Rituximab Monotherapy Is Effective as First-Line Treatment for Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in CVID Patients.

Granulomatous lymphocytic interstitial lung disease (GLILD) represents a fatal immune dysregulatory complication in common variable immunodeficiency (CVID). Evidence-based diagnostic guidelines are lacking, and GLILD treatment consists in immunosuppressive drugs; nonetheless, therapeutical strategies are heterogeneous and essentially based on experts' opinions and data from small case series or case reports.We aimed to evaluate the efficacy and safety of first-line Rituximab monotherapy for CVID-related GLILD, by assessing symptoms and quality of life alterations, immunological parameters, pulmonary function tests, and lung computed tomography.All six GLILD patients received Rituximab infusions as a first-line treatment. Rituximab was administered at 375 mg/m2 monthly for six infusions followed by maintenance every 3 months; none of the patients experienced severe adverse events. Symptom burden and quality of life significantly improved in treated patients compared to a control group of CVID patients without GLILD. Rituximab treatment indirectly caused a trend toward reduced T-cell activation and exhaustion markers sCD25 and sTIM-3. Lung function improved in treated patients, with statistically significant increases in TLC and DLCO. Lung CT scan findings expressed by means of Baumann scoring system displayed a reduction in the entire cohort.In conclusion, first-line monotherapy with Rituximab displayed high efficacy in disease remission in all treated patients, with improvement of symptoms and amelioration of quality of life, as well as restoration of PFTs and lung CT scan findings.

Common and Uncommon CT Findings in CVID-Related GL-ILD: Correlations with Clinical Parameters, Therapeutic Decisions and Potential Implications in the Differential Diagnosis.

PURPOSE: To investigate computed tomography (CT) findings of Granulomatous Lymphocytic Interstitial Lung Disease (GL-ILD) in Common Variable Immunodeficiency (CVID), also in comparison with non-GL-ILD abnormalities, correlating GL-ILD features with functional/immunological parameters and looking for GL-ILD therapy predictive elements. METHODS: CT features of 38 GL-ILD and 38 matched non-GL-ILD subjects were retrospectively described. Correlations of GL-ILD features with functional/immunological features were assessed. A logistic regression was performed to find a predictive model of GL-ILD therapeutic decisions. RESULTS: Most common GL-ILD CT findings were bronchiectasis, non-perilymphatic nodules, consolidations, Ground Glass Opacities (GGO), bands and enlarged lymphnodes. GL-ILD was usually predominant in lower fields. Multiple small nodules (≤10 mm), consolidations, reticulations and fibrotic ILD are more indicative of GL-ILD. Bronchiectasis, GGO, Reticulations and fibrotic ILD correlated with decreased lung performance. Bronchiectasis, GGO and fibrotic ILD were associated with low IgA levels, whereas high CD4+ T cells percentage was related to GGO. Twenty out of 38 patients underwent GL-ILD therapy. A model combining Marginal Zone (MZ) B cells percentage, IgA levels, lower field consolidations and lymphnodes enlargement showed a good discriminatory capacity with regards to GL-ILD treatment. CONCLUSIONS: GL-ILD is a lower field predominant disease, commonly characterized by bronchiectasis, non-perilymphatic small nodules, consolidations, GGO and bands. Multiple small nodules, consolidations, reticulations and fibrotic ILD may suggest the presence of GL-ILD in CVID. MZ B cells percentage, IgA levels at diagnosis, lower field consolidations and mediastinal lymphnodes enlargement may predict the need of a specific GL-ILD therapy.

Paediatric MAS/HLH caused by a novel monoallelic activating mutation in p110δ.

This study provides evidence for the first time for APDS-1 presenting as MAS/HLH, with evident clinical implications in patient's management and prognosis.

Early B cell developmental impairment with progressive B cell deficiency in NFKB2 mutated CVID disease without autoimmunity.

This study provides evidence for a novel role for NFKB2 in human B cell development in the bone marrow and in the periphery, leading to progressive peripheral B cell deficiency not always combined with autoimmune phenomena, broadening thus the clinical spectrum of NFKB2 mutated CVID disease and implying an essential role for NFKB2 in early human B cell development.

A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1).

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.

Early Identification of Lung Fungal Infections in Chronic Granulomatous Disease (CGD) Using Multidetector Computer Tomography.

