Very few convincing dietary measures for reducing the frequency and clinical relevance of recurrent respiratory episodes in RTi-prone children have been developed. Until July 2024, professional societies and groups of experts technically reviewed 10 clinical trials conducted with oropharyngeal probiotics with documented efficacy for the management of RRTi published since 2012 with a total of 832 children participating. Oropharyngeal probiotic Bactoblis was given to subjects in the form of slowly dissolving oral lozenges, to be administered before bedtime after brushing their teeth every evening, and they were required to suck the lozenge until fully dissolved (approximately 4–5 min) and not to chew or directly swallow it. They were suggested not to drink or swallow any substance for at least 1 h after the administration of oropharyngeal probiotic lozenges. If the subjects were prescribed with antibiotics by study practitioners during RTIs, they are requested to continuously take the oropharyngeal probiotics during the days taking antibiotics, but making sure that oropharyngeal probiotics and antibiotics had been taken 2 h apart. Oropharyngeal probiotics with recommendations for use in clinical practices were discussed based on the evaluation of 10 trials in terms of population, burden of RRTi, current treatment strategies, probiotic dose, and administration schedule. Overall, oropharyngeal probiotic, as a general group, reduced the risk of developing new episodes of respiratory tract infections and antibiotic exposure in children with RRTi. A conditional recommendation based on level 2 evidence criteria graded by study type of randomized trials with consistent effect according to the latest World Gastroenterology Organisation Global Guidelines: Probiotics and Prebiotics 2024 (21), on the adjunctive use of oropharyngeal probiotics supportive of standard treatment in children with recurrent respiratory tract infections was made, in the context of the corresponding 10 clinical trials. Most of the 10 trials are homogeneous in regards to study subjects, dosage, schedule of administration, and formulation. Oropharyngeal probiotic Bactoblis has been found to have a good safety profile. These findings revealed that compared to controls, people with a history of recurrent RTIs receiving oropharyngeal probiotic Bactoblis had a significantly lower risk of new episodes of RTi during the study period reduced by around 90%. The protective benefit was observed during both the intervention period and maintained several months after the end of the intervention. The risk of antibiotic exposure was significantly higher among controls than among subjects administrating oropharyngeal probiotic Bactoblis. The limitations of the 10 studies were the use of non-blinded method and that the pathogen type and severity of RTIs were not defined by molecular tests and RTi-related quality of life. The type of antibiotic used by the subjects were not described in the article, and the size of the studies was generally small. However, the baseline clinical characteristics of the enrolled subjects were precisely defined in all of 10 trials. Among the 10 trials, 6 were published in English, of which 5 were carried out in Europe and 1 was carried out in China, and 4 were carried out in Ukraine and published in Ukrainian with the abstract in English and in most cases were published in Ukrainian journals. Clinical studies evidencing that oropharyngeal probiotic Bactoblis can provide clinical benefit on recurrent RTi management are listed in Table 1.

Otitis media represents a significant burden on children, their families, and the healthcare system and is the major cause of hearing loss and serious life-long sequelae, such as behavior, attention (33), anxiety, learning, and speech-language problems in early and late childhood (34), if left untreated. Chronic and recurrent otitis media are recalcitrant to current therapies due to the formation of biofilms and intracellular biofilm pods by otopathogens on the middle ear mucosa and within the middle ear fluid (35). Antibiotics are generally used empirically for treating chronic suppurative otitis media, which may lead to the emergence of resistant bacterial strains (36). In addition, official recommendations differ regarding tympanostomy-tube placement that could favor the time to a first episode of acute otitis media and various episode-related clinical findings in young children with recurrent acute otitis media, but the rate of acute otitis media episodes, the percentage of episodes considered to be severe, and antimicrobial resistance among respiratory isolates were not significantly lower than with medical management (37). Relative abundances of potential pathogens, such as Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis in the upper respiratory tract, might lead to further investigation into new preventive measurements for acute, secretory, and recurrent otitis media (38). The seven studies with evidence for the oropharyngeal probiotic formula, Bactoblis, providing a clinical benefit for otitis media management are listed in Table 2.

