RESUMO
Streptococcus pyogenes causes at least 750 million infections and more than 500,000 deaths each year. No vaccine is currently available for S. pyogenes and the use of human challenge models offer unique and exciting opportunities to interrogate the immune response to infectious diseases. Here, we use high-dimensional flow cytometric analysis and multiplex cytokine and chemokine assays to study serial blood and saliva samples collected during the early immune response in human participants following challenge with S. pyogenes. We find an immune signature of experimental human pharyngitis characterised by: 1) elevation of serum IL-1Ra, IL-6, IFN-γ, IP-10 and IL-18; 2) increases in peripheral blood innate dendritic cell and monocyte populations; 3) reduced circulation of B cells and CD4+ T cell subsets (Th1, Th17, Treg, TFH) during the acute phase; and 4) activation of unconventional T cell subsets, γδTCR + Vδ2+ T cells and MAIT cells. These findings demonstrate that S. pyogenes infection generates a robust early immune response, which may be important for host protection. Together, these data will help advance research to establish correlates of immune protection and focus the evaluation of vaccines.
Assuntos
Faringite/imunologia , Streptococcus pyogenes/imunologia , Adulto , Antígenos de Bactérias/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Masculino , Células T Invariantes Associadas à Mucosa , Faringite/microbiologia , Infecções Estreptocócicas , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores , Células Th17/imunologiaRESUMO
Pharyngitis and tonsillitis are the most common acute respiratory infections (ARIs) in children aged ≤5 years. The analysis of published data showed that some probiotics could decrease the frequency and number of days with ARIs. This study evaluated the safety and efficacy of Limosilactobacillus reuteri ATCC PTA 5289 and DSM 17938 to reduce the duration and severity of ARI symptoms. This randomised controlled trial included children aged from 6 months to 5 years, with pharyngitis or tonsillitis, who were randomised to receive a probiotic product containing L. reuteri ATCC PTA 5289 and L. reuteri DSM 17938 or placebo, as drops, ingested orally for 10 days as adjuvants to the use of non-steroidal anti-inflammatory drugs. The main outcomes were the duration and severity of ARI symptoms. The secondary outcomes were changes in salivary immunoglobulin A and inflammatory biomarkers. There was no fever on day 2 and subsequent days in the L. reuteri group (37.3 ±0.5 °C vs 38.6±0.3 °C, P<0.05). Beginning on day 3, the severity of sore throat (5±0.9 vs 8±1.2, P<0.05) was lower in the L. reuteri group. Significant differences in the days with runny nose, nasal congestion, days of non-programmed visits to the medical office or emergency department, levels in tumoral necrosis factor-alpha (TNF-alpha) and related costs of treatment were observed in the L. reuteri group. The frequency of adverse events was similar between the groups. Therefore, L. reuteri ATCC PTA 5289 combined with L. reuteri DSM 17938 is a safe and effective adjunct to reduce the symptoms of pharyngitis or tonsillitis in children.
Assuntos
Limosilactobacillus reuteri/fisiologia , Faringite/tratamento farmacológico , Probióticos/administração & dosagem , Tonsilite/tratamento farmacológico , Pré-Escolar , Feminino , Humanos , Imunoglobulina A/imunologia , Lactente , Masculino , Faringite/imunologia , Saliva/imunologia , Tonsilite/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Group A Streptococcus (GAS) is the etiologic agent of numerous high-morbidity and high-mortality diseases. Infections are typically highly proinflammatory. During the invasive infection necrotizing fasciitis, this is in part due to the GAS protease SpeB directly activating interleukin-1ß (IL-1ß) independent of the canonical inflammasome pathway. The upper respiratory tract is the primary site for GAS colonization, infection, and transmission, but the host-pathogen interactions at this site are still largely unknown. We found that in the murine nasopharynx, SpeB enhanced IL-1ß-mediated inflammation and the chemotaxis of neutrophils. However, neutrophilic inflammation did not restrict infection and instead promoted GAS replication and disease. Inhibiting IL-1ß or depleting neutrophils, which both promote invasive infection, prevented GAS infection of the nasopharynx. Mice pretreated with penicillin became more susceptible to GAS challenge, and this reversed the attenuation from neutralization or depletion of IL-1ß, neutrophils, or SpeB. Collectively, our results suggest that SpeB is essential to activate an IL-1ß-driven neutrophil response. Unlike during invasive tissue infections, this is beneficial in the upper respiratory tract because it disrupts colonization resistance mediated by the microbiota. This provides experimental evidence that the notable inflammation of strep throat, which presents with significant swelling, pain, and neutrophil influx, is not an ineffectual immune response but rather is a GAS-directed remodeling of this niche for its pathogenic benefit.
