Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

Biologics in pediatric lung disease.

PURPOSE OF REVIEW: Although biologic therapies can provide outstanding efficacy in the management of lung disease, especially asthma, most of these agents have been approved only for adults. Recent findings provide new strategies for using these agents in children. RECENT FINDINGS: Extensive evidence has consistently demonstrated the efficacy and safety of biologic therapy for asthma. In addition, some studies have documented potentially important secondary effects, such as improving response to respiratory virus infection in asthmatic patients. Additional strategies for improving asthma control using biologic therapy, such as seasonal administration, have been suggested, and may limit cost while still providing a high degree of efficacy. SUMMARY: Many of the current biologics are able to readily establish control even in asthmatic patients for whom inhaled steroid and long-acting ß agonist have failed. However, biologics currently have limited regulatory approval and availability in the pediatric age range, despite this age being disproportionately affected by asthma. In addition, successful biologics for asthma to date have largely been limited to the Th2-high endotype of asthma, and there is great need for similar medications to target the Th2-low endotype. Other pediatric lung disease might well benefit from the specificity allowed by biologic therapy.

Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.

BACKGROUND: Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive. OBJECTIVE: We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM. METHODS: We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation. RESULTS: We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM. CONCLUSION: PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.

Primary Immune Deficiency Treatment Consortium (PIDTC) report.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years.

BACKGROUND: Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID). OBJECTIVE: We sought to report the first 2 years of TREC NBS in California. METHODS: Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked. RESULTS: Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry. CONCLUSIONS: TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population.

How the practice of allergy shows the promise and challenge of personalized medicine.

Personalized medicine seeks to stratify therapies according to individual characteristics, and by so doing improve effectiveness and reduce complications. However, there are not many models of care that is highly stratified within a single diagnosis in this manner. One potential model is the practice of allergy, in which care is tailored to specific allergens for individual patients within the broader context of care for rhinitis or asthma. Allergists have already confronted many of the same regulatory issues anticipated for personalized medicine. The history of allergy practice also anticipates some of the patient safety concerns that may arise from tracking and using highly personalized medical information. Finally, the therapy of allergy and asthma has been at the forefront of attempts to incorporate pharmacogenomics information into patient care. Individualized therapy has always been central to the practice of allergy, and so provides a useful proving ground for personalized medicine as a concept of care.

Infant Allergy Testing and Food Allergy Diagnoses Before and After Guidelines for Early Peanut Introduction.

BACKGROUND: A landmark 2015 trial on early exposure to peanuts led to expert recommendations for screening and early peanut introduction in high-risk (severe eczema and/or egg allergy) infants, but the impact of this paradigm shift on allergy testing and diagnosis is unknown. OBJECTIVE: We assessed the effects of the Learning Early About Peanut Allergy (LEAP) trial and guideline publications on allergy testing and food allergy diagnoses in infants. METHODS: In this retrospective cohort study, deidentified administrative health claims from a commercial and Medicare advantage claims database were used. Infants with at least 1 year of continuous coverage were selected using newborn codes for birth hospitalizations from January 2010 to June 2018. Interrupted time series models were used to compare the prevalence of allergy testing before and after LEAP publication in February 2015 and formal guideline publication in January 2017. RESULTS: For 487,533 included infants, allergy testing increased after LEAP (risk ratio [RR]: 1.11 [95% confidence interval (CI), 1.07-1.15]) and guidelines (1.21 [1.18-1.23]). This increase of testing was also seen in infants not considered high risk, both after LEAP (1.12 [1.08-1.17]) and guidelines (1.20 [1.16, 1.23]). For first-time allergy tests, post-guideline median number of allergens tested was 9 for serum tests and 10 for skin tests. Post-guidelines, there was a significant increase in diagnosis of peanut (RR: 1.08 [1.00, 1.16]), egg (1.12 [1.05, 1.20]), and other food allergies (excluding milk) (1.22 [1.14, 1.31]). CONCLUSION: Allergy testing has increased, including in non-high-risk infants. Multiallergen testing may be contributing to an increase in the diagnosis of other food allergies.

Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome.

