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Phenotypic variations of cartilage hair hypoplasia: granulomatous skin inflammation and severe T cell immunodeficiency as initial clinical presentation in otherwise well child with short stature.

October 18, 2014 By Manish Butte

Phenotypic variations of cartilage hair hypoplasia: granulomatous skin inflammation and severe T cell immunodeficiency as initial clinical presentation in otherwise well child with short stature.

J Clin Immunol. 2014 Jan;34(1):42-8

Authors: McCann LJ, McPartland J, Barge D, Strain L, Bourn D, Calonje E, Verbov J, Riordan A, Kokai G, Bacon CM, Wright M, Abinun M

Abstract
We report a child with short stature since birth who was otherwise well, presenting at 2.8 years with progressive granulomatous skin lesions when diagnosed with severe T cell immunodeficiency. When previously investigated for short stature, and at the time of current investigations, she had no radiological skeletal features characteristics for cartilage hair hypoplasia, but we found a disease causing RMRP (RNase mitochondrial RNA processing endoribonuclease) gene mutation. Whilst search for HLA matched unrelated donor for haematopoietic stem cell transplantation (HSCT) was underway, she developed rapidly progressive EBV-related lymphoproliferative disorder requiring laparotomy and small bowel resection, and was treated with anti-B cell monoclonal antibody and eventually curative allogeneic HSCT. Screening for RMRP gene mutations should be part of immunological evaluation of patients with ‘severe and/or combined’ T cell immunodeficiency of unknown origin, especially when associated with short stature and regardless of presence or absence of radiological skeletal features.

PMID: 24217815 [PubMed – indexed for MEDLINE]

Activity, severity and impact of respiratory disease in primary antibody deficiency syndromes.

October 18, 2014 By Manish Butte

Activity, severity and impact of respiratory disease in primary antibody deficiency syndromes.

J Clin Immunol. 2014 Jan;34(1):68-75

Authors: Hurst JR, Workman S, Garcha DS, Seneviratne SL, Haddock JA, Grimbacher B

Abstract
PURPOSE: Some patients with primary antibody deficiency (PAD) syndromes develop bronchiectasis. In immunocompetent patients with bronchiectasis, key clinico-pathophysiological relationships exist between exacerbation frequency, lung function, health-status, infection and inflammation. It is not known whether such relationships are present in PAD. It is also not known how local and systemic inflammation in PAD compares with that in immunocompetent (non-PAD) bronchiectasis patients.
METHOD: We assessed symptoms, exacerbation frequency, health-status, lung function, CT, airway and systemic inflammation and infection in 33 PAD patients and 20 immunocompetent controls with bronchiectasis.
RESULTS: Despite less severe airflow obstruction, PAD patients had similar health-status impairment and greater airway (sputum log10 IL-6 2.71 vs. 1.81 pg/ml, p = 0.001) and greater systemic inflammation than immunocompetent bronchiectasis controls (serum log10 CRP 0.77 vs. 0.36 mg/l, p = 0.001). In PAD, cross-sectional markers of disease severity (CT and lung function) did not relate to inflammatory markers of disease activity, however there was a relationship between FEV1 decline rate and systemic inflammation (IL-6; r = 0.42, p = 0.036) and the magnitude of the systemic inflammatory response was related to that in the airway. Correlation between generic SF36 and respiratory SGRQ questionnaires (r = -0.79, p < 0.001) suggests that much health-status impairment in PAD relates to respiratory involvement. Health-status was associated with dyspnoea (rho = 0.77, p < 0.001), respiratory infection frequency (rho = 0.48, p = 0.016), lung function (FEV1: r = -0.60, p = 0.001) and rate of lung function decline (r = 0.41, p = 0.047).
CONCLUSION: The major findings of this analysis are that in patients with PAD, cross-sectional markers of disease severity such as lung function and CT extent of disease do not reflect disease activity as assessed by airway and systemic inflammation. In addition, there is a relationship between the rate of progression of lung disease and the severity of the systemic inflammatory response which itself is related to that in the airway. Much of the quality of life impact in PAD relates to respiratory involvement, specifically the severity of airflow obstruction, respiratory exacerbation frequency and dyspnoea. Finally, patients with PAD had greater airway and systemic inflammation than a control population with non-PAD bronchiectasis which may suggest a dysregulated airway immune response.

