Desmond A. Nunez

Low CD4 T Cell Immunity to Pneumolysin Is Associated with Nasopharyngeal Carriage of Pneumococci in Children

BACKGROUND Recent studies in mice have suggested that T cell immunity may be protective against pneumococcal infection. METHODS CD4 T cell proliferative responses to the pneumococcal proteins pneumolysin (Ply), Ply toxoid (F433), and choline-binding protein A were investigated in peripheral blood mononuclear cells (PBMCs) and adenoidal mononuclear cells (MNCs) obtained from children undergoing adenoidectomy. RESULTS Ply and F433 induce significant proliferation of CD4 T cells in both PBMCs and adenoidal MNCs, and both memory and naive phenotypes of CD4 T cells proliferated after stimulation. In PBMCs, CD4 T cell proliferation induced by Ply and F433, which was associated with increased production of interferon (IFN)- gamma and tumor necrosis factor (TNF)- alpha , was significantly lower in children who were culture positive for pneumococcus than in those who were culture negative for pneumococcus (P<.05). Between groups, no such difference was observed in adenoidal MNC CD4 T cell proliferation, which was associated with production of IFN- gamma and interleukin (IL)-10. The CD4 T cell proliferation induced by Ply and F433 was inhibited by antibodies to Toll-like receptor 4. CONCLUSION These data suggest that Ply induces CD4 T cell proliferative responses with production of IFN- gamma and TNF- alpha in PBMCs or of IFN- gamma and IL-10 in adenoidal MNCs, which may be important in modulating pneumococcal carriage in children.

Regulation of Production of Mucosal Antibody to Pneumococcal Protein Antigens by T-Cell-Derived Gamma Interferon and Interleukin-10 in Children

ABSTRACT Nasopharyngeal tonsils (adenoids) are part of human nasopharynx-associated lymphoid tissue, which may play an important role in local defense against pneumococci. Recent studies with animals have suggested that several pneumococcal proteins, including CbpA and pneumolysin (Ply), may be vaccine candidates. Our recent data obtained with children suggest that antibodies to these proteins may protect against carriage. This study was performed to investigate the regulation of the T-cell-dependent antibody responses to CbpA and pneumolysin by cytokines in adenoidal immune cells from children. Adenoidal mononuclear cells (MNC) were cultured with pneumococcal concentrated culture supernatants (CCS) or recombinant proteins. Cytokine expression profiles in adenoidal MNC after antigen stimulation were analyzed by reverse transcription-PCR, protein array analysis, and an immunoassay, along with an antibody production analysis. The roles, interactions, and cellular sources of the main cytokines identified were evaluated further. Pneumococcal CCS induced production of CbpA- and Ply-specific antibodies in association with several chemokines and cytokines, including gamma interferon (IFN-γ) and interleukin-10 (IL-10) in MNC. The antibody production correlated well with the concentrations of these two cytokines. Addition of recombinant IFN-γ or IL-10 enhanced antibody production, and monoclonal antibodies to these two cytokines and T-cell depletion significantly reduced antibody production. Intracellular cytokine staining showed that T cells are a major source of IFN-γ and IL-10. Recombinant Ply and, to a lesser extent, recombinant CbpA induced significant production of IFN-γ and IL-10 in MNC. T-cell-derived IFN-γ and IL-10 may be key regulators of production of mucosal antibody to pneumococcal protein antigens in the nasopharynx and may play an important role in local protection against pneumococcal infection in children.

Bacterial lipoproteins differentially regulate human primary and memory CD4+ T and B cell responses to pneumococcal protein antigens through Toll-like receptor 2.

BACKGROUND Bacterial lipoproteins (BLPs) are expressed across a range of bacteria and are able to activate Toll-like receptor 2 (TLR-2). BLPs enhance immune responses in naive individuals and have therefore been tested as candidate vaccine adjuvants. It is not known whether BLPs affect any preexisting immunity (eg, memory cell response in primed individuals). Colonization with pneumococcus (PNC), which primes for memory cell response, is common in young children. METHODS We studied effects of BLPs on memory and primary B and CD4+ T cell responses to pneumococcal proteins using adenoidal cells from children. RESULTS Although BLPs enhanced the primary antibody responses seen in some children with no detectable nasal PNC, BLPs unexpectedly reduced the memory antibody responses in children with positive nasal culture results. Likewise, BLPs augmented the naive but inhibited the memory antigen-driven CD4+ T cell response. The downregulation of the memory responses was associated with increases in interleukin 10 and inducible costimulatory molecule expression, as well as a decrease in CD28 expression in memory CD4+ T cells; all were blocked by anti-TLR2 and anti-B7h antibodies. Augmentation of naive CD4+ T cell proliferation was blocked by anti-B7.2. CONCLUSION Differential regulation of primary and memory responses by BLPs through TLR2 may have important implications for therapeutic and vaccination strategies against bacterial infection.

Incidence of meningitis secondary to suppurative otitis media in adults.

AIM Meningitis is the commonest intracranial complication of suppurative otitis media, and carries the risk of death and life-changing morbidity. This study aimed to estimate the risk of an adult in the UK developing otogenic meningitis. METHODS Adults hospitalised with meningitis in Bristol from 1997 to 2002 were identified retrospectively. Cases confirmed by positive blood culture or cerebrospinal fluid investigation were studied. A case was classified as otogenic if there was coexistent evidence of ear infection. RESULTS Eighty-seven cases of meningitis were analysed. The overall mortality rate was 5.7 per cent. Acute and chronic suppurative otitis media accounted for 13 and three cases, respectively. The adult population of Bristol at the midpoint of the study was 635,976. CONCLUSION In this study, the age-adjusted incidence of otogenic meningitis was 0.42 per 100,000 per year.

The Role of Vestibular Caloric Tests in Cochlear Implantation

Objective Vestibular function tests are often undertaken before cochlear implantation, in part to help select the side of surgery. The authors aim to determine whether implantation on the side of better vestibular function leads to greater perception of dizziness by patients than implantation on the side of worse or similar function. Study Design Historical cohort study. Setting Tertiary cochlear implantation center. Subjects and Methods The records of 177 adult recipients of a unilateral cochlear implant were reviewed retrospectively in 2 groups. Group A included patients with an implant in the ear with worse or similar caloric responses. Group B included patients with an implant in the ear with the stronger caloric response. All patients underwent preoperative bithermal caloric testing: a clinically significant difference was defined by a 20% lateral canal paresis. They were assessed postoperatively by the Dizziness Handicap Inventory and supplementary questions. Results Fifty-seven percent of both groups reported dizziness in the first 7 days postoperatively. At 2 months, 20% of group A and 34% of group B experienced some dizziness. Fourteen percent of group A and 10% of group B felt that cochlear implantation had resulted in impaired balance. The Dizziness Handicap Inventory scores of 86% of group A (median score 0) and 76% of group B (median score 10) corresponded with low handicap. None of these results differed significantly between groups A and B. Conclusion Although cochlear implantation may result in dizziness, it is almost always short-lived and mild, even when the ear with the stronger caloric response is implanted.

Direct referral hearing aid provision in the over sixties age group

A prospective study was designed in which General Practitioners were issued with a standard referral letter for hearing aid provision. Unknown to the General Practitioner an independent otolaryngologist assessment was obtained at the time of first attendance. Three hundred consecutive patients selected by General Practitioners applying these guidelines were seen in a designated hearing aid clinic staffed by audiological technicians of senior grade or above. Referral pro formata were incomplete in 75 patients who were not assessed. Ninety-four patients (31 per cent) (95 per cent confidence interval 29-36 per cent) were accepted by the audiologist. Obstructing wax was the most common criterion failed. Clinical agreement between audiologist and otolaryngologist was 57 per cent greater than chance. None of the cases of clinical disagreement altered treatment. A direct referral system as proposed could have processed only 31 per cent of 300 referrals. However, experienced technical staff reliably detected otological pathology and with aural toilet facilities 91 per cent of 225 patients (confidence interval 88-94 per cent) were aided.

