Research

Plasma levels of TNF-α, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23 in achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD).

BMC Gastroenterol. 2019 Feb 11;19(1):28

Authors: Clayton S, Cauble E, Kumar A, Patil N, Ledford D, Kolliputi N, Lopes-Virella MF, Castell D, Richter J

Abstract
An elevation of serum inflammatory biomarkers in achalasia patients compared with controls recently was demonstrated. It has not been determined whether the elevation of inflammatory cytokines is unique to achalasia or occurs with other diseases involving the esophagus. The primary aim of our study was to compare the differences in plasma immunological profiles (TNF- α receptor, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23) of patients with achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD). A secondary aim of this study was to classify these same plasma cytokine profiles in the three achalasia subtypes.
METHODS: Plasma from 53 patients with achalasia, 22 with EoE, and 20 with GERD (symptoms plus esophagitis or + reflux study) were analyzed.
EXCLUSION CRITERIA: malignancy, autoimmune condition, immunodeficiency disorder, and treatment with steroids/immune modulating drugs. Cytokine levels were assayed via multiplex enzyme-linked immunosorbent assay (ELISA).
RESULTS: Our key finding revealed significant elevations in IL- 6 (p = 0.0158) in achalasia patients compared with EoE patients. Overall, plasma inflammatory biomarker patterns were not different in the three subtypes of achalasia.
CONCLUSION: There were no differences between the cytokine levels of any of the measured biomarkers between the achalasia and GERD groups suggesting that luminal stasis does increase biomarker levels for any of the cytokines examined in our study. While these results are an early first step towards clarifying some aspects of the pathogenesis of achalasia, they bring about many more questions that require further investigation and expansion. Further investigation with a larger cohort and a broader panel of biomarkers is needed.

PMID: 30744559 [PubMed – in process]

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ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase 20.

Drug Deliv. 2019 Dec;26(1):98-106

Authors: Locke KW, Maneval DC, LaBarre MJ

Abstract
ENHANZE® drug delivery technology is based on the proprietary recombinant human hyaluronidase PH20 enzyme (rHuPH20; Halozyme Therapeutics, Inc.) that facilitates the subcutaneous (SC) delivery of co-administered therapeutics. rHuPH20 works by degrading the glycosaminoglycan hyaluronan (HA), which plays a role in resistance to bulk fluid flow in the SC space, limiting large volume SC drug delivery, dispersion, and absorption. Co-administration of rHuPH20 with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations, and has been shown to reduce the burden on patients and healthcare providers compared with intravenous formulations. rHuPH20 (as HYLENEX® recombinant) is currently FDA-approved for subcutaneous fluid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in subcutaneous urography for improving resorption of radiopaque agents. rHuPH20 is also co-formulated with two anticancer therapies, trastuzumab (i.e. Herceptin® SC) and rituximab (i.e. RITUXAN HYCELA®/RITUXAN® SC/MabThera® SC) and dosed sequentially with human immunoglobin to treat primary immunodeficiency (i.e. HyQvia®/HYQVIA®). This article reviews pharmaceutical properties of rHuPH20, its current applications with approved therapeutics, and the potential for future developments.

PMID: 30744432 [PubMed – in process]

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A Syrian Refugee in Iraq Diagnosed as a Case of IL12RB1 Deficiency in Japan Using Dried Blood Spots.

Front Immunol. 2019;10:58

Authors: Al-Kzayer LFY, Yassin AK, Salih KH, Shigemura T, Sano K, Al-Simaani RBY, Tanaka M, Nakazawa Y, Okuno Y

Abstract
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare condition of primary immunodeficiency disorder. Interleukin-12 receptor β1 (IL12RB1) deficiency, is the most common genetic etiology of MSMD, which is characterized by the selective predisposition to clinical disease caused by weakly-virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines, and environmental non-tuberculous mycobacteria (NTM). To the best of our knowledge, this is the first case of IL12RB1 deficiency to be reported from Iraq. Our case is an 8-year-old Syrian girl, for first-cousin parents, with a refugee-status in the North of Iraq. She had a history of disseminated BCG infection 2 months after receiving BCG vaccine, in addition to repeated episodes of mild or severe illnesses, such as maculopapular skin rash, lymphadenopathy, gastroenteritis, meningitis, and clinically diagnosed tuberculosis (TB) based on local TB-prevalence setting. Because of limited medical facilities in the war-torn countries; in Syria and Iraq, no diagnosis could be reached. We used Flinders Technology Associates (FTA) cards to transfer her bone marrow aspirate to Japan. A homozygous IL12RB1 mutation was detected by whole exome sequencing in Japan, using genomic-DNA extracted from dried bone marrow sample spots on FTA filter paper. In conclusion, diagnosis of MSMD due to IL12RB1 deficiency was possible by transferring the FTA sample of the patient for genetic evaluation in Japan. Our report recalls the need of pediatricians in countries with TB-prevalence and high parental consanguinity, to consider IL12RB1 deficiency in the differential diagnosis of a child with clinical evidence of TB, especially with the history of disseminated BCG disease.

PMID: 30740107 [PubMed – in process]

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[Oral manifestations in patients with primary immunodeficiencies].