Background: The prevalence and impact of allergic and immune-mediated food disorders in pediatric acute-onset neuropsychiatric syndrome (PANS) are mostly unknown. Objective: We sought to explore the prevalence of atopic dermatitis (AD), asthma, allergic rhinitis (AR), IgE-mediated food allergies (FAs), and other immune-mediated food disorders requiring food avoidance in patients with PANS. In addition, to further understand the extent of food restriction in this population, we investigated the empiric use of dietary measures to improve PANS symptoms. Methods: Pediatric patients in a PANS Clinic and Research Program were given surveys regarding their caregiver burdens, allergic and food-related medical history, and whether food elimination resulted in perception of improvement of PANS symptoms. A review of health records was conducted to confirm that all responses in the survey were concordant with documentation of each patient's medical chart. Results: Sixty-nine (ages 4-20 years) of 80 subjects who fulfilled PANS criteria completed the surveys. Thirteen (18.8%) had AD, 11 (15.9%) asthma, 33 (47.8%) AR, 11 (15.9%) FA, 1 (1.4%) eosinophilic gastrointestinal disorders, 1 (1.4%) food protein-induced enterocolitis syndrome, 3 (4.3%) milk protein-induced proctocolitis syndrome, and 3 (4.3%) celiac disease. Thirty subjects (43.5%) avoided foods due to PANS; elimination of gluten and dairy was most common and was associated with perceived improvement of PANS symptoms (by parents). This perceived improvement was not confirmed with objective data. Conclusions: The prevalence of allergic and immune-mediated food disorders in PANS is similar to the general population as reported in the literature, with the exception of AR that appears to be more prevalent in our PANS cohort. More research will be required to establish whether diet or allergies influence PANS symptoms.

Persistent parvovirus-associated chronic fatigue treated with high dose intravenous immunoglobulin.

We report a 16-year-old boy with no evidence of immunodeficiency who had a 2-year history of chronic fatigue, low grade fever and slapped-cheek rash associated with chronic parvovirus B19 viremia. Prolonged intravenous immunoglobulin therapy resulted in resolution of his symptoms and viremia. Intravenous immunoglobulin may be useful in the resolution of parvovirus viremia regardless of immune status.

Long-term sinonasal outcomes of aspirin desensitization in aspirin exacerbated respiratory disease.

OBJECTIVE: This study aimed to assess sinonasal outcomes in patients with aspirin exacerbated respiratory disease (AERD) undergoing aspirin desensitization following endoscopic sinus surgery (ESS). STUDY DESIGN: Case series with chart review. SETTING: University hospital. SUBJECTS AND METHODS: A retrospective review of sinonasal outcomes was conducted for 30 AERD patients undergoing aspirin desensitization and maintenance therapy following ESS. Sinonasal outcomes were prospectively assessed by the Sinonasal Outcomes Test-22 (SNOT-22) and endoscopic polyp grading system. Data were collected preoperatively, 1 and 4 weeks postsurgery (before desensitization), and 1, 6, 12, 18, 24, and 30 months after aspirin desensitization. RESULTS: Twenty-eight of 30 patients (93.3%) successfully completed aspirin desensitization, whereas 2 of 30 (6.7%) were unable to complete desensitization due to respiratory intolerance. Of the 21 patients who successfully completed a minimum of 24 weeks of follow-up, 20 (95.2%) patients demonstrated sustained endoscopic and symptomatic improvement for a median follow-up period of 33 months. After surgical treatment but before desensitization, patients experienced significant reductions in SNOT-22 and polyp grade scores. In the first 6 months after aspirin desensitization, patients experienced further significant reductions in SNOT-22 scores, whereas polyp grade remained stable. The improvements in symptom endoscopic scores were preserved throughout the follow-up period after desensitization. No patients required additional sinus surgery. One patient had to discontinue aspirin therapy due to gastrointestinal side effects. No other adverse reactions to aspirin were noted. CONCLUSION: Aspirin desensitization following ESS appears to be a well-tolerated and effective adjunctive therapy for long-term control of nasal polyposis in patients with AERD.

DOCK8 immune deficiency as a model for primary cytoskeletal dysfunction.

DOCK8 deficiency is a newly described primary immune deficiency resulting in profound susceptibility to cutaneous viral infections, elevated IgE levels, and eosinophilia, but lacking in the skeletal manifestations commonly seen in hyper IgE syndrome, which it otherwise resembles. Although little is known about the DOCK8 protein, it resembles other atypical guanine exchange factors in the DOCK family, and is known to bind to CDC42. This suggests that a likely role for DOCK8 is in modulating signals that trigger cytoskeletal reorganization. As a result, DOCK8 may also be related to other immune deficiencies that involve the cytoskeleton and Rho GTPase signaling pathways, such as Wiskott-Aldrich syndrome and Rac2 deficiency.

