Efrem Eren

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

BACKGROUND The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells. OBJECTIVE To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. METHODS We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. RESULTS In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells. CONCLUSION We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia

Royal Bournemouth Hospital, Bournemouth, 2 Royal Marsden Hospital, London, 3 Southampton General Hospital, Southampton, Cardiff and Vale NHS Trust, Cardiff Cambridge University Hospitals NHS Foundation Trust, Cambridge UK; St. Jamess Institute of Oncology, Leeds, Christie Hospital NHS Trust, Manchester Royal Marsden Hospital London; Heart of England NHS Foundataion Trust, Birmingham; 10 Royal Liverpool University Hospital, Liverpool; Churchill Hospital, Headington, Oxford, Norfolk and Norwich University Hospital, Norwich

Association between Micronutrient Levels and Chronic Spontaneous Urticaria

Previous reports have suggested a possible role for vitamin D in the etiology of chronic spontaneous urticaria (CSU); however, little information is available regarding the role of other micronutrients. We, therefore, analyzed vitamin D, vitamin B12, and ferritin levels in CSU patients (n = 282) from a preexisting database at Southampton General Hospital. Data were compared against mean micronutrient levels of the general population of the UK, obtained from the National Diet and Nutrition Survey. Vitamin D levels of CSU patients were found to be higher than those of the general UK population (P = 0.001). B12 levels were lower in patients with CSU (P < 0.001) than in the general population. Ferritin levels were found to be lower in male CSU patients than in the general male population (P = 0.009). This association between low B12 and iron levels and CSU might indicate a causal link, with micronutrient replacement as a potential therapeutic option.

Mucosal-Associated Invariant T (MAIT) Cells Are Impaired in Th17 Associated Primary and Secondary Immunodeficiencies

The recently described Mucosal Associated Invariant T (MAIT) cells mediate specific recognition of bacterial and fungal vitamin B2 metabolites. As innate T cells, they possess broad effector responses, including IFN- including Iproduction, that are comparable to conventional T cell responses. Immunodeficiencies associated with systemic Th17 deficiency may also be compounded by defects in MAIT immunity. We evaluated Th17 immunity in this innate T cell compartment in primary (AD-HIES) and secondary immunodeficiency (thymoma) patients with conventional Th17 deficiency and susceptibility to fungal and bacterial disease. Our results suggest that MAIT cells are both reduced and functional deficient in STAT3 deficiency and thymoma patients with IL-12/23 autoantibodies. In contrast, thymoma patients without autoantibodies preserved the normal number and functional MAIT cells.

An Observational Study of the Diagnosis and Management of Chronic Urticaria in the UK

Background: Patients with chronic urticaria (CU) in the UK could be referred to health care professionals (HCPs) with diverse specialties using different guidelines. The aims of the present study were to determine which CU guidelines HCPs in the UK use, which tests they use for the diagnosis of CU, and how they manage CU. Methods: In this UK-wide survey, we designed a questionnaire covering the diagnosis and management of CU based on current guidelines. The link to the questionnaire was sent to the British Society for Allergy and Clinical Immunology (BSACI), the British Association of Dermatologists (BAD), the British Society of Immunology (BSI), and the Food Allergy and Intolerance Specialist Group (FAISG) of the British Dietetic Association (BDA), who distributed the link to their members. Results: The questionnaire was completed by 55 allergists/immunologists, 64 dermatologists, and 43 dietitians. More dermatologists used the BAD guidelines in comparison with allergists and immunologists (93.6 vs. 12.5%; p < 0.001). On the other hand, the BSACI guidelines (83.3 vs. 14.9%; p < 0.001) and the European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) guidelines (2013) (52.1 vs. 10.6%; p < 0.001) were used by more allergists and immunologists compared to dermatologists. Differences were found between allergists/immunologists and dermatologists with regard to guidelines used, investigations performed, preference of first-line antihistamine, and prescription of alternative treatment methods. Conclusion: In conclusion, differences in the diagnosis and management of CU between HCPs of diverse specialties were identified, which reflected differences among the guidelines used.

Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics

Primary immunodeficiencies (PIDs) are rare monogenic inborn errors of immunity that result in impairment of functions of the human immune system. PIDs have a broad phenotype with increased morbidity and mortality, and treatment choices are often complex. With increased accessibility of next‐generation sequencing (NGS), the rate of discovery of genetic causes for PID has increased exponentially. Identification of an underlying monogenic diagnosis provides important clinical benefits for patients with the potential to alter treatments, facilitate genetic counselling, and pre‐implantation diagnostics. We investigated a NGS PID panel of 242 genes within clinical care across a range of PID phenotypes. We also evaluated Phenomizer to predict causal genes from human phenotype ontology (HPO) terms. Twenty‐seven participants were recruited, and a total of 15 reportable variants were identified in 48% (13/27) of the participants. The panel results had implications for treatment in 37% (10/27) of participants. Phenomizer identified the genes harbouring variants from HPO terms in 33% (9/27) of participants. This study shows the clinical efficacy that genetic testing has in the care of PID. However, it also highlights some of the disadvantages of gene panels in the rapidly moving field of PID genomics and current challenges in HPO term assignment for PID.

Scedosporium apiospermum causing otomycosis in an immunocompetent child with tympanostomy tubes: Management of this rare entity.

Infection following a tympanostomy tube insertion is a common occurrence. Scedosporium apiospermum is a filamentous fungus mainly isolated in water and soil. There have been no reported cases of S. apiospermum infection of an immunocompetent individual with a tympanostomy tube in situ. A child was referred with unilateral otorrhoea failing to respond to conventional treatment in the community. S. apiospermum was identified following specialist testing. An extended course of anti-fungal treatment led to complete resolution. Due to the rare occurrence of aural S. apiospermum and unreported nature, it should be managed in a multidisciplinary setting.

A novel insight into the immunologic basis of chronic granulomatous invasive fungal rhinosinusitis

Background Chronic granulomatous invasive fungal rhinosinusitis (CGIFRS) is a rare disease. The underlying immune responses that drive the development of CGIFRS, as opposed to successful pathogen clearance and controlled inflammation, are not currently known. Objective To characterize the immune responses associated with CGIFRS. Methods In addition to a battery of basic investigations, more in-depth immunologic testing involves ex vivo whole-blood stimulation with the polyclonal T-cell mitogen phytohemagglutinin and fungal antigens with interleukin (IL) 12, was undertaken to investigate cell-mediated immune responses associated with CGIFRS. Results Ex vivo whole-blood stimulation with the polyclonal T-cell mitogen phytohemagglutinin and fungal antigens with IL-12 identified reduced interferon gamma and increased IL-17A levels within the supernatant, which indicated increased in vivo T-helper (Th)17 responses and impaired Th1 responses compared with healthy controls. Conclusion These findings suggest that the development of CGIFRS may be associated with an abnormally exaggerated host Th17 response, which caused failure to clear the fungal pathogen with refractory fungal infection of mucosal membranes, resulting in chronic tissue inflammation.

Differential Impairment of Interferon-γ Responses in Two Cases of Pulmonary Nontuberculous Mycobacterial Disease

Nontuberculous mycobacteria (NTMs) are weakly virulent intracellular pathogens that are common in food and water supplies. The persistent culture of these organisms in the setting of clinical infection warrants investigation of immune function. In cases of isolated pulmonary NTM (PNTM) disease, underlying immune defects have not been clearly identified. We present two patients with isolated PNTM infection who demonstrated differentially impaired IFN-γ production across a range of stimuli. These cases show that cellular IFN-γ responses may be defective in a proportion of patient suffering PNTM disease and that when assessing responses, the stimulant used in the testing is important to delineate defective cell populations. Impaired IFN-γ responses to IL-12 + BCG seem to be a poor prognostic indicator in PNTM disease and in these cases were not improved by adjuvant IFN-γ.

Linezolid an oral treatment option for staphylococcal liver abscess in chronic granulomatous disease.

tion with PCR-based methods. However, the causative role of HBoV remains unclear. HBoV is also detected in children without respiratory illness, and coinfection with other viruses has been examined in several studies. In our case, we observed HBoV DNA in intratracheal aspirates, and no other causative pathogen was found. HBoV DNA was also detected in blood only in the acute phase. The titers of IgG antibody against HBoV VP1 increased. Thus, we diagnosed the case as acute HBoV infection. In the pediatric age group, plastic bronchitis is often associated with inflammatory lung disease, sickle-cell anemia, congenital heart disease and so on. In our case, the histopathological findings suggest that the boy had an allergy state such as asthma, but he had no episode of wheezing before or after hospitalization. HBoV DNAs were detected from children with wheezing, but bronchial histopathology of HBoV or its relation with bronchial asthma remains unknown. In this case, he had no underlying condition, or other causative pathogen, so we speculate that acute HBoV infection caused inflammatory lung disease followed by mucous plugging. There has been no previous case report of plastic bronchitis related to HBoV infection. As methods such as real-time PCR or serologic studies that can easily detect HBoV infection become widely available, there will be increasing number of reports with varied symptoms.