels of MCL1 (P < 0.05). GATA2 expression led to significant repression of miR-181c expression in transfection experiments. Conversely, knockdown of GATA2 led to increased miR-181c expression. These findings indicate that miR-181c expression is increased and MCL1 levels decreased in GATA2 deficiency cells, and that GATA2 represses miR-181c transcription. Increased miR-181c may contribute to elevated cell death and cytopenia in GATA2 deficiency potentially through down-regulation of MCL1., (©2021 Society for Leukocyte Biology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch of our immune system. There is ample evidence that vaccines such as bacillus Calmette-Guérin (BCG) induce protective innate immune memory responses (trained immunity) against heterologous pathogens. Here we show that while BCG vaccination significantly reduces morbidity and mortality against influenza A virus (IAV), it fails to provide protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In contrast to IAV, SARS-CoV-2 infection leads to unique pulmonary vasculature damage facilitating viral dissemination to other organs, including the bone marrow (BM), a central site for BCG-mediated trained immunity. Finally, monocytes from BCG-vaccinated individuals mount an efficient cytokine response to IAV infection, while this response is minimal following SARS-CoV-2. Collectively, our data suggest that the protective capacity of BCG vaccination is contingent on viral pathogenesis and tissue tropism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. Patients with WHIM syndrome are more susceptible to human papillomavirus (HPV) infections and commonly present to a dermatologist with recalcitrant to treatment warts. Other cardinal features of WHIM syndrome include recurrent sinopulmonary bacterial infections, neutropenia/lymphopenia, low levels of immunoglobulins (IgG, IgA, IgM) and myelokathexis. Research demonstrated that truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) are responsible for this disease. Plerixafor, a specific small molecule antagonist of CXCR4, is currently used for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. It has recently shown promise for the treatment of WHIM syndrome in phase I/II clinical trials. In this paper we review the emerging patient clinical data for this medication and highlight the role of CXCR4 in other important skin diseases including keratinocyte carcinomas, psoriasis and cutaneous T-cell lymphoma., Competing Interests: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The use of COVID-19 vaccines has been prioritised to protect the most vulnerable-notably, older people. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been used. However, the effectiveness of these strategies in frail, older people are unknown. We aimed to assess the antigenicity of mRNA-based COVID-19 vaccines in frail, older people in a real-world setting, with a rationed interval dosing of 16 weeks between the prime and boost doses., Methods: This prospective observational cohort study was done across 12 long-term care facilities of the Montréal Centre-Sud - Integrated University Health and Social Services Centre in Montréal, Québec, Canada. Under a rationing strategy mandated by the provincial government, adults aged 65 years and older residing in long-term care facilities in Québec, Canada, with or without previously documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. All older residents in participating long-term care facilities who received two vaccine doses were eligible for inclusion in this study. Participants were enrolled from Dec 31, 2020, to Feb 16, 2021, and data were collected up to June 9, 2021. Clinical data and blood samples were serially collected from participants at the following timepoints: at baseline, before the first dose; 4 weeks after the first dose; 6-10 weeks after the first dose; 16 weeks after the first dose, up to 2 days before administration of the second dose; and 4 weeks after the second dose. Sera were tested for SARS-CoV-2-specific IgG antibodies (to the trimeric spike protein, the receptor-binding domain [RBD] of the spike protein, and the nucleocapsid protein) by automated chemiluminescent ELISA. Two cohorts were used in this study: a discovery cohort, for which blood samples were collected before administration of the first vaccine dose and longitudinally thereafter; and a confirmatory cohort, for which blood samples were only collected from 4 weeks after the prime dose. Analyses were done in the discovery cohort, with validation in the confirmatory cohort, when applicable., Findings: The total study sample consisted of 185 participants. 65 participants received two doses of mRNA-1273 (Spikevax; Moderna), 36 received two doses of BNT162b2 (Comirnaty; Pfizer-BioNTech), and 84 received mRNA-1273 followed by BNT162b2. In the discovery cohort, after a significant increase in anti-RBD and anti-spike IgG concentrations 4 weeks after the prime dose (from 4·86 log binding antibody units [BAU]/mL to 8·53 log BAU/mL for anti-RBD IgG and from 5·21 log BAU/mL to 8·05 log BAU/mL for anti-spike IgG), there was a significant decline in anti-RBD and anti-spike IgG concentrations until the boost dose (7·10 log BAU/mL for anti-RBD IgG and 7·60 log BAU/mL for anti-spike IgG), followed by an increase 4 weeks later for both vaccines (9·58 log BAU/mL for anti-RBD IgG and 9·23 log BAU/mL for anti-spike IgG). SARS-CoV-2-naive individuals showed lower antibody responses than previously infected individuals at all timepoints tested up to 16 weeks after the prime dose, but achieved similar antibody responses to previously infected participants by 4 weeks after the second dose. Individuals primed with the BNT162b2 vaccine showed a larger decrease in mean anti-RBD and anti-spike IgG concentrations with a 16-week interval between doses (from 8·12 log BAU/mL to 4·25 log BAU/mL for anti-RBD IgG responses and from 8·18 log BAU/mL to 6·66 log BAU/mL for anti-spike IgG responses) than did those who received the mRNA-1273 vaccine (two doses of mRNA-1273: from 8·06 log BAU/mL to 7·49 log BAU/mL for anti-RBD IgG responses and from 6·82 log BAU/mL to 7·56 log BAU/mL for anti-spike IgG responses; mRNA-1273 followed by BNT162b2: from 8·83 log BAU/mL to 7·95 log BAU/mL for anti-RBD IgG responses and from 8·50 log BAU/mL to 7·97 log BAU/mL for anti-spike IgG responses). No differences in antibody responses 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations., Interpretation: Interim results of this ongoing longitudinal study show that among frail, older people, previous SARS-CoV-2 infection and the type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. In these cohorts of frail, older individuals with a similar age and comorbidity distribution, we found that serological responses were similar and clinically equivalent between the discovery and confirmatory cohorts. Homologous and heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following the second dose, supporting their interchangeability., Funding: Public Health Agency of Canada, Vaccine Surveillance Reference Group; and the COVID-19 Immunity Task Force., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: DCV is funded by the Fonds de la recherche en santé du Québec clinician-scientist scholar Junior 2 Program; has received clinical trial support from Cidara Therapeutics, CSL Behring, and Janssen Pharmaceuticals; has served on advisory boards for CSL Behring, Novartis Canada, and UCB Biosciences; has received speaker honoraria from CSL Behring and Merck Canada; and has a patent application pending (Electronic Filing System ID: 40101099) and a report of invention to McGill University (Track code: D2021-0043), both unrelated to this work. J-PG is funded by a Canada Research Chair award. Production of COVID-19 reagents was financially supported by National Research Council Canada's Pandemic Response Challenge Program. All other authors declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