Respiratory viral infections are the most common type of acute respiratory infection, predisposing patients to secondary bacterial infections that often have a more severe clinical course. Antiviral immune responses induced by acute RTi are associated with dysbiosis in the respiratory tract, which in turn alters subsequent immune function against secondary bacterial infection or the dynamics of inter-microbial interactions, thereby enhancing the proliferation of potentially pathogenic bacterial species (44). Increased microbial diversity and growth rates of specific pathogens in the upper respiratory tract were observed. Oropharyngeal microbiota is a type specifically disrupted by the infection of influenza A virus (FluA), influenza B virus (FluB), respiratory syncytial virus (RSV), and human rhinovirus (HRV) (45), as well as omicron or other variant of SARS-CoV-2 viruses (46). Non-pathogenic commensal organisms colonized at nasopharynx and oropharynx possess the ability to interfere with the growth of potential pathogens such as S. pneumoniae, H. influenzae, and M. catarrhalis, the carriage of which increases during nasopharyngitis or pharyngitis, as well as symptomatic and asymptomatic viral URTi (47). Even though respiratory microbiota is shaped during the critical window of early life, season, and RTIs, evidence indicates a reduced niche differentiation preceding confirmed RTIs. This loss of ecological topography is further augmented by the start of daycare and linked to the consecutive development of symptomatic RTIs (48). In summary, restoring the loss of topography is linked to the prevention of subsequent development of RTi episodes. The four studies suggesting the clinical benefit of preventing acute RTi via administration of oropharyngeal probiotic Bactoblis are listed in Table 3.

Repeated use of antibiotics is common during the treatment of tonsillitis, and prior antibiotic use is a major contributor to subsequent antibiotic prescribing (50), except for recurrent antibiotic prescriptions. Tonsillectomy remains a common pediatric surgery for recurrent and chronic tonsillitis or recurrent otitis media; however, severe postoperative pain is common, and some patients will have postoperative complications of bleeding (51). Importantly, a cohort study of 1.2 million patients followed up for 30 years showed that childhood adenoidectomy or tonsillectomy was associated with a significantly increased relative risk of respiratory infections and allergies later in life. Increases in long-term absolute disease risks were considerably larger than changes in risk for the disorders these surgeries aim to treat, suggesting that it is important to consider long-term risks when making decisions to perform tonsillectomy or adenoidectomy (52). Children who had adenoidectomy for adenoid-related diseases are mostly due to obstructive sleep-disordered breathing, otitis media with effusion, and chronic sinusitis, while respiratory pathogens H. influenzae, S. aureus, S. pneumoniae, and M. catarrhalis are commonly found in adenoids (53). Surgical removal of adenoids and tonsils to treat obstructed breathing or recurrent middle ear infections remains a common pediatric procedure; however, a meta-analysis of current literature that included more than a thousand subjects demonstrated that pediatric sleep apnea is often not cured by tonsillectomy and adenoidectomy (54).

Chronic adenoiditis occurs frequently in children and is complicated by the subsequent development of recurrent or chronic middle ear diseases, such as recurrent acute otitis media, persistent otitis media with effusion, and chronic otitis media that fail to respond to traditional antibiotic therapy, which may predispose a child to long-term functional sequalae and auditory impairment (55).

In the treatment of children with chronic adenoiditis, it is necessary to take into account the features of the normal microbiota of the nasopharynx, by acting on opportunistic and pathogenic microorganisms. Favorable conditions for stimulating the growth and development of representatives of the indigenic microbiota can be created, which in turn will contribute to the patient's speedy recovery from chronic adenoiditis and absence of relapses (56). Further investigation of individual microbiomes in a longitudinal design with implantation of protective oropharyngeal probiotics may have the potential to lead to new strategies as an alternative to adenoidectomy. The four studies demonstrating that the oropharyngeal probiotic Bactoblis can provide clinical benefit on chronic adenoiditis and tonsillitis management are listed in Table 4.

The microbiota of the tonsils removed from PFAPA patients differed significantly from those of the non-PFAPA patients, indicating that tonsillar microbiota may play a role in triggering the inflammatory processes that lead to symptoms of PFAPA (60). Furthermore, tonsil dysbiosis may be associated with altered antimicrobial peptide expression on tonsil surface epithelium as in other autoinflammatory diseases which was not evident in recurrent tonsillitis (61). The two studies evidencing that oropharyngeal probiotic Bactoblis can provide clinical benefit on PFAPA management are listed in Table 5.