PMID: 24136152 [PubMed – indexed for MEDLINE]

Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency.

October 17, 2014 By Manish Butte

Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency.

Curr Opin Pediatr. 2014 Oct 15;

Authors: Kotlarz D, Ziętara N, Milner JD, Klein C

Abstract
PURPOSE OF REVIEW: This review highlights the recent identification of human interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) deficiencies as novel entities of primary immunodeficiency.
RECENT FINDINGS: We recently described the first patients with IL-21R deficiency who had cryptosporidial infections associated with chronic cholangitis and liver disease. All IL-21R-deficient patients suffered from recurrent upper or lower respiratory tract infections, or a combination of both conditions. Immunological work-up revealed impaired B cell proliferation and immunoglobulin class-switch, reduced T cell effector functions, and variable natural killer cell dysfunctions. Recently, these findings have been extended by the discovery of one patient with a mutation in the IL21 gene. This patient predominantly manifested with very early onset inflammatory bowel disease and recurrent respiratory infections. Laboratory examination showed reduced circulating B cells and impaired B cell class-switch.
SUMMARY: Human IL-21 and IL-21R deficiencies cause severe, primary immunodeficiency reminiscent of common variable immunodeficiency. Early diagnosis is critical to prevent life-threatening complications, such as secondary liver failure. In view of the critical role of IL-21 in controlling immune homeostasis, early hematopoietic stem cell transplantation might be considered as therapeutic intervention in affected children.

PMID: 25321844 [PubMed – as supplied by publisher]

Primary immunodeficiency in infection-prone children in southern Sweden: occurrence, clinical characteristics and immunological findings.

October 17, 2014 By Manish Butte

Primary immunodeficiency in infection-prone children in southern Sweden: occurrence, clinical characteristics and immunological findings.

BMC Immunol. 2014 Aug 14;15(1):31

Authors: Brodszki N, Jönsson G, Skattum L, Truedsson L

Abstract
BACKGROUND: Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of disorders mainly characterized by increased susceptibility to infections. The aims of this study were to estimate the occurrence rate of PID in the paediatric (age ≤ 18 years) population of southern Sweden (approx. 265,000 children) and to describe their demographic, clinical and immunological characteristics. During a period of 4 years, in four paediatric speciality clinics in Skåne County in southern Sweden, children being seen for infections and fulfilling specific criteria were evaluated according to a predefined examination schedule. The initial analysis consisted of complete blood counts with analysis of lymphocyte subpopulations (T, B, NK cells), measurement of immunoglobulins (IgG, IgA, IgM, IgE and IgG subclasses), and assessment of the complement system (classical, alternative and lectin pathways). In addition, results of these immunological analyses in other children from the same area and time period were evaluated.
RESULTS: In total, 259 children (53.6% males) met the criteria and were included. The most common infection was recurrent otitis media. Immunological analyses results for about two thirds of the patients were outside age-related reference intervals. Further examination in this latter group identified 15 children with PID (9 males); 7 (2.7%) had genetically defined PID, representing 4 different diagnoses, and another 8 (3.1%) had a clinically defined PID – common variable immunodeficiency. No additional PID patient was identified from the evaluation of laboratory results in children not included in the study. The median age at diagnosis was 3.5 years (range 1-12 years).
CONCLUSIONS: The occurrence rate of PID was about 4 new cases per year in this population. Several different PID diagnoses were found, and the application of specified criteria to identify PID patients was useful. In children who are prone to infection, the use of a predefined set of immunological laboratory analyses at their first examination was beneficial for early identification of patients with PID.