PURPOSE: The purpose of this study is to evaluate the possibility of early detection of pulmonary fungal infections by lung CT scan in chronic granulomatous disease (CGD). METHODS: A retrospective study on 14 patients affected with CGD for a total of 18 infectious episodes was performed. Revision of clinical data and CT scan analysis before and after treatment was performed. RESULTS: The presence of lung nodules <30 mm was evaluated in 18 infectious episodes in 14 patients. A total of 125 nodules in 18 CT scans were identified. Identification of the infectious agent through biopsy and in vitro culture resulted positive only in 3/18 cases. The remaining cases received clinical/radiologic diagnosis of suspected pulmonary fungal infection. In all cases, the introduction of empirical antifungal treatment resulted in reduction in size or complete resolution of the pulmonary lung nodules in all patients affected with CGD. CONCLUSIONS: Lung CT scan allows for early detection of pulmonary fungal infection in CGD. Pulmonary nodules (<30 mm), single or multiple, uni- or bilateral, with or without a halo sign may represent the first radiologic sign of pulmonary fungal infection in CGD.

Comparative X-ray morphometry of prenatal osteogenesis imperfecta type 2 and thanatophoric dysplasia: a contribution to prenatal differential diagnosis.

OBJECTIVE: The purpose of the paper was to assess the morphometric parameters to improve the specificity of the ultrasound (US) signs for the early differential diagnosis between two lethal dysplasias, as thanatophoric dysplasia (TD) and osteogenesis imperfecta type 2 (OI-2). METHOD: The diaphyseal length and the bowed shape of long bones associated with vertebral body dimension assessment were investigated in a group of 14 pregnancy terminations carried out in the time period 2007-2013. The definitive diagnosis was established after pregnancy termination by means of skeletal standardized X-rays, histopathology and gene analysis. RESULTS: TD and OI-2 long bones were significantly shorter than controls. No significant differences were observed between the two dysplasias. The bowing angle was higher in OI-2; a true angulation or eventually axial displacement was present only in the latter. Furthermore, they did not show any evidence of vertebral collapse. The thanatophoric dysplasia presented less bowed long bones, and never true angulation. The spine was steadily characterized by flattened anterior vertebral bodies. CONCLUSION: Long bone shortening is not a sufficient and accurate sign for early sonographic differential diagnosis between TD and OI-2. Angled diaphysis, axial diaphyseal displacement and a conserved vertebral body height in the prenatal period support the diagnosis of osteogenesis imperfecta type 2, while moderately regular bowed diaphysis associated with platyspondyly that of thanatophoric dysplasia.

Congenital cystic lung disease: prenatal ultrasound and postnatal multidetector computer tomography evaluation. Correlation with surgical and pathological data.

PURPOSE: The aim of this study was to evaluate the diagnostic accuracy of postnatal multidetector computed tomography (MDCT) compared with prenatal ultrasound (US), surgical findings, and histology, in 33 patients with congenital cystic lung disease. METHODS: Thirty-three patients, 17 males and 16 females, were evaluated by MDCT. Twenty-seven of these patients underwent prenatal US between week 18 and 22, and between week 32 and 35 of gestation. Lung lobectomy, segmentectomy, atypical resection, lesion resection were performed in 31 patients and surgical specimens were analysed. RESULTS: Prenatal US and MDCT correctly diagnosed 76.9 and 94 % of the lesions, respectively. Disagreement occurred in six lesions with prenatal US and in two lesions with MDCT. No statistically significant differences were observed between the two techniques (P = 0.122). CONCLUSIONS: As most surgeons consider the surgical resection of these lesions mandatory, our study underscores the essential role of imaging, in particular CT, in providing invaluable preoperative information on congenital cystic lung diseases recognised in uterus.

Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R.

Wave-shaped ribs were detected at prenatal ultrasound in a 20(+1) week female fetus. At birth, skeletal radiographs showed marked hypomineralization and suggested hypophosphatasia. However, elevated blood calcium and alkaline phosphatase excluded hypophosphatasia and raised the possibility of Jansen metaphyseal dysplasia. Molecular analysis of the PTH/PTHrP receptor gene (PTH1R) showed heterozygosity for a previously undescribed transversion variant (c.1373T>A), which predicts p.Ile458Lys. In vitro evaluation of wild type and mutant PTH/PTHrP receptors supported the pathogenic role of the p.Ile458Lys substitution, and confirmed the diagnosis of Jansen metaphyseal dysplasia. This disorder may present prenatally with wavy ribs and in the newborn with hypomineralization, and may therefore be confused with hypophosphatasia. The mottled metaphyseal lesions typically associated with this disease appear only in childhood.

Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis.

