Research

Update on Vaccine-Derived Polioviruses – Worldwide, January 2014-March 2015.

June 19, 2015 By Manish Butte

Update on Vaccine-Derived Polioviruses – Worldwide, January 2014-March 2015.

MMWR Morb Mortal Wkly Rep. 2015 Jun 19;64(23):640-646

Authors: Diop OM, Burns CC, Sutter RW, Wassilak SG, Kew OM

Abstract
Since the World Health Assembly’s 1988 resolution to eradicate poliomyelitis, one of the main tools of the World Health Organization (WHO) Global Polio Eradication Initiative (GPEI) has been the live, attenuated oral poliovirus vaccine (OPV). OPV might require several doses to induce immunity but provides long-term protection against paralytic disease. Through effective use of OPV, GPEI has brought polio to the threshold of eradication. Wild poliovirus type 2 (WPV2) was eliminated in 1999, WPV3 has not been detected since November 2012, and WPV1 circulation appears to be restricted to parts of Pakistan and Afghanistan. However, continued use of OPV carries two key risks. The first, vaccine-associated paralytic poliomyelitis (VAPP) has been recognized since the early 1960s. VAPP is a very rare event that occurs sporadically when an administered dose of OPV reverts to neurovirulence and causes paralysis in the vaccine recipient or a nonimmune contact. VAPP can occur among immunologically normal vaccine recipients and their contacts as well as among persons who have primary immunodeficiencies (PIDs) manifested by defects in antibody production; it is not associated with outbreaks. The second, the emergence of genetically divergent, neurovirulent vaccine-derived polioviruses (VDPVs) was recognized more recently. Circulating VDPVs (cVDPVs) resemble WPVs and, in areas with low OPV coverage, can cause polio outbreaks. Immunodeficiency-associated VDPVs (iVDPVs) can replicate and be excreted for years in some persons with PIDs; GPEI maintains a registry of iVDPV cases. Ambiguous VDPVs (aVDPVs) are isolates that cannot be classified definitively. This report updates previous surveillance summaries and describes VDPVs detected worldwide during January 2014-March 2015. Those include new cVDPV outbreaks in Madagascar and South Sudan, and sharply reduced type 2 cVDPV (cVDPV2) circulation in Nigeria and Pakistan during the latter half of 2014. Eight newly identified persons in six countries were found to excrete iVDPVs, and a patient in the United Kingdom was still excreting iVDPV2 in 2014 after more than 28 years. Ambiguous VDPVs were found among immunocompetent persons and environmental samples in 16 countries. Because the large majority of VDPV case-isolates are type 2, WHO has developed a plan for coordinated worldwide withdrawal of trivalent (types 1, 2, and 3) OPV (tOPV) and replacement with bivalent (types 1 and 3) OPV (bOPV) in April 2016, preceded by introduction of at least 1 dose of injectable inactivated poliovirus vaccine (IPV) into routine immunization schedules worldwide to maintain immunity to type 2 viruses.

PMID: 26086635 [PubMed – as supplied by publisher]

Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition.

June 18, 2015 By Manish Butte

Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition.

Nat Commun. 2015;6:7335

Authors: Rodríguez-Cortez VC, Del Pino-Molina L, Rodríguez-Ubreva J, Ciudad L, Gómez-Cabrero D, Company C, Urquiza JM, Tegnér J, Rodríguez-Gallego C, López-Granados E, Ballestar E

Abstract
Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals.

PMID: 26081581 [PubMed – in process]

Neutrophil functional disorder in childhood.

June 17, 2015 By Manish Butte

Neutrophil functional disorder in childhood.