PMID: 25318568 [PubMed – as supplied by publisher]

Peri-Operative Considerations in the Patient with Primary Immune Deficiency: A Review.

October 16, 2014 By Manish Butte

Peri-Operative Considerations in the Patient with Primary Immune Deficiency: A Review.

Surg Infect (Larchmt). 2014 Oct 15;

Authors: Pagovich OE, Lebastchi AH, Romberg N

Abstract
Abstract Background: Patients with inherited immune deficiency diseases often require surgical procedures, and their immune defects may predispose them to surgical complications. Methods: A thorough review of pertinent literature and current practice guidelines on surgery in patients with immune deficiency. Results: Peri-operative infections are a key, but not a singular, consideration in managing patients with a primary immune deficiency. Bleeding diathesis, gastrointestinal complications, pulmonary complications, and poor incision healing may also be idiosyncratic features unique to particular immune deficiency diseases. Patients with complex genetic syndromes that include immune deficiency also may display non-immunologic abnormalities that are equally important to surgical care. Conclusion: Greater awareness of primary immune deficiencies and a comprehensive evaluation of such patients in close consultation with an immunologist can minimize surgical complications and optimize patient outcomes.

PMID: 25317569 [PubMed – as supplied by publisher]

Screening for Long-term Poliovirus Excretion Among Children With Primary Immunodeficiency Disorders: Preparation for the Polio Posteradication Era in Bangladesh.

October 16, 2014 By Manish Butte

Screening for Long-term Poliovirus Excretion Among Children With Primary Immunodeficiency Disorders: Preparation for the Polio Posteradication Era in Bangladesh.

J Infect Dis. 2014 Nov 1;210 Suppl 1:S373-9

Authors: Sazzad HM, Rainey JJ, Kahn AL, Mach O, Liyanage JB, Alam AN, Kawser CA, Hossain A, Sutter R, Luby SP

Abstract
BACKGROUND: Persons with primary immune deficiency disorders (PIDD) who receive oral poliovirus vaccine (OPV) may transmit immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) and cause paralytic polio. The objective of this study was to identify children with PIDD in Bangladesh, and estimate the proportion with chronic poliovirus excretion.
METHODS: Patients admitted at 5 teaching hospitals were screened for PIDD according to standardized clinical case definitions. PIDD was confirmed by age-specific quantitative immunoglobulin levels. Stool specimens were collected from patients with confirmed PIDD.
RESULTS: From February 2011 through January 2013, approximately 96 000 children were screened, and 53 patients were identified who met the clinical case definition for PIDD. Thirteen patients (24%) had age-specific quantitative immunoglobulins results that confirmed PIDD. Of these, 9 (69%) received OPV 3-106 months before stool specimen collection. Among 11 patients, stool specimens from 1 patient tested positive for polioviruses 34 months after OPV ingestion. However, the poliovirus isolate was not available for genetic sequencing, and a subsequent stool specimen 45 days later was negative.
CONCLUSIONS: The risk of chronic poliovirus excretion among children with PIDD in Bangladesh seems to be low. The national polio eradication program should incorporate strategies for screening for poliovirus excretion among patients with PIDD.

PMID: 25316858 [PubMed – in process]

Vaccine-derived polioviruses.

October 16, 2014 By Manish Butte

Vaccine-derived polioviruses.

