Julie L. Goldman

Mortality and major morbidity after tonsillectomy

To report data on death or permanent disability after tonsillectomy.

Leukotriene Pathways and In Vitro Adenotonsillar Cell Proliferation in Children With Obstructive Sleep Apnea

INTRODUCTION The abundant expression of leukotrienes (LTs) and their receptors in adenotonsillar tissues of children with obstructive sleep apnea (OSA) suggest that LT antagonists could be useful in treating OSA. METHODS The effects of LTD4 and of LT receptor antagonists zileuton, montelukast, and BAY u9773 were examined on mixed cell cultures prepared from dissociated tonsils or adenoids harvested intraoperatively from children with polysomnographically diagnosed OSA. Proliferation was assessed by (3)[H]-thymidine incorporation, and inflammatory cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, IL-8, IL-10, and IL-12) was assessed in supernatants using enzyme-linked immunosorbent assay. RESULTS LTD4 elicited dose-dependent increases in adenotonsillar cell proliferation (p < 0.001; n = 12). All LT antagonists exhibited dose-dependent reductions in adenotonsillar cellular proliferation rates, with montelukast more than BAY u9773 more than zileuton (n = 14/group; p < 0.001). However, BAY u9773 showed partial agonist effects and increased cellular proliferation at higher concentrations (10(-4) mmol/L; p < 0.01; n = 12). LTD4 effects were partially blocked by montelukast and BAY u9773 but not by zileuton. All three antagonists reduced TNF-alpha, IL-6, and IL-12 concentrations, with selective changes in IL-8 and no effects on IL-10 levels. CONCLUSIONS LT pathways mediate intrinsic proliferative and inflammatory signaling pathways in adenotonsillar tissues from children with OSA, and targeted pharmacologic disruption of these pathways may provide nonsurgical alternatives for prevention and treatment of this disease.

Increased Cellular Proliferation and Inflammatory Cytokines in Tonsils Derived From Children With Obstructive Sleep Apnea

Adenotonsillar hypertrophy is the major pathophysiological mechanism underlying obstructive sleep apnea (OSA) and recurrent tonsillitis (RI) in children. The increased expression of various mediators of the inflammatory response in tonsils of patients with OSA prompted our hypothesis that the enhanced local and systemic inflammation in children with OSA would promote tonsillar proliferation. Mixed cell cultures from tonsils recovered during adenotonsillectomy in children with OSA and RI were established, and proliferative rates were assessed. Cells were also cultured to determine the levels of proinflammatory cytokines and antioxidant protein levels and mRNA expression. Global cell proliferative rates from OSA tonsils were significantly higher than RI (p < 0.01), with CD3+, CD4+, and CD8+ cell proliferation being higher in OSA (p < 0.05). Moreover, proinflammatory cytokines, such as TNF-α, IL-6, and IL-1α, were highly expressed in OSA-derived tonsils. Furthermore, thioredoxin (TRX), an antioxidant protein, was also highly expressed in OSA tonsils at the mRNA and protein levels (p < 0.01). Thus, T cells are in a highly proliferative state in the tonsils of children with OSA and are associated with increased production of proinflammatory cytokines and TRX, when compared with children with RI.

Glucocorticoid receptor subunit expression in adenotonsillar tissue of children with obstructive sleep apnea.

Tonsillectomy and adenoidectomy (T&A) is a frequent surgical procedure in children with obstructive sleep apnea (OSA). Many symptomatic children who do not fulfill the currently recommended criteria for T&A may benefit from topical intranasal steroid therapy. However, the expression of glucocorticoid receptor (GCR) expression in adenoid and tonsillar tissue is currently unknown. The objective of this study was to assess and compare expression patterns of the human GCR in children who undergo T&A for either recurrent throat infections (RI) or OSA. Adenotonsillar tissues from 36 children with OSA or RI were subjected to quantitative PCR using specific primers for GCR-α and GCR-β and to immunohistochemistry and Western blotting for protein expression of GCR isoforms. mRNA encoding for expression of both GCR-α and GCR-β was detected in the tonsils and adenoids of all children, with markedly higher relative abundance of the GCR-α. Furthermore, GCR-α mRNA expression was increased in OSA-derived adenoid and tonsil tissues compared with RI, whereas no differences emerged for GCR-β. Immunoblots confirmed these findings for the protein transcripts of these genes, and immunohistochemistry showed a specific topographic pattern of distribution for both receptors in tonsillar tissue. GCR-α and GCR-β are expressed in pediatric adenotonsillar tissue, are more abundant in OSA patients, and demonstrate a specific topographic pattern of expression. These findings along with the high GCR-α:GCR-β ratio suggest a favorable profile for topical steroid therapy in snoring children with adenotonsillar hypertrophy.

Neurotrophins and Tonsillar Hypertrophy in Children With Obstructive Sleep Apnea

Enlarged adenotonsillar tissue (AT) is a major determinant of obstructive sleep apnea (OSA) severity in children; however, mechanisms of AT proliferation are poorly understood. We hypothesized that early exposure to respiratory syncytial virus (RSV) may modify AT proliferation through up-regulation of nerve growth factor (NGF)-neurokinin 1 (NK1) receptor dependent pathways. AT harvested from 34 children with OSA and 25 children with recurrent tonsillitis (RI) were examined for mRNA expression of multiple growth factors and their receptors. In addition, NK1 receptor expression and location, and substance P tissue concentrations were compared in AT from OSA and RI children. NGF mRNA and its high-affinity tyrosine kinase receptor (trkA) expression were selectively increased in OSA (p < 0.001). NK1 receptor mRNA and protein expression were also enhanced in OSA (p < 0.01), and substance P concentrations in OSA patients were higher than in RI (p < 0.0001). AT from OSA children exhibit distinct differences in the expression of NGF and trkA receptors, NK1 receptors, and substance P. The homology between these changes and those observed in the lower airways following RSV infection suggests that RSV may have induced neuro-immunomodulatory changes within AT, predisposing them to increased proliferation, and ultimately contribute to emergence of OSA.

