Raffi Tachdjian

Effect of environmental intervention on mouse allergen levels in homes of inner-city Boston children with asthma

BACKGROUND Recent studies have suggested that mouse allergen exposure and sensitization are common in urban children with asthma. The effectiveness of environmental intervention in reducing mouse allergen exposure has not been established. OBJECTIVE To evaluate whether environmental intervention of mouse extermination and cleaning results in a reduction in mouse allergen levels. METHODS Eighteen homes of children with positive mouse allergen skin test results and at least mild persistent asthma in urban Boston, MA, with evidence of mouse infestation or exposure were randomized in a 2:1 ratio (12 intervention and 6 control homes). The intervention homes received an integrated pest management intervention, which consisted of filling holes with copper mesh, vacuuming and cleaning, and using low-toxicity pesticides and traps. Dust samples were collected and analyzed for major mouse allergen (Mus m 1) and cockroach allergen (Bla g 1) at baseline and 1, 3, and 5 months after the intervention was started and compared with control homes. RESULTS Mouse allergen levels were significantly decreased compared with control homes by the end of the intervention period at month 5 in the kitchen and bedroom (kitchen intervention, 78.8% reduction; control, 319% increase; P = .02; bedroom intervention, 77.3% reduction; control, 358% increase; P < .01; and living room intervention, 67.6% reduction; control, 32% reduction; P = .07). CONCLUSIONS Mouse allergen levels were significantly reduced during a 5-month period using an integrated pest management intervention.

Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling.

In vivo regulation of the allergic response by the IL-4 receptor α chain immunoreceptor tyrosine-based inhibitory motif

BACKGROUND Signaling by IL-4 and IL-13 through the IL-4 receptor alpha chain (IL-4Ralpha) plays a critical role in the pathology of allergic diseases. The IL-4Ralpha is endowed with an immunoreceptor tyrosine-based inhibitory motif (ITIM) centered on tyrosine 709 (Y709) in the cytoplasmic domain that binds a number of regulatory phosphatases. The function of the ITIM in the in vivo regulation of IL-4 receptor signaling remains unknown. OBJECTIVE We sought to determine the in vivo function of the IL-4Ralpha ITIM by using mice in which the ITIM was inactivated by mutagenesis of the tyrosine Y709 residue into phenylalanine (F709). METHODS F709 ITIM mutant mice were derived by means of knock-in mutagenesis. Activation of intracellular signaling cascades by IL-4 and IL-13 was assessed by means of intracellular staining of phosphorylated signaling intermediates and gene expression analysis. In vivo responses to allergic sensitization were assessed by using models of allergic airway inflammation. RESULTS The F709 mutation increased signal transducer and activator of transcription 6 phosphorylation by IL-4 and, disproportionately, by IL-13. This was associated with exaggerated T(H)2 polarization, enhanced alternative macrophage activation by IL-13, augmented basal and antigen-induced IgE responses, and intensified allergen-induced eosinophilic airway inflammation and hyperreactivity. CONCLUSIONS These results point to a physiologic negative regulatory role for the Y709 ITIM in signaling through IL-4Ralpha, especially by IL-13.

Use of Ecallantide in Pediatric Hereditary Angioedema

OBJECTIVE: Hereditary angioedema (HAE) due to C1-inhbitor deficiency is a rare autosomal dominant disease that manifests as sudden unpredictable attacks of subcutaneous or submucosal edema affecting the skin, intestine, and upper airway. Ecallantide is a plasma kallikrein inhibitor indicated for treatment of HAE attacks in patients aged 16 years and older. This analysis examines safety and efficacy of ecallantide for treatment of HAE attacks in patients <18 years of age. METHODS: Data for patients aged 9 to 17 years treated subcutaneously with 30 mg ecallantide or placebo were pooled from 4 clinical studies (2 double-blind, placebo-controlled and 2 open-label). Efficacy end points included 2 HAE-specific patient-reported outcome measures: mean symptom complex severity (MSCS) score and treatment outcome score (TOS). Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated. Treatment-emergent adverse events were examined. RESULTS: Overall, 29 pediatric patients were included; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks. Ecallantide-treated attacks revealed clinically relevant reduction in symptom severity at 4 hours postdosing based on mean change in MSCS score (−1.4 ± 0.9 ecallantide versus −0.9 ± 0.6 placebo) and TOS (73.9 ± 35.50 ecallantide versus 45.0 ± 43.78 placebo). Patients treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes). No serious adverse events related to treatment were observed. CONCLUSIONS: Ecallantide appears effective for HAE attacks in adolescents, with rapid symptom improvement. No unexpected safety issues were identified.

