Research

The incidental pulmonary nodule in a child : Part 1: recommendations from the SPR Thoracic Imaging Committee regarding characterization, significance and follow-up.

Pediatr Radiol. 2015 Feb 6;

Authors: Westra SJ, Brody AS, Mahani MG, Guillerman RP, Hegde SV, Iyer RS, Lee EY, Newman B, Podberesky DJ, Thacker PG

Abstract
No guidelines are in place for the follow-up and management of pulmonary nodules that are incidentally detected on CT in the pediatric population. The Fleischner guidelines, which were developed for the older adult population, do not apply to children. This review summarizes the evidence collected by the Society for Pediatric Radiology (SPR) Thoracic Imaging Committee in its attempt to develop pediatric-specific guidelines.Small pulmonary opacities can be characterized as linear or as ground-glass or solid nodules. Linear opacities and ground-glass nodules are extremely unlikely to represent an early primary or metastatic malignancy in a child. In our review, we found a virtual absence of reported cases of a primary pulmonary malignancy presenting as an incidentally detected small lung nodule on CT in a healthy immune-competent child.Because of the lack of definitive information on the clinical significance of small lung nodules that are incidentally detected on CT in children, the management of those that do not have the typical characteristics of an intrapulmonary lymph node should be dictated by the clinical history as to possible exposure to infectious agents, the presence of an occult immunodeficiency, the much higher likelihood that the nodule represents a metastasis than a primary lung tumor, and ultimately the individual preference of the child’s caregiver. Nodules appearing in children with a history of immune deficiency, malignancy or congenital pulmonary airway malformation should not be considered incidental, and their workup should be dictated by the natural history of these underlying conditions.

PMID: 25655369 [PubMed – as supplied by publisher]

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The Cause of Acute Respiratory Failure Predicts the Outcome of Noninvasive Ventilation in Immunocompromised Children.

Klin Padiatr. 2015 Feb 4;

Authors: Fuchs H, Schoss J, Mendler MR, Lindner W, Hopfner R, Schulz A, Hoenig M, Steinbach D, Debatin KM, Hummler HD, Schmid M

Abstract
Background: Noninvasive ventilation (NIV) may be superior to conventional therapy in immunocompromised children with respiratory failure. Methods: Mortality, success rate, prognostic factors and side effects of NIV for acute respiratory failure (ARF) were investigated retrospectively in 41 in children with primary immunodeficiency, after stem cell transplantation or chemotherapy for oncologic disease. Results: In 11/41 (27%) children invasive ventilation was avoided and patients were discharged from ICU. In children with NIV failure ICU-mortality was 19/30 (63%). 8/11 (72%) children with NIV success had recurrence of ARF after 27 days. Only 4/11 (36%) children with first episode NIV success and 8/30 (27%) with NIV failure survived to hospital discharge. Lower FiO2, SpO2/FiO2 and blood culture positive bacterial sepsis were predictive for NIV success, while fungal sepsis or culture negative ARF were predictive for NIV failure. We observed catecholamine treatment in 14/41 (34%), pneumothorax in 2/41 (5%), mediastinal emphysema in 3/41 (7%), a life threatening nasopharyngeal hemorrhage and need for resuscitation during intubation in 5/41 (12%) NIV-episodes. Conclusions: The prognosis of ARF in immunocompromised children remains guarded independent of initial success or failure of NIV due to a high rate of recurrent ARF. Reversible causes like bacterial sepsis had a higher NIV response rate. Relevant side effects of NIV were observed.

PMID: 25650869 [PubMed – as supplied by publisher]

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Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind.

Curr Opin Immunol. 2015 Jan 30;32C:90-105

Authors: Boisson B, Quartier P, Casanova JL

Abstract
All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity.

PMID: 25645939 [PubMed – as supplied by publisher]

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Splice-Correction Strategies for Treatment of X-Linked Agammaglobulinemia.

