Hyper IgM Syndrome: a Report from the USIDNET Registry.

PURPOSE: The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). METHODS: The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. RESULTS: Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years). CONCLUSIONS: Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.

Disseminated Mycobacterium kansasii disease in complete DiGeorge syndrome.

PURPOSE: Complete DiGeorge syndrome (cDGS) describes a subset of patients with DiGeorge syndrome that have thymic aplasia, and thus are at risk for severe opportunistic infections. Patients with cDGS and mycobacterial infection have not previously been described. We present this case to illustrate that patients with cDGS are at risk for nontuberculous mycobacterial infections and to discuss further antimicrobial prophylaxis prior to thymic transplantation. METHODS: A 13-month old male was identified as T cell deficient by the T cell receptor excision circle (TREC) assay on newborn screening, and was subsequently confirmed to have cDGS. He presented with fever and cough, and was treated for chronic aspiration pneumonia as well as Pneumocystis jirovecii infection without significant improvement. It was only after biopsy of mediastinal lymph nodes seen on CT that the diagnosis of disseminated Mycobacterium kansasii was made. We reviewed the literature regarding atypical mycobacterial infections and prophylaxis used in other immunocompromised patients, as well as the current data regarding cDGS detection through TREC newborn screening. RESULTS: Multiple cases of cDGS have been diagnosed via TREC newborn screening, however this is the first patient with cDGS and disseminated mycobacterial infection to be reported in literature. Thymic transplantation is the definitive treatment of choice for cDGS. Prophylaxis with either clarithromycin or azithromycin has been shown to reduce mycobacterial infections in children with advanced human immunodeficiency virus infection. CONCLUSIONS: Children with cDGS should receive thymic transplantion as soon as possible, but prior to this are at risk for nontuberculous mycobacterial infections. Severe, opportunistic infections may require invasive testing for diagnosis in patients with cDGS. Antimicrobial prophylaxis should be considered to prevent disseminated mycobacterial infection in these patients.

Case Report: Nontuberculous mycobacterial infections in children with complete DiGeorge anomaly.

Children with complete DiGeorge anomaly (cDGA) have congenital athymia, resulting in severe T cell immunodeficiency and susceptibility to a broad range of infections. We report the clinical course, immunologic phenotypes, treatment, and outcomes of three cases of disseminated nontuberculous mycobacterial infections (NTM) in patients with cDGA who underwent cultured thymus tissue implantation (CTTI). Two patients were diagnosed with Mycobacterium avium complex (MAC) and one patient with Mycobacterium kansasii. All three patients required protracted therapy with multiple antimycobacterial agents. One patient, who was treated with steroids due to concern for immune reconstitution inflammatory syndrome (IRIS), died due to MAC infection. Two patients have completed therapy and are alive and well. T cell counts and cultured thymus tissue biopsies demonstrated good thymic function and thymopoiesis despite NTM infection. Based on our experience with these three patients, we recommend that providers strongly consider macrolide prophylaxis upon diagnosis of cDGA. We obtain mycobacterial blood cultures when cDGA patients have fevers without a localizing source. In cDGA patients with disseminated NTM, treatment should consist of at least two antimycobacterial medications and be provided in close consultation with an infectious diseases subspecialist. Therapy should be continued until T cell reconstitution is achieved.

Correlation of a unique "Los Angeles" phonospirometry technique with peak expiratory flows in children with asthma.

BACKGROUND: Measurement of peak expiratory flow (PEF) is recommended as part of the assessment of patients with asthma. However, there are multiple barriers in the use of PEF, even for older pediatric patients. OBJECTIVE: Phonospirometry, as measured by the Los Angeles (LA) technique, was assessed and compared with standard PEF measurements in patients with asymptomatic and symptomatic asthma. METHODS: A convenience sample of patients with asthma aged 8-17 years was enrolled from visits in the Allergy/Immunology Clinic and in the Emergency Department of Children's Hospital Los Angeles. The phonospirometry technique was demonstrated, and the length of time the patient repeated the syllable "lah" continuously with the same breath was measured. After a brief interval of time to recover, the patient performed conventional PEF measurement. RESULTS: Using the first observation for each patient in our study, the Pearson correlation coefficient between phonospirometry and PEF was r = 0.67, p = .0016 for asymptomatic asthma patients and r = 0.77, p < .0001 for symptomatic asthma patients. Analysis of the first and last measurements of the symptomatic asthma patients who had multiple measurements revealed a Pearson correlation coefficient between phonospirometry and PEF at first measurement r = 0.69, p = .0008 and at the last measurement r = 0.76, p < .0001. CONCLUSIONS: Using the LA technique, phonospirometry was shown to have a linear correlation with PEF in pediatric patients with asymptomatic and symptomatic asthma. It is simple and easily reproducible, as well as cross-cultural. This novel technique shows promise to aid the assessment of patients with acute asthma exacerbations.

