Otitis media: Interactions between host and environment, immune and inflammatory responses.

OBJECTIVE: To review and highlight progress in otitis media (OM) research in the areas of immunology, inflammation, environmental influences and host-pathogen responses from 2019 to 2023. Opportunities for innovative future research were also identified. DATA SOURCES: PubMed database of the National Library of Medicine. REVIEW METHODS: Key topics were assigned to each panel member for detailed review. Search of the literature was from June 2019 until February 2023. Draft reviews were collated, circulated, and discussed among panel members at the 22nd International Symposium on Recent Advances in Otitis Media in June 2023. The final manuscript was prepared and approved by all the panel members. CONCLUSIONS: Important advances were identified in: environmental influences that enhance OM susceptibility; polymicrobial middle ear (ME) infections; the role of adaptive immunity defects in otitis-proneness; additional genes linked to OM; leukocyte contributions to OM pathogenesis and recovery; and novel interventions in OM based on host responses to infection. Innovative areas of research included: identification of novel bacterial genes and pathways important for OM persistence, bacterial adaptations and evolution that enhance chronicity; animal and human ME gene expression, including at the single-cell level; and Sars-CoV-2 infection of the ME and Eustachian tube.

Do tonsils regrow after partial tonsillectomy? - Histology of regrown tonsils and predisposing factors for tonsillar regrowth.

OBJECTIVES: It has been suggested that after partial tonsillectomy, referred here as tonsillotomy (TT), the remaining tonsillar tissue might be altered, leading to scarring or chronic tonsillitis. The objectives were to compare the histology of regrown tonsillar tissues with native tonsils and to assess the incidence of reoperations and predictive factors for tonsillar regrowth after TT. METHODS: Tonsillar tissues of 1) children that underwent TT and later requiring resurgery and 2) children operated on for the first time with TT were prospectively analysed. To assess the incidence of resurgery because of tonsillar regrowth and predictive factors for tonsillar regrowth, the data covering TTs and tonsillectomies performed in 2009-2020 were retrospectively retrieved. RESULTS: Altogether 11 children formed the regrowth group, with the control group consisting of 19 children. In the histological analysis of tonsillar tissues, neutrophil infiltration in the epithelium and crypts and severe lymphoplasmacytic infiltration in the epithelium were significantly more frequent in samples of the regrowth group relative to the control group. The number of germinal centres was greater in the regrowth group. In the retrospective analysis of 3141 children, the incidence of resurgery after primary TT was 1.9%. Logistic regression analysis showed that age was the only significant predisposing factor for resurgery. CONCLUSION: Inflammatory cells were present more often in regrown tonsillar tissues but there was no evidence of severe chronic inflammation or scarring in the regrown tonsils. The risk of resurgery after TT was low. Young age predisposed to tonsillar regrowth, no other risk factors were found.

Persistence of Human Bocavirus 1 in Tonsillar Germinal Centers and Antibody-Dependent Enhancement of Infection.

Human bocavirus 1 (HBoV1), a nonenveloped single-stranded DNA parvovirus, causes mild to life-threatening respiratory tract infections, acute otitis media, and encephalitis in young children. HBoV1 often persists in nasopharyngeal secretions for months, hampering diagnosis. It has also been shown to persist in pediatric palatine and adenoid tonsils, which suggests that lymphoid organs are reservoirs for virus spread; however, the tissue site and host cells remain unknown. Our aim was to determine, in healthy nonviremic children with preexisting HBoV1 immunity, the adenotonsillar persistence site(s), host cell types, and virus activity. We discovered that HBoV1 DNA persists in lymphoid germinal centers (GCs), but not in the corresponding tonsillar epithelium, and that the cell types harboring the virus are mainly naive, activated, and memory B cells and monocytes. Both viral DNA strands and both sides of the genome were detected, as well as infrequent mRNA. Moreover, we showed, in B-cell and monocyte cultures and ex vivo tonsillar B cells, that the cellular uptake of HBoV1 occurs via the Fc receptor (FcγRII) through antibody-dependent enhancement (ADE). This resulted in viral mRNA transcription, known to occur exclusively from double-stranded DNA in the nucleus, however, with no detectable productive replication. Confocal imaging with fluorescent virus-like particles moreover disclosed endocytosis. To which extent the active HBoV1 GC persistence has a role in chronic inflammation or B-cell maturation disturbances, and whether the virus can be reactivated, will be interesting topics for forthcoming studies.IMPORTANCE Human bocavirus 1 (HBoV1), a common pediatric respiratory pathogen, can persist in airway secretions for months hampering diagnosis. It also persists in tonsils, providing potential reservoirs for airway shedding, with the exact location, host cell types, and virus activity unknown. Our study provides new insights into tonsillar HBoV1 persistence. We observed HBoV1 persistence exclusively in germinal centers where immune maturation occurs, and the main host cells were B cells and monocytes. In cultured cell lines and primary tonsillar B cells, we showed the virus uptake to be significantly enhanced by HBoV1-specific antibodies, mediated by the cellular IgG receptor, leading to viral mRNA synthesis, but without detectable productive replication. Possible implications of such active viral persistence could be tonsillar inflammation, disturbances in immune maturation, reactivation, or cell death with release of virus DNA, explaining the long-lasting HBoV1 airway shedding.

