Robert Hostoffer

Recurrent Mycobacterium avium Osteomyelitis Associated With a Novel Dominant Interferon Gamma Receptor Mutation

Mycobacterium avium causes infections in immunocompromised individuals. Recurrent infection with this organism has been associated with a deletion at the 818 residue of the interferon-γ receptor (IFN-γR). This mutation produces a truncated receptor without an intracytoplasmic tail, resulting in diminished signaling. We describe a substitution at the 832 residue of the IFN-γR causing a similar truncated receptor in a 7-year-old girl with recurrent M avium osteomyelitis.

Health-related quality of life of children with primary immunodeficiency disease: a comparison study

BACKGROUND Many symptoms of primary immunodeficiency (PI) disease can be successfully managed with intravenous immunoglobulin infusion. Although survival rates and prognosis have greatly improved, children with PI disease are still at risk for physical, social, and psychological problems owing to their chronic health condition. However, to our knowledge, there are no empirical data concerning health-related quality of life (HRQOL) in children with PI disease receiving intravenous immunoglobulin infusion. OBJECTIVE To compare parental reports of HRQOL of children with PI disease receiving intravenous immunoglobulin infusion with children with juvenile idiopathic arthritis (JIA) and a healthy sample. METHODS Demographic, illness, and HRQOL data were collected from parents of 4- to 18-year-old children with PI disease (n = 36), children with JIA (n = 36), and healthy children (n = 36). The HRQOL was evaluated using the Child Health Questionnaire-Parent Report version. RESULTS Compared with children with JIA, children with PI disease were similar in many aspects of their HRQOL. However, parents of children with PI disease reported greater limitations in their personal time, poorer general health of their children, greater limitations in their childrens physical functioning and family activities, and less bodily pain than children with JIA. In contrast, children with PI disease scored lower on most HRQOL domains compared with healthy children. CONCLUSION Children with PI disease experience similar HRQOL to children with JIA and poorer HRQOL than healthy children, indicating potential areas to be addressed by future medical and psychosocial interventions.

Quality of life in common variable immunodeficiency requiring intravenous immunoglobulin therapy

BACKGROUND There are no studies of patients with primary immunodeficiency states receiving intravenous immunoglobulin (IVIG) therapy that assess health-related quality of life (HRQOL) using a well-standardized and reproducible method. OBJECTIVES To determine the HRQOL of patients with common variable immunodeficiency (CVID) requiring IVIG therapy, to compare these patients with patients with diabetes mellitus (DM) and congestive heart failure (CHF), to determine the factors that affect HRQOL, and to develop normative data on the HRQOL of these CVID patients, which can be used to follow the effects of future therapies. METHODS Fifty-eight adults with CVID receiving IVIG therapy completed the Medical Outcomes Study 36-Item Short-Form Health Survey to evaluate their HRQOL and were compared with DM and CHF patients. The impact of demographic, socioeconomic, and disease-related variables and comorbid conditions was examined in the CVID population. RESULTS Patients with CVID had lower HRQOL scores in all dimensions compared with patients with DM and in 4 of 8 dimensions compared with patients with CHF. Increasing age and female sex were negatively associated with certain aspects of HRQOL. There were no significant effects from other socioeconomic or disease-related variables or comorbid conditions examined. CONCLUSIONS Patients with CVID receiving IVIG therapy have a significantly worse HRQOL than patients with other chronic illnesses, indicating there is much room for improvement in future therapies for this primary immunodeficiency state. The effects of future therapies can be evaluated by comparison with the normative data developed in this study.

Rubinstein–Taybi syndrome with humoral and cellular defects: a case report

THE FIRST ASSOCIATION OF RUBINSTIEN Taybi syndrome with immunodeficiency and the successful prevention of infection with intravenous IgG is reported in a 4 year old boy. This case suggests that immunodeficiency maybe a prominent feature of this syndrome and may predispose these patients to recurrent infections.

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

baseline in the AIA group. Taken together, these data suggest that increased mast cell activation is involved in the pathophysiology of AIA even in the clinically stable baseline condition. Song et al demonstrated that urinary tetranor-PGDM concentrations were suppressed by inhibition of aspirin but not by selective inhibition of COX-2. Interestingly, Daham et al recently demonstrated that the urinary tetranor-PGDM concentration remains unchanged in both the AIA and aspirin-tolerant asthma groups following the administration of the selective COX-2 inhibitor celecoxib. Taken together, despite the fact that COX-1 is the dominant in vivo PGD2 biosynthesis pathway, the precise mechanism underlying the putative mast cell–associated PGD2 overproduction through the pharmacological effect of COX-1 inhibitors in the AIA group remains unknown. In conclusion, among the urinary metabolites of PGD2, the new biomarker tetranor-PGDM exhibited a higher concentration in urine, which may prove useful in the monitoring of mast cell activation in allergic diseases. The PGD2 production was clearly indicated by both the ‘‘D-ring’’ and ‘‘F-ring’’ metabolites in anaphylaxis and AIA. HPLC purification is convenient and can serve as a highly useful quantification procedure, when urinary tetranor-PGDM concentrations are determined with EIA. Noritaka Higashi, MD, PhD Haruhisa Mita, PhD Hiromichi Yamaguchi, MD Yuma Fukutomi, MD Kazuo Akiyama, MD Masami Taniguchi, MD, PhD

