Francesca Conti

Oramai nota è l’associazione tra immunodeficienze primitive (IDP) e manifestazioni di immunodisregolazione quali linfoproliferazione e autoimmunità. Queste sono espressione di un’alterazione dei meccanismi di omeostasi e dei check-point che regolano il ciclo cellulare delle cellule linfoidi. La linfoproliferazione impatta in modo negativo sulla qualità di vita dei pazienti, rendendo spesso necessarie numerose biopsie e interventi chirurgici e trattamenti prolungati con steroidi o immunosoppressori. Nondimeno, elevato è il rischio di evoluzione verso forme neoplastiche. Questi quadri sono spesso di difficile interpretazione sia per il clinico che per l’anatomopatologo. Il quadro istologico può mostrare alterazioni difficilmente ascrivibili a categorie specifiche di malattia in cui l’architettura del linfonodo risulta alterata dalla sottostante IDP. In alcuni casi le nuove tecniche di biologia molecolare (next generation sequencing) mediante analisi dell’esoma o dell’intero genoma, permettono di identificare l’immunodeficienza sottostante. Per alcune IDP associate a linfoproliferazione sono disponibili farmaci specifici efficaci nel ridurre i sintomi, migliorare la qualità di vita e probabilmente ridurre il rischio di complicanze e degenerazione maligna. Si consideri, ad esempio, il caso della rapamicina per il trattamento della sindrome da fosfoinositide 3-chinasi attivata (APDS) e dell’abatacept nel trattamento del deficit della proteina 4 associata ai linfociti T citotossici (CTLA4). Oramai nota è l’associazione tra immunodeficienze primitive (IDP) e manifestazioni di immunodisregolazione quali linfoproliferazione e autoimmunità. Queste sono espressione di un’alterazione dei meccanismi di omeostasi e dei check-point che regolano il ciclo cellulare delle cellule linfoidi. La linfoproliferazione impatta in modo negativo sulla qualità di vita dei pazienti, rendendo spesso necessarie numerose biopsie e interventi chirurgici e trattamenti prolungati con steroidi o immunosoppressori. Nondimeno, elevato è il rischio di evoluzione verso forme neoplastiche. Questi quadri sono spesso di difficile interpretazione sia per il clinico che per l’anatomopatologo. Il quadro istologico può mostrare alterazioni difficilmente ascrivibili a categorie specifiche di malattia in cui l’architettura del linfonodo risulta alterata dalla sottostante IDP. In alcuni casi le nuove tecniche di biologia molecolare (next generation sequencing) mediante analisi dell’esoma o dell’intero genoma, permettono di identificare l’immunodeficienza sottostante. Per alcune IDP associate a linfoproliferazione sono disponibili farmaci specifici efficaci nel ridurre i sintomi, migliorare la qualità di vita e probabilmente ridurre il rischio di complicanze e degenerazione maligna. Si consideri, ad esempio, il caso della rapamicina per il trattamento della sindrome da fosfoinositide 3-chinasi attivata (APDS) e dell’abatacept nel trattamento del deficit della proteina 4 associata ai linfociti T citotossici (CTLA4).

Corrigendum: Case Report: Hodgkin Lymphoma and Refractory Systemic Lupus Erythematosus Unveil Activated Phosphoinositide 3-Kinase-δ Syndrome 2 in an Adult Patient

Introduction: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is a rare primary immune regulatory disorder caused by heterozygous gain of function mutation in the PIK3R1 gene encoding PI3Kδ regulatory p85α subunit and resulting in PI3Kδ hyperactivation. Clinical features range from recurrent infections to manifestations of immune dysregulation like autoimmunity, inflammation, systemic lymphoproliferation, and increased risk of cancer. We describe a new dominant PIK3R1 mutation causing APDS2 presenting with lymphoma and systemic refractory autoimmunity.Case Presentation: A 30-year-old woman was referred to the Immunology Unit of our hospital for uncontrolled systemic lupus erythematosus, including chilblains lesions, systemic lymphoproliferation and IgA deficiency. At 19 years of age, she was diagnosed with Hodgkin's lymphoma. Subsequently, she presented systemic lupus erythematosus onset, with episodes of severe exacerbation, including autoimmune hemolytic anemia and pleuro-pericarditis. Initial clinical response to conventional treatments was reported. Immunological investigations performed during our first observation showed severe lymphopenia, IgA deficiency, elevated IgM with reduced IgG2 levels, and low vaccination antibody titers. Quantitative real-time polymerase chain reaction (PCR) assay for Cytomegalovirus and Epstein-Barr virus showed low viral loads for both viruses in serum. An increase of serum inflammatory markers highlighted persistent systemic hyperinflammation. The next-generation sequencing (NGS)-based gene panel tests for primary immunodeficiency showed a heterozygous A>G substitution in the splice acceptor site at c.1300-2 position of PIK3R1, leading to exon-skipping.Conclusion: This case emphasizes the importance of suspecting primary immune regulatory disorders in young adults, predominantly showing a severe, aggressive, and refractory to treatment immune dysregulation phenotype, even in the absence of major infectious diseases at the onset. Different treatments can be promptly started, and a delayed diagnosis can highly impact the outcome. Targeted therapy against PI3Kδ pathway defect effectively improves drug-resistant autoimmunity, lymphoproliferation, and risk of progression to malignancy; eligible patients could benefit from its use even as a bridge therapy to transplantation, currently the only definitive curative treatment. Therefore, identifying genetic mutation and prompt targeted treatment are essential to control disease manifestations, prevent long-term sequelae, and enable curative HSCT in APDS2 patients.

Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The aim of this narrative review is to discuss the epidemiology, the pathogenesis and the correct management of tumours in patients with IEI. PubMed was used to search for all of the studies published over the last 20 years using the keywords: “inborn errors of immunity” or “primary immunodeficiency” and “cancer” or “tumour” or “malignancy”. Literature analysis showed that the overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. The knowledge of a specific tumour risk in the presence of IEI highlights the importance of a synergistic effort by immunologists and oncologists in tracking down the potential development of cancer in known IEI patients, as well as an underlying IEI in patients with newly diagnosed cancers. In the current genomic era, the creation of an international registry of IEI cases integrated with malignancies occurrence information is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the hope to obtain a better prognosis for these patients.

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During acute upper respiratory tract infections (AURTIs) caused by Adenoviruses, the mix of severe clinical presentation, together with elevation of white blood cells (WBCs) and C-reactive protein (CRP), often mimicking bacterial infection, leads to an inappropriate use of antibiotics. We studied 23 immunocompetent children admitted to our Pediatric Emergency Unit with signs of acute Adenoviral AURTIs, aiming at better clarifying the biological background sustaining this clinical presentation. Infection etiology was tested with nasopharyngeal swabs, serology, and DNA-PCR. During fever peaks and subsequent recovery, we assessed WBC count with differential, CRP, procalcitonin, serum concentration of six inflammatory cytokines, and lymphocyte subset populations. Results: IL-6 and IL-8 were found elevated in the acute phase, whereas a significant decrease during recovery was found for IL-6 and IL-10. We highlighted an increase of B lymphocytes in the acute phase; conversely, during recovery, an increase in T regulatory cells was noted. Monocytes and leukocytes were found markedly elevated during fever peaks compared to convalescence. All patients recovered uneventfully. The composition of lymphocyte population subsets and serum alterations are the main drivers of an overprescribed antibiotic. Examination of hospital admissions and performance is needed in further investigations to rule out bacterial infections or inflammatory syndromes.