Monopolar tonsillotomy versus cold dissection tonsillectomy in children: Prospective study on postoperative recovery.

OBJECTIVES: To compare postoperative self-reported recovery results with monopolar tonsillotomy and cold dissection tonsillectomy in children. To evaluate the feasibility of the monopolar technique in tonsillotomy. METHODS: Children <12 years undergoing tonsillotomy or tonsillectomy between April 2018 and March 2020 who (with a caregiver) were willing to participate in a two-week follow-up formed the study group. They filled in a questionnaire about pain-related outcomes, return to normal activities, weight changes, complications, and length of home care. RESULTS: Altogether 166 patients were recruited; 103 (62%) returned the questionnaire. The first pain-free day with tonsillotomy was day 5 and with tonsillectomy day 11. After tonsillotomy, patients returned to normal activities faster, e.g. they were able to eat normally 6.5 days earlier than tonsillectomy patients. During the first postoperative week weight dropped after tonsillectomy, but not after tonsillotomy. The length of home care was 6 days with tonsillotomy and 10 days with tonsillectomy. The incidence of postoperative hemorrhage (including minor bleedings at home) was 14% after tonsillotomy and 32% after tonsillectomy. Hemorrhages needing interventions were 0% with tonsillotomy and 2% with tonsillectomy. CONCLUSION: Children operated on with monopolar tonsillotomy recovered faster and had less postoperative hemorrhage than those undergoing tonsillectomy. They were able to return earlier to daycare/school and their caregivers back to work. Recovery results with monopolar tonsillotomy were equal to other tonsillotomy techniques reported in the literature, hence the monopolar technique can be considered an alternative method to perform tonsillotomy.

Childhood nontuberculous mycobacterial lymphadenitis-observation alone is a good alternative to surgery.

OBJECTIVE: Cervicofacial lymphadenitis caused by nontuberculous mycobacteria (NTM) is commonly treated with surgery or antimicrobial therapy. The aim of this study was to analyze the utility of our new blood-based diagnostic method and the treatment protocol, surgery or observation alone, in NTM lymphadenitis in children. METHODS: All patients under 16 years of age with cervicofacial NTM lymphadenitis diagnosed and treated at Children's Hospital or at the Department of Otorhinolaryngology, Helsinki University Hospital (Helsinki, Finland) in 2007-2017 were retrospectively reviewed. RESULTS: Fifty-two patients, 33 (63%) of whom were girls, were included in the study. The median age at initial presentation of the NTM lymphadenitis was 2.9 years. The novel blood-test had been performed on 49 (94%) of the patients and in all of them it was indicative of NTM infection. A sample for mycobacterial culture was available from 34 patients, and Mycobacterium avium was the most common species detected. Most patients (n = 33, 63%) were treated conservatively with observation alone. Of these, nine patients (27%) did not develop a skin fistula, and the lymphadenitis resolved without drainage. CONCLUSIONS: The novel blood test is clinically feasible method for diagnosing childhood cervicofacial NTM lymphadenitis noninvasively. Observation alone is a good alternative to surgery, without the risk of complications.