Curr Allergy Asthma Rep. 2015 Mar;15(3):510

Authors: Bestas B, Turunen JJ, Blomberg KE, Wang Q, Månsson R, El Andaloussi S, Berglöf A, Smith CI

Abstract
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the gene coding for Bruton’s tyrosine kinase (BTK). Deficiency of BTK leads to a developmental block in B cell differentiation; hence, the patients essentially lack antibody-producing plasma cells and are susceptible to various infections. A substantial portion of the mutations in BTK results in splicing defects, consequently preventing the formation of protein-coding mRNA. Antisense oligonucleotides (ASOs) are therapeutic compounds that have the ability to modulate pre-mRNA splicing and alter gene expression. The potential of ASOs has been exploited for a few severe diseases, both in pre-clinical and clinical studies. Recently, advances have also been made in using ASOs as a personalized therapy for XLA. Splice-correction of BTK has been shown to be feasible for different mutations in vitro, and a recent proof-of-concept study demonstrated the feasibility of correcting splicing and restoring BTK both ex vivo and in vivo in a humanized bacterial artificial chromosome (BAC)-transgenic mouse model. This review summarizes the advances in splice correction, as a personalized medicine for XLA, and outlines the promises and challenges of using this technology as a curative long-term treatment option.

PMID: 25638286 [PubMed – as supplied by publisher]

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Frequency and risk factors of low immunoglobulin levels in patients with inflammatory bowel disease.

Gastroenterol Rep (Oxf). 2015 Jan 30;

Authors: Rai T, Wu X, Shen B

Abstract
BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) are considered to be dysregulated, immune-mediated disorders; and immunosuppressive medications are the mainstay of their treatment. Clinically, we have often observed low serum immunoglobulin (Ig) levels in these patients. The aim of this study was to assess the frequency and risk factors of secondary humoral immunodeficiency in IBD patients.
METHODS: We conducted a cross-sectional study of eligible IBD patients with Crohn’s disease (CD), ulcerative colitis (UC), indeterminate colitis (IC) or restorative proctocolectomy with ileal pouch, who having serum Ig measured. Demographic and clinical variables were measured. Univariate and multivariate analyses were performed.
RESULTS: A total of 324 patients was included, with a mean age of 38.8 years and 158 (48.8%) being male. Low IgG, IgG1, IgA, and IgM were found in 22.7%, 23.4%, 7.9%, and 10.9% of patients, respectively. The shared risk factors for a low IgG or IgM level were increasing age [odds ratio (OR) = 1.13; 95% confidence interval (CI) 1.03-1.23 for low IgG level and OR = 1.33; 95% CI 1.15-1.56 for low IgM level] and hypoalbuminemia (OR = 1.83; 95% CI 1.01-3.33 for low IgG level and OR = 3.17; 95% CI 1.23-8.15 for low IgM level). In addition, thioprine use was associated with low IgA level (OR = 2.76; 95% CI 1.03-7.39). IBD disease duration was a risk factor for low IgG1 level (OR = 1.40; 95% CI 1.12-1.76). The presence of concurrent primary sclerosing cholangitis (OR = 0.064; 95% CI 0.007-0.60) and the use of biologics (OR = 0.16; 95% CI 0.033-0.79) were associated with normal IgG1 level. IgG level was lower in CD patients than that in UC/IC and ileal pouch patients (P = 0.042). IgG and IgA levels were elevated in patients with inflammatory conditions of the pouch (P = 0.01; P = 0.003, respectively).
CONCLUSIONS: Low Ig level appears to be common in IBD patients. Increasing age, disease duration and hypoalbuminemia appeared to be risk factors. The findings may provide rationale for targeted therapy to boost humoral immunity in selected patients with IBD.

PMID: 25638221 [PubMed – as supplied by publisher]

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Clinical and Immunological Features of Common Variable Immunodeficiency in China.