Prilozi. 2015;36(1):183-90

Authors: Mironska K

Abstract
(Full text is available at http://www.manu.edu.mk/prilozi). Neutrophil functional disorders thought to be uncommon, yet important as a cause of morbidity and mortality in infants and children. During the first years of life, when the immune system is still not completely mature, when the viral infections are frequent and antibiotic overuse can damage and alter the immune response, the inadequate nutrition followed with iron deficient anemia and malnutrition can lead the child`s organism in state of immunodeficiency. Sometimes is difficult to distinguish at the beginning weather the cause of patient suffering from frequent infections is existing of primary immunodeficiency disorder or the cause of the immunodeficiency state is just from exogenous factors. Fortunately, primary immune deficiencies are rare diseases and only 6-7% of all of them, due to the neutrophilic functional disorders. Unfortunately, many exogenous and environmental factors have influence to the immune system, and the percentage of secondary caused neutrophilic functional disorders is much higher and should be considered when children are investigated for immunodeficiency. So, when to suspect neutrophil functional disorder? The hallmarks for diseases related to the neutrophilic functional disorders are discussed in this article. Key words: neutrophil, phagocytosis, NBT test, Neutrophil function, Neutrophil functional disorder, malnutration.

PMID: 26076788 [PubMed – in process]

Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience.

June 16, 2015 By Manish Butte

Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience.

Pediatr Transplant. 2015 Jun 13;

Authors: Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, Al-Muhsen S, Al-Seraihy A, Arnaout R, Al-Dhekri H, Hawwari A

Abstract
HIGMI is a disease with a high risk for morbidity and mortality. HSCT has been shown to be a curative option. This study retrospectively reviewed and analyzed data from five patients who received HSCT at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia, between 2005 and 2013. Five patients with HIGMI syndrome underwent HSCT at a median age of 41 months (range, 9-72 months). The median time from diagnosis to transplantation was 30 months (range, 5-58 months). For all five patients, the donors were HLA-identical siblings. In three patients, the conditioning regimen was composed of BU and CY. Fludarabine and melphalan with either ATG or alemtuzumab was used in two patients. For GVHD prophylaxis, cyclosporine was used in two patients, and the combination of cyclosporine and MTX was used in three patients. The survival rate was 100%, with a median follow-up of 69 months (range, 13-100 months). All patients engrafted. Two patients developed acute GVHD. Four patients showed complete immune recovery with positive CD40L expression in activated T cells and discontinued IVIG replacement. HSCT in early stage from an HLA-matched sibling donor is potentially effective at curing the disease.

PMID: 26073206 [PubMed – as supplied by publisher]

Inborn errors of metabolism underlying primary immunodeficiencies.

June 16, 2015 By Manish Butte

Inborn errors of metabolism underlying primary immunodeficiencies.

J Clin Immunol. 2014 Oct;34(7):753-71

Authors: Parvaneh N, Quartier P, Rostami P, Casanova JL, de Lonlay P

Abstract
A number of inborn errors of metabolism (IEM) have been shown to result in predominantly immunologic phenotypes, manifesting in part as inborn errors of immunity. These phenotypes are mostly caused by defects that affect the (i) quality or quantity of essential structural building blocks (e.g., nucleic acids, and amino acids), (ii) cellular energy economy (e.g., glucose metabolism), (iii) post-translational protein modification (e.g., glycosylation) or (iv) mitochondrial function. Presenting as multisystemic defects, they also affect innate or adaptive immunity, or both, and display various types of immune dysregulation. Specific and potentially curative therapies are available for some of these diseases, whereas targeted treatments capable of inducing clinical remission are available for others. We will herein review the pathogenesis, diagnosis, and treatment of primary immunodeficiencies (PIDs) due to underlying metabolic disorders.

PMID: 25081841 [PubMed – indexed for MEDLINE]

A novel treatment in X-linked agammaglobulinaemia – hyperbaric oxygen therapy in refractory chronic wounds.

June 16, 2015 By Manish Butte

A novel treatment in X-linked agammaglobulinaemia – hyperbaric oxygen therapy in refractory chronic wounds.