Assuntos
Nasofaringe/imunologia , Receptores Tipo I de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/patogenicidade , Animais , Antibacterianos/efeitos adversos , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Caspase 1/genética , Caspase 1/imunologia , Quimiotaxia de Leucócito , Exotoxinas/genética , Exotoxinas/imunologia , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/imunologia , Camundongos , Nasofaringe/microbiologia , Neutrófilos/imunologia , Faringite/genética , Faringite/imunologia , Faringite/microbiologia , Receptores Tipo I de Interleucina-1/genética , Transdução de Sinais/efeitos dos fármacos , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/genética , Streptococcus pyogenes/crescimento & desenvolvimento , Virulência/efeitos dos fármacos , Virulência/genéticaRESUMO
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.
Assuntos
Síndrome de Behçet/genética , Febre/genética , Predisposição Genética para Doença , Linfadenite/genética , Faringite/genética , Estomatite Aftosa/genética , Alelos , Síndrome de Behçet/imunologia , Criança , Estudos de Coortes , Febre/imunologia , Genes MHC Classe I/genética , Genes MHC Classe I/imunologia , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Loci Gênicos/imunologia , Humanos , Linfadenite/imunologia , Faringite/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estomatite Aftosa/imunologia , SíndromeRESUMO
Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1ß positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome.
Assuntos
Microambiente Celular/imunologia , Febre/imunologia , Linfadenite/imunologia , Tonsila Palatina/imunologia , Faringite/imunologia , Estomatite Aftosa/imunologia , Adolescente , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Inflamação/imunologia , Masculino , Síndrome , Tonsilectomia/métodosRESUMO
Voice disorder is occasionally associated with systemic autoimmune diseases. Bamboo nodes of the vocal fold have a characteristic bamboo-shaped appearance and strongly indicate the presence of an underlying autoimmune disorder. Both mechanical and immunologic mechanisms are assumed to be involved in the pathogenesis of vocal disorder. We present a 27-year-old woman with hoarseness, sore throat, and a unilateral bamboo node of the vocal fold. Serum anti-SS-A and -SS-B antibodies were positive, but she had no systemic signs or symptoms suggestive of Sjögren's syndrome. Oral systemic glucocorticoid treatment was not effective, but surgical resection improved her hoarseness. Histopathologic findings of the resected vocal node revealed fibrosis with hyaline degeneration. Thereafter, she had no recurrence of hoarseness for 2 years. Bamboo nodes of the vocal fold may occur without definitive autoimmune diseases, although immunologic abnormalities such as autoantibody-positivity may occur.
Assuntos
Anticorpos Antinucleares/imunologia , Rouquidão/imunologia , Doenças da Laringe/imunologia , Prega Vocal/cirurgia , Adulto , Doenças do Tecido Conjuntivo/imunologia , Feminino , Rouquidão/etiologia , Rouquidão/fisiopatologia , Humanos , Doenças da Laringe/patologia , Doenças da Laringe/fisiopatologia , Doenças da Laringe/cirurgia , Laringoscopia , Faringite/etiologia , Faringite/imunologia , Faringite/fisiopatologia , Prega Vocal/patologia , Distúrbios da Voz/etiologia , Distúrbios da Voz/fisiopatologiaRESUMO
OBJECTIVES: Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge regarding the immunological role of the tonsils in the PFAPA syndrome. METHODS: We searched PubMed, Medline, EMBASE and Cochrane for papers written in English dated from 1 January 1987 to 30 April 2019. The search included all studies reporting histological, immunological or microbiological workup of tonsil specimens from children aged 0-18 years with PFAPA. RESULTS: Thirteen articles reported histological, immunological or microbiological workup of tonsil specimens in children with PFAPA. The histology of tonsil specimens from children with PFAPA displayed chronic tonsillar inflammation with lymphoid hyperplasia. No uniform immunological pattern was identified, but some studies found fewer B-lymphocytes and smaller germinal centers in PFAPA compared to controls. A difference in tonsillar microbiota between PFAPA and controls was found in one study. CONCLUSION: A uniform immunological or microbiological pattern explaining the clinical effect of TE in children with PFAPA has not been revealed. Future targeted immunological studies of tonsils in PFAPA patients could possibly illuminate the understanding of the immunology in this disease.
