Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). METHODS: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. RESULTS: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. CONCLUSIONS: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.

The chitinase-like protein YKL-40 is not a useful biomarker for severe persistent asthma in children.

BACKGROUND: The chitinase-like protein YKL-40 is thought to play a role in inflammation and tissue remodeling. In adults with severe asthma, YKL-40 is expressed in the airway and YKL-40 levels are elevated in the serum. OBJECTIVE: To compare YKL-40 levels in children with severe persistent asthma with those in adults with severe persistent asthma and to determine whether YKL-40 levels correlate with increasing asthma severity in childhood asthma. METHODS: In this prospective, cross-sectional study, 23 adults and 19 children with severe persistent asthma, 23 children with moderate persistent asthma, and 19 children with mild persistent asthma were enrolled. The following data were collected on each patient: spirometry, exhaled nitric oxide, percutaneous skin testing results to aeroallergens, peripheral eosinophils, serum IgE levels, and serum YKL-40 levels. RESULTS: Compared with adults, children with severe persistent asthma had significantly lower YKL-40 levels, higher values for forced vital capacity and forced expiration volume in 1 second, higher serum IgE levels, and higher exhaled nitric oxide levels. YKL-40 levels did not correlate with increasing asthma severity in the pediatric cohort. CONCLUSION: Severe persistent asthma in childhood is not associated with elevated YKL-40 levels, unlike in adults with severe persistent asthma. YKL-40 is not a useful biomarker for asthma severity in childhood asthma.

Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy.

BACKGROUND: Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. OBJECTIVE: We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. METHODS: The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n= 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. RESULTS: Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG(4) levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4(+)CD25(high)CD127(low)CD45RO(+) forkhead box protein 3 (Foxp3)(+) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. CONCLUSION: The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells.

Is there a need for clinical guidelines in the United States for the diagnosis of hereditary angioedema and the screening of family members of affected patients?

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by a deficiency of C1 esterase inhibitor (C1 INH) protein or function. Guidelines do not exist regarding diagnostic criteria or routine testing of family members of patients with HAE. Laboratory data for diagnosis include complement factor 4 level; C1 INH antigenic protein level, which is reduced in approximately 85% of patients with HAE; and C1 INH functional assay, which is considered an unreliable test in the United States secondary to inconsistent standardization of assays. OBJECTIVES: To assess the shortcomings of diagnosing HAE and to determine whether family members of patients with HAE are being adequately screened. METHODS: The top physician prescribers of danazol in the United States were screened via an Internet questionnaire focusing on the diagnosis and current management of HAE. To assess the patient perspective on HAE, affected individuals in the United States, the United Kingdom, France, Germany, and The Netherlands participated in the Web-based International Survey of Patient Experience of Hereditary Angioedema. RESULTS: All 80 physicians who completed the survey were allergist or immunologists with a mean of 7 patients with C1 INH deficiency in their practices. Almost 84% of physician respondents used C1 INH level and function for diagnosis, and 63.8% used complement factor 4 levels. A total of 313 patients with HAE completed the survey. Respondents noted that only 48% of immediate family members and 26% of extended family members had been tested. CONCLUSION: Guidelines could potentially alleviate delays in diagnosis and incorrect diagnoses and could lead to adequate screening of family members.

The role of montelukast on perennial allergic rhinitis and associated sleep disturbances and daytime somnolence.

Perennial allergic rhinitis (PAR) often causes sleep disturbances and associated daytime somnolence, thus resulting in a poor quality of life. Various clinical interventions in patients suffering from the disorder seek to improve symptoms and quality of life. Additional studies are needed to establish whether the alleviation of PAR symptoms, particularly the reduction of congestion, will improve sleep quality and reduce daytime somnolence. This study seeks to determine whether treatment with montelukast is more effective than placebo in reducing nasal congestion and sleep disturbances, resulting in reduced daytime somnolence and fatigue in patients with PAR. Thirty-one subjects were enrolled in a double-blinded, placebo-controlled study using Balaam's design. Patients were treated with montelukast or placebo. Collected subjective data included a daily diary recording nasal symptoms, sleep issues, and daytime fatigue, the Functional Outcomes of Sleep Questionnaire, the Epworth Sleepiness Scale, Juniper's Rhinoconjunctivitis Quality of Life Questionnaire, the Rhinitis Severity Scale, the Calgary Sleep Apnea Quality of Life Index, and Trail Making tests. Subjects treated with montelukast, compared with placebo, showed a statistically significant improvement in daytime somnolence (p = 0.0089) and daytime fatigue (p = 0.0087), with both factors improving with montelukast and worsening with placebo. In a small cohort of subjects, montelukast, when compared with placebo, improved the symptoms of PAR and reduced the fatigue and daytime somnolence associated with the disorder.

Allergic rhinitis and its effect on sleep, fatigue, and daytime somnolence.

OBJECTIVE: To examine the adverse effects of sleep impairment on the quality of life of patients with the disorder and how these effects can be treated with therapies targeted at the underlying problems that influence sleep. DATA SOURCES: Medline and Ovid search for sleep and rhinitis. STUDY SELECTION: All literature on this topic were reviewed, and, if significant, were incorporated into this review. RESULTS: Intranasal corticosteroids used as treatment for allergic rhinitis have been shown to reduce the nasal congestion characteristic of the disorder. Data on sleep-related end points from clinical trials on intranasal corticosteroids also reveal that the treatment's effectiveness in alleviating nasal congestion leads to better sleep, reduced daytime somnolence, and improved quality of life. CONCLUSION: Further research, specifically using sleep measurements as primary end points, is needed to definitively show that intranasal corticosteroids reduce nasal congestion, thereby improving sleep and, consequently, quality of life in patients with allergic rhinitis. These future trials will serve to identify the most effective therapies that target the adverse effects of sleep impairment in this disorder.