Impaired Timing and Frequency Discrimination in High-functioning Autism Spectrum Disorders

Individuals with autism spectrum disorders (ASD) frequently demonstrate preserved or enhanced frequency perception but impaired timing perception. The present study investigated the processing of spectral and temporal information in 12 adolescents with ASD and 15 age-matched controls. Participants completed two psychoacoustic tasks: one determined frequency difference limens, and the other determined gap detection thresholds. Results showed impaired frequency discrimination at the highest standard frequency in the ASD group but no overall difference between groups. However, when groups were defined by auditory hyper-sensitivity, a group difference arose. For the gap detection task, the ASD group demonstrated elevated thresholds. This supports previous research demonstrating a deficit in ASD in temporal perception and suggests a connection between hyper-sensitivity and frequency discrimination abilities.

Type III mixed cryoglobulinemia and antiphospholipid syndrome in a patient with partial DiGeorge syndrome

We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated β2-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection.

Risk‐based decision making and ethical considerations in donor compensation for plasma‐derived medicinal products

F or years, policymakers have debated the appropriateness of compensating plasma donors for the manufacture of plasma-derived medicinal products (PDMPs). Recently, the Alliance of Blood Operators (ABO) developed a risk-based decision-making framework for blood safety. In light of these two parallel discussions, now seems to be an opportune time to reanalyze whether an absolutist position against compensation is any longer relevant or would be appropriate if evaluated utilizing a risk-based decision-making approach. Meeting the health needs of patients by providing an adequate supply of safe and effective blood components and PDMPs is the principal goal of blood operators and the plasma industry. Data demonstrate a large and increasing unmet demand for PDMPs worldwide, and there is a growing consensus that an insufficient supply of PDMP treatment products is a major safety risk to patients. Accordingly, it has been argued that a “vein-to-vein” approach to risk-based decision making that encompasses patient needs, product safety, ethical treatment of donors, and other ethical issues should be adopted when considering topics like PDMP donor compensation. In 2010, an International Consensus Conference on Risk-Based Decision Making for Blood Safety noted that, “As blood systems are focusing more on responsible use of health care resources, questions arise as to the most effective way to manage risk at a level that is tolerable and sustainable. Because of the increasing complexity and inconsistency in blood safety decision making, it is timely to explore whether it is possible to create a better decisionmaking framework based on risk management principles that can be used in various jurisdictions, taking into account social values, ethics, politics, economics, public expectations, and the historical context in which we operate.” In conducting the current analysis, we use these findings of the 2010 Consensus Conference and the subsequent framework developed by the ABO to integrate all stakeholder concerns into an overall risk profile to inform the decision-making process (the ABO Framework). In particular, we draw on the two elements of the framework most relevant to our analysis: the assessment component as a refresh of the ethical discussion around compensated plasma donation and the participation strategy for relevant stakeholder engagement that has been missing from past analyses of compensated plasma donation. We note that the economic considerations of compensation for PDMPs have been explored by Grabowski and Manning. In addition, we draw in part from the analytical structure of the Nuffield Council on Bioethics (Nuffield), which posed the question: How far can society go in its demands on people to act in what many regard as a good cause— that of providing bodily material to benefit others? The welfare of the many patients who do and could benefit from PDMPs is central to our analysis, and the welfare of donors is a powerful complementary consideration. There are notable distinctions between donor plasma destined for further manufacture into PDMPs and labile whole blood and its components (e.g., red blood cells

A Bad Case of Good’s Syndrome

Good’s syndrome is a relatively rare immunodeficiency condition that presents in the fourth or fifth decade of life and is defined by hypogammaglobulinemia in the setting of a thymoma. The humoral defect may be severe enough to cause an absence in B cells, with a consequent recurrence of sinopulmonary disease, chronic non-infectious diarrhea and opportunistic infections. The prognosis in patients with Good’s syndrome appears to be worse than in those with X-linked agammaglobulinemia (XLA) and common variable immune deficiency (CVID). There have only been three cases of Good’s syndrome associated with mycobacterium, and only one case with a cavitary lesion in the lungs. We present here a unique case of Good’s syndrome with a non-mycobacterial cavitary lesion.

Urticaria associated with necrotic uterine leiomyomas infected with salmonella.

BACKGROUND: We describe a unique case of urticaria associated with a Salmonella infection of uterine leiomyomas. CASE: A 55-year-old woman with a known history of uterine leiomyomas and a chief complaint of recurrent small and coalescing urticarial lesions confined to the abdomen presented with an 18-year history of recurrent fever and flu-like symptoms associated with the urticaria. After confirming the presence of a leiomyoma containing necrotic tissue on the computed tomography scan, a hysterectomy was performed. A large, 11-cm intramural leiomyoma was removed, and a culture of the purulent content grew a previously untyped Salmonella. The urticaria resolved on removal of the necrotic tissue. Subsequent follow-up for more than 2 years shows no relapse of symptoms. CONCLUSION: Our patient harbored Salmonella bacteria in a necrotic uterine leiomyoma, where it was difficult to detect until the time of surgery. In patients presenting with localized urticaria of the abdomen, an infection in the pelvic and abdominal tissue should be considered in the differential diagnosis.