Qiang Wang ^1* Yatong Zhang ² Xiaoling Cheng ³ ZHI GUO ⁴ Yang Liu ⁵ Li-Hong Xia ⁶ Zhigang Liu ⁷ Junqing Zheng ⁷ Zihe Zhang ⁸ Kai Sun ⁹ Guanxin Shen ¹⁰

• ¹ School of Medicine, Wuhan University of Science and Technology, Wuhan, Hebei Province, China
• ² Beijing Hospital, Beijing, China
• ³ Beijing Children’s Hospital, Capital Medical University, Beijing, Beijing Municipality, China
• ⁴ Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
• ⁵ Wuhan Asian General Hospital,, Wuhan, China
• ⁶ Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
• ⁷ Jinan Maternity And Child Care Hospital, Jinan, Shandong Province, China
• ⁸ Shandong Maternity and Child Care Hospital, Jinan , China, Jinan, Shandong Province, China
• ⁹ First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
• ¹⁰ Tongji Medical College Huazhong University of Science and Technology, Wuhan, China

infection or allergic constitution. In recent years, many studies have attempted to explore the effects of human microbiome-based interventions on the regulation of host immunity and the prevention of respiratory tract infections. However, the heterogeneous and inconsistent reproducibility between studies resulted in inconsistent opinions among physicians in terms of the recommendation of probiotics to patients. As an evidence-based research method recommended by academia in recent years, probiotic finished product research is an effective method to promote the development of probiotics industry. The research results are more consistent with the clinical outcomes in a realworld setting and hence conducive to experts' clinical use and also inform consumer decisions. This expert panel suggests that the upper respiratory tract probiotic Bactoblis can be a valuable tool for physicians to recommend to patients in addition to standard drug therapy. This recommendation is based on its successful application in clinical practice in China and Europe, positive patient feedback, and evidence from multiple clinical trials limited to those where a single finished product was admistered to subjects. The panel also encourages physicians to explore new research areas related to respiratory microbiota, believing that such interventions hold great potential for improved disease management and enhancing patients' quality of life. Expert Consensus Complementary use together with standard treatment to ameliorate disease when standard therapy does not improve health conditions effectively Complementary use together with standard treatment to ameliorate disease when standard therapy does not improve health conditions effectively The upper respiratory tract is a crucial site for host defense, as it is home to bacterial communities that both modulate host immune defense and serve as a reservoir of potential pathogens. During the first few years of life, much like the gastrointestinal tract microbiome, nasopharyngeal microbiota in young children changes from an immature state to a more diverse state as it matures to resemble the adult microbiota, resulting in a higher risk of respiratory illness in young children [1]. According to a systematic analysis on respiratory infections for 33 provinces in China from 1990 to 2019, a consistently increasing trend in the number of RTi cases was observed. RTi cases in 2019 was 3%, 5% and 11% higher than that in 2010, 2000 and 1990, respectively. The incidence rate of URTis was the largest in younger children indicating that the future URTi and LRTi prevention strategies should focus on the maternal and child health, especially in young children [2]. URTIs, although they are generally mild and resolve spontaneously, can significantly impact the quality of life, school attendance of children work absence for caregivers. Paediatricians andcaregivers require prevention strategies to reduce the recurrence incidence in children prone to frequent RTIs to reduce medical visits. Risk factors that are significantly associated through odds ratio (OR) with recurrent respiratory tract infection include asthma(OR = 8.31 (P < 0.001)), allegry (OR = 2.31 (P < 0.001)), initial use of antibiotics (OR = 1.72 (P < 0.001)), breastfeeding duration < 6months (OR = 1.24 (P<0.002)), and maternal body mass index 1.19 (P < 0.001) [4]. In general, distinct microbial maturation patterns involved with early asymptomatic respiratory viral presence and dynamics in gene expression profiles [5], translate into either a beneficial microbiota or susceptibililty to RTI development and/or asthma and/or allergic rhinitis. A "three-hit" model for chronic RTI development begins with an establishment of non-beneficial respiratory microbiota as the first hit, suffering RTi with varying degree of severity as second hit, and progression to a long-term inflammatory airway status as the third hit [6]. The strategies for managing pediatric recurrent respiratory tract infections (RRTi) can be built on several key approaches. One approach focuses on modulating non-specific immune responses to strengthen the body's natural defenses against infectious agents. Another involves enhancing specific immune responses to directly combat respiratory pathogens. Additionally, managing inflammation through anti-inflammatory responses can help reduce infection-or pathogeninduced airway inflammation. Modulating respiratory microflora through the administration of probiotics that colonize the airway is also promising. This approach aims to improve the interaction between host commensal bacteria and the immune system, ultimately reducing susceptibility to RRTi.To date, unnecessary antibiotics are widely prescribed for pediatric RTIs and most pediatric patients with RTIs do not receive guideline-recommended antibiotic classes in Chinese primary healthcare facilities [7],. Meanwhileparents often resort to self-medication with antibiotics to their children in China [8]. Unfortunately, microbiome recovery lost diversity after short courses of antibiotics and can be delayed by Azithromycin, the long-term effect of altered diversity, resistance and composition is considered as "antibiotic scarring" [9].Well documented evidence suggests that early antibiotic exposure affects the development of infant gut microbiota and the disturbances in host increase the susceptibility to variety of diseases later in life including respiratory infections.[10],In addition, antibiotic use in early life preferentially impairs the development of lung mucosal-associated invariant T (MAIT) cell which plays an important role in recognizing a