Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic ...leukocytes. CGD is a genetically heterogeneous disease with an X‐linked recessive (XR‐CGD) form caused by mutations in the CYBB gene encoding the gp91phox protein, and an autosomal recessive (AR‐CGD) form caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes encoding p22phox, p47phox, p67phox, and p40phox, respectively. Patients suffering from this disease are susceptible to severe life‐threatening bacterial and fungal infections and excessive inflammation characterized by granuloma formation in any organ, for instance, the gastrointestinal and genitourinary tract. An early diagnosis of and the prompt treatment for these conditions are crucial for an optimal outcome of affected patients. To prevent infections, CGD patients should receive lifelong antibiotics and antifungal prophylaxis. These two measures, as well as newer more effective antimicrobials, have significantly modified the natural history of CGD, resulting in a remarkable change in overall survival, which is now around 90%, reaching well into adulthood. At present, hematopoietic stem cell transplantation (HSCT) is the only definitive treatment that can cure CGD and reverse organ dysfunction. Timing, donor selection, and conditioning regimens remain the key points of this therapy. In recent years, gene therapy (GT) for XR‐CGD has been proposed as an alternative to HSCT for CGD patients without a matched donor. After the failure of the first trials performed with retroviral vectors, some groups have proposed the use of regulated SIN‐lentiviral vectors targeting gp91phox expression in myeloid cells to increase the safety and efficacy of the GT protocols.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Mass SARS-Cov-2 vaccination campaign represents the only strategy to defeat the global pandemic we are facing. Immunocompromised patients represent a vulnerable population at high risk of developing ...severe COVID-19 and thus should be prioritized in the vaccination programs and in the study of the vaccine efficacy. Nevertheless, most data on efficacy and safety of the available vaccines derive from trials conducted on healthy individuals; hence, studies on immunogenicity of SARS-CoV2 vaccines in such populations are deeply needed. Here, we perform an observational longitudinal study analyzing the humoral and cellular response following the BNT162b2 mRNA COVID-19 vaccine in a cohort of patients affected by inborn errors of immunity (IEI) compared to healthy controls (HC). We show that both IEI and HC groups experienced a significant increase in anti-SARS-CoV-2 Abs 1 week after the second scheduled dose as well as an overall statistically significant expansion of the Ag-specific CD4+CD40L+ T cells in both HC and IEI. Five IEI patients did not develop any specific CD4+CD40L+ T cellular response, with one of these patients unable to also mount any humoral response. These data raise immunologic concerns about using Ab response as a sole metric of protective immunity following vaccination for SARS-CoV-2. Taken together, these findings suggest that evaluation of vaccine-induced immunity in this subpopulation should also include quantification of Ag-specific T cells.
Background Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or ...radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos–XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). Methods Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. Results Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC ( P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 46% vs 12/21 57%, P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. Conclusion RIC HCT resolves DNA repair disorder–associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. ...Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatment choice should be guided by the underlying disease. The study of the pathogenic mechanisms involved in the genesis of AIC in PID and our growing ability to define the molecular underpinnings of immune dysregulation has paved the way for the development of novel targeted treatments. Ideally, targeted therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway. Actually, the molecular diagnosis or a specific drug is not always available. However, defining the category of PID or the immunological phenotype can help to choose a semi-targeted therapy directed towards the suspected pathogenic mechanism. In this review we overview all the therapeutic interventions available for AIC in PID patients, according to different immunologic targets. In particular, we focus on T and/or B cells targeting therapies. To support decision making in the future, prospective studies to define treatment response and predicting/stratifying biomarkers for patients with AIC and PID are needed.
Background Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined ...immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and “atypical” SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. Objectives We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. Methods In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. Results A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of “atypical” SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution. Conclusions The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Ataxia Teleangiectasia AT is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and ...proneness to cancer. No therapies are available for this devastating disease. Recent observational studies in few patients showed beneficial effects of short term treatment with betamethasone. To avoid the characteristic side effects of long-term administration of steroids we developed a method for encapsulation of dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EryDex) allowing slow release of dexamethasone for up to one month after dosing. Aims of the study were: the assessment of the effect of EryDex in improving neurological symptoms and adaptive behaviour of AT patients; the safety and tolerability of the therapy.
Twenty two patients (F:M=1; mean age 11.2 ± 3.5) with a confirmed diagnosis of AT and a preserved or partially supported gait were enrolled for the study. The subjects underwent for six months a monthly infusion of EryDex. Ataxia was assessed by the International Cooperative Ataxia Rating Scale (ICARS) and the adaptive behavior by Vineland Adaptive Behavior Scales (VABS). Clinical evaluations were performed at baseline and 1, 3, and 6 months.
An improvement in ICARS (reduction of the score) was detected in the intention-to-treat (ITT) population (n=22; p=0.02) as well as in patients completing the study (per protocol PP) (n=18; p=0.01), with a mean reduction of 4 points (ITT) or 5.2 points (PP). When compared to baseline, a significant improvement were also found in VABS (increase of the score) (p<0.0001, ITT, RMANOVA), with statistically significant increases at 3 and 6 months (p<0.0001). A large inter-patient variability in the incorporation of DSP into erythrocytes was observed, with an evident positive effect of higher infusion dose on ICARS score decline. Moreover a more marked improvement was found in less neurologically impaired patients. Finally, a 19 month-extension study involving a subgroup of patients suggested that Erydex treatment can possibly delay the natural progression of the disease.EryDex was well tolerated; the most frequent side effects were common AT pathologies.
EryDex treatment led to a significant improvement in neurological symptoms, without association with the typical steroid side effects.
Current Controlled Trial 2010-022315-19SpA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A ...retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Chronic granulomatous disease (CGD) is a primary immune deficiency characterized by a defect in reactive oxygen species production. Although the effect of CGD mainly reflects on the ...phagocytic compartment, B-cell responses are also impaired in patients with CGD. Objective We sought to investigate how defective gp91phox expression in patients with CGD and CGD carriers might affect the B-cell compartment and maintenance of long-term memory. Methods We studied the B-cell compartment of patients with CGD in terms of phenotype and ability to produce reactive oxygen species and proliferate on stimuli differently directed to the B-cell receptor and Toll-like receptor 9. We further studied their capacity to maintain long-term memory by measuring cellular and serologic responses to measles. Results We show that the memory B-cell compartment is impaired among patients with CGD, as indicated by reduced total (CD19+ CD27+ ) and resting (CD19+ CD27+ CD21+ ) memory B cells in parallel to increased naive (CD19+ CD27− IgD+ ) B-cell frequencies. Data on CGD carriers reveal that such alterations are related to gp91phox expression. Moreover, proliferative capabilities of B cells on selective in vitro stimulation of B-cell receptor or Toll-like receptor 9 pathways were reduced in patients with CGD compared with those seen in age-matched healthy control subjects. Significantly lower measles-specific antibody levels and antibody-secreting cell numbers were also observed, indicating a poor ability to maintain long-term memory in these patients. Conclusion Altogether, our data suggest that patients with CGD present a defective B-cell compartment in terms of frequencies of memory B cells, response to in vitro stimulation, and maintenance of long-term antigen-specific memory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it is characterized by an ...increased susceptibility to a narrow spectrum of opportunistic infection. A few cases of HIGM patients with Cryptococcal meningoencephalitis (CM) have been described in the literature. Herein we report the case of a young male diagnosed in infancy with HIGM who developed CM complicated by a post-infectious inflammatory response syndrome (PIIRS), despite regular immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis. The patient was admitted because of a headache and CM was diagnosed through detection of
in the cerebrospinal fluid. Despite the antifungal therapy resulting to negative CSF culture, the patient exhibited persistent headaches and developed diplopia. An analysis of inflammatory cytokines on CSF, as well as the brain MRI, suggested a diagnosis of PIIRS. Therefore, a prolonged corticosteroids therapy was started obtaining a complete resolution of symptoms without any relapse.
Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical ...phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.
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