CO2 laser supraglottic resurfacing for non-granulomatous chronic supraglottitis in two children.

Chronic epiglottitis and supraglottitis are clinical entities that present with respiratory distress and are primarily associated with autoimmune disorders, gastroesophageal reflux disease, or angioedema. First described in adults with sarcoidosis in 2010, CO2 laser epiglottis resurfacing has been effective in reducing epiglottic edema. We present two cases of adolescent males with non-granulomatous chronic supraglottitis who were successfully treated with CO2 laser supraglottic resurfacing.

Patient injuries in pediatric otorhinolaryngology.

OBJECTIVES: Patient injuries in children can have lifelong effects on the patient and a marked impact on the whole family. The aim of this study was to identify the errors and incidents leading to patient injuries in pediatric otorhinolaryngology (ORL) by evaluating accepted patient injury claims. METHODS: The records of all accepted patient injury claims in ORL between 2001 and 2011 were searched from the nationwide Patient Insurance Centre registry. Pediatric injuries were reviewed and evaluated in detail, and factors contributing to injury were identified. RESULTS: In the 10-year study period, 17 (7.6%) of the 223 patient injuries occurred in children, and of these, 15 (88%) were considered operative care. The median age of the patients was 8 years (range 3-16 years). All operations were performed as daytime elective surgery and by a fully trained specialist in 93% of the cases. One-half of the cases were routine surgeries for common ORL diseases. The most common incidences were incomplete surgery, retained gauze or foreign body, injury to adjacent anatomic structure, and insufficient charts or instructions (each occurred in 3 cases). The most frequent consequence was burn (n = 4). One child died because of post-tonsillectomy hemorrhage. CONCLUSIONS: Patient injuries in pediatric ORL are strongly related to surgery. Most injuries occurred after routine operations by a fully trained specialist. Clinicians should be aware of the most likely scenarios resulting in claims.

Changing trends in pediatric tonsil surgery.

OBJECTIVES: We analyzed trends in tonsil surgery over a 10-year period in a single tertiary care hospital and evaluated the effects of these changes on use of hospital services and healthcare costs. METHODS: This was a retrospective cohort study based on data from databases at the Department of Otorhinolaryngology, Helsinki University Hospital, Helsinki, Finland. Children under 16 years of age with tonsillectomy (TE) or tonsillotomy (TT) performed during 2007-2016 were included in the study. RESULTS: In 10 years, 4979 tonsil surgeries were performed on 4951 children: TE in 3170 (64%) and TT in 1781 (36%) children. The total number of tonsil surgeries stayed nearly constant. TT operations commenced in the study hospital in 2009 and from 2012 onwards have been more common than TE procedures. Altogether 279 patients visited the emergency department because of complications; TE patients had 9.0 visits/100 surgeries and TT patients 1.8 visits/100 surgeries. The most common complication was postoperative hemorrhage: 200 cases (6.3%) in the TE group and 11 cases (0.6%) in the TT group. During the two-year follow-up after tonsil surgery the total costs of healthcare services were significantly lower in the TT group than in the TE group. CONCLUSION: Considerable changes have occurred in tonsil surgery in children during the 10-year study period; TT is today performed more often than TE. As a consequence, complications, readmissions to hospital, and number of patients treated in the operating room because of postoperative hemorrhage have decreased, lowering the costs of healthcare.

Panel 4: Report of the Microbiology Panel.

Objective To perform a comprehensive review of the literature from July 2011 until June 2015 on the virology and bacteriology of otitis media in children. Data Sources PubMed database of the National Library of Medicine. Review Methods Two subpanels comprising experts in the virology and bacteriology of otitis media were created. Each panel reviewed the relevant literature in the fields of virology and bacteriology and generated draft reviews. These initial reviews were distributed to all panel members prior to meeting together at the Post-symposium Research Conference of the 18th International Symposium on Recent Advances in Otitis Media, National Harbor, Maryland, in June 2015. A final draft was created, circulated, and approved by all panel members. Conclusions Excellent progress has been made in the past 4 years in advancing our understanding of the microbiology of otitis media. Numerous advances were made in basic laboratory studies, in animal models of otitis media, in better understanding the epidemiology of disease, and in clinical practice. Implications for Practice (1) Many viruses cause acute otitis media without bacterial coinfection, and such cases do not require antibiotic treatment. (2) When respiratory syncytial virus, metapneumovirus, and influenza virus peak in the community, practitioners can expect to see an increase in clinical otitis media cases. (3) Biomarkers that predict which children with upper respiratory tract infections will develop otitis media may be available in the future. (4) Compounds that target newly identified bacterial virulence determinants may be available as future treatment options for children with otitis media.