Orv Hetil. 2018 Dec;159(49):2079-2086

Authors: Szegedi M, Erdős M, Tar I

Abstract
Characteristic lesions of the oral cavity in primary immunodeficiencies are commonly found in the form of periodontal disease, tooth decay and disorders of the oral mucosa. Humoral immunodeficiencies may cause tooth decay, while severe forms of plaque-induced periodontal disease are common in phagocytic deficiencies. The structural abnormalities of the teeth can occur in immunodeficiencies associated with apoptosis defect. Oral squamous cell carcinoma is a possible complication of immunodeficiencies associated with DNA repair defects. Orv Hetil. 2018; 159(49): 2079-2086.

PMID: 30525885 [PubMed – indexed for MEDLINE]

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The total IgM, IgA and IgG antibody responses to pneumococcal polysaccharide vaccination (Pneumovax®23) in a healthy adult population and patients diagnosed with primary immunodeficiencies.

Vaccine. 2019 Feb 05;:

Authors: Parker AR, Park MA, Harding S, Abraham RS

Abstract
BACKGROUND: Interpretation of the responses to the pneumococcal polysaccharide vaccine (Pneumovax®23, PPV) has proven challenging. In addition, there are few studies documenting the longevity of these responses.
METHODS: The age-specific PPV IgM, IgA, IgG and IgG2 concentrations were determined pre, 4-6 weeks and 6 years post-vaccination in the serum of Prevnar®-naïve adults using VaccZyme™ pneumococcal capsular polysaccharide ELISAs.
RESULTS: The median pre-vaccination concentrations were; PPV IgM 53 U/mL (5-95% CI: 16-169 U/mL), IgA 23 U/mL (6-103 U/mL), IgG 41 mg/L (10-184 U/mL) and IgG2 18 mg/L (3-95 U/mL). 4-6 weeks post-vaccination there was a median 6-fold (5-95% CI: 2-24) increase in PPV IgM (median 315 U/mL (5-95% CI: 60-1133 U/mL), 18-fold (4-74) increase in IgA (369 U/mL (78-1802 U/mL)), 9-fold (2-19) increase in IgG (375 mg/L (77-1238 mg/L)) and 8-fold (1-20) increase in IgG2 (141 mg/L (25-573 mg/L)). This was significant for all isotypes in all age ranges (p < 0.0001). Six years post-vaccination median PPV concentrations were; IgM 54 U/mL (17-128), IgA 85 U/mL (19-279), IgG 148 mg/L (30-997) and IgG2 57 mg/L (9-437). The median concentrations for all ages 6 years post-vaccination were significantly elevated compared to the pre-vaccination titres for PPV IgA, IgG and IgG2 isotypes only. The PPV IgM and IgA responses were influenced by age. At 6 years post vaccination, in individuals with normal PPV IgG, 34 individuals had PPV IgM and/or IgA concentrations below the lower limit of the healthy adult ranges. We also used the healthy adult reference ranges developed in this study to assess a cohort of primary immunodeficiency (PID) patients.
CONCLUSION: These ranges will help to provide a framework for assessment and definition of normal response to PPV, which will facilitate clinical interpretation of a deficient polysaccharide response in those suspected of antibody deficiency.

PMID: 30737041 [PubMed – as supplied by publisher]

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Primary pulmonary lymphoma in children.

Orphanet J Rare Dis. 2019 Feb 08;14(1):35

Authors: Wu X, Zhou C, Jin L, Liu H, Liu J, Zhao S

Abstract
BACKGROUND: Primary pulmonary lymphoma (PPL) is a rare disease, especially in children. We analyse the clinical features of PPL in 4 children to strengthen a understanding of it.
RESULTS: We reported a case series of 4 pediatric patients with PPLs including three diffuse large B-cell lymphomas and one natural killer-T cell lymphoma. All patients presented with unknown fever and cough as well as weight loss and fatigue. The white blood cell count was reduced in three patients and increased in the other one. The level of C-reactive protein was increased in all patients. The procalcitonin concentrations and bone marrow specimens were normal. Multiple or single pulmonary nodules with halo signs were found in all patients and air bronchograms found in 3 of them on chest computed tomography scan. Primary immunodeficiency was diagnosed in two patients who was performed genetic analysis.
CONCLUSIONS: When a patient presents with long-term fever, high C-reactive protein level, leukopenia/leukocytosis, and multiple or single pulmonary nodules with a “halo sign” and air bronchogram on computed tomography, a possibility of PPL should be considered. A co-existance of immunodeficiency needs to be further investigated in patients with PPL.

PMID: 30736822 [PubMed – in process]

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Pulmonary artery pseudoaneurysm causing massive hemoptysis in hyperimmunoglobulin E syndrome: a case report.