Short falls in epistaxis management. A Nationwide Survey in UK

Sir, Epistaxis is one of the most frequently managed ENT emergencies. Sixty per cent of the population experience epistaxis and 6% of those will seek medical attention. Recently, Ahmed et al performed a cost-benefit analysis in a study of 38 adult patients with epistaxis, who were treated with bipolar diathermy, using the rigid nasal endoscope. They showed that there could be a potential saving of at least £6804 by avoiding the admission of 28 patients. The aim of the present study was to put forward a snap shot of management of epistaxis prior to the full impact of the changes imposed by European working time directive (EWDT) and agenda for change in the United Kingdom. A confidential telephone enquiry using a unified standard proforma was used to survey the secondary/tertiary Otolaryngology Care Centres in the UK. The resident on call Otolaryngologist in 175 NHS trusts in the UK, regardless of their grade or experience, in the period between October 2002 and January 2003 were surveyed. The questions were mainly on the use of nasal endoscopes in the management of epistaxis, written protocols in the department, availability of bipolar diathermy machines and the training received. The list of units involved in the study was obtained from the Institute of Healthcare Management year book, 2002–2003 register of NHS Trusts in the UK. Doctors from 165 trusts completed the telephone survey (93%) The majority of those surveyed (90 doctors, 55%) had a success rate of <50% in visualising the site of epistaxis, 65 doctors (41%) had a success rate between 50% and 75%, and only seven doctors (4%) could correctly identify the bleeding point. Localisation of the bleeding points in epistaxis avoids unnecessary nasal packing. The effort to visualise and cauterise adequately is an important skill for junior doctors in their learning curve. It is important to note that identification of bleeding point would be difficult in few patients with posterior epistaxis. To claim 100% success rate in identification of the bleeding point in patients with epistaxis would be delusional. Figure 1 shows the frequency of performing nasendoscopy per week in general and for management of epistaxis. A median of 10 nasal endoscopies per week (range: 2–25) were performed, but only a median of three endoscopies were performed for the management of epistaxis (range: 0– 7). An initial endoscopic assessment before the application of a nasal pack was carried out by only 25 doctors (15%) and 105(65%) perform after removal of the nasal pack. The flexible nasendoscope was used by the vast majority of doctors 150 (93%). Fifty-five (33%) of those surveyed would perform a nasendoscopy as a routine before discharging the patient from the hospital. Figure 2 shows the training received in the use of the nasendoscope, the majority of which was with the flexible nasal endoscope. Most units 150 (85%) lack a written protocol or policy for epistaxis. Only in 12 places (7%) had suction diathermy units available to junior doctors. Nasendoscopy coupled with bipolar diathermy in the management of patients with epistaxis can obviate the need for nasal packing with its potential morbidity and need for admission. Midwinter et al showed that rigid endoscopes were significantly better than the flexible endoscope for nasal examination. Our survey results have highlighted the patchy use of rigid nasendoscopy, lack of bipolar diathermy units and lack of universal formal training for junior on-call doctors. With the introduction of the EWDT and shortening of training periods under the modernisation agenda, equipment shortfall and lack of written protocols will have further implications for the effective and safe management of epistaxis. C O R R E S P O N D E N C E

Lacrimal Sac Mucocoele After Septorhinoplasty

Lacrimal sac mucocoele formation after septorhinoplasty has not been previously described. We believe it occured secondary to the trauma of an external osteotomy. Through attention to detail, it should be avoidable.

Diagnostic Accuracy of Parallel vs Perpendicular Orientation of the Tuning Fork in the Identification of Conductive Hearing Loss

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Goman and Lin are consultants for Cochlear Ltd. Dr Lin is a consultant for the Gerson Lehrman Group, has served on the scientific advisory boards of Pfizer and Autifony, has served as a speaker for Amplifon and has received a research grant from Cochlear Ltd. No other conflicts are reported.

Trends in American and Canadian Contribution to the Otolaryngology Literature

Objectives: Assess the 2008-2012 American and Canadian contribution to the world otolaryngology literature. Methods: All articles published from January 2008 to December 2012 in 8 otolaryngology journals were reviewed. Book reviews, letters, correspondence, and meeting abstracts were excluded. Nationality, author numbers, and study types were extracted. Nationality of the article was defined by the publishing department’s country of origin. Articles were categorized into primary clinical research, primary basic science research, secondary research such as systematic reviews and meta-analyses, and other articles that did not fit the aforementioned classifications. Articles originating from the United States, Canada, and the rest of the world were statistically compared using Mantel-Haenszel Common Odds Ratio Estimate, Pearsons chi-squared, and Fisher exact tests. Results: A total of 3635 articles published in the journals surveyed were analyzed. Canadian-authored papers decreased from 12.8% in 2008-2009 to 10.2% in 2011-2012, whereas American-authored papers increased from 27.9% in 2008-2009 to 30.1% in 2011-2012. These changes were statistically significant (P = .031). Multiauthorship (≥5 authors) increased in Canadian papers (P = .015), whereas this trend had not been observed in American papers (P = .566). Study types from the United States and Canada had not significantly changed from 2008-2009 to 2011-2012 (P = .137). Conclusions: There were significant changes in otolaryngology publishing trends in the United States and Canada. Increase in multiauthorship in Canadian-authored papers possibly suggests increased collaboration with multi-disciplines and decreased investigator productivity.