Panel 6: Vaccines.

Objective To review the literature on progress regarding (1) effectiveness of vaccines for prevention of otitis media (OM) and (2) development of vaccine antigens for OM bacterial and viral pathogens. Data Sources PubMed database of the National Library of Science. Review Methods We performed literature searches in PubMed for OM pathogens and candidate vaccine antigens, and we restricted the searches to articles in English that were published between July 2011 and June 2015. Panel members reviewed literature in their area of expertise. Conclusions Pneumococcal conjugate vaccines (PCVs) are somewhat effective for the prevention of pneumococcal OM, recurrent OM, OM visits, and tympanostomy tube insertions. Widespread use of PCVs has been associated with shifts in pneumococcal serotypes and bacterial pathogens associated with OM, diminishing PCV effectiveness against AOM. The 10-valent pneumococcal vaccine containing Haemophilus influenzae protein D (PHiD-CV) is effective for pneumococcal OM, but results from studies describing the potential impact on OM due to H influenzae have been inconsistent. Progress in vaccine development for H influenzae, Moraxella catarrhalis, and OM-associated respiratory viruses has been limited. Additional research is needed to extend vaccine protection to additional pneumococcal serotypes and other otopathogens. There are likely to be licensure challenges for protein-based vaccines, and data on correlates of protection for OM vaccine antigens are urgently needed. Implications for Practice OM continues to be a significant health care burden globally. Prevention is preferable to treatment, and vaccine development remains an important goal. As a polymicrobial disease, OM poses significant but not insurmountable challenges for vaccine development.

Acute Otitis Media and Other Complications of Viral Respiratory Infection.

BACKGROUND: Viral upper and lower respiratory tract infections (URI, LRI) are common in infants. We determined the prevalence of viral URI and its complications, including acute otitis media (AOM) and LRI, and assessed the effect of bacterial-viral interactions, and genetic and environmental risks on AOM development. METHODS: Healthy infants were enrolled from near birth and followed to the first episode of AOM up to 12 months of age. Nasopharyngeal specimens were collected at monthly intervals (months 1-6, 9) and during viral URI episodes for bacterial culture and viral polymerase chain reaction studies. Subjects were followed closely for AOM development. RESULTS: A total of 367 infants were followed for 286 child-years; 887 URI (305 infants) and 180 AOM episodes (143 infants) were documented. Prevalence of URI, LRI, and AOM in the first year was 3.2, 0.25, and 0.67 per child-year, respectively. Cumulative AOM incidence by ages 3, 6, and 12 months was 6%, 23%, and 46%. Infants with and without AOM had 4.7 and 2.3 URI episodes per child-year, respectively (P < .002). Pathogenic bacterial colonization rates by month were significantly higher in infants with AOM (P < .005). Breastfeeding reduced both URI and AOM risks (P < .05). Significant bacterial-viral interactions occurred with Moraxella catarrhalis and a variety of respiratory viruses and altered URI and AOM risks. CONCLUSIONS: Almost half of infants experienced AOM by age 1. Important AOM risk factors included frequent viral URI, pathogenic bacterial colonization, and lack of breastfeeding. Bacterial-viral interactions may play a significant role in AOM pathogenesis and deserve further investigation.

Importance of viruses in acute otitis media.