BMC Pulm Med. 2019 Feb 08;19(1):34

Authors: Hakim A, Bazan IS, Sanogo ML, Manning EP, Pollak JS, Chupp GL

Abstract
BACKGROUND: Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder defined by high serum immunoglobulin E titers that is associated with recurrent respiratory infections, formation of pneumoatoceles, recurrent skin abscesses, and characteristic dental and skeletal abnormalities.
CASE PRESENTATION: We report a case of a 56-year-old male with a history of HIES, cavitary mycetomas, and allergic bronchopulmonary aspergillosis who presented with recurrent massive hemoptysis. Bronchial artery angiography and bronchoscopy failed to identify active hemorrhage, and two embolizations of the bronchial artery did not resolve the bleeding. Subsequently, selective pulmonary artery angiography was conducted that demonstrated a subsegmental pulmonary artery branch pseudoaneurysm with extravasation into an adjacent lung cavity. This was treated successfully with transcatheter embolization.
CONCLUSIONS: To our knowledge, this is the first case reported of pulmonary artery pseudoaneurysm in HIES in the medical literature. Pulmonary artery pseudoaneurysm should be considered in the differential diagnosis in patients with HIES and massive hemoptysis.

PMID: 30736787 [PubMed – in process]

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Fifteen-minute consultation: Recognising primary immune deficiencies in children.

Arch Dis Child Educ Pract Ed. 2019 Feb 07;:

Authors: Wekell P, Hertting O, Holmgren D, Fasth A

Abstract
Children with primary immunodeficiency syndromes present with broad variation of clinical features and the consequences are often severe if not promptly recognised. Here, support is provided for the general paediatrician to recognise primary immunodeficiencies among the many children they meet in their clinical practice.

PMID: 30733240 [PubMed – as supplied by publisher]

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Hyper IgE syndrome associated with novel and recurrent STAT3 mutations: Two case reports.

Medicine (Baltimore). 2019 Feb;98(6):e14003

Authors: Deng Y, Li T, Xie X, Xia D, Ding L, Xiang H, Ma JJ, Li W

Abstract
RATIONALE: Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency presenting as two forms including autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES), which are mainly caused by mutations in STAT3 and DOCK8, respectively. To date, only about 500 cases have been reported worldwide including 37 cases in China. The spectrum and prevalence of mutations and molecular pathogenesis in HIES remain poorly understood.
PATIENT CONCERNS: Here we reported two Chinese children presenting clinical manifestations of HIES.
DIAGNOSIS: Based on medical history, clinical manifestations, and laboratory findings, a diagnosis of HIES was made for both children. Targeted next-generation sequencing (NGS) identified a novel heterozygous deletion of 15 bp (c.1960_1974del, p.G654_D658del or alternatively c.1966_1980del, and p.G656_D660del), and a recurrent missense mutation (c.1144C>T, p.R382W) in STAT3 in the two patients, respectively.
INTERVENTIONS: The two patients have been given the successful treatment of skin infections with cefaclor.
OUTCOMES: Both patients have been under follow-up for more than 6 months, with no signs of recurrent infections.
LESSONS: Our results extend the spectrum of STAT3 mutations associated with ADHIES and highlight the value of targeted NGS in confirming diagnosis of genetic disorders.

PMID: 30732127 [PubMed – in process]

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New graft manipulation strategies improved outcome of mismatched stem cell transplantation in children with primary immunodeficiencies.

J Allergy Clin Immunol. 2019 Feb 04;:

Authors: Elfeky R, Shah RM, Unni MN, Ottaviano G, Rao K, Chiesa R, Amrolia P, Worth A, Flood T, Abinun M, Hambleton S, Cant AJ, Gilmour K, Adams S, Ahsan G, Barge D, Gennery AR, Qasim W, Slatter M, Veys P

Abstract
BACKGROUND: Mismatched stem cell transplantation is associated with high risk of graft loss, graft versus host disease (GvHD) and transplant related mortality (TRM). Alternative graft manipulation strategies have been employed over the last 11 years to reduce these risks.
OBJECTIVE: We investigated the outcome of using different graft manipulation strategies among children with primary immunodeficiency (PID).
METHODS: Between 2006-2017, 147 PID patients received 155 mismatched grafts; 30 TCRαβ/CD19 depleted, 43 cords (72% with no serotherapy), 17 CD34+ selection with T cell add-back and 65 unmanipulated grafts.
RESULTS: The estimated 8-year survival of the entire cohort was 79%, TRM was 21.7% and graft failure rate was 6.7%. Post-transplant viral reactivation, aGvHD grades II-IV and chronic GvHD complicated 49.6%, 35% and 15% transplants, respectively. The use of TCR αβ/CD19 depletion was associated with a significantly lower incidence of grade II-IV aGvHD (11.5%) and cGvHD (0%) however with a higher incidence of viral reactivation (70%) in comparison to other grafts. T cell immune reconstitution was robust among cord transplants however with a high incidence of aGvHD grade II-IV 56.7%. Stable full donor engraftment was significantly higher at 80% among TCRαβ+/CD19+depleted and cord transplants versus 40-60% among the other groups.
CONCLUSIONS: Rapidly accessible cord and haploidentical grafts are suitable alternatives for patients with no HLA matched donor. Cord transplantation without serotherapy and TCRαβ+/CD19+depleted grafts produced comparable survival rates of around 80% albeit with a high rate of aGvHD with the former and high risk of viral reactivation with the latter that need to be addressed.

PMID: 30731121 [PubMed – as supplied by publisher]

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