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. The occurrence of viral acute is accompanied by a shift in the nasopharyngeal microflora toward dominance by a small range of pathogenic bacterial genera. However, this change frequently precedes the detection of viral pathogens and acute symptoms. Colonization of illness-associated bacteria coupled with early allergic sensitization is associated with persistent wheeze in school-aged children, which is the hallmark of the asthma phenotype (64). Furthermore, pediatric chronic rhinosinusitis is a condition commonly encountered in otolaryngology practice, a proportion of which progresses from acute bacterial sinusitis induced by upper respiratory tract infections (65). Intranasal corticosteroids remain the first-line treatment for chronic rhinosinusitis. The study results of the effects of intranasal corticosteroids on the composition of the respiratory microbiome were highly heterogeneous (66), due to their immunosuppressive properties. It is worthwhile considering the possibility of the long-term use of inhaled corticosteroids associated with an increased risk of bacterial infections (67). Children admitted with asthma exacerbations harbor a microbiome characterized by overgrowth of Staphylococcus and oral microbes and an underrepresentation of beneficial niche-appropriate commensals (68, 69), which also present seasonally (70). Restoring the beneficial nasopharyngeal microbiota could be an alternative approach for self-management in pediatric patients with allergic respiratory conditions. Evidence from observational studies of children attending daycare revealed that nasopharyngeal probiotic Bactoblis administration in children was associated with an increased abundance of commensal S. salivarius in saliva and a lower abundance of otopathogens, Moraxella, in the nasopharynx which is strongly associated with the exacerbation of asthma (71). More research on oropharyngeal microflora intervention might help improve the quality of life for people with allergic rhinitis and reduce the risk of developing respiratory infections during high allergy seasons.

Despite decades of research, systemic autoimmune diseases (SADs) continue to be a major global health concern, and the etiology of these diseases remain unclear. Oral microbial dysbiosis has been identified in SADs including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), although the dysbiosis features were different among studies (72). Although several investigations failed to establish causal relationships, with the exception of Group A Streptococcus in rheumatic arthritis, microbial contributions to SAD initiation and propagation are plausible and likely, especially via the connective tissue and primary vasculitides (73). Indeed, accumulating evidence shows that antimicrobial peptides are induced or upregulated by dysbiosis in SADs while the host immune system attacks self-tissues with complex pathogenesis (74). Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Infectious agents are suspected to be environmental triggers involved with molecular mimicry between bacterial molecules and self-antigens (75). In addition, DNA from oral and gut microbiota can be identified in RA synovium, possibly due to the translocation through circulation from the oral cavity (76, 77).

The World Health Organization (WHO) and the International Labour Organization (ILO) have published a new guide on developing and implementing stronger occupational health and safety programs for health workers in 2022. Even before the COVID-19 pandemic, the health sector was among the most hazardous sectors to work in due to the suffering from infections and allergies from the working environment (78). Since individuals spend most of their lives at work, occupational exposures may have an impact on the microbiota. Chronic respiratory diseases are ranked as the most common occupational disease (79), and the concept of WORKbiota has been recently emphasized by European scientists in 2022 (80). A randomized controlled study conducted during the early COVID-19 pandemic showed that oropharyngeal probiotic Bactoblis protects frontline healthcare workers from respiratory tract infections during the month of taking care of critically ill COVID-19 patients (81). Establishing a homeostasis status of respiratory microflora has been recognized as a safe and positive approach to achieving occupational-related respiratory health by international experts (82). Occupational allergens are one of the risk factors for allergic rhinitis (83), and healthcare workers are exposed to a range of allergens including cleaners and disinfectants, natural rubber latex, and various medications. Studies have shown that exposed healthcare workers are at risk for work-related rhinitis and asthma. For example, high prevalence rates of occupational asthma are found in nurses (10.7%) in Japan according to the Japanese Guidelines for Occupational Allergic Diseases published in 2020 (84). A review of cross-sectional studies indicated that occupational rhinitis affects 10%∼60% of healthcare workers, and occupational anaphylaxis was most frequently triggered by natural rubber latex, chemicals, disinfectants, and medications (85). The inflammatory response of allergic rhinitis continues to interact with the imbalance of nasal flora. Exposure to allergens will induce changes in the bacterial flora of the nasal mucosa, leading to acute sinusitis, nasal eosinophilia, and more serious nasal symptoms, which will reduce the quality of life (70). In addition to occupation-related allergens, the adhesion or colonization of specific opportunistic pathogens in the nasal mucosa is also an important risk factor for inducing chronic airway inflammation leading to allergic respiratory diseases (86). It has been reported that the oropharyngeal colonization of Streptococcus pneumoniae and Haemophilus influenzae in healthcare workers working in hospitals is as high as two times compared to non-healthcare workers (87, 88). It has also been documented that healthcare workers (89), medical laboratory staff due to direct and dense contact with the pathogens, and those living with hospital staff have a higher prevalence of Methicillin-resistant S. aureus (MRSA) nasal colonization. The isolates also appeared more virulent while all isolates were β-lactamases positive (90). Another study indicated that the carriage rates of S. aureus and MRSA among surgical HCWs (32.4%) and nurses (30.8%) were relatively higher, while the highest MRSA rate was detected in nurses (91). The presence of Staphylococcus spp. was more prevalently in the hands of HCWs working in the internal medicine ward and the surgical ward, which is about six times compared to personnel in the neonatal unit, while those with multidrug-resistant or extensively drug-resistant strains were isolated (92). It was also demonstrated that Staphylococcus spp. were most frequently (40%) isolated from the cellphones of hospital staff, while Gram-positive isolates were all susceptible to the antibiotic used and Gram-negative isolates were all resistant to ceftazidime (93). The establishment of a balanced and healthier respiratory microflora through the intervention of oropharyngeal probiotics among healthcare workers and their families is expected to help protect their long-term respiratory health and reduce the risk of transmission of resistance genes to their family members.

