Regulation of plasma soluble receptors of TNF and IL-1 in patients with COVID-19 differs from that observed in sepsis.

Objectives: IL-1α/β and TNF are closely linked to the pathology of severe COVID-19 and sepsis. The soluble forms of their receptors, functioning as decoy receptors, exhibit inhibitory effects. However, little is known about their regulation in severe bacterial and viral infections, which we aimed to investigate in this study.

Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis.

Background: Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies.

COVID-19 Pneumonia and Cytokine Storm Syndrome.

Virus-associated cytokine storm syndrome (CSS) has been recognized for a long time and the classic viruses associated are the herpes viruses EBV, CMV, and HHV-8 as described in chapters IVa,b. In addition, pandemic viruses such as influenza, SARS, and MERS can result in severe CSS that might ultimately lead to severe acute respiratory distress syndrome (ARDS) and death [1-3]. A new pandemic caused by SARS-CoV-2 that started in 2019 has defined another chapter in the virus-associated CSS.

Influenza-associated and COVID-19-associated pulmonary aspergillosis in critically ill patients.

Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are increasingly recognised as important complications in patients requiring intensive care for severe viral pneumonia. The diagnosis can typically be made in 10-20% of patients with severe influenza or COVID-19, but only when appropriate diagnostic tools are used. Bronchoalveolar lavage sampling for culture, galactomannan testing, and PCR forms the cornerstone of diagnosis, whereas visual examination of the tracheobronchial tract during bronchoscopy is required to detect invasive Aspergillus tracheobronchitis.

Cryptococcosis Associated With Biologic Therapy: A Narrative Review.

is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes.

Profiling Bacteria in the Lungs of Patients with Severe Influenza Versus COVID-19 with or without Aspergillosis.

The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza-associated pulmonary aspergillosis (IAPA) or coronavirus disease (COVID-19)-associated pulmonary aspergillosis (CAPA) has yet to be explored. To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity, and outcome in severe influenza versus COVID-19 with or without aspergillosis. We performed a retrospective study in mechanically ventilated patients with influenza and COVID-19 with or without invasive aspergillosis in whom BAL for bacterial culture (with or without PCR) was obtained within 2 weeks after ICU admission.

Immunogenicity of COVID-19 booster vaccination in IEI patients and their one year clinical follow-up after start of the COVID-19 vaccination program.

Purpose: Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign.

Integrating genetic and immune factors to uncover pathogenetic mechanisms of viral-associated pulmonary aspergillosis.

Invasive pulmonary aspergillosis is a severe fungal infection primarily affecting immunocompromised patients. Individuals with severe viral infections have recently been identified as vulnerable to developing invasive fungal infections. Both influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are linked to high mortality rates, emphasizing the urgent need for an improved understanding of disease pathogenesis to unveil new molecular targets with diagnostic and therapeutic potential.

Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.

Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash.

Lower respiratory tract single-cell RNA sequencing and neutrophil extracellular trap profiling of COVID-19-associated pulmonary aspergillosis: a single centre, retrospective, observational study.

Background: COVID-19-associated pulmonary aspergillosis (CAPA) is a severe superinfection with the fungus Aspergillus affecting patients who are critically ill with COVID-19. The pathophysiology and the role of neutrophil extracellular traps (NETs) in this infection are largely unknown. We aimed to characterise the immune profile, with a focus on neutrophils and NET concentrations, of critically ill patients with COVID-19, with or without CAPA.

Anticytokine Autoantibodies in Infectious Diseases: A Practical Overview.

Anticytokine autoantibodies (ACAAs) are a fascinating group of antibodies that have gained more and more attention in the field of autoimmunity and secondary immunodeficiencies over the years. Some of these antibodies are characterized by their ability to target and neutralize specific cytokines. ACAAs can play a role in the susceptibility to several infectious diseases, and their infectious manifestations depending on which specific immunological pathway is affected.

The pathophysiology of sepsis and precision-medicine-based immunotherapy.

Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance.

Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.

The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown.

OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition.

Here, we describe an adult female with severe fasciitis and skin necrosis who carried a private, predicted deleterious missense mutation in OTULIN in heterozygosity. OTULIN is a cellular regulator of deubiquitination that has been shown to play a key role in intrinsic immunity against staphylococcal α-toxin. The patient was treated with broad-spectrum antibiotics, and multiple surgical explorations were conducted without clinical response.

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.

Objective: To determine whether vitamin C improves outcomes for patients with COVID-19.

Design, Setting, And Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents.

Peripheral T Cell Populations are Differentially Affected in Familial Mediterranean Fever, Chronic Granulomatous Disease, and Gout.

Both innate errors of immunity, such as familial Mediterranean fever (FMF) and chronic granulomatous disease (CGD), and the common inflammatory disease gout are characterized by episodes of sterile inflammatory attacks in the absence of an infection. While these disorders encompass distinct pathologies due to differentially affected metabolic pathways and inflammasome activation mechanisms, their common features are the excessive production of interleukin (IL)-1ß and innate immune cell hyperreactivity. On the other hand, the role of T cells and innate-like lymphocytes such as gamma delta (γδ) T cells in these pathologies is ill-defined.

The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses.

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 via induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. Here, we investigated the adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants and its effects on the responsiveness of immune cells upon stimulation with heterologous stimuli.

Dexamethasone attenuates interferon-related cytokine hyperresponsiveness in COVID-19 patients.

Background: Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.

Objective: We combined functional immunological assays and an omics-based approach to investigate the and effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.

Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.

Background: Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C.

Gallium-68 labelled RGD PET/CT imaging of endothelial activation in COVID-19 patients.

In coronavirus disease 2019 (COVID-19), endothelial cells play a central role and an inadequate response is associated with vascular complications. PET imaging with gallium-68 labelled RGD-peptide (Ga-RGD) targets αβ integrin expression which allows quantification of endothelial activation. In this single-center, prospective observational study, we included ten hospitalized patients with COVID-19 between October 2020 and January 2021.

Dimethyl itaconate induces long-term innate immune responses and confers protection against infection.

Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation.

Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity.

Purpose: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).