Chin Med J (Engl). 2015 5th February;128(3):310-315

Authors: Lin LJ, Wang YC, Liu XM

Abstract
Background: Common variable immunodeficiency (CVID) is one of the most common symptomatic primary immunodeficiency syndromes. The purpose of this article was to broaden our knowledge about CVID for better diagnosis and treatment. Methods: Clinical and immunological features of 40 Chinese patients with CVID were analyzed retrospectively. Results: The median age at onset was 11-year-old (range 4-51 years). The median age at diagnosis was 14.5-year-old (range 5-66 years). The average time of delay in diagnosis was 5.3 years (range 1-41 years). The most common main complaint was fever due to infections (35 cases, 87.5%). Pneumonia (28 cases, 70%) was the most common type of infections. Bronchiectasis was present in 6 patients (15%). Autoimmune disease was detected in 6 cases of CVID, and malignancy in 2 cases. The median total serum levels of IgG, IgA, and IgM at diagnosis were 1.07 g/L, 0.07 g/L, and 0.28 g/L, respectively. The percentages of CD3- /CD19 + B-cells were 1%-3.14%. Conclusions: Infection is the most frequent presentation of CVID. Patients with unexplainable infections should receive further examination including serum immunoglobulin (Ig) and lymphocyte subset analysis. Regular and sufficient substitution with Ig is recommended.

PMID: 25635425 [PubMed – as supplied by publisher]

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20% subcutaneous immunoglobulin for patients with primary immunodeficiency diseases: A systematic review.

Int Immunopharmacol. 2015 Jan 26;

Authors: Song J, Zhang L, Li Y, Quan S, Liang Y, Zeng L, Liu Y

Abstract
BACKGROUND: Primary immunodeficiency diseases (PID) are a group of rare disorders that patients do not have normal function of the immune system. Subcutaneous immunoglobulin 20% (SCIG-20%) was a candidate when considering replacement therapy with immunoglobulin in PID, but the evidence was not clear. To understand and interpret the available evidence, we conducted a systematic review to assess the efficacy and safety of SCIG-20% for patients with PID.
METHOD: Literature searches were conducted in PUBMED, EMBASE, Cochrane Library, CBM, VIP, CNKI, WanFang, LILACS and U.S. ClinicalTrials.gov. Clinical studies published in full text that met predefined inclusion criteria were eligible irrespective of language. Reviewers independently assessed all potential studies and extracted data. The fixed-effect model was used in meta-analysis.
RESULTS: 4 studies involving 100 patients were included. The pooled rate of infection was 0.80 with the annual rate of 3.74. 38% patients missed days from work/school and annual rate was 4.54days in one year per patient. Only 4% patients were hospitalized due to infection and it costs 1.57days in one year per patient. 70% patients used antibiotics during 58.4days in one year per patient. 80 patients (80.0%) who experienced 1630 AEs were considered related to SCIG-20%. Only 7 related AEs were severe, of which, 4 were local reactions and 3 were headaches. Studies on health related quality of life and satisfaction suggested that patients with SCIG-20% had a good life quality and satisfied with SCIG treatment.
CONCLUSIONS: SCIG-20% treatment was not recommended for patients with primary immunodeficiency. Low quality of each outcome suggested that the evidence on effect of SCIG-20% for patients with PID is inadequate. Further comparative studies are urgently needed, especially in comparison with IVIG or SCIG of other concentrations.

PMID: 25633961 [PubMed – as supplied by publisher]

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Antibody Levels to Bordetella pertussis and Neisseria meningitidis in Immunodeficient Patients Receiving Immunoglobulin Replacement Therapy.

J Clin Immunol. 2015 Jan 29;