Assuntos
Febre Familiar do Mediterrâneo/imunologia , Linfadenite/imunologia , Tonsila Palatina/patologia , Faringite/imunologia , Estomatite Aftosa/imunologia , Tonsilectomia , Adenoidectomia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Linfadenite/cirurgia , Masculino , Microbiota , Faringite/cirurgia , SíndromeRESUMO
Macroscopic hematuria concomitant with acute pharyngitis is a characteristic feature of immunoglobulin A nephropathy (IgAN). Although the underlying mechanism of worsening hematuria has not been fully elucidated, activation of the innate immune system of nasopharynx-associated lymphoid tissue is thought to play an important role. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. As latent but significant epipharyngitis presents in most IgAN patients, it is plausible that acute pharyngitis due to airway infection may contribute as a trigger of the epipharyngeal innate immune system, which is already upregulated in the chronically inflamed environment. The aim of this review was to discuss the mechanism of epipharynx-kidney axis involvement in glomerular vasculitis responsible for the worsening of hematuria in IgAN.
Assuntos
Imunidade Inata , Glomérulos Renais , Faringite , Faringe , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Humanos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Faringite/complicações , Faringite/imunologia , Faringite/patologia , Faringe/imunologia , Faringe/patologiaRESUMO
The pharyngeal organ is located at the crossroad of the respiratory and digestive tracts in vertebrate, and it is continuously challenged by varying Ags during breathing and feeding. In mammals, the pharyngeal mucosa (PM) is a critical first line of defense. However, the evolutionary origins and ancient roles of immune defense and microbiota homeostasis of PM are still unknown. In this study, to our knowledge, we are the first to find that diffuse MALT is present in PM of rainbow trout, an early vertebrate. Importantly, following parasitic infection, we detect that strong parasite-specific mucosal IgT and dominant proliferation of IgT+ B cell immune responses occurs in trout PM, providing, to our knowledge, the first demonstration of local mucosal Ig responses against pathogens in pharyngeal organ of a nonmammal species. Moreover, we show that the trout PM microbiota is prevalently coated with secretory IgT and, to a much lesser degree, by IgM and IgD, suggesting the key role of mucosal Igs in the immune exclusion of teleost pharyngeal bacteria. Overall, to our knowledge, our findings provide the first evidence that pharyngeal mucosal immunity appear earlier than tetrapods.
Assuntos
Evolução Biológica , Homeostase/imunologia , Oncorhynchus mykiss/imunologia , Faringite/imunologia , Mucosa Respiratória/imunologia , Animais , Faringite/patologia , Mucosa Respiratória/patologiaRESUMO
OBJECTIVE: To investigate the therapeutic effects and mechanisms of Bianyanning on acute pharyngitis in rats, and to provide evidence and experimental data for its clinical application. METHODS: The acute pharyngitis of rats was induced by spraying ammonia directly to their throat. The model rats were randomly divided into model control group, the high-, medium- and low-dose group of Bianyanning, while normal rats were used as control group, 10 in each group. After the corresponding drug treatment, the symptoms and manifestations of each group were observed and recorded; 24 hours after last gavaging, blood samples of each group were collected from the abdominal aorta. The serum contents of interleukin 1-beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) were detected by ELISA. HE method was used to observe the characteristic of the lung tissues and the transmission electron microscopy method was used to observe the trachea cilia. RESULTS: After the treatment, compared with the model control group, the high-, medium- and low-dose group of Bianyanning, the symptoms of acute pharyngitis such as inflamed and congestive throat were relieved obviously. The morphological changes of lung and bronchus tissues were apparently improved. The contents of IL-1ß and TNF-α in serum were decreased significantly. CONCLUSION: Compound Bianyanning can promote the recovering process of acute pharyngitis, improve the morphology of lungs and bronchus, which may be related to inhibiting the releasing of the IL-1ß and TNF-α in serum.