Selective antipolysaccharide antibody deficiency associated with peripheral blood CD5+ B-cell predominance

BACKGROUND Primary humoral deficiencies vary from complete absence of B cells and/or serum immunoglobulin to lacunar deficits involving specific antibody responses to polysaccharides. OBJECTIVES We compared the B-cell CD5 expression in patients with selective antipolysaccharide antibody deficiencies (SPADs), common variable immunodeficiency (CVID), and IgG subclass deficiency and in normal control subjects. METHODS Five patient populations were evaluated: (1) patients with severe SPAD (no protective serologic postvaccine response to any of 12 polysaccharide antigens tested); (2) patients with intermediate SPAD (diminished response to polysaccharide antigens and adequate response to 1 to 3 of 12 serotypes tested); (3) patients with IgG subclass deficiency; (4) patients with CVID; and (5) age-matched control subjects. Blood was collected from all patients and evaluated by using flow cytometry. Results were compared by using the Student t test. RESULTS Patients with severe SPAD deficiencies had a marked predominance of CD5+ B cells in the peripheral blood (93% to 97% of total B cells, n = 2). The intermediate SPAD group had a mean CD5+ B-cell percentage that was significantly higher than that of the age-matched control group (87. 4%, n = 7, vs 52.5%, n = 20; P =.007). Patients with CVID and IgG subclass deficiency had mean CD5+ B-cell percentages that were similar to those of the age-matched control subjects. CONCLUSIONS Our studies demonstrate that patients with SPAD had a markedly increased percentage of CD5+ B cells in the peripheral blood as compared with age-matched control subjects and patients with other humoral deficiencies. This observation suggests that an association may be present between CD5+ B-cell predominance and SPAD.

Otitis Media Following Tympanostomy Tube Placement in Children With IgG2 Deficiency

Children with IgG2 deficiency commonly develop recurrent acute otitis media. It is believed that these infections are secondary to impaired antibody response rather than eustachian tube dysfunction and are therefore less responsive to treatment with tympanostomy tubes.

Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia

X‐linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B‐cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patients leukemia. Pediatr Blood Cancer 2015;62:1674–1676.

The rate of epinephrine administration associated with allergy skin testing in a suburban allergy practice from 1997 to 2010.

Allergy skin testing is considered a safe method for testing for IgE-mediated allergic responses although anaphylactic events can occur. Reported rates of anaphylaxis per patient are not consistent and range from 0.008 to 4%. The aim of this study was to determine the rate of epinephrine use associated with allergy skin-prick testing (SPT) and intradermal testing (IDT) in a suburban practice over 13 years. This retrospective chart review used billing and procedure coding records during the time period from January 1997 to June 2010 to identify encounters where epinephrine was administered after SPT or IDT. Patient encounters with procedure codes for skin testing plus either parenteral epinephrine, corticosteroid, antihistamine, or i.v. fluid administration were identified. These patient charts were reviewed to determine if epinephrine was administered, whether systemic reactions developed, and rates of epinephrine administration were calculated. There were 28,907 patient encounters for SPT and 18,212 for IDT. Epinephrine was administered in six patient encounters (0.02%) where SPT was performed; no IDT encounters led to epinephrine administration. There were no fatalities. Allergy skin testing to a variety of allergens, when administered by well-trained personnel, is a safe procedure. This study, involving the largest population to date, showed a rate of systemic reactions requiring epinephrine of 20 per 100,000 SPT visits. No epinephrine was given after IDT.

Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1)

Desirée Schubert, Marie-Christine Klein, Sarah Hassdenteufel, Andrés CaballeroOteyza, Linlin Yang, Michele Proietti, Alla Bulashevska, Janine Kemming, Johannes Kühn, Sandra Winzer, Stephan Rusch, Manfred Fliegauf, Alejandro A. Schäffer, Stefan Pfeffer, Roger Geiger, Adolfo Cavalié, Hongzhi Cao, Fang Yang, Yong Li, Marta Rizzi, Hermann Eibel, Robin Kobbe, Amy L. Marks, Brian P. Peppers, Robert W. Hostoffer, Jennifer M. Puck, Richard Zimmermann, Bodo GrimbacherBackground: Primary antibody deficiencies (PADs) are the most frequent primary immunodeficiencies in human subjects. The genetic causes of PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide‐conducting channel in the endoplasmic reticulum membrane. SEC61A1 is a target gene of spliced X‐box binding protein 1 and strongly induced during plasma cell (PC) differentiation. Objective: We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs. Methods: Whole‐exome and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B‐cell differentiation and survival. Results: We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B‐ and T‐cell subpopulations. On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs. Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1‐V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1‐V85D triggered the terminal unfolded protein response in multiple myeloma cell lines. Conclusion: We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies.