Antonio Pecoraro

Malignancies are the major cause of death in patients with adult onset common variable immunodeficiency

To the editor: In the paper by Resnick et al, the authors clearly defined lymphoma, lung impairment, hepatitis, and gastrointestinal disease as the main causes of mortality in 411 subjects with common variable immunodeficiency (CVID) followed over 4 decades in New York.[1][1] This careful analysis

IL-3 synergises with basophil-derived IL-4 and IL-13 to promote the alternative activation of human monocytes

Basophil‐derived IL‐4 is involved in the alternative activation of mouse monocytes, as recently shown in vivo. Whether this applies to human basophils and monocytes has not been established yet. Here, we sought to characterise the interaction between basophils and monocytes and identify the molecular determinants. A basophil‐monocyte co‐culture model revealed that IL‐3 and basophil‐derived IL‐4 and IL‐13 induced monocyte production of CCL17, a marker of alternative activation. Critically, IL‐3 and IL‐4 acted directly on monocytes to induce CCL17 production through histone H3 acetylation, but did not increase the recruitment of STAT5 or STAT6. Although freshly isolated monocytes did not express the IL‐3 receptor α chain (CD123), and did not respond to IL‐3 (as assessed by STAT5 phosphorylation), the overnight incubation with IL‐4 (especially if associated with IL‐3) upregulated CD123 expression. IL‐3‐activated JAK2‐STAT5 pathway inhibitors reduced the CCL17 production in response to IL‐3 and IL‐4, but not to IL‐4 alone. Interestingly, monocytes isolated from allergen‐sensitised asthmatic patients exhibited a higher expression of CD123. Taken together, our data show that the JAK2‐STAT5 pathway modulates both basophil and monocyte effector responses. The coordinated activation of STAT5 and STAT6 may have a major impact on monocyte alternative activation in vitro and in vivo.

Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia.

In this study, we compared intravenous immunoglobulins (IVIG) and subcutaneous immunoglobulins (SCIG) in terms of serum IgG concentration and incidence of infections in patients with hypogammaglobulinemia secondary to chemo-immunotherapy regimens including the anti-CD20 monoclonal antibody rituximab. Fourteen patients with a B-cell lymphoproliferative disease treated for at least six months with a rituximab-including chemo-immunotherapy regimen were recruited. Mean serum levels of IgG were higher during replacement therapy than at the end of rituximab treatment (p<0.001). Moreover, serum IgG level was higher during replacement therapy with SCIG than with IVIG (p<0.001). No differences in the incidence of infections were observed. Although the non-randomized design and the small number of patients do not allow definitive conclusions to be drawn, study results suggest that higher mean serum IgG levels are reached when using the subcutaneous route after a switch from the intravenous regimen, and that IVIG and SCIG offer comparable protection against infections.

Shift from intravenous or 16% subcutaneous replacement therapy to 20% subcutaneous immunoglobulin in patients with primary antibody deficiencies.

In patients with primary antibody deficiencies, subcutaneous administration of IgG (SCIG) replacement is effective, safe, well-tolerated, and can be self-administered at home. A new SCIG replacement at 20% concentration (Hizentra®) has been developed and has replaced Vivaglobin® (SCIG 16%). An observational prospective multi-centric open-label study, with retrospective comparison was conducted in 15 Italian centers, in order to investigate whether and to what extent switching to Hizentra® would affect frequency of infusions, number of infusion sites, patients’ satisfaction, and tolerability in patients previously treated with Vivaglobin® or intravenous immunoglobulins (IVIG). Any variations of dosage, frequency and duration of the infusions, and of number of infusion sites induced by Hizentra® with respect to the former treatment were recorded. Practical advantages and disadvantages of Hizentra®, with respect to the medicinal product formerly used, and the variations in patients’ therapy-related satisfaction were monitored by means of the TSQM (Treatment Satisfaction Questionnaire for Medication); number, frequency, and duration of infectious events and adverse effects were recorded. Eighty-two patients switched to Hizentra®: 19 (23.2%) from IVIG and 63 (76.8%) from Vivaglobin®. The mean interval between infusions was not affected by the shift (7.0 ± 2.0 days with previous treatment versus 7.1 ± 1.2 during Hizentra®). A decrease in the number of infusion sites with Hizentra® was recorded in 12 out of 56 patients for whom these data were available. At 6 months, 89.7% of patients were satisfied with Hizentra®; no difference in terms of effectiveness, side effects, convenience, and global satisfaction was observed. No difference in the incidence of adverse events was reported.

Delay in diagnosis affects the clinical outcome in a cohort of cvid patients with marked reduction of iga serum levels

Common variable immunodeficiency disorders (CVID) represent a collection of diseases leading to an absent or strongly impaired antibody production. CVID presents a wide range of immunological abnormalities and clinical manifestations, including infections, inflammatory and autoimmune diseases, and malignancies. The aim of this observational study was to analyze the epidemiological and clinical features of a cohort of 75 Italian CVID patients, and evaluate the correlation with comorbidity and mortality. Clinical data were retrospectively collected: the cohort was followed-up for a maximum of 30years (mean time of 10.24years, median of 9years). An higher age at the diagnosis of CVID and an higher age at onset of symptoms were significantly associated with a reduction of patients survival if stratified per median of IgA (less than or >8.00mg/dl). Thus IgA levels at diagnosis are correlated with patients survival contributing to identify a subset with a worse prognostic outcome.

Total and High Molecular Weight Adiponectin Expression Is Decreased in Patients with Common Variable Immunodeficiency: Correlation with Ig Replacement Therapy

Adiponectin (Acrp30) is an adipokine widely studied for its beneficial metabolic properties. It circulates as low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) oligomers. The latter exerts the most potent biological effects. Acrp30 attracted renewed interest with the finding that it was associated with the development and progression of immune disorders. The mechanisms underlying this association and the role of Acrp30 in the pathophysiology of immune-mediated conditions remain unknown. Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic activation of the immune system, impaired antibody production, and imbalanced cytokine production. In the attempt to shed light on the expression of Acrp30 in CVID, we: (a) investigated total Acrp30 and its oligomerization state in CVID patients undergoing maintenance Ig replacement therapy; (b) assessed the effects of Ig replacement therapy on Acrp30 expression in treatment-naïve CVID patients, namely, patients not treated before diagnosis, before and after the first Ig administration; and (c) evaluated the correlation between Acrp30 levels and clinical phenotypes of the disease. As controls, we analyzed healthy subjects and patients affected by a non-immunodeficiency chronic inflammatory demyelinating polyneuropathy (CIDP), before and after Ig infusion. We found that total Acrp30 and HMW oligomers were decreased in CVID but not in CIDP patients versus controls. Moreover, Acrp30 levels were correlated with IgA levels and were associated with two CVID phenotypes, namely, autoimmune cytopenia and enteropathy. Receiver operating characteristic curve analysis indicated that Acrp30 modulation is specific for CVID patients. Acrp30 and HMW levels quickly and dramatically increased after Ig infusion only in eight treatment-naïve CVID patients but not in five CIDP patients. This finding indicates that Ig administration per se is not able to induce an increase of Acrp30, but the specific cellular and/or molecular background proper of CVID seems to be essential. In conclusion, our data indicate that Acrp30 is specifically related to CVID activity. Further studies are required to understand the biological role of Acrp30 and its possible use as disease biomarker in CVID.

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective

Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.

Heart failure not responsive to standard immunosuppressive therapy is successfully treated with high dose intravenous immunoglobulin therapy in a patient with Eosinophilic Granulomatosis with Polyangiitis (EGPA).

Glucocorticoids and immunosuppressive drugs represent the first-line treatment of eosinophilic granulomatosis with polyangiitis (EGPA, former Churg-Strauss syndrome), even though the combined therapy is not successful in achieving the disease remission in some patients with neurological or cardiac involvement. We describe a case of an EGPA male patient with impaired left ventricular function not responsive to glucocorticoid and immunosuppressive therapy. We observed that high-dose (2g/kg/4weeks) intravenous immunoglobulin (IVIG) therapy significantly improved cardiac function, which was deteriorated after reducing IVIG dose at 0.5g/kg/4weeks, and was restored increasing again IVIG dose to 2g/kg/4weeks. The finding highlights the relevance of IVIG as treatment of choice in EGPA patients with cardiac involvement not responsive to the standard glucocorticoid and immunosuppressive therapy. Moreover, at a follow-up of 24months, the continuance of high dose IVIG therapy was required to maintain a sustained remission of the heart failure.

Immunoglobulin replacement therapy in primary and secondary antibody deficiency: The correct clinical approach

ABSTRACT Immunoglobulin therapy is the administration of human polyvalent IgG and represents the most effective treatment to prevent recurrent infections in antibody deficiency patients. Primary antibody deficiency represents the main indication of immunoglobulin replacement therapy and includes a wide range of disorders characterized by impaired antibody production in response to pathogens and recurrent infections. However, not all primary antibody deficiency patients require immunoglobulin replacement. Indeed, immunoglobulin preparations are expensive and, once prescribed, usually result in lifelong therapy. Moreover, many patients significantly benefit from a long‐term antibiotic prophylaxis and a prompt begin of antibiotic therapy in case of infectious events. Even more controversial is the decision to initiate immunoglobulin replacement therapy in secondary antibody deficiency, a heterogeneous and expanding group including B‐cell lymphoproliferative syndromes, protein losing states and therapeutic agents. This review seeks to define the indication to immunoglobulin replacement in primary and secondary antibody deficiency disorders, distinguishing those in which the beginning of immunoglobulin therapy is always indicated at the same time as the diagnosis has been made, from those lacking of defined indication to replacement therapy. In addition, we propose a clinical approach, mainly based on the evaluation of infectious history, vaccine response and bronchiectasis finding, to support the decision to initiate immunoglobulin therapy in an individual patient. HighlightsImmunoglobulin therapy prevents recurrent infections in antibody deficiency patients.Not all antibody deficiency patients require immunoglobulin replacement therapy.The patients assessment supports the decision to initiate immunoglobulin therapy.

Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.