Assuntos
Medicamentos de Ervas Chinesas , Faringite , Animais , Medicamentos de Ervas Chinesas/farmacologia , Interleucina-1beta/metabolismo , Faringite/tratamento farmacológico , Faringite/imunologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Streptococcal pharyngitis (or strep throat) is a common childhood disease affecting millions of children each year, but it is one of the only childhood diseases for which a vaccine does not exist. While for decades the development of a vaccine has been the center of attention in many laboratories worldwide, with some successes, no corporate development has yet to be initiated. The reason for this probably lies in our inability to conclusively identify the streptococcal molecule or molecules responsible for the heart cross-reactive antibodies observed in the serum of rheumatic fever patients. Without this specific knowledge, any streptococcal vaccine antigen is suspect and thus not the target for a billion-dollar investment, despite the fact that the exact role of cross-reactive antibodies in rheumatic fever is still questionable. This article will describe the development of several approaches to protect against Streptococcus pyogenes infections over the past several decades.
Assuntos
Faringite/imunologia , Faringite/prevenção & controle , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/prevenção & controle , Vacinas Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Criança , Reações Cruzadas/imunologia , Bactérias Gram-Positivas/imunologia , Humanos , Imunidade nas Mucosas , Febre Reumática/imunologia , Vacinação , Vaccinia virusRESUMO
Candida albicans is a fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses. We find that both C. albicans and candidalysin activate human epithelial EGFR receptors and candidalysin-deficient fungal mutants poorly induce EGFR phosphorylation during murine oropharyngeal candidiasis. Furthermore, inhibition of EGFR impairs candidalysin-triggered MAPK signalling and release of neutrophil activating chemokines in vitro, and diminishes neutrophil recruitment, causing significant mortality in an EGFR-inhibited zebrafish swimbladder model of infection. Investigation into the mechanism of EGFR activation revealed the requirement of matrix metalloproteinases (MMPs), EGFR ligands and calcium. We thus identify a PAMP-independent mechanism of immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.
Assuntos
Candida albicans/imunologia , Proteínas Fúngicas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Sacos Aéreos/microbiologia , Animais , Candida albicans/genética , Candida albicans/metabolismo , Candidíase/imunologia , Candidíase/microbiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Receptores ErbB/genética , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Feminino , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/imunologia , Metaloproteinases da Matriz/imunologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mucosa/imunologia , Mucosa/microbiologia , Faringite/imunologia , Faringite/microbiologia , Fosforilação , Peixe-ZebraRESUMO
AIM: The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory. METHOD: The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases. RESULTS: Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis. CONCLUSION: Our new criteria are useful for diagnosing PFAPA.
Assuntos
Febre/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Linfadenite/diagnóstico , Faringite/diagnóstico , Estomatite Aftosa/diagnóstico , Biomarcadores/sangue , Pré-Escolar , Citocinas/sangue , Feminino , Febre/sangue , Febre/imunologia , Febre/terapia , Glucocorticoides/uso terapêutico , Doenças Hereditárias Autoinflamatórias/sangue , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/terapia , Hereditariedade , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Lactente , Mediadores da Inflamação/sangue , Japão , Linfadenite/sangue , Linfadenite/imunologia , Linfadenite/terapia , Masculino , Proteína Cofatora de Membrana/sangue , Neutrófilos/imunologia , Linhagem , Faringite/sangue , Faringite/imunologia , Faringite/terapia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estomatite Aftosa/sangue , Estomatite Aftosa/imunologia , Estomatite Aftosa/terapia , Síndrome , Tonsilectomia , Resultado do TratamentoRESUMO
Group A Streptococcus (GAS) is a highly-adapted and human-restricted pathogen responsible for a high global burden of disease across a diverse clinical spectrum. Vaccine development has been impeded by scientific, regulatory, and commercial obstacles. Human infection studies (HIS) are increasingly contributing to drug, diagnostics, and vaccine development, reducing uncertainty at early stages, especially for pathogens with animal models that incompletely reproduce key elements of human disease. We review the small number of historical GAS HIS and present the study protocol for a dose-ranging inpatient study in healthy adults. The primary objective of the study is to establish a new GAS pharyngitis HIS with an attack rate of at least 60% as a safe and reliable platform for vaccine evaluation and pathogenesis research. According to an adaptive dose-ranging study design, emm75 GAS doses manufactured in keeping with principles of Good Manufacturing Practice will be directly applied by swab to the pharynx of carefully screened healthy adult volunteers at low risk of severe complicated GAS disease. Participants will remain as closely monitored inpatients for up to six days, observed for development of the primary outcome of acute symptomatic pharyngitis, as defined by clinical and microbiological criteria. All participants will be treated with antibiotics and followed as outpatients for six months. An intensive sampling schedule will facilitate extensive studies of host and organism dynamics during experimental pharyngitis. Ethics approval has been obtained and the study has been registered at ClinicalTrials.gov (NCT03361163).
