Effectiveness of the AS04-adjuvanted HPV-16/18 vaccine in reducing oropharyngeal HPV infections in young females-Results from a community-randomized trial.

We studied effectiveness of the AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) vaccine against human papillomavirus (HPV) oropharyngeal infections associated with the increase of head/neck cancers in western countries. All 38,631 resident adolescents from 1994 to 1995 birth cohorts of 33 Finnish communities were invited in this community-randomized trial (NCT00534638). During 2008-2009, 11,275 girls and 6,129 boys were enrolled in three arms of 11 communities each. In Arm A, 90% of vaccinated girls/boys, and in Arm B, 90% of vaccinated girls received AS04-HPV-16/18 vaccine. Other Arm A/B and all Arm C vaccinated participants received control vaccine. All Arm A participants and Arm B female participants were blinded to vaccine allocation. Oropharyngeal samples were analyzed from 4,871 18.5-year-old females who attended follow-up visit 3-6 years postvaccination. HPV DNA prevalence was determined by SPF-10 LiPA and Multiplex type-specific PCR. Total vaccine effectiveness (VE) was defined as relative reduction of oropharyngeal HPV prevalence in pooled Arms A/B HPV-vaccinated females vs. all Arm C females. VE against oropharyngeal HPV-16/18, HPV-31/45 and HPV-31/33/45 infections were 82.4% (95% confidence intervals [CI]: 47.3-94.1), 75.3% (95%CI: 12.7-93.0) and 69.9% (95% CI: 29.6-87.1), respectively. In conclusion, the AS04-HPV-16/18 vaccine showed effectiveness against vaccine and nonvaccine HPV-types oropharyngeal infections in adolescent females up to 6 years postvaccination.

Pathogenic role of palatine tonsils in palmoplantar pustulosis: A review.

Palmoplantar pustulosis (PPP) is characterized by symmetrical, erythematous, scaly plaques, with numerous, sterile, non-bacterial, pinpoint pustules, which are restricted to the palms and soles. Because several reports have described the efficacy of tonsillectomy for improvement in PPP skin lesions, we consider that PPP is tonsil-induced autoimmune/inflammatory syndrome (TIAS) while other factors are also involved in the pathogenesis of PPP. Here, the association between PPP pathogenesis and TIAS was examined, with a focus on results of previous studies. PPP patients show a hyperimmune response to indigenous bacteria such as α-streptococci, due to impaired immunological tolerance towards such organisms. Such a novel immune response leads to T-cell activation through the abnormal expression of secondary stimulation molecules, including cytotoxic T-lymphocyte-associated antigen 4, inducible T-cell co-stimulator and Smad7, in the tonsils of PPP patients. Activated tonsillar T cells express cutaneous lymphocyte antigen (CLA), CCR6 and ß1-integrin, enter the blood circulation and are recruited to PPP skin lesions. Within lesions, T cells roll onto endothelial cells through the interaction between CLA and E-selectin, migrate into the extravascular area through ß1-integrin-vascular cell adhesion molecule 1 binding, and assemble in the skin through CCL20-CCR6 binding. Hyperimmune responses to autoantigens such as keratin and heat shock proteins could also be involved in PPP pathogenesis, through the stimulation of the T-helper 17 reaction.

Oropharyngeal histoplasmosis: a report of 10 cases.

A wide differential diagnosis must be entertained in patients with unusual oral and pharyngeal ulcerations. A mucosal biopsy is essential. We retrospectively reviewed 10 cases from the Infectious Diseases Division at Mayo Clinic Rochester (MN, USA), in which the diagnosis proved to be Histoplasma capsulatum infection. Between 1995 and 2016, 10 patients were diagnosed with oropharyngeal histoplasmosis. Common presenting symptoms included weight loss, weakness and oropharyngeal pain with ulcerations. Despite specialty evaluation at other facilities, diagnostic delay occurred in six patients due to lack of biopsy or fungal staining. Yeast forms consistent with H. capsulatum were identified in the biopsy specimens of all our patients. Treatment included intravenous amphotericin B and prolonged courses of azoles. Oral histoplasmosis occurred in both immunocompetent and immunosuppressed patients, and was a manifestation of disseminated infection. Severe pain involving all areas of the mouth was typical. Diagnostic delay may be avoided by early biopsy using fungal stains.