PURPOSE OF REVIEW: Acute otitis media occurs as a complication of viral upper respiratory tract infection. Bacterial otopathogens and respiratory viruses interact and play important roles in acute otitis media development. A better understanding of viral and bacterial interactions may lead to innovative ways to lessen the burden of this common childhood disease. RECENT FINDINGS: There has been increasing evidence that acute otitis media occurs during upper respiratory infection, even in the absence of nasopharyngeal bacterial colonization. Among the types of viruses associated with acute otitis media, respiratory syncytial virus continues to be the most commonly detected. It is still unclear whether viral load plays an important role in acute otitis media development, but symptomatic upper respiratory tract infection (as opposed to asymptomatic viral infection) is crucial. Widespread use of bacterial and viral vaccines in young children, including pneumococcal conjugate and influenza vaccines, has led to the reduction in otitis media-related healthcare use between 2001 and 2011. There has been no new vaccine against respiratory viruses other than influenza. SUMMARY: Progress has been made toward the reduction of the burden of acute otitis media in the last decade. Success in reducing acute otitis media incidence will rely mainly on prevention of nasopharyngeal otopathogen colonization, as well as reduction in the incidence of viral upper respiratory tract infection.

Impact of tonsillectomy on health-related quality of life and healthcare costs in children and adolescents.

BACKGROUND: Tonsillectomy is a common surgical intervention in children, but its efficacy is under debate. We studied whether tonsillectomy is a cost-effective intervention with a positive impact on health-related quality of life (HRQoL). METHODS: Children (aged 7-11 years) and adolescents (aged 12-15 years) undergoing tonsillectomy answered the 17D or 16D HRQoL questionnaires before tonsillectomy and at 6 and 12 months postoperatively. At the same time-points, data on the use of healthcare services and school absenteeism were collected by questionnaire. RESULTS: Altogether 49 children and 42 adolescents returned all HRQoL questionnaires. Tonsillectomy improved the mean total HRQoL score clinically and statistically significantly in both children (from 0.935 at baseline to 0.958 at 12 months, p = 0.002) and adolescents (from 0.930 to 0.957, p = 0.004). The mean direct self-reported healthcare service costs diminished after tonsillectomy in both groups. The mean number of days on sick leave due to oropharyngeal problems during the preceding 3 months decreased from the preoperative 4.6 days to postoperative 0.5 days (p < 0.001) in children, and from 4.9 days to 0.8 days (p < 0.001) in adolescents at 12 months. CONCLUSIONS: Tonsillectomy improves HRQoL in both school-aged children and adolescents and reduces healthcare service needs and school absenteeism due to oropharyngeal symptoms.

Polymorphisms of immunity genes and susceptibility to otitis media in children.

BACKGROUND: Acute otitis media (OM) is a common disease which often develops through complex interactions between the host, the pathogen and environmental factors. We studied single nucleotide polymorphisms (SNPs) of genes involved in innate and adaptive immunity, and other host and environmental factors for their role in OM. METHODS: Using Sequenom Massarray platform, 21 SNPs were studied in 653 children from prospective (n = 202) and retrospective (n = 451) cohorts. Data were analyzed for the relationship between SNPs and upper respiratory infection (URI) frequency, risk of acute OM during URI episodes, and proneness to recurrent OM. RESULTS: Increased risk for OM proneness was associated with CX3CR1 (Thr280Met) SNP and with a jointly interactive group of IL-10 (-1082) SNP, IL-1ß (-511) wild type genotype and white race. Family history of OM proneness independently increased the risk for frequent URIs, OM occurrence during URI, and OM proneness. Additionally, IL-1ß (-31) SNP was associated with increased risk for frequent URIs, but IL-10 (-592), IL-1ß (-511), IL-5 (-746) and IL-8 (-251) SNPs were associated with decreased risk of URI. CONCLUSION: IL-1ß (-31), CX3CR1 (Thr280Met), IL-10 (-1082) and IL-1ß (-511) SNPs were associated with increased risk for frequent URIs or OM proneness.

Role of Human Bocavirus in Upper Respiratory Tract Infections and Acute Otitis Media.