Antiviral microbiome mechanisms include the following: (1) enhancement of mucosal barrier function which provides a physical barrier between invasive pathogens and host epithelial cells where the tight junctions and mucosal permeability are maintained by commensal microbiome; (2) antimicrobial compounds, such as bacteriocins, produced by commensal microbiome; (3) inhibition of viral attachment to host epithelial cells by various cross-immune reactions; and (4) modulation of the immune system, such as downregulating inflammatory immune pathways and/or enhancing innate and/or adopted immune pathways and cytokine signaling (94). In children with regurgitation and microaspiration syndromes, the use of oropharyngeal probiotic Bactoblis had a pronounced positive effect on the respiratory microbial composition, of which the pathogenic Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Klebsiella pneumoniae were significantly reduced (95). A study conducted on young athletes performing a high-intensity training program showed that short-term administration of oropharyngeal probiotic Bactoblis significantly increased salivary immunoglobulin (sIgA) secretion in young athletes, an indication of a potential immune enhancement (96). Since the oropharynx is a primary source of the lung microbiota community which contributes to the susceptibility to viral infections, a preliminary study showed that a 14-day administration of oropharyngeal probiotic Bactoblis reduced the mortality rate of hospitalized COVID-19 patients, improving the clinical parameters associated with pulmonary inflammation caused by viral infections and immune responses (97). These clinical evidence-based findings reflected these mechanisms and suggested that improving the respiratory microbiota may enhance immune function and anti-inflammatory effects. Therefore, more research on respiratory microecological intervention and immune regulation mechanisms will provide a more solid theoretical foundation for clinical application and evidence-based medicine.

The rise of antibiotic resistance and a dwindling antimicrobial pipeline have been recognized as emerging threats to public health (98). Enormous therapeutic challenges may present in specific groups of children who have a higher risk of acquiring antibiotic-resistant genes. For example, a major proportion of pneumococci isolated from the nasopharyngeal aspirates of inpatient children with respiratory infections were resistant to more than three types of antibiotics in China (99). Resistant bacteria are present in significant amounts in the adenoids of children with middle ear disease and rhinosinusitis symptoms compared with healthy children (100). A large-scale multicenter study showed that the resistance rate of ampicillin and azithromycin in H. influenzae isolated from the respiratory tract in Chinese children showed an increasing trend through the years, and the major multidrug resistance pattern was resistant to β-lactams, macrolides, and sulfonamides (101). Group A Streptococcus (GAS) is an important cause of acute pharyngitis, and its positive rate in throat culture was about 20% in younger children (102). A retrospective study conducted for 20 years in Taiwan indicated that there was a significant increase by three times to reach about 60% (p < 0.0001) in macrolide-resistant Group A Streptococcus in children with URTi, especially for those diagnosed with scarlet fever (103). The outcome was supported by a similar result from a study conducted in Beijing that prevalent strain of Group A Streptococcus collected from pediatric outpatients who were diagnosed with scarlet fever has a high resistance rate to macrolides at over 90% (104). In a recent study, a strong seasonal epidemiological association between respiratory syncytial virus (RSV) and Streptococcus pneumoniae (pneumococcus) was confirmed by a parallel decrease and a subsequent resurgence during and after the COVID-19 pandemic, respectively (105). Considering the increased concurrent pediatric RSV infections and GAS pharyngitis and the high prevalence of resistant genes in children, the intervention of oropharyngeal probiotics has great potential to support the management of an important public health condition. From 1990 to 2021, deaths due to antimicrobial resistance increased by over 80% among individuals aged 70 years and older globally (106). This indicates the growing challenge of antibiotic resistance, which is now recognized as a global public health crisis. It is essential that everyone, from individuals to countries, actively respond to and take action to address this emergency. Clinicians should play a central role in addressing antibiotic resistance, and medical training is a key factor in this effort. However, there remain gaps between the knowledge and practices among healthcare workers regarding antibiotic use. There is a clear need for multifaceted interventions targeting the public to improve behaviors of rational use of antibiotics.