Prospective Longitudinal Analysis of Immune Responses in Pediatric Subjects After Pharyngeal Acquisition of Group A Streptococci.

BACKGROUND.: Despite the significant burden of disease associated with infection by group A streptococcus (GAS), little is known about the human immune response to GAS antigens after natural infection. METHODS.: We evaluated 195 serum samples obtained prospectively over a consecutive 24-month period from 41 pediatric subjects who experienced a new pharyngeal GAS acquisition. An enzyme-linked immunoassay was used to determine the kinetics and antigen specificity of antibodies against 13 shared GAS antigens and 18 type-specific M peptides. The majority of the antigens tested are currently being considered as vaccine candidates. RESULTS.: Twelve M types of GAS were recovered from 41 subjects who experienced 51 new GAS acquisitions that elicited antibody responses against at least 1 of the 31 antigens tested (immunologically significant new GAS acquisitions). The immune responses to the 13 shared antigens were highly variable. Increases in antibody levels were detected against a mean of 3.5 shared antigens (range, 1-8). Antibody responses to the homologous M peptide were observed in 32 (63%) of the 51 episodes. Seven subjects acquired more than 1 M type of GAS. There were no new immunologically significant acquisitions of an M type against which the subject had preexisting antibodies to the homologous M peptide. Of the subjects with new GAS acquisition, 65% were asymptomatic, yet immune responses were detected against 1 or more GAS antigens. Immune responses to streptolysin O and/or deoxyribonuclease B were observed after 67% of the new GAS acquisitions. Persistently positive (>12 weeks) throat culture results were returned for 20% of the 41 subjects despite immune responses to homologous M peptides and/or shared antigens. CONCLUSIONS.: The availability of throat culture results, GAS isolates, and serial serum samples collected prospectively over a 2-year period of observation provided a unique opportunity for us to assess the serologic status of pediatric subjects before and after new pharyngeal acquisitions of GAS. With the exception of antibody responses to the homologous M peptides, no clear pattern of immune responses against the remaining GAS antigens was seen. There were no new immunologically significant acquisitions of emm types of GAS against which the subjects had preexisting elevated levels of antibodies against the homologous M peptide. The observation that 65% of new GAS acquisitions caused no symptoms yet were immunologically significant suggests that the majority of infections are not detected, which would result in missed opportunities for primary prevention of rheumatic fever and rheumatic heart disease with appropriate antimicrobial therapy.

Clinical Manifestations of IgG4-Related Disease in the Pharynx: Case Series and Review of the Literature.

OBJECTIVE: The objective of this report is to characterize IgG4-related disease (IgG4-RD) as it is manifested in the head and neck and describe a series of patients with a rarely described presentation in laryngopharyngeal subsites. METHODS: Here, we illustrate the presentation and clinical course of 3 patients with laryngopharyngeal manifestations of IgG4-RD, including the manner of diagnosis and effective treatment. RESULTS: Three patients with laryngopharyngeal lesions were ultimately diagnosed with IgG4-RD after lengthy work-up. The diagnostic criteria and treatment protocols are explained. CONCLUSION: IgG4-related disease is a fibroinflammatory disorder now described in almost every organ system. The head and neck regions are among the most common areas of involvement, however, reports of laryngopharyngeal involvement are rare. We also summarize current knowledge of this entity and discuss established diagnostic criteria and clinical findings.

Autoimmune disease as a risk factor for globus pharyngeus: a cross-sectional epidemiological study.

OBJECTIVE: To assess the prevalence and severity of globus-type symptoms in individuals who have a prior diagnosis of autoimmune disease. DESIGN: Cross-sectional questionnaire. PARTICIPANTS AND SETTING: One hundred and nine patients with autoimmune disease (rheumatoid arthritis, seronegative spondarthritis, connective tissue disease, systemic vasculitis) and 41 patients with non-autoimmune disease (osteoarthritis/osteoporosis) attending a rheumatology tertiary referral clinic at Norfolk & Norwich University Hospitals NHS Foundation Trust. The results from this study were compared to previous published figures in patients with globus pharyngeus (n = 105) and normal population (n = 174). MAIN OUTCOME MEASURES: Glasgow Edinburgh Throat Scale questionnaire; Reflux Symptom Index; Anxiety/Depression Scale. RESULTS: Patients with autoimmune disease demonstrate a significantly higher prevalence for 5/10 symptoms on the Glasgow Edinburgh Throat scale score when compared to the non-autoimmune control group (P ≤ 0.01). This significant difference increases to 9/10 symptoms when compared to published results for the normal population (P = 0.01). No significant difference was found when comparing the autoimmune and non-autoimmune control group reflux symptom index (P = 0.64) or anxiety depression scale (P = 0.71). CONCLUSION: Patients with autoimmune disease have a significantly increased prevalence of globus symptoms when compared to the healthy population. A further prospective study is required to decipher the effect of pharmacotherapy as a possible causative factor.