The ongoing coronavirus disease 2019 (COVID-19) pandemic has left patients with current or past history of cancer facing disparate consequences at every stage of the cancer trajectory. This comprehensive review offers a landscape analysis of the current state of the literature on COVID-19 and cancer, including the immune response to COVID-19, risk factors for severe disease, and impact of anticancer therapies. We also review the latest data on treatment of COVID-19 and vaccination safety and efficacy in patients with cancer, as well as the impact of the pandemic on cancer care, including the urgent need for rapid evidence generation and real-world study designs. SIGNIFICANCE: Patients with cancer have faced severe consequences at every stage of the cancer journey due to the COVID-19 pandemic. This comprehensive review offers a landscape analysis of the current state of the field regarding COVID-19 and cancer. We cover the immune response, risk factors for severe disease, and implications for vaccination in patients with cancer, as well as the impact of the COVID-19 pandemic on cancer care delivery. Overall, this review provides an in-depth summary of the key issues facing patients with cancer during this unprecedented health crisis., (©2021 American Association for Cancer Research.)

SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection., (© 2021. Springer Nature America, Inc.)

Real-world data are lacking to identify patients with secondary immunodeficiency (SID) who may benefit most from anti-infective interventions. This retrospective analysis used the IQVIA PharMetrics® Plus database to assess baseline characteristics associated with risk of severe infections post-SID diagnosis in patients with hematological malignancies. In 4066 patients included, the mean number of any and severe infections per patient in the one-year pre-SID diagnosis period was 9.5 and 0.7, respectively. Post-SID diagnosis, the mean annualized number of any and severe infections was 19.1 and 1.5, respectively. Receiver operating characteristic curve analysis identified a threshold (cutoff) of three bacterial infections at baseline as optimally predictive of severe infections post-SID diagnosis. Multivariate analysis indicated that hospitalizations, infections (≥3), or antibiotic use pre-SID diagnosis were predictive of severe infections post-SID diagnosis. Evaluation of these risk factors could inform clinical decisions regarding which patients may benefit from prophylactic anti-infective treatment, including immunoglobulin replacement if warranted.

Competing Interests: Declaration of interests DCV is funded by Fonds de la recherche en santé du Québec clinician-scientist scholar Junior 2 programme. DCV has received clinical trial support from: Cidara Therapeutics; CSL Behring; and Janssen Pharmaceuticals. DCV has served on advisory boards for: CSL Behring; Novartis Canada; and UCB Biosciences GmbH. DCV has received speaker honoraria from: CSL Behring; Merck Canada. DCV has a patent application pending (Electronic Filing System ID: 40101099) and a report of invention to McGill University (Track code: D2021-0043), both unrelated to this work.

B cell-derived lymphoproliferative disorders are associated with secondary immunodeficiency (SID); some patients require immunoglobulin replacement therapy (IgRT) to mitigate infections. Using IQVIA's PharMetrics ® Plus database, patients with SID who received IgPro10/IgPro20 in the 12 months post-diagnosis (IgRT users) were matched to patients with SID not receiving IgRT (non-IgRT users). The risk of severe infection was compared using within-patient change from baseline to follow-up as well as between cohorts. Overall, 277 IgRT users were matched to 1019 non-IgRT users. Before IgRT, more IgRT users experienced any bacterial infection (88.4% vs. 72.9%; p <.0001) or ≥1 severe bacterial infection (SBI) (42.2% vs. 31.8%; p =.0011) vs. non-IgRT users. During follow-up, risk of SBI among IgRT users (21.7%) reached parity with non-IgRT users (21.2%). IgRT was associated with a reduction in SBIs to levels comparable with the lower 'baseline infection risk' of non-IgRT users. These criteria help define SID patients who may benefit from IgRT.