Allergic bronchopulmonary aspergillosis: diagnostic and treatment challenges

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder, occurring mostly in asthmatic and cystic fibrosis patients, caused by an abnormal T-helper 2 lymphocyte response of the host to Aspergillus fumigatus antigens. ABPA diagnosis is defined by clinical, laboratory and radiological criteria including active asthma, immediate skin reactivity to A. fumigatus antigens, total serum IgE levels>1000 IU/mL, fleeting pulmonary parenchymal opacities and central bronchiectases that represent an irreversible complication of ABPA. Despite advances in our understanding of the role of the allergic response in the pathophysiology of ABPA, pathogenesis of the disease is still not completely clear. In addition, the absence of consensus regarding its prevalence, diagnostic criteria and staging limits the possibility of diagnosing the disease at early stages. This may delay the administration of a therapy that can potentially prevent permanent lung damage. Long-term management is still poorly studied. Present primary therapies, based on clinical experience, are not yet standardized. These consist in oral corticosteroids, which control acute symptoms by mitigating the allergic inflammatory response, azoles and, more recently, anti-IgE antibodies. The latter two are used as a steroid-sparing agent to prolong the remission stage of the disease. Anti-IgE antibodies also have immunomodulatory properties. At present, the only way to bypass these limits and allow for an early diagnosis, is to assume ABPA in all patients with difficult-to-control asthma or cystic fibrosis. They should then be screened for sensitization to A. fumigatus antigens and, if positive, monitored more closely. Future controlled studies are needed to standardize present therapy, standardize cut-off values of various investigations, define the role of different novel immunomodulatory therapies, define the role of novel assays (such as recombinant A. fumigatus antigens and CCL17) and confirm new diagnostic and staging criteria

Case Report: Interindividual variability and possible role of heterozygous variants in a family with deficiency of adenosine deaminase 2: are all heterozygous born equals?

Deficiency of adenosine deaminase 2 (DADA2) is a rare systemic autoinflammatory disease, typically with autosomal recessive inheritance, usually caused by biallelic loss of function mutations in the ADA2 gene. The phenotypic spectrum is broad, generally including fever, early-onset vasculitis, stroke, and hematologic dysfunction. Heterozygous carriers may show related signs and symptoms, usually milder and at an older age. Here we describe the case of two relatives, the proband and his mother, bearing an ADA2 homozygous pathogenic variant, and a heterozygous son. The proband was a 17-year-old boy with intermittent fever, lymphadenopathies, and mild hypogammaglobulinemia. He also had sporadic episodes of aphthosis, livedo reticularis and abdominal pain. Hypogammaglobulinemia was documented when he was 10 years old, and symptoms appeared in his late adolescence. The mother demonstrated mild hypogammaglobulinemia, chronic pericarditis since she was 30 years old and two transient episodes of diplopia without lacunar lesions on MRI. ADA2 (NM_001282225.2) sequencing identified both mother and son as homozygous for the c.1358A>G, p.(Tyr453Cys) variant. ADA2 activity in the proband and the mother was 80-fold lower than in the controls. Clinical features in both patients improved on anti-tumor necrosis factor therapy. An older son was found to be heterozygous for the same mutation post-mortem. He died at the age of 12 years due to a clinical picture of fever, lymphadenitis, skin rash and hypogammaglobulinemia evolving toward fatal multiorgan failure. Biopsies of skin, lymph nodes, and bone marrow excluded lymphomas and vasculitis. Despite being suspected of symptomatic carrier, the contribution of an additional variant in compound heterozygosity, or further genetic could not be ruled out, due to poor quality of DNA samples available. In conclusion, this familiar case demonstrated the wide range of phenotypic variability in DADA2. The search for ADA2 mutations and the assessment of ADA2 activity should be considered also in patients with the association of hypogammaglobulinemia and inflammatory conditions, also with late presentation and in absence of vasculitis. Furthermore, the clinical picture of the deceased carrier suggests a possible contribution of heterozygous pathogenic variants to inflammation

COVID-19-related anosmia: the olfactory pathway hypothesis and early intervention