Assuntos
Faringite/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Adolescente , Adulto , Animais , Antibacterianos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Incidência , Masculino , Faringite/tratamento farmacológico , Faringe/imunologia , Faringe/microbiologia , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes/efeitos dos fármacos , Vacinação/métodos , Adulto JovemRESUMO
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a recurrent fever syndrome of early childhood with increasing number of adult-onset cases. Although it is a self-limited disease, it may negatively affect the quality of life. The aim of this review is to present a detailed analysis of PFAPA syndrome and an algorithm for diagnosis, therapeutic options, and evaluation of outcome. A comprehensive literature search was conducted through the Cochrane Library, Scopus, and MEDLINE/PubMed databases. The main topics covered are the epidemiology, clinical manifestations, diagnosis, differential diagnosis, etiopathogenesis, genetics, management, disease course and prognosis, disease in adults, unsolved issues, and unmet needs in PFAPA. The diagnosis of PFAPA is mainly based on clinical classification criteria. The most relevant hypothesis for pathogenesis is that dysregulated immune system in a genetically predisposed individual responds to a yet unidentified trigger in an exaggerated way. The pedigree analyses suggest a genetic background for the disease with an autosomal dominant pattern of inheritance. For management, single-dose corticosteroids during attacks and tonsillectomy remain the most effective therapies, while colchicine is a promising option to decrease attack frequency. There remain unsolved issues in PFAPA such as the exact etiopathogenesis and genetic background, the reason why the inflammation is restricted to the oropharyngeal lymphoid tissue, reasons for clock-work regularity of attacks, and self-limited disease course. There is need for a valid diagnostic criteria set with a high performance for both children and adults and consensus on management of PFAPA.
Assuntos
Febre/imunologia , Inflamação/imunologia , Linfadenite/imunologia , Faringite/imunologia , Estomatite Aftosa/imunologia , Corticosteroides/uso terapêutico , Febre/complicações , Febre/diagnóstico , Febre/terapia , Humanos , Inflamação/diagnóstico , Inflamação/terapia , Linfadenite/complicações , Linfadenite/diagnóstico , Linfadenite/terapia , Pescoço , Faringite/complicações , Faringite/diagnóstico , Faringite/terapia , Recidiva , Estomatite Aftosa/complicações , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/terapia , Síndrome , TonsilectomiaRESUMO
A previously healthy 6-year-old boy was referred to us by his primary provider, with a history of sudden onset behavioural abnormalities including irritability, sleep disturbance and anxiety. Physical examination revealed no significant findings; further analyses were not suggestive of meningitis, encephalitis, metabolic abnormalities, toxicity or any other obvious cause. On rechecking the patient's history, an episode of throat pain 1 week prior to the symptom onset was noted. Therefore, the possibility of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) was considered. The antistreptolysin O titre was high (1078 IU/mL), and it increased to 1194 IU/mL 4 weeks later, leading to a diagnosis of PANDAS. He was started on ampicillin and administered one dose of intravenous immunoglobulin. His abnormal behaviours subsided and he returned to a normal state within 48 hours of treatment. This report aims to provide insights into the symptomology and diagnosis of PANDAS in children.