Immunologic reconstitution in 22q deletion (DiGeorge) syndrome.

Adoptive transfer of mature T cells (ATMTC) through bone marrow (BM) transplantation, first attempted over 20 years ago, has recently emerged as a successful therapy for complete 22q deletion syndrome (22qDS). This provides a potential option to thymic transplantation (TT) for immune reconstitution in 22qDS. Compared to thymic transplant, ATMTC is an easier procedure to accomplish and is available at more centers. However, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant. There are no significant differences in mortality between the two procedures, but the number of patients is too limited to conclude that the procedures are equally effective. Adoptive transfer should be pursued as a reasonable treatment for 22qDS patients requiring immune reconstitution when thymus transplant is not available.

Long-term results of bone marrow transplantation in complete DiGeorge syndrome.

BACKGROUND: Therapeutic options for DiGeorge syndrome (DGS) with profound T-cell deficiency are very limited. Thymic transplantation has shown promising results but is not easily available. Hematopoietic cell transplantation (HCT) has been successful in restoring immune competence in the short term. OBJECTIVE: Present the long-term follow-up of 2 patients with complete DGS who received bone marrow transplants in the neonatal period from HLA-matched siblings, and perform a multicenter survey to document the status of other patients with DGS who have undergone HCT. METHODS: Immune function assessment by immunophenotyping, lymphocyte proliferation, T-cell receptor excision circles, single nucleotide polymorphism mapping arrays, spectratyping, cytogenetics, and fluorescence in situ hybridization were used. RESULTS: Among reported patients with DGS receiving HCT, survival is greater than 75%. Our patients are in their 20s and in good health. Their hematopoietic compartment shows continuous engraftment with mixed chimerism, normal T-cell function, and humoral immunity. Circulating T cells exhibit a memory phenotype with a restricted repertoire and are devoid of T-cell receptor excision circles. CONCLUSION: These features suggest that T-cell reconstitution has occurred predominantly through expansion of the donors' mature T-cell pool. Although restricted, their immune systems are capable of providing substantial protection to infection and respond to vaccines. We conclude that bone marrow transplant achieves long-lived reconstitution of immune function in complete DGS and is a good alternative to thymic transplantation in patients with a suitable donor. CLINICAL IMPLICATIONS: Bone marrow transplant in complete DGS using an HLA-matched sibling donor provides long-lasting immunity and is a suitable and more available alternative to thymic transplantation.

Two-tiered universal newborn screening strategy for severe combined immunodeficiency.

Outcomes for infants with severe combined immunodeficiency (SCID) would be improved by universal newborn screening, but there are not yet screening tests of sufficient accuracy for the disorder. In a pilot study, we assessed the ability of a two-tiered strategy to improve accuracy. Dried blood samples from patients were assessed with two tests for lymphopenia: interleukin-7, a T-cell growth cytokine, and TRECs, a byproduct of T-cell receptor recombination. IL-7 screening has a specificity of 96.1% and TRECs have a specificity of 92.3%. Combining these tests in a two-tiered strategy increases specificity to 100% (97-100% CI). Sensitivity was 85% for IL-7 screening and 100% for TREC screening. A two-tiered strategy may be of sufficient accuracy to enable universal SCID screening, and should be assessed in a prospective trial.

Potential costs and benefits of newborn screening for severe combined immunodeficiency.

OBJECTIVE: Severe combined immunodeficiency (SCID) is a rare, treatable disorder of the immune system. The incidence is unknown but may be more common than published estimates because infants frequently die of infection before diagnosis. SCID is a candidate for universal newborn screening, so there is a need to determine under which circumstances screening would be cost-effective. STUDY DESIGN: We assumed a screening program for SCID would use T-cell lymphopenia as the screening criterion and performed a cost-utility analysis comparing universal screening with screening only those with a family history of SCID. RESULTS: Assuming society is willing to pay $50,000 for every quality-adjusted life-year saved, a SCID screening test that cost less than $5 with a false-negative rate of 0.9% and a false-positive rate of 0.4% would be considered cost-effective. A nationwide screening program would cost an additional $23.9 million per year for screening costs but would result in 760 years of life saved per year of screening. The cost to detect 1 case of SCID would be $485,000. CONCLUSION: SCID screening could result in a large benefit to detected individuals, making screening relatively cost-effective in spite of the low incidence of the disease. However, an adequate test is critical to cost-effectiveness.