Anosmia is a well-described symptom of Corona Virus Disease 2019 (COVID-19). Several respiratory viruses are able to cause post-viral olfactory dysfunction, suggesting a sensorineural damage. Since the olfactory bulb is considered an immunological organ contributing to prevent the invasion of viruses, it could have a role in host defense. The inflammatory products locally released in COVID-19, leading to a local damage and causing olfactory loss, simultaneously may interfere with the viral spread into the central nervous system. In this context, olfactory receptors could play a role as an alternative way of SARS-CoV-2 entry into cells locally, in the central nervous system, and systemically. Differences in olfactory bulb due to sex and age may contribute to clarify the different susceptibility to infection and understand the role of age in transmission and disease severity. Finally, evaluation of the degree of functional impairment (grading), central/peripheral anosmia (localization), and the temporal course (evolution) may be useful tools to counteract COVID-19

Genetic bases of C7 deficiency: systematic review and report of a novel deletion determining functional hemizygosity

Primary complement system (C) deficiencies are rare but notably associated with an increased risk of infections, autoimmunity, or immune disorders. Patients with terminal pathway C-deficiency have a 1,000- to 10,000-fold-higher risk of Neisseria meningitidis infections and should be therefore promptly identified to minimize the likelihood of further infections and to favor vaccination. In this paper, we performed a systematic review about clinical and genetic patterns of C7 deficiency starting from the case of a ten-year old boy infected by Neisseria meningitidis B and with clinical presentation suggestive of reduced C activity. Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum. Sanger sequencing of genomic DNA extracted from peripheral blood of the patient allowed the identification of two pathogenetic variants in the C7 gene: the already well-characterized missense mutation G379R and a novel heterozygous deletion of three nucleotides located at the 3’UTR (c.*99_*101delTCT). This mutation resulted in an instability of the mRNA; thus, only the allele containing the missense mutation was expressed, making the proband a functional hemizygote for the expression of the mutated C7 allele

The bnt162b2 vaccine induces humoral and cellular immune memory to sars-cov-2 Wuhan strain and the Omicron variant in children 5 to 11 years of age

SARS-CoV-2 mRNA vaccines prevent severe COVID-19 by generating immune memory, comprising specific antibodies and memory B and T cells. Although children are at low risk of severe COVID-19, the spreading of highly transmissible variants has led to increasing in COVID-19 cases and hospitalizations also in the youngest, but vaccine coverage remains low. Immunogenicity to mRNA vaccines has not been extensively studied in children 5 to 11 years old. In particular, cellular immunity to the wild-type strain (Wuhan) and the cross-reactive response to the Omicron variant of concern has not been investigated. We assessed the humoral and cellular immune response to the SARS-CoV-2 BNT162b2 vaccine in 27 healthy children. We demonstrated that vaccination induced a potent humoral and cellular immune response in all vaccinees. By using spike-specific memory B cells as a measurable imprint of a previous infection, we found that 50% of the children had signs of a past, undiagnosed infection before vaccination. Children with pre-existent immune memory generated significantly increased levels of specific antibodies, and memory T and B cells, directed against not only the wild type virus but also the omicron variant

Low grade endotoxemia and oxidative stress in offspring of patients with early myocardial infarction

Background and aims: Offspring of patients with early myocardial infarction are at higher cardiovascular risk, but the underlying physio-pathological mechanism is unclear. NADPH oxidase-type 2 (NOX-2) plays a pivotal role as mediator of oxidative stress and could be involved in activating platelets in these patients. Furthermore, altered intestinal permeability and serum lipopolysaccharide (LPS) could be a trigger to promote NOX-2 activation and platelet aggregation. This study aims to evaluate the behavior of low grade endotoxemia, oxidative stress and platelet activation in offspring of patients with early myocardial infarction. Methods: We enrolled, in a cross-sectional study, 46 offspring of patients with early myocardial infarction and 86 healthy subjects (HS). LPS levels and gut permeability (assessed by zonulin), oxidative stress (assessed by serum NOX-2-derived peptide (sNOX2-dp) release, hydrogen peroxide (H2O2) production and isoprostanes), serum nitric oxide (NO) bioavailability and platelet activation (by serum thromboxane B2 (TXB2) and soluble P-Selectin (sP-Selectin)) were analyzed. Results: Compared to HS, offspring of patients with early myocardial infarction had higher values of LPS, zonulin, serum isoprostanes, sNOX2-dp H2O2, TXB2, p-selectin and lower NO bioavailability. Logistic regression analysis showed that the variables associated with offspring of patients with early myocardial infarction were LPS, TXB2 and isoprostanes. The multiple linear regression analysis confirmed that serum NOX-2, isoprostanes, p-selectin and H2O2 levels were significantly associated to LPS. Furthermore, serum LPS, isoprostanes and TXB2 levels were significantly associated with sNOX-2-dp. Conclusions: Offspring of patients with early myocardial infarction have a low grade endotoxemia that could generate oxidative stress and platelet activation increasing their cardiovascular risk. Future studies are needed to understand the role of dysbiosis in this population

Association between PaO2/FiO2 ratio and thrombotic events in COVID-19 patients

PaO2/FiO(2) (P/F ratio) is considered a marker of hypoxia/hypoxemia and mortality. Several prothrombotic changes are associated with the decrease of P/F ratio. The role of P/F ratio in patients with arterial and venous thrombosis remains unclear. The aim of this study was to assess in patients with coronavirus disease 2019 (COVID-19), the association between P/F ratio and arterial/venous thrombosis. One thousand and four hundred and six COVID-19 patients were recruited; 289 (21%) patients had P/F ratio < 200 and 1117 (79%) >= 200. Compared to the patients with P/F ratio >= 200, those with P/F ratio < 200 were older and with higher levels of glycemia, D-dimer and lower levels of albumin. Multiple linear regression analysis showed that albumin (standardized coefficient beta: 0.156; SE: 0.001; p = 0.0001) and D-dimer (standardized coefficient beta: -0.135; SE: 0.0001; p = 0.0001) were associated with P/F ratio. During the hospitalization 159 patients were transferred in intensive care unit (ICU), 253 patients died, 156 patients had arterial or venous thrombotic events. A bivariate logistic analysis was performed to analyze the predictors of thrombosis in COVID-19 patients; P/F ratio < 200 (Odds Ratio: [OR] 1.718, 95% Confidence Interval [CI] 1.085-2.718, p = 0.021), albumin (OR 1.693, 95% CI 1.055-2.716, p = 0.029), D-dimer (OR 3.469, 95% CI 2.110-5.703, p < 0.0001), coronary artery disease (CAD) (OR 1.800, 95% CI 1.086-2.984, p = 0.023) and heart failure (OR 2.410 95% CI 1.385-4.193, p = 0.002) independently predicted thrombotic events in this population. This study suggests that the P/F ratio is associated with thrombotic events by promoting a hypercoagulation state in patients hospitalized for COVID-19

Real-life data on monoclonal antibodies and antiviral drugs in Italian inborn errors of immunity patients during COVID-19 pandemic

BackgroundSince the beginning of the COVID-19 pandemic, patients with Inborn Errors of Immunity have been infected by SARS-CoV-2 virus showing a spectrum of disease ranging from asymptomatic to severe COVID-19. A fair number of patients did not respond adequately to SARS-CoV-2 vaccinations, thus early therapeutic or prophylactic measures were needed to prevent severe or fatal course or COVID-19 and to reduce the burden of hospitalizations.MethodsLongitudinal, multicentric study on patients with Inborn Errors of Immunity immunized with mRNA vaccines treated with monoclonal antibodies and/or antiviral agents at the first infection and at reinfection by SARS-CoV-2. Analyses of efficacy were performed according to the different circulating SARS-CoV-2 strains.ResultsThe analysis of the cohort of 192 SARS-CoV-2 infected patients, across 26 months, showed the efficacy of antivirals on the risk of hospitalization, while mabs offered a positive effect on hospitalization, and COVID-19 severity. This protection was consistent across the alpha, delta and early omicron waves, although the emergence of BA.2 reduced the effect of available mabs. Hospitalized patients treated with mabs and antivirals had a lower risk of ICU admission. We reported 16 re-infections with a length of SARS-CoV-2 positivity at second infection shorter among patients treated with mabs. Treatment with antivirals and mabs was safe.ConclusionsThe widespread use of specific therapy, vaccination and better access to care might have contributed to mitigate risk of mortality, hospital admission, and severe disease. However, the rapid spread of new viral strains underlines that mabs and antiviral beneficial effects should be re- evaluated over time

Selective IgA Deficiency and Allergy: A Fresh Look to an Old Story

Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD

Inherited defects in the complement system

The complement system plays an essential role in both innate and adaptive immune responses. Any dysregulation in this system can disturb normal host defense and alter inflammatory response leading to both infections and autoimmune diseases. The complement system can be activated through three different pathways. Inherited complement deficiencies have been described for all complement components and their regulators. Despite being rare diseases, complement deficiencies are often severe, with a frequent onset during childhood. We provide an overview of clinical disorders related to these disorders and describe current diagnostic strategies required for their comprehensive characterization and management