[Linear IgA disease of the oral mucosa with pharyngeal and esophageal involvement]. / Lineare IgA-Erkrankung der Mundschleimhaut mit pharyngealer und ösophagealer Beteiligung.

A 69-year-old man presented with multiple recurrent oral ulcerations for about 20 years. After he began having difficulty in breathing and swallowing, esophagogastroscopy was performed and showed ulcerations, erosions and scars on the mucous membrane of the pharynx as well of the esophagus. Linear IgA disease (LAD) was diagnosed based on histopathological and immunofluorescence examinations. In this patient with LAD, the buccal, pharyngeal and esophageal mucosa was affected without involvement of the skin.

[Morphological and immunohistochemical studies of palatine tonsillar hypertrophy in children].

The paper presents the results of immunohistochemical and morphometric studies conducted to examine an association of the site, the expression of virus antigens, and the nature of morphological changes in the hypertrophic palatine tonsils in children. The distribution of CD3+ and CD20+ cells was explored in tonsillar tissue. The greatest changes were shown in the epithelium, the antigens of herpex simplex virus being more frequently detected than those of human papillomavirus. The presented data may be suggestive of the important role of viruses in the development of palatine tonsillar pathology, different protective reactions of various palatine tonsillar structures, which should be borne in mind during etiopathogenetic therapy.

Immune defence mechanisms and immunoenhancement strategies in oropharyngeal candidiasis.

The prevalence of oropharyngeal candidiasis continues to be high, mainly because of an increasing population of immunocompromised patients. Traditional treatment of oropharyngeal candidiasis has relied on the use of antimicrobial drugs. However, unsatisfactory results with drug monotherapy and the emergence of resistant strains have prompted investigations into the potential use of adjunctive immunoenhancing therapies for the treatment of these infections. Here we review the host-recognition systems of Candida albicans, the immune and inflammatory response to infection, and antifungal effector mechanisms. The potential of immune modulation as a therapeutic strategy in oropharyngeal candidiasis is also discussed.

Laryngopharyngeal reflux: diagnosis and treatment of a controversial disease.

PURPOSE OF REVIEW: Laryngopharyngeal reflux is a well-recognized and widely used term in ear, nose and throat practice. However, the symptoms and signs attributed to laryngopharyngeal reflux are non-specific and treatment is usually empirical. This review discusses current knowledge on diagnosis and treatment of laryngopharyngeal reflux. RECENT FINDINGS: Information is evolving regarding the implications of laryngopharyngeal reflux in the development of pathological conditions affecting the upper aerodigestive tract epithelium such as chronic laryngitis, otitis media with effusion and chronic sinusitis. However, there is still much to learn about the pathophysiologic mechanisms of laryngopharyngeal reflux and their role in its related disease conditions and there is still considerable controversy on diagnostic as well as therapeutic parameters for this condition. There is no consensus on the diagnosis and treatment of laryngopharyngeal reflux and the majority of clinicians depend mainly on clinical findings and empirical therapeutic tests rather than more specific investigations. SUMMARY: The concept of laryngopharyngeal reflux is still controversial. The current practice of empirical treatment with proton-pump inhibitors is based on weak evidence. However, this practice seems to be widely accepted and will not change until further clinical and laboratory studies improve our understanding of this common and well-recognized condition.

HIV-1 pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with CCR5- and CXCR4-tropic HIV-1.