J Clin Immunol. 2014 Oct;34(7):784-7

Authors: Steele CL, Cridge C, Edgar JD

Abstract
Chronic wounds are a rare complication of X-linked agammaglobulinaemia (XLA). Fastidious organisms such as helicobacter bills have been reported in XLA with chronic wounds but sterile chronic wounds also occur. Hyperbaric Oxygen Therapy has been used in chronic wounds but has not previously been reported in primary antibody deficiencies. We present a case of a chronic wound in a patient with XLA refractory to antimicrobial therapy that made a remarkable recovery following Hyperbaric Oxygen Therapy.

PMID: 25091287 [PubMed – indexed for MEDLINE]

Adequate patient's outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies.

June 16, 2015 By Manish Butte

Adequate patient’s outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies.

J Clin Immunol. 2014 Oct;34(7):813-9

Authors: Milito C, Pulvirenti F, Pesce AM, Digiulio MA, Pandolfi F, Visentini M, Quinti I

Abstract
PURPOSE: The optimal immune globulin replacement dosages required over time to minimize infection risks in patients with Primary Antibody Deficiencies are not definitely established. As with many interventions, there may be specific subgroups of patients who are more likely to benefit from treatment with higher or lower dosages. The aim of the study was to verify the efficacy of a rationale for individualized immune globulin utilization and to elucidate the effects of care on patient outcome.
METHODS: Single centre interventional study on 108 patients with Primary Antibody Deficiencies. The objective was to determine for each patient the best interval between immune globulins administration in order to: • Keep IgG trough levels >500 mg/dL, • Minimize of major infections (pneumonias and infections requiring hospitalization), • Minimize of adverse events (AE).
RESULTS: Ninthly eight per cent of patients achieved the objective of the study. Patients who had low switched memory B cells and low IgA serum levels and/or are affected by bronchiectasis and/or enteropathy and/or continued to experience adverse events despite pre-medications, achieved the study objective by shortening the administration intervals to 2-weeks or to 1-week without the need to increase the monthly cumulative immunoglobulin dosage and its relative cost. The adverse events were reduced by administrating low Ig dosages in a single setting. Patients without risk factors achieved the study objective with immune globulin replacement administered with the widely used interval of 3 or 4 weeks.
CONCLUSIONS: The exact timing and optimal immunoglobulin prophylaxis regimen might be tailored according to clinical and immunological markers.

PMID: 25047154 [PubMed – indexed for MEDLINE]

Quality of life in children with primary antibody deficiency.

June 16, 2015 By Manish Butte

Quality of life in children with primary antibody deficiency.

J Clin Immunol. 2014 Oct;34(7):844-52

Authors: Titman P, Allwood Z, Gilmour C, Malcolmson C, Duran-Persson C, Cale C, Davies G, Gaspar H, Jones A

Abstract
Primary antibody deficiency disorders (PADs) can have an excellent outlook if diagnosed early and treated appropriately, but require lifelong treatment with immunoglobulin replacement. Some carry risks of inflammatory complications even with optimal treatment. Quality of life (QoL) and the psychological impact of PADs has been relatively little studied, particularly in children. The purpose of this study was to evaluate QoL and psychological impact in a large group of children affected by a range of PADs, as well as a group with transient hypogammaglobulinemia of infancy (THI). Both parental and, where appropriate, child ratings, were collected using standardised questionnaires (PedsQL and SDQ). Higher rates of psychological difficulties, particularly emotional and peer-relationship difficulties were found in children with PAD when compared with healthy controls. Quality of life was poorer than in healthy controls, and also worse than in children affected by diabetes mellitus. Variations in QoL and the degree of psychological difficulties were found between specific diagnostic groups, with children affected by THI being amongst those with the lowest scores for QoL. Further studies are needed to corroborate and extend these findings, but this study confirms previous findings that primary antibody deficiency has a significant impact on quality of life and psychological well-being, and additionally suggests that the impact varies according to severity of the underlying condition. For those with significant difficulties psychological intervention at an early stage may be beneficial.

PMID: 25005831 [PubMed – indexed for MEDLINE]

Positive Impact of Fungal Histopathology on Immunocompromised Pediatric Patients With Histology-Proven Invasive Fungal Infection.

June 14, 2015 By Manish Butte

Positive Impact of Fungal Histopathology on Immunocompromised Pediatric Patients With Histology-Proven Invasive Fungal Infection.

Am J Clin Pathol. 2015 Jul;144(1):61-7

Authors: Dekio F, Bhatti TR, Zhang SX, Sullivan KV

Abstract
OBJECTIVES: We investigated the performance and the clinical impact of histologic examination of infected tissue in patients with suspected invasive fungal infection (IFI) at a tertiary pediatric center.
METHODS: Unique episodes of IFI were identified from January 1, 2001, through December 31, 2012. Surgical pathology reports, fungal culture results, and clinical data were abstracted from medical records.
RESULTS: Forty-seven patients with IFI were identified. Each patient had one episode of IFI. Risk factors included chemotherapy for an oncologic condition (n = 35), hematopoietic stem cell transplantation (n = 6), solid organ transplantation (n = 4), and primary immunodeficiency (n = 2). Tissue was obtained from deep subcutaneous tissue (n = 21), visceral organs (14 lungs, five livers, and one spleen), or the sinonasal cavity (n = 6). Fungal culture was ordered in 40 of the 47 episodes of IFI. Fungus grew in 27 (68%) of the 40 cultures submitted, and all isolates were concordant with histology. Medical records were available for 36 (77%) of 47 patients. Communication of histology results prompted changes in antifungal therapy 64% of the time. This included initiation of antifungal therapy in 13 patients who were not previously receiving therapy. Fifteen (42%) patients underwent surgical excision within 48 hours of histologic diagnosis.
CONCLUSIONS: Histology can provide rapid, accurate, and clinically actionable information to clinicians caring for children with IFI.

PMID: 26071462 [PubMed – in process]

Lung Magnetic Resonance Imaging with Diffusion Weighted Imaging Provides Regional Structural as well as Functional Information Without Radiation Exposure in Primary Antibody Deficiencies.

June 13, 2015 By Manish Butte

Lung Magnetic Resonance Imaging with Diffusion Weighted Imaging Provides Regional Structural as well as Functional Information Without Radiation Exposure in Primary Antibody Deficiencies.

J Clin Immunol. 2015 Jun 12;

Authors: Milito C, Pulvirenti F, Serra G, Valente M, Pesce AM, Granata G, Catalano C, Fraioli F, Quinti I

Abstract
PURPOSE: Primary antibody deficiency patients suffer from infectious and non-infectious pulmonary complications leading over time to chronic lung disease. The complexity of this pulmonary involvement poses significant challenge in differential diagnosis in patients with long life disease and increased radio sensitivity. We planned to verify the utility of chest Magnetic Resolution Imaging with Diffusion-Weighted Imaging as a radiation free technique.
METHODS: Prospective evaluation of 18 patients with Common Variable Immunodeficiency and X-linked Agammaglobulinemia. On the same day, patients underwent Magnetic Resonance Imaging with Diffusion Weighted Imaging sequences, High Resolution Computerized Tomography and Pulmonary Function Tests, including diffusing capacity factor for carbon monoxide. Images were scored using a modified version of the Bhalla scoring system.
RESULTS: Magnetic Resonance Imaging was non-inferior to High Resolution Computerized Tomography in the capacity to identify bronchial and parenchymal abnormalities. HRCT had a higher capacity to identify peripheral airways abnormalities, defined as an involvement of bronchial generation up to the fifth and distal (scores 2-3). Bronchial scores negatively related to pulmonary function tests. One third of consolidations and nodules had Diffusion Weighted Imaging restrictions associated with systemic granulomatous disease and systemic lymphadenopathy. Lung Magnetic Resolution Imaging detected an improvement of bronchial and parenchymal abnormalities, in recently diagnosed patients soon after starting Ig replacement.
CONCLUSIONS: Magnetic Resonance Imaging with Diffusion Weighted Imaging was a reliable technique to detect lung alterations in patients with Primary Antibody Deficiencies.

PMID: 26067227 [PubMed – as supplied by publisher]