Assuntos
Doenças Autoimunes/diagnóstico , Sintomas Comportamentais/etiologia , Faringite/complicações , Infecções Estreptocócicas/diagnóstico , Administração Intravenosa , Assistência ao Convalescente , Ampicilina/administração & dosagem , Ampicilina/uso terapêutico , Antibacterianos/uso terapêutico , Antiestreptolisina/análise , Doenças Autoimunes/tratamento farmacológico , Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/imunologia , Criança , Diagnóstico Diferencial , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Transtorno Obsessivo-Compulsivo , Faringite/diagnóstico , Faringite/imunologia , Faringite/microbiologia , Doenças Raras , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/tratamento farmacológico , Resultado do TratamentoRESUMO
The application and clinical impact of rapid antigen detection test (RADT) in the treatment of acute pharyngitis is unknown in Japan. We aimed to examine the proportions of RADT usage to identify Group A ß-hemolytic Streptococcus (GAS) in outpatients with acute pharyngitis and evaluate the association between RADT and antibiotic treatment. We analyzed health insurance claims data from 2013 to 2015. Logistic regression models were used to analyze associated factors with RADT, overall antibiotic prescription, or penicillin use. We analyzed 1.27 million outpatient visits with acute pharyngitis, in which antibiotics were prescribed in 59.3% of visits. Of the total visits, 5.6% of patients received RADT, and 10.8% of the antibiotics were penicillin. Penicillin selection rates were higher in cases with RADT (25.4%) than those without RADT (9.7%). Compared to large-scale facilities, antibiotic prescription rates were higher in physicians' offices. For factor analysis, age (3-15 years), diagnosis code (streptococcal pharyngitis), size of the medical facility (large-scale hospitals), and physician's specialty (pediatrics) were associated with RADT use. Penicillin selection rate increased with RADT implementation (25.4% vs. 9.7%: adjusted odds ratio 1.55; 95% CI, 1.50-1.60). At 63% of the facilities, the RADT implementation rate was <5% of acute pharyngitis visits prescribed antibiotics. In conclusion, the proportion of RADT usage for outpatients with acute pharyngitis was low in Japan. With appropriate indication and evaluation, we expect that more utilization of RADT can help promote antimicrobial stewardship for outpatients with acute pharyngitis by prompting penicillin therapy. Further investigation with detailed clinical data are warranted.
Assuntos
Antibacterianos/uso terapêutico , Antígenos de Bactérias/isolamento & purificação , Testes Imunológicos/estatística & dados numéricos , Faringite/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Doença Aguda/terapia , Adolescente , Adulto , Idoso , Antibacterianos/farmacologia , Gestão de Antimicrobianos/normas , Gestão de Antimicrobianos/estatística & dados numéricos , Criança , Pré-Escolar , Humanos , Testes Imunológicos/instrumentação , Lactente , Recém-Nascido , Japão , Pessoa de Meia-Idade , Penicilinas/farmacologia , Penicilinas/uso terapêutico , Faringite/imunologia , Faringite/microbiologia , Guias de Prática Clínica como Assunto , Kit de Reagentes para Diagnóstico/estatística & dados numéricos , Estudos Retrospectivos , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/imunologia , Streptococcus pyogenes/isolamento & purificação , Adulto JovemRESUMO
BACKGROUND/PURPOSE: To report two novel cases of intermediate uveitis associated with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome. METHODS: Observational case reports and review of the literature. RESULTS: Both patients in this report had an established diagnosis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome before the onset of ocular inflammation. Infectious and noninfectious systemic conditions known to be associated with intermediate uveitis were excluded. Intermediate uveitis was confirmed clinically in both patients by the presence of vitritis, snowballs, and peripheral snowbanks in the region of the pars plana. Both cases had a course characterized by recurrent inflammation; in which systemic steroid treatment, and in one case, immunomodulatory therapy was necessary. CONCLUSION: Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome is an auto-inflammatory fever disorder in childhood. Although other auto-inflammatory disorders such as, Blau syndrome, Muckle-Wells syndrome, and Behcets disease have been associated with various forms of uveitis, Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis has never been reported to be associated with any type of ocular inflammation. We describe for the first time, two cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome presenting with intermediate uveitis.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Febre/complicações , Linfadenite/complicações , Faringite/complicações , Estomatite Aftosa/complicações , Uveíte Intermediária/etiologia , Acuidade Visual , Criança , Diabetes Mellitus Tipo 1/imunologia , Febre/imunologia , Angiofluoresceinografia , Fundo de Olho , Humanos , Linfadenite/imunologia , Masculino , Pescoço , Faringite/imunologia , Estomatite Aftosa/imunologia , Síndrome , Tomografia de Coerência Óptica/métodos , Uveíte Intermediária/diagnósticoRESUMO
We report a previously well paediatric patient with two distinct presentations of invasive group A streptococcus (GAS) infection resulting in significant morbidity. The first episode, following GAS pharyngitis, involved multiorgan dysfunction syndrome. This included cardiorespiratory and acute hepatorenal failure and purpura fulminans that eventually necessitated four-limb amputation. The second episode occurred 12 months later, from undetermined aetiology, and resulted in septic shock. Molecular analysis of the emm gene and PCR for Serum Opacity Factor revealed that the initial isolate was M Type 4 and sof gene positive while the second isolate was M Type 1 and sof gene negative. Immunological investigations, including CH50, quantitative IgA, IgM and IgG, and flow cytometry measuring lymphocyte subsets, and vaccine response to measles, mumps, rubella and pneumococcus were normal. This is the first report of recurrent bacteraemia from different strains of Streptococcus pyogenes infection in an apparently immunocompetent child.
