Comparison of pulmonary lesions using lung ultrasound and high-resolution computed tomography in adult patients with primary humoral immunodeficiencies.

Pulmonary involvement is the most common complication in patients with predominantly antibody deficiencies (PADs). Therefore, patients require repeated imaging tests. Unlike high-resolution computed tomography (HRCT), lung ultrasonography (LUS) does not expose patients to X-rays or contrast agents, and can be performed even at the bedside. This study aimed to evaluate lung lesions using simultaneous LUS and HRCT in a group of patients with PADs. Twenty-nine adult patients (13 women and 16 men) diagnosed with PADs according to the ESID criteria (23 Common variable immunodeficiency, 2 X-linked agammaglobulinemia, 2 IgG subclass deficiencies, and 2 Unspecified hypogammaglobulinemia) were included in the study. The mean age was 39.0 ± 11.9 years. The mean time elapsed between the first symptoms of PADs and the examination was 15.4 ± 10.1 years. Lung ultrasonography and high-resolution computed tomography were performed simultaneously according to a defined protocol during the clinic visits. In both examinations, lesions were compared in the same 12 regions: for each lung in the upper, middle, and lower parts, separately, front and back. A total of 435 lesions were described on LUS, whereas 209 lesions were described on HRCT. The frequencies of lesions in the lung regions were similar between LUS and HRCT. In both examinations, lesions in the lower parts of the lungs were most often reported (LUS 60.9% vs. HRCT 55.5%) and least often in the upper parts of the lungs (LUS 12.7% vs. HRCT 12.0%). The most frequently described lesions were LUS consolidations (99; 22.8%) and HRCT fibrosis (74; 16.5%). A statistically significant relationship was found in the detection of fibrosis in 11 of the 12 regions (phi = 0.4-1.0). Maximum values of the phi coefficient for the upper part of the left lung were recorded. Compared with HRCT, LUS is an effective alternative for evaluating and monitoring pulmonary lesions in adult patients with PADs, especially for pulmonary fibrosis.

Monogenic lupus due to spondyloenchondrodysplasia with spastic paraparesis and intracranial calcification: case-based review.

Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia characterized with platyspondyly and metaphyseal lesions of the long bones mimicking enchondromatosis, resulting in short stature. SPENCD often coexists with neurologic disorders and immune dysregulation. Spasticity, developmental delay and intracranial calcification are main neurologic abnormalities. Large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders with autoimmune thrombocytopenia and systemic lupus erythematosus as the most common phenotypes. SPENCD is caused by loss of tartrate-resistant acid phosphatase (TRAP) activity, due to homozygous mutations in ACP5, playing a role in non-nucleic acid-related stimulation/regulation of the type I interferon pathway. We present two siblings, 13-year-old girl and 25-year-old boy with SPENCD, from consanguineous parents. Both patients had short stature, platyspondyly, metaphyseal changes, spastic paraparesis, mild intellectual disability, and juvenile-onset SLE. The age at disease-onset was 2 years for girl and 19 years for boy. Both had skin and mucosa involvement. The age at diagnosis of SLE was 4 years for girl, and 19 years for boy. The clinical diagnosis of SPENCD was confirmed by sequencing of ACP5 gene, which revealed a homozygous c.155A > C (p.K52T), a variant reported before as pathogenic. Juvenile-onset SLE accounts for about 15-20% of all SLE cases. But, the onset of SLE before 5-years of age and also monogenic SLE are rare. Our case report and the literature review show the importance of multisystemic evaluation in the diagnosis of SPENCD and to remind the necessity of investigating the monogenic etiology in early-onset and familial SLE cases.

GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner.

GATA2 deficiency, first described in 2011, is a bone marrow failure disorder resulting in a complex haematological and immunodeficiency syndrome characterised by cytopenias, severe infections, myelodysplasia and leukaemia. The only curative treatment is allogeneic haematopoietic stem cell transplantation (HSCT). Although knowledge on this syndrome has greatly expanded, in clinical practice many challenges remain. In particular, guidelines on optimal donor and stem cell source and conditioning regimens regarding HSCT are lacking. Additionally, genetic analysis of GATA2 is technically cumbersome and could easily result in false-negative results. With this report, we wish to raise awareness of these pitfalls amongst physicians dealing with haematological malignancies and primary immunodeficiencies.

Cerebellar involvement in warts Hypogammaglobulinemia immunodeficiency myelokathexis patients: neuroimaging and clinical findings.

BACKGROUND: Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing. RESULTS: In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8-51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6). CONCLUSIONS: Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.

Evaluation of Radiation Dose and Image Quality using High-Pitch 70-kV Chest CT in Immunosuppressed Patients. / Evaluation der Strahlendosis und Bildqualität von High-Pitch-70-kV-CT-Untersuchungen des Thorax bei immunsupprimierten Patienten.