BACKGROUND: Human bocavirus (HBoV) is a newly described parvovirus. HBoV1 has been associated with respiratory infections, including acute otitis media (AOM), but the knowledge on the significance of HBoV1 in upper respiratory tract infections (URI) and AOM in relation to other respiratory viruses is limited. The objective of this study was to compare the rate of detection of HBoV1 to that of other respiratory viruses in specimens from children with URI, with and without AOM complication. METHODS: Nasopharyngeal secretions (NPS) were collected during URI from healthy children (6-35 months) followed prospectively for 1 year; specimens have been previously analyzed for broad spectrum of respiratory viruses. Archived NPS were analyzed for HBoV1 using a high-throughput, quantitative polymerase chain reaction method. RESULTS: Seven hundred and seven NPS samples collected during URI episodes from 201 children were studied for HBoV1. A total of 94 (47%) children tested positive for HBoV1 DNA during 172 (24%) URI episodes; HBoV1 was present as the only virus in 44 (6%) URI episodes. Overall, 37% of URI episodes were complicated by AOM. Of URI associated with single virus (n = 303), the rate of AOM complicating URI associated with HBoV1 only was 52% (23 of 44); this was a higher AOM rate, compared to that of other respiratory viruses. CONCLUSIONS: Among URI associated with single respiratory virus, HBoV1-URI was commonly associated with AOM complication. The important role of HBoV1 on AOM pathogenesis needs to be studied further.

[Update on Current Care Guideline: Sinusitis]. / Sivuontelotulehdus.

Patients with common cold have often symptoms similar to sinusitis. These symptoms often resolve in time, but symptomatic treatment (e.g. analgesics, decongestants) may be used. If symptoms continue for over 10 days, or severe symptoms continue for over 3 days, or symptoms turn worse in the course of the disease, bacterial sinusitis should be suspected. Diagnosis is based on clinical findings, and can be confirmed with ultrasound examination. Amoxicillin, penicillin or doxicyclin are recommended for bacterial sinusitis. Patients with chronic or recurrent sinusitis should be referred to specialist care.

[Tonsillotomy]. / Tonsillotomia.

In tonsillotomy, only the obstructive tonsillar tissue is removed without touching the surrounding tissue of the palatine tonsil. Tonsillotomies have been mainly performed for children due to tonsillar hypertrophy. Less postoperative pain is recorded after tonsillotomy compared with tonsillectomy. In addition, recovery is quicker and there are fewer complications. Tonsillotomy is an effective method in cases where the indication for surgery is tonsillar hypertrophy and associated symptoms such as snoring or difficulties in swallowing.

Panel 5: Microbiology and immunology panel.

OBJECTIVE: The objective is to perform a comprehensive review of the literature from January 2007 through June 2011 on the virology, bacteriology, and immunology related to otitis media. DATA SOURCES: PubMed database of the National Library of Medicine. REVIEW METHODS: Three subpanels with co-chairs comprising experts in the virology, bacteriology, and immunology of otitis media were formed. Each of the panels reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a second draft was created. The entire panel met at the 10th International Symposium on Recent Advances in Otitis Media in June 2011 and discussed the review and refined the content further. A final draft was created, circulated, and approved by the panel. CONCLUSION: Excellent progress has been made in the past 4 years in advancing an understanding of the microbiology and immunology of otitis media. Advances include laboratory-based basic studies, cell-based assays, work in animal models, and clinical studies. IMPLICATIONS FOR PRACTICE: The advances of the past 4 years formed the basis of a series of short-term and long-term research goals in an effort to guide the field. Accomplishing these goals will provide opportunities for the development of novel interventions, including new ways to better treat and prevent otitis media.

Viral-bacterial interactions in acute otitis media.

Acute otitis media (AOM) is a polymicrobial disease, which usually occurs as a complication of viral upper respiratory tract infection (URI). While respiratory viruses alone may cause viral AOM, they increase the risk of bacterial middle ear infection and worsen clinical outcomes of bacterial AOM. URI viruses alter Eustachian tube (ET) function via decreased mucociliary action, altered mucus secretion and increased expression of inflammatory mediators among other mechanisms. Transient reduction in protective functions of the ET allows colonizing bacteria of the nasopharynx to ascend into the middle ear and cause AOM. Advances in research help us to better understand the host responses to viral URI, the mechanisms of viral-bacterial interactions in the nasopharynx and the development of AOM. In this review, we present current knowledge regarding viral-bacterial interactions in the pathogenesis and clinical course of AOM. We focus on the common respiratory viruses and their established role in AOM.