Assuntos
Amputação Cirúrgica , Antibacterianos/administração & dosagem , Insuficiência de Múltiplos Órgãos/microbiologia , Faringite/imunologia , Choque Séptico/microbiologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Criança , Feminino , Humanos , Unidades de Terapia Intensiva Pediátrica , Extremidade Inferior/cirurgia , Insuficiência de Múltiplos Órgãos/imunologia , Insuficiência de Múltiplos Órgãos/fisiopatologia , Insuficiência de Múltiplos Órgãos/terapia , Faringite/fisiopatologia , Faringite/terapia , Recidiva , Choque Séptico/imunologia , Choque Séptico/terapia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/fisiopatologia , Infecções Estreptocócicas/terapia , Resultado do Tratamento , Extremidade Superior/cirurgiaRESUMO
Objective: To investigate the clinical, inflammatory and genetic characteristics of cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. Methods: Clinical and inflammatory manifestations and gene sequencing of 11 cases with PFAPA were retrospectively analyzed. Inflammatory markers including white blood cell (WBC) , C reactive protein (CRP) , and serum amyloid A (SAA) were compared between febrile period and intermittent period. Fifteen normal children were taken as healthy controls. The levels of plasma inflammatory cytokines including interleukin(IL)1ß, IL-6, IL-17, tumor necrosis factor(TNF)-α, interferon (IFN)-γ, and granulocyte-colony stimulating factor(G-CSF) were compared between febrile period and intermittent period with paired-sample t test, and compared between febrile cases and healthy controls with independent t test. Results: A total of 11 cases (7 females and 4 males) were included. The median onset age was 24 (3-60) months, and the median age of diagnosis was 69 (11-151) months. The median febrile duration was 4 (1-8) days, and the intermittent period lasted 1 to 8 weeks. All the cases had periodic fever and pharyngitis/tonsillitis, 7 of whom had combined lymphadenitis, and 5 of whom suffered from oral ulcers. Compared to intermittent-period-status,WBC ((14.7±4.1) ×10(9)/L vs. (8.4±1.9) ×10(9)/L, P<0.05), CRP((24.2±21.1) vs. (3.3±2.1)mg/L, P<0.05), SAA ((136.4±47.7) vs. (7.1±1.1)mg/L, P<0.05) were significantly elevated in febrile period. Compared to intermittent-period-status and healthy controls, plasma levels of IL-6 ((38±10) vs. (8±4) and (8±5)ng/L, t=6.514 and 6.830 respectively, P<0.05), IFN-γ ((132±43) vs.(49±21) and (53±21)ng/L, t=4.069 and 4.276 respectively, P<0.05), G-CSF ((403±12) vs. (175±90) and (121±49)ng/L, t=4.219 and 9.047 respectively, P<0.05) were significantly higher in febrile period, while no differences were found in levels of IL-1ß, IL-17 and TNF-α. Gene sequencing found MEFV gene heterozygous variation in 8 cases. Conclusions: PFAPA often manifests as periodic fever, pharyngitis, tonsillitis, aphthous stomatitis and adenitis. Gene sequencing analysis, detection of inflammation markers and cytokines could help with the diagnose of this disease.