What Is Anaphylaxis? Pediatric Residents' Perception and Treatment of Anaphylactic Reactions.

To assess knowledge regarding symptoms and treatment of anaphylaxis, a vignette of a child having an allergic reaction to a peanut was presented to residents in an allergy clinic. Twelve sets of clinical outcomes ranging from severe multi-organ to mild single organ involvement were described, and residents were asked if each symptom set met criteria for diagnosis of anaphylaxis, whether epinephrine should be administered acutely and prescribed at follow-up, and whether peanuts should be avoided in the future. Of cases that met the definition of anaphylaxis 28.8% were incorrectly diagnosed, in 13.6% of cases they would allow peanuts to be eaten again, and in 23.9% of cases they would not prescribe epinephrine at follow-up. In 26.1% of cases meeting criteria for acute anaphylaxis residents would not administer epinephrine. Deficits regarding the diagnosis and treatment of anaphylaxis by residents were identified, and increased educational efforts are needed.

Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency.

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

Association of staphylococcal superantigen-specific immunoglobulin e with mild and moderate atopic dermatitis.

OBJECTIVE: To examine the frequency of allergic sensitization to staphylococcal superantigens in young children with mild to moderate atopic dermatitis (AD). STUDY DESIGN: AD severity was assessed with objective Scoring AD. Serum IgE to staphylococcal enterotoxin (SE) A, SEB, SEC, SED, and toxic shock syndrome toxin-1 were measured with ImmunoCAP. Comparisons between mild AD and moderate AD were performed by using logistic regressions. RESULTS: The prevalence of allergic sensitization to staphylococcal superantigens in patients with mild and moderate AD was 38% and 63%, respectively. Allergic sensitization to staphylococcal superantigens, particularly SEA and SED, was found to be associated with moderate AD, compared with mild AD. CONCLUSIONS: Our results suggest that allergic sensitization to staphylococcal superantigens is common even in young children with mild to moderate AD, and such sensitization may contribute to the disease severity of these patients.

Mixed-up nuts: identification of peanuts and tree nuts by children.

BACKGROUND: Peanuts and tree nuts frequently cause severe allergic reactions. Nut avoidance is the key treatment, and accurate identification of nuts is essential for successful avoidance. OBJECTIVES: To determine the age at which nut-allergic and nonallergic children can accurately identify various nuts and whether nut-allergic children can identify nuts they should avoid. METHODS: A "nut box" was constructed containing samples of 11 common nuts and pine nuts. Nut-allergic and nonallergic children were asked to identify the nuts, and their responses were compared and correlated by age. Nut-allergic children were asked to identify the nut(s) that they should not eat. RESULTS: One hundred children (37 allergic and 63 nonallergic) were enrolled. The mean number of nuts correctly identified was only 2.7 per child and increased with age, but there was large variation. Fifty-nine children identified 2 or fewer nuts. Peanuts in the shell were identified most often (89% of children), followed by peanuts out of the shell (52%). Other nuts were identified less commonly, ranging from 32% for pistachios to 0% for Brazil nuts. Nut-allergic children were not better able to correctly identify tree nuts and were less able in the case of peanuts. Of the nut-allergic children, 10 (27%) could not identify the peanut or tree nut to which they were allergic. CONCLUSIONS: In general, children, including those who are allergic to nuts, can identify few nuts. This lack of recognition could put them at increased risk for unintentional ingestion. As part of an overall educational plan, nut-allergic children should be taught not only to avoid but also to identify the nut to which they are allergic.

Pectin anaphylaxis and possible association with cashew allergy.

BACKGROUND: Inhalation of pectin has been identified as a cause of occupational asthma. However, allergic reactions to orally ingested pectin have not been reported. OBJECTIVES: To describe a child with pectin-induced food anaphylaxis and to discuss its possible relationship to cashew allergy. METHODS: A 3 1/2-year-old boy developed anaphylaxis once after eating cashews and later after eating a pectin-containing fruit "smoothie." He also has a history of generalized pruritus after eating grapefruit. Skin tests or radioallergosorbent tests (RASTs) were performed to pectin and other suspected food allergens. RESULTS: The child had a positive skin prick test reaction to pectin and a high RAST reaction to cashew and pistachio. He had a low-level positive RAST reaction to grapefruit. Results of allergy tests for the other potential food allergens were negative. The pectin in the smoothie was confirmed to be of citrus origin. Review of previous case reports of pectin-induced occupational asthma revealed several patients with allergies to and cross-reactivity with cashew. CONCLUSIONS: Ingestion, not only inhalation, of pectin can cause hypersensitivity reactions. Cashew, and possibly pistachio, allergy may be associated with pectin allergy, and the possibility of pectin allergy should be considered in cashew- or pistachio-allergic patients who have unexplained allergic reactions.