J Infect Dis. 2014 Nov 1;210 Suppl 1:S283-93

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

Abstract
The attenuated oral poliovirus vaccine (OPV) has many properties favoring its use in polio eradication: ease of administration, efficient induction of intestinal immunity, induction of durable humoral immunity, and low cost. Despite these advantages, OPV has the disadvantage of genetic instability, resulting in rare and sporadic cases of vaccine-associated paralytic poliomyelitis (VAPP) and the emergence of genetically divergent vaccine-derived polioviruses (VDPVs). Whereas VAPP is an adverse event following exposure to OPV, VDPVs are polioviruses whose genetic properties indicate prolonged replication or transmission. Three categories of VDPVs are recognized: (1) circulating VDPVs (cVDPVs) from outbreaks in settings of low OPV coverage, (2) immunodeficiency-associated VDPVs (iVDPVs) from individuals with primary immunodeficiencies, and (3) ambiguous VDPVs (aVDPVs), which cannot be definitively assigned to either of the first 2 categories. Because most VDPVs are type 2, the World Health Organization’s plans call for coordinated worldwide replacement of trivalent OPV with bivalent OPV containing poliovirus types 1 and 3.

PMID: 25316847 [PubMed – in process]

Cerebellar involvement of Griscelli syndrome type 2.

October 16, 2014 By Manish Butte

Cerebellar involvement of Griscelli syndrome type 2.

BMJ Case Rep. 2014;2014

Authors: Işikay S

Abstract
Griscelli syndrome type 2 is characterised by partial albinism and primary immunodeficiency. We present a case of a 3-year-old girl diagnosed with cerebellar involvement of Griscelli syndrome type 2. Neurological complications may accompany Griscelli syndrome, however, to the best of my knowledge there are only a few case reports of cerebellar involvement of Griscelli syndrome type 2 in the literature.

PMID: 25315806 [PubMed – in process]

Epidemiology of Primary Immunodeficiency in Iceland.

October 16, 2014 By Manish Butte

Epidemiology of Primary Immunodeficiency in Iceland.

J Clin Immunol. 2014 Oct 15;

Authors: Ludviksson BR, Sigurdardottir ST, Johannsson JH, Haraldsson A, Hardarson TO

Abstract
PURPOSE: Primary immunodeficiencies (PID) are rare heterogeneous diseases. Little is known about the prevalence of PID in Iceland and no national registry exists. The aim of the study was to describe the epidemiology of PID in Iceland.
METHODS: Using The European Society’s for Immunodeficiencies (ESID) criteria for PID, information about individuals with a known PID between 1990 and 2010 in Iceland were collected from inpatient registries of the National University Hospital of Iceland, the Department of Immunology and from clinical immunologists. Selective IgA deficiency, mannan binding lectin deficiency and secondary immunodeficiencies were excluded RESULTS: Sixty six individuals met the study criteria, 35 of them (53 %) were females. Four patients died during the study period from PID- or treatment related complications and two moved abroad. In the beginning of 2011 there were 60 individuals living in Iceland with a known PID diagnosis meeting ESID’s criteria. Estimated prevalence for PID in the Icelandic population of 318.452 habitants was 18.8 for 100.000 inhabitants. Predominantly antibody disorders comprised the largest category of PID in Iceland.
CONCLUSIONS: The prevalence of PID is high in Iceland compared to reports from other nations. Our patient data are easily accessible and a central laboratory measures the immune parameters. This high prevalence may indicate that PID is more common than generally recognized.

PMID: 25315263 [PubMed – as supplied by publisher]

An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex.

October 15, 2014 By Manish Butte

An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex.

J Allergy Clin Immunol. 2014 Oct 10;

Authors: Kracker S, Di Virgilio M, Schwartzentruber J, Cuenin C, Forveille M, Deau MC, McBride KM, Majewski J, Gazumyan A, Seneviratne S, Grimbacher B, Kutukculer N, Herceg Z, Cavazzana M, Jabado N, Nussenzweig MC, Fischer A, Durandy A

Abstract
BACKGROUND: Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level.
OBJECTIVE: This study’s objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR).
METHODS: Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR.
RESULTS: We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients’ fibroblastic cells corrected their hypersensitivity to high doses of γ-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Sα and Eμ regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity.
CONCLUSION: INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis.

PMID: 25312759 [PubMed – as supplied by publisher]