PURPOSE: The aim of the study was to evaluate high-pitch 70-kV CT examinations of the thorax in immunosuppressed patients regarding radiation dose and image quality in comparison with 120-kV acquisition. MATERIALS AND METHODS: The image data from 40 patients (14 women and 26 men; mean age: 40.9 ±â€Š15.4 years) who received high-pitch 70-kV CT chest examinations were retrospectively included in this study. A control group (n = 40), matched by age, gender, BMI, and clinical inclusion criteria, had undergone standard 120-kV chest CT imaging. All CT scans were performed on a third-generation dual-source CT unit. For an evaluation of the radiation dose, the CT dose index (CTDIvol), dose-length product (DLP), effective dose (ED), and size-specific dose estimates (SSDE) were analyzed in each group. The objective image quality was evaluated using signal-to-noise (SNR) and contrast-to-noise ratios (CNR). Three blinded and independent radiologists evaluated subjective image quality and diagnostic confidence using 5-point Likert scales. RESULTS: The mean dose parameters were significantly lower for high-pitch 70-kV CT examinations (CTDIvol, 2.9 ±â€Š0.9 mGy; DLP, 99.9 ±â€Š31.0 mGyxcm; ED, 1.5 ±â€Š0.6 mSv; SSDE, 3.8 ±â€Š1.2 mGy) compared to standard 120-kV CT imaging (CTDIvol, 8.8 ±â€Š3.7mGy; DLP, 296.6 ±â€Š119.3 mGyxcm; ED, 4.4 ±â€Š2.1 mSv; SSDE, 11.6 ±â€Š4.4 mGy) (P≤ 0.001). The objective image parameters (SNR: 7.8 ±â€Š2.1 vs. 8.4 ±â€Š1.8; CNR: 7.7 ±â€Š2.4 vs. 8.3 ±â€Š2.8) (P≥ 0.065) and the cumulative subjective image quality (4.5 ±â€Š0.4 vs. 4.7 ±â€Š0.3) (p = 0.052) showed no significant differences between the two protocols. CONCLUSION: High-pitch 70-kV thoracic CT examinations in immunosuppressed patients resulted in a significantly reduced radiation exposure compared to standard 120-kV CT acquisition without a decrease in image quality. KEY POINTS: · Third-generation dual-source CT units enable high-pitch 70-kV CT examinations of the chest.. · High-pitch 70-kV CT examinations show a significantly reduced radiation dose compared to standard 120-kV CT examinations.. · High-pitch 70-kV CT examinations of the chest show comparable objective and subjective image quality.. · Subjectively deteriorated image noise and sharpness of 70-kV CT did not impact diagnostic confidence.. CITATION FORMAT: · Yel I, Martin SS, Wichmann JL et al. Evaluation of Radiation Dose and Image Quality using High-Pitch 70-kV Chest CT in Immunosuppressed Patients . Fortschr Röntgenstr 2019; 191: 122 - 129.

[Percutaneous nephrolithotripsy in a patient with primary immunodeficiency (a case report)].

This article presents a case study of a female patient with primary immunodeficiency, who underwent percutaneous nephrolithotripsy. The presence of a serious concomitant disease affects different aspects of preoperative and postoperative management of the patient. The choice of percutaneous nephrolithotripsy is necessitated by the need to render the patient stone free using a one-stage and the most effective surgical modality. The article describes the choice of antibacterial therapy to treat inflammatory complications in this category of patients. Broad-spectrum antibiotics should be used to prevent the onset of pyelonephritis, while pyelonephritis exacerbation requires administration of reserve antibiotics in combination with human immunoglobulin.

Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

Imaging findings of Copa syndrome in a 12-year-old boy.

Copa syndrome is a newly described autosomal dominant autoinflammatory disease that presents as pulmonary hemosiderosis and polyarticular arthritis. Twenty-one cases from five families have been reported to date. We present chest computed tomography (CT) and temporomandibular joint magnetic resonance (MR) findings of a 12-year-old boy presenting with dyspnea on exertion, fatigue and clubbing. Additional findings included a restrictive pattern of pulmonary involvement and positive inflammatory markers and autoantibodies. Genetic testing revealed a p.W240R variant of the COPA gene confirming the diagnosis of Copa syndrome. CT of the chest showed a nonspecific interstitial pneumonia pattern distributed mainly in the lower lobes. MR of the temporomandibular joints and follow-up CT three years later are also described.

Autopsy findings in EPG5-related Vici syndrome with antenatal onset.

Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome-lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870-1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.

Evaluation of pulmonary complications in patients with primary immunodeficiency disorders.

SUMMARY: Background. Primary immunodeficiencies (PIDs) are inherited disorders in which one or several components of immune system are defected. Moreover, affected patients are at high risk for developing recurrent infections, particularly pulmonary infections. The spectrum of pulmonary manifestations in PIDs is broad, and includes acute and chronic infection, structural abnormalities (eg, bronchiectasis), malignancy and dysregulated inflammation resulting in tissue damage. In this study, our aims are to evaluate pulmonary complications in PID patients. Patients and Methods. We studied 204 cases with confirmed PID. To evaluate pulmonary complications in these patients, we used pulmonary function test (PFT), high resolution computed tomography (HRCT) scan and bronchoalveolar lavage (BAL). Results. Our results showed that pneumonia was the most frequent clinical manifestations in all PID patients. There were significantly greater numbers of episodes of pneumonia in HIgM, XLA and CVID patients with delayed diagnoses < 6 years. Moreover, of 57.4% CVID patients, 55% XLA patients and 33.3% HIgM patients had abnormal PFT results, and bronchiectasis was showed in 9 (42.9%) of XLA, 6 (11.8%) of HIES, 3 (21.4%) of HIgM and 38 (62.3%) of CVID patients. Conclusion. Pulmonary complications should be considered in cases with PIDs especially in CVID cases.

Humoral primary immunodeficiency diseases: clinical overview and chest high-resolution computed tomography (HRCT) features in the adult population.

Humoral primary immunodeficiency diseases (hPIDs) are a heterogeneous group of hereditary disorders resulting in abnormal susceptibility to infections of the sinopulmonary tract. Some of these conditions (e.g., common variable immunodeficiency disorders [CVID]) imply a number of non-infectious thoracic complications such as non-infectious airway disorders, diffuse lung parenchymal diseases, and neoplasms. Chest high-resolution computed tomography (HRCT) is a key imaging tool to characterise and quantify the extent of underlying thoracic involvement, as well as to direct and monitor treatment. The aims of this review are to provide a brief clinical overview of hPIDs and describe the related chest HRCT imaging features in the adult population, with a special focus on CVID and its complications.

Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy.

Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection. By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p.H375D and c.1430delC, p.F478Sfs*14), namely a missense variant and a frameshift deletion, of which the latter leads to a truncated RAG1 protein. The other allele revealed a previously described missense mutation (c.1420C>T, p.R474C, rs199474678). Functional analysis of the p.R474C variant in an in vitro V(D)J recombination assay exhibited reduced recombination activity compared to a wild-type control. Our findings suggest that mutations in RAG1, specifically the p.R474C variant, can be associated with relatively mild clinical symptoms or delayed occurrence of T cell and B cell deficiencies but may predispose to PML.

Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype.

The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (-1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10-nucleotide duplication at position -13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS -1.6 at 14 years and -3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations.

A Rare Case of Primary Myelofibrosis in a 14-Year-Old Patient With Congenital Asplenia.

Primary myelofibrosis (PMF) is rarely diagnosed in children, and in most cases in children younger than 3 years old. Pediatric PMF generally follows a benign course and is usually managed supportively with blood transfusions and prophylactic antibiotics for infections. We present a case of a 17-year-old girl diagnosed with PMF at the age of 14 years. A computed tomography scan performed at the time of an appendectomy showed congenital asplenism. To our knowledge, this is only the third case of myelofibrosis and congenital asplenism to be reported in the literature. Whether asplenism contributed to the development of myelofibrosis is not known.

Efficacy and safety of human mesenchymal stromal cells in healing of critical-size bone defects in immunodeficient rats.

To evaluate the preclinical efficacy and safety of human mesenchymal stem cells (hMSC) rapidly expanded in growth medium for clinical use with human serum and recombinant growth factors, we conducted a controlled, randomized trial of plasma clots with hMSC vs. plasma clots only in critical segmental femoral defects in rnu/rnu immunodeficient rats. X-ray, microCT and histomorphometrical evaluation were performed at 8 and 16 weeks. MSC were obtained from healthy volunteers and patients with lymphoid malignancy. Human MSC survived in the defect for the entire duration of the trial. MSC from healthy volunteers, in contrast to hMSC from cancer patients, significantly improved bone healing at 8, but not 16 weeks. However, at 16 weeks, hMSC significantly improved vasculogenesis in residual defect. We conclude that hMSC from healthy donors significantly contributed to the healing of bone defects at 8 weeks and to the vascularisation of residual connective tissue for up to 16 weeks. We found the administration of hMSC to be safe, as no adverse reaction to human cells at the site of implantation and no evidence of migration of hMSC to distant organs was detected.

Clinical and imaging considerations in primary immunodeficiency disorders: an update.

Primary immunodeficiencies are a group of genetically determined disorders with diverse presentations. The purpose of this review is to provide a practical and brief description of a select number of these diseases and to discuss the important role the radiologist can have in making an early diagnosis and in detecting and following disease complications. The role of diagnostic imaging and informed performance and interpretation are vital in the diagnosis, surveillance and management of all primary immunodeficiency disorders.

Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder Presenting as Primary Bone Lymphoma in a Patient with Rheumatoid Arthritis.

Primary bone lymphoma (PBL) is a rare disorder. We herein present a case of other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) presenting as PBL. A 63-year-old woman was diagnosed with rheumatoid arthritis and had been treated with methotrexate for seven years. Two months before admission, she suffered from pain in the limbs. Magnetic resonance imaging revealed multiple irregular lesions in the bones of the limbs, which showed an uptake of (18)F-FDG on positron emission tomography. A biopsy of the right radius revealed diffuse large B-cell lymphoma, leading to the diagnosis of OIIA-LPD. She received rituximab-containing regimens resulting in a complete response.