Gut-associated lymphoid tissue (GALT) has been identified as the primary target of HIV-1 infection. To investigate why GALT is especially vulnerable to HIV-1, and to determine whether the selective transmission of CCR5-using viral variants (R5) in vivo is the result of a greater susceptibility of GALT to this viral variant, we performed comparative studies of CXCR4-using (X4) and R5 HIV-1 infections of human lymphoid (tonsillar) and rectosigmoid tissues ex vivo under controlled laboratory conditions. We found that the relative level of R5 replication in rectosigmoid tissue is much greater than in tonsillar tissue. This difference is associated with the expression of the CCR5 co-receptor on approximately 70% of CD4 T cells in rectosigmoid tissue, whereas in tonsillar tissue it is expressed on fewer than 15% of CD4 T cells. Furthermore, tonsillar tissue responds to X4 HIV-1 infection by upregulating the secretion of CC-chemokines, providing a potential CCR5 blockade and further resistance to R5 infection, whereas gut tissue failed to increase such innate immune responses. Our results show that rectosigmoid tissue is more prone than tonsillar lymphoid tissue to R5 HIV-1 infection, primarily because of the high prevalence and availability of R5 cell targets and reduced chemokine blockade. The majority of CD4 T cells express CXCR4, however, and X4 HIV-1 readily replicates in both tissues, suggesting that although the differential expression of co-receptors contributes to the GALT vulnerability to R5 HIV-1, it alone cannot account for the selective R5 infection of the rectal mucosa in vivo.

Correlation between CD4 count and intensity of Candida colonization in the oropharynx of HIV-infected/ AIDS patient.

AIM: To know the correlation between CD4 count and intensity of Candida colonizations in the oropharynx of HIV-infected/AIDS patients, to get the prevalence of oropharyngeal candidiasis (OPC), and to know what kind of Candida species that causes oropharynx candidiasis of HIV-infected/AIDS patients. METHODS: A cross-sectional study was conducted in HIV-infected/AIDS patients who came as outpatients and inpatients in Cipto Mangunkusumo Hospital. The patients were interviewed, physically examined, their CD4 counts were checked, and their mouth rinse samples were taken to be cultured. Candida species was identified in CHROMagar media, and data were processed. RESULTS: From September 2004 until January 2005, 60 HIV-infected/AIDS patients were included in this study. There were 86.7% males and 13.3% females. Majority of the patients were from 20-30 years age group (85%). The most frequent transmission was among drug users (75%) followed by sexual contact (18.3%). The median of CD4 counts was 100 cells/il, ranged from 2 to 842 cells/il. Proportion of the OPC was 63.3% (CI 95% = 51.1 - 75.5). From 59 Candida isolates in this study, 74.58% were C. albicans. Candida non C. albicans species that were found in this trial were C. krusei, C. parapsilosis and C. tropicalis. There was significant correlation between low CD4 counts and high intensity of Candida colonization on the oropharynx of the subjects (r = -0.756). CONCLUSION: There was strong negative correlation (r = -0.756) between CD4 count and intensity of Candida colonization in the oropharynx of HIV-infected/AIDS patients. Proportion of OPC in this study was 63.3%. The most frequent species found in the oropharynx of the subjects was C. albicans.

A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid.

We conducted a prospective study between 1995 and 2002 to investigate nose and throat (NT) manifestations of mucous membrane pemphigoid (MMP). One hundred ten consecutive patients with clinical, histologic, and immunologic criteria of MMP were seen in 2 referral centers for bullous diseases. They were systematically asked about the existence of persistent NT symptoms. Patients who had any were examined with a flexible nasopharyngolaryngoscope by the same otorhinolaryngologist. When possible, NT mucous membrane (MM) biopsies were taken for direct immunofluorescence (IF) assays to determine lesion specificity. Thirty-eight (35%) patients (23 F/15 M; mean age, 58.5 yr) had the following NT symptoms: 35 (92%) nasal, 19 (50%) pharyngeal, and 10 (26%) laryngeal. Five (13%) had acute dyspnea. Thirty-three (87%) of the 38 symptomatic patients had lesions at physical examination: 30 (79%) nasal, 6 (16%) pharyngeal, and 19 (50%) laryngeal. Laryngeal involvement was asymptomatic in 11 patients. Lesions were mainly atrophic rhinitis and oropharyngeal and epiglottal erosions. Nasal valves, choanae, pharynx, and/or larynx were severely scarred in 7 (18%) patients, causing the death of 3. Direct IF showed malpighian epithelium associated with linear immune deposits (IgG, IgA, or C3) along the chorioepithelial junction in all 18 biopsies performed, including those of 4 symptomatic patients without lesions at physical examination. The presence of severe ophthalmologic lesions (p = 0.02) and > or =3 sites involved other than NT (p = 0.02) were predictive of laryngeal involvement. In contrast, laryngeal symptoms, disease duration, HLA DQB1*0301, and smoking were not significantly associated with laryngeal lesions. In conclusion, at least 35% of MMP patients had NT involvement. Atrophic rhinitis was the most frequent lesion. The most severe were the laryngeal lesions that were significantly associated with severe ocular involvement and disseminated disease, and could be fatal. Our results highlight the necessity of a multidisciplinary approach to MMP management to assure early diagnosis of NT involvement, to guide therapeutic choices, and to improve patient survival and functional outcomes.

The host cytokine responses and protective immunity in oropharyngeal candidiasis.

Over the last three decades, the prevalence of oropharyngeal fungal infections has increased enormously, mainly due to an increasing population of immunocompromised patients, including individuals with HIV infection, transplant recipients, and patients receiving cancer therapy. The vast majority of these infections are caused by Candida species. The presence of cytokines in infected tissues ultimately dictates the host defense processes that are specific to each pathogenic organism. During oral infection with Candida, a large number of pro-inflammatory and immunoregulatory cytokines are generated in the oral mucosa. The main sources of these cytokines are oral epithelial cells, which maintain a central role in the protection against fungal organisms. These cytokines may drive the chemotaxis and effector functions of innate and/or adaptive effector cells, such as infiltrating neutrophils and T-cells in immunocompetent hosts, and CD8(+) T-cells in HIV(+) hosts. Epithelial cells also have direct anti-Candida activity. Several studies have provided a potential link between lower levels of certain pro-inflammatory cytokines and susceptibility to oral C. albicans infection, suggesting that such cytokines may be involved in immune protection. The exact role of these cytokines in immune protection against oropharyngeal candidiasis is still incompletely understood and requires further investigation. Identification of such cytokines with the ability to enhance anti-fungal activities of immune effector cells may have therapeutic implications in the treatment of this oral infection in the severely immunocompromised host.

Characterization of CD8+ T cells and microenvironment in oral lesions of human immunodeficiency virus-infected persons with oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC), the most common oral infection in human immunodeficiency virus-positive persons, correlates with reduced blood CD4+ T cells. In those with OPC, CD8+ T cells accumulate at the lamina propria-epithelium interface at a distance from the organism at the outer epithelium. The present study aimed to characterize the tissue-associated CD8+ T cells and tissue microenvironment in both OPC+ and OPC- persons. The results show that the majority of CD8+ T cells possess the alphabeta T-cell receptor, the thymus-derived alphabeta CD8 antigen heterodimer, and similar levels of the alpha(4)beta(7), alpha(4)beta(1), and alpha(e)beta(7) homing receptors. Studies to evaluate the tissue microenvironment showed that in OPC+ persons, the adhesion molecule for T cells to enter mucosa, mucosal addressin cell adhesion molecule, is significantly increased, whereas E-cadherin, which allows T cells to migrate through mucosa, is significantly decreased compared to OPC- persons. These results continue to support a role for CD8+ T cells against OPC under conditions of reduced numbers of CD4+T cells, with susceptibility to infection potentially associated with a dysfunction in mucosal CD8+ T-cell migration by reduced tissue-associated E-cadherin.

Allergy and the contemporary laryngologist.

The author believes that allergy plays an important role in the field of laryngology. Not every patient has significant allergic problems, but the allergic factor in laryngeal problems should not be underestimated. The insights and technology for research have never been better. Many cause-and-effect relationships have been suggested and often provide the working basis for current therapeutics. Many current models of operation need to be verified, explored further, and modified through research. It is hoped that new technologies will achieve a higher degree of sensitivity without sacrificing specificity. Better specificity is particularly needed in allergy testing and in testing thyroid and pulmonary function. The author hopes that the contemporary laryngologist/otolaryngologist will use this overview to formulate a complete and orderly approach to laryngeal problems. Because of the complexity of laryngeal problems, referral to other specialists may be necessary. The laryngologist, however, should be able to orchestrate the appropriate use of technologies and health care specialists to address these problems.