PURPOSE: To retrospectively evaluate the utility of gadoxetic acid-enhanced magnetic resonance (MR) imaging in the differential diagnosis of hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH). MATERIALS AND METHODS: This study had institutional review board approval; the requirement for informed consent was waived. Eighty-two patients (58 patients with FNH and 24 patients with HCAs) with 111 lesions were included in the study. There were 74 female patients and eight male patients (mean age, 41.9 years±13.2 [standard deviation]; age range, 11-78 years). Two readers reviewed all images in terms of signal intensity (SI) features on unenhanced, dynamic, and hepatobiliary phase images. For quantitative analysis, contrast enhancement ratio (CER), lesion-to-liver contrast (LLC), and SI ratio on dynamic and hepatobiliary phase images were calculated. RESULTS: The CER of FNH in the arterial phase (mean, 94.3%±33.2) was significantly higher than that of HCAs (mean, 59.3%±28.1) (P<.0001). During the hepatobiliary phase, the LLC of FNH showed minimally positive values (mean, 0.05±0.01) and that of HCAs demonstrated strong negative values (mean, -0.67±0.24) (P<.0001). The area under the receiver operating characteristic curve of the hepatobiliary phase SI ratio for differentiation of the two tumors was 0.97, and a sensitivity of 92% and specificity of 91% were found with a cutoff value of 0.87. Among six FNH lesions that showed atypical hypointensity during the hepatobiliary phase, four had a large central scar, one contained a substantial fat component, and one had abundant radiating fibrous septa. Three HCAs were isointense during the hepatobiliary phase owing to severe hepatic steatosis. CONCLUSION: Gadoxetic acid-enhanced MR imaging facilitates the differentiation of FNH from HCA.

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

A review of the actual knowledge of the processes governing growth and development of long bones.

Autoptic samples of human bones (from 8 weeks of gestation to 12 years of age) and a second group of serial, skeletal x-rays (required for pathologies not related to bone dysplasia in children from 4 months to 17 years of age) provided the material for the analysis of the physes normal growth mechanism presented in this review. Before the appearance of the ossification centers epiphyseal growth rests exclusively on chondrocytes proliferation (interstitial growth), without any detectable differentiated cellular organization. When endochondral ossification starts a defined spatial disposition of chondrocytes and a corresponding organization of the intercellular matrix is set up, so that it is possible to identify a growth vector corresponding to the columns of piled chondrocytes with direction from hypertrophic toward the proliferative cell layers. The complexity of the tubular bones growth process is well represented by the spatial arrangement of the growth vectors. In the late epiphyseal growth another mechanism is active in addition to endochondral ossification, namely, articular cartilage interstitial growth and subchondral remodelling. The knowledge of the normal mode of organization of the physis and its temporal sequence can help to better understand of the deviaton from the normal development of metaphyseal and epiphyseal dysplasias.

Endoscopic treatment of periampullary duodenal duplication cysts in children: Four case reports and review of the literature.

BACKGROUND: Duodenal duplications are rare congenital anomalies of the gastrointestinal tract. As the periampullary variant is much rarer, literature is scant and only few authors have reported their experience in diagnosis and treatment, particularly with operative endoscopy. CASE SUMARY: To report our experience with the endoscopic treatment in a series of children with periampullary duodenal duplication cysts, focusing on the importance of obtaining an accurate preoperative anatomic assessment of the malformations. The pediatric periampullary duodenal duplication cyst literature is reviewed. We conducted a systematic review according to the PRISMA guidelines. The PubMed database was searched for original studies on "duodenal duplication", "periampullary duplication" or "endoscopic management" published since 1990, involving patients younger than 18 years of age. Eligible study designs were case report, case series and reviews. We analyzed the data and reported the results in table and text. Fifteen eligible articles met the inclusion criteria with 16 patients, and analysis was extended to our additional 4 cases. Median age at diagnosis was 13.5 years. Endoscopic treatment was performed in 10 (50%) patients, with only 2 registered complications. CONCLUSION: Periampullary duodenal duplication cysts in pediatric patients are very rare. Our experience suggests that an accurate preoperative assessment is critical. In the presence of sludge or stones inside the duplication, endoscopic retrograde cholangio-pancreatography is mandatory to demonstrate a communication with the biliary tree. Endoscopic treatment resulted in a safe, minimally invasive and effective treatment. In periampullary duodenal duplication cyst endoscopically treated children, long-term follow-up is still necessary considering the potential malignant transformation at the duplication site.

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers.

Background: Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis. Methods: In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD. Results: In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97). Conclusions: we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.

Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα).

Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB­inducing kinase and impairs lymphotoxin-ß­driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVß repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.