Transcriptomic Analysis Identifies Phosphatases as Novel Targets for Adenotonsillar Hypertrophy of Pediatric Obstructive Sleep Apnea

RATIONALE Obstructive sleep apnea (OSA) is a highly prevalent disorder in children, in which enlarged adenotonsillar tissues (AT) play a major pathophysiologic role. Mechanisms leading to the proliferation and hypertrophy of AT in children who subsequently develop OSA remain unknown, and surgical extirpation of AT is associated with potential morbidity and mortality. OBJECTIVES We hypothesized that a computationally based analysis of gene expression in tonsils from children with OSA and children with recurrent tonsillitis without OSA can identify putative mechanistic pathways associated with tonsillar proliferation and hypertrophy in OSA. METHODS Palatine tonsils from children with either polysomnographically documented OSA or recurrent infectious tonsillitis were subjected to whole-genome microarray and functional enrichment analyses followed by significance score ranking based on gene interaction networks. The latter enabled identification and confirmation of a candidate list of tonsil-proliferative genes in OSA. MEASUREMENTS AND MAIN RESULTS In vitro studies using a mixed tonsil cell culture system targeting one of these candidates, phosphoserine phosphatase, revealed that it was more abundantly expressed in tonsils of children with OSA, and that pharmacological inhibition of phosphoserine phosphatase led to marked reductions in T- and B-lymphocyte cell proliferation and increased apoptosis. CONCLUSIONS A systems biology approach revealed a restricted set of candidate genes potentially underlying the heightened proliferative properties of AT in children with OSA. Furthermore, functional studies confirm a novel role for protein phosphatases in AT hypertrophy, and may provide a promising strategy for discovery of novel, nonsurgical therapeutic targets in pediatric OSA.

A Mixed Cell Culture Model for Assessment of Proliferation in Tonsillar Tissues From Children with Obstructive Sleep Apnea or Recurrent Tonsillitis

Recurrent infective tonsillitis (RI) and obstructive sleep apnea (OSA) are the major indications for adenotonsillectomy (T&A) in children. However, little is known on the determinants of lymphadenoid tissue proliferation in the pediatric upper airway.

Rate of persistent perforation after elective tympanostomy tube removal in pediatric patients.

This study was performed to determine the rate of persistent perforations according to age, tube type and duration of intubation in children who underwent elective tympanostomy tube removal. Our retrospective analysis of hospital and clinic charts included all patients who underwent elective tube removal from July 1995 to December 1997 at our institution. Information from the chart review included patient age at time of tube removal, type of tube removed, duration of intubation, presence of granulation tissue/polyps, and concomitant paper patch placement. The outcome of each surgical removal was determined by examining follow-up clinic charts. A patient was deemed to have a persistent perforation if the eardrum had not adequately healed within 3 months after surgery. Data on 201 patients were gathered. These patients had 273 tube removals. Eleven percent of ears (29/273) had persistent perforations. According to tube type, no perforations (0/48) occurred with Collar Bobbin tubes, 6% (3/50) with Tytan tubes, 7% (3/44) with Duravent tubes, and 22% (16/74) with Paparella II tubes. Three percent (3/101) of tubes in place for <3 years and 15% (26/172) of tubes in place for >3 years showed persistent perforations after removal. Ears with granulation polyps had a 9% (18/203) rate of perforations, whereas those without granulation polyps had a 16% (11/70) rate of perforations. Forty percent (4/10) of ears were treated with paper patches at the time of tube removal showed persistent perforations. Our data indicate that the rate of persistent perforation (11%) after elective tympanostomy tube removal is high. The factors associated with higher rates of persistent perforation (P<0.05) include duration of intubation >3 years prior to removal and the use of long-term Paparella II tubes.

Otolaryngologic Clinical Patterns in Pediatric Infectious Mononucleosis

PURPOSE Classic infectious mononucleosis (IM) is uncommon in children; therefore, the incidence of severe pharyngotonsillitis complicating the infection is not well established. This study was undertaken to better define the management of complications with special emphasis on the use of parenteral steroids and the role and timing of surgical management. MATERIALS AND METHODS A retrospective review of all cases of IM encountered between January 1989 through December 1993 was undertaken. RESULTS There were 109 patients admitted with IM. Sixty patients (55%) were admitted for severe pharyngotonsillitis. Twenty-nine patients in this subgroup were felt to have symptoms of severe upper airway obstruction and were treated with parenteral steroids. Surgical intervention was required in three patients. CONCLUSION The study shows a higher incidence of admissions for severe pharyngotonsillitis complicating IM than reported in the adult literature. It suggests that routine use of parenteral steroids is indicated in cases of severe upper airway obstruction and may decrease the need for surgical intervention.

Otolaryngology practice patterns in pediatric tonsillectomy: The impact of the codeine boxed warning

To determine if otolaryngologists at a single childrens hospital were adherent to the boxed warning for codeine use in post‐tonsillectomy patients and the implications for practice patterns.