Authors: Adam E, Church JA

Abstract
PURPOSE: Patients with antibody deficiency rely on immunoglobulin products for protection against many vaccine-preventable diseases. We measured antibody titers against Bordetella pertussis and Neisseria meningitidis in patients receiving immunoglobulin (IG) therapy to determine if they have any protection against infections from these organisms.
METHODS: In an unblinded, prospective assessment we measured antibody titers against B. pertussis filamentous hemagglutinin (FHA) and pertussis toxin (PT) antigens and N. meningitidis serogroups A, C, W-135, and Y in patients receiving immunoglobulin therapy for primary immune deficiency (PI). We measured steady state levels in patients receiving subcutaneous immunoglobulin therapy while in patients receiving intravenous immunoglobulin therapy we measured titers immediately before and after infusion to more clearly define the contribution of the infused product.
RESULTS: Thirty subjects, 17 females and 13 males, participated in the study, 22 were receiving intravenous IG products and 8 were receiving subcutaneous IG products. Diagnoses included common variable immunodeficiency in 12, combined immunodeficiency in 6, specific antibody deficiency in 6, X-linked agammaglobulinemia in 4 and ataxia telangiectasia and hyper-IgE syndrome in one each. All subjects had detectable IgG antibodies against the pertussis antigens measured and most had antibody to the meningococcus serotypes measured. However, only 26.6 % had protective levels (>= 2 mcg/mL) against serogroup C at trough or steady state.
CONCLUSIONS: Patients receiving immunoglobulin therapy have antibodies against B. pertussis and most of them have antibodies against the four measured serogroups of N. meningitidis. There is significant variability in the levels of antibody between patients and the low titers against group C may suggest a role for active immunization in those who may respond to conjugated polysaccharide vaccine administration.

PMID: 25631528 [PubMed – as supplied by publisher]

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Mechanisms of action of Ig preparations: immunomodulatory and anti-inflammatory effects.

Front Immunol. 2014;5:690

Authors: Matucci A, Maggi E, Vultaggio A

Abstract
Primary immunodeficiency (PID) disorders that predispose patients to recurrent infections require immunoglobulin (Ig) replacement therapy. Ig replacement therapy has been stated as beneficial, although the optimal IgG trough level to be maintained over time in order to minimize infectious risk has not been established. The most common route of administration of Ig has been intravenously, although there are different options, one of them being the subcutaneous route. Ig replacement therapy has been a life-saving treatment for patients suffering from primary and secondary antibody immunodeficiency. The key role of regular Ig replacement in patients with antibody deficiencies is related to the ability to provide specific antibodies that could not be produced by these patients as demonstrated by the reduction of severe infections such as meningitis and pneumonia. The therapeutic benefits of Ig may also be due to an active role in various anti-inflammatory and immunomodulatory activities, which may complicate the clinical picture of PID. Anti-inflammatory activities are seen more generally when intravenous Ig is administered at high dose. The immunomodulatory and anti-inflammatory activities are important not only in the treatment of autoimmune diseases but also in patients suffering from immunodeficiency.

PMID: 25628625 [PubMed]

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BAY 41-2272 activates host defence against local and disseminated Candida albicans infections.

Mem Inst Oswaldo Cruz. 2015 Jan 23;:0

Authors: Soeiro-Pereira PV, Falcai A, Kubo CA, Antunes E, Condino-Neto A

Abstract
In our previous study, we have found that 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a guanylate cyclase agonist, activates human monocytes and the THP-1 cell line to produce the superoxide anion, increasing in vitro microbicidal activity, suggesting that this drug can be used to modulate immune functioning in primary immunodeficiency patients. In the present work, we investigated the potential of the in vivo administration of BAY 41-2272 for the treatment of Candida albicans and Staphylococcus aureus infections introduced via intraperitoneal and subcutaneous inoculation. We found that intraperitoneal treatment with BAY 41-2272 markedly increased macrophage-dependent cell influx to the peritoneum in addition to macrophage functions, such as spreading, zymosan particle phagocytosis and nitric oxide and phorbol myristate acetate-stimulated hydrogen peroxide production. Treatment with BAY 41-2272 was highly effective in reducing the death rate due to intraperitoneal inoculation of C. albicans, but not S. aureus. However, we found that in vitro stimulation of peritoneal macrophages with BAY 41-2272 markedly increased microbicidal activities against both pathogens. Our results show that the prevention of death by the treatment of C. albicans-infected mice with BAY 41-2272 might occur primarily by the modulation of the host immune response through macrophage activation.

PMID: 25626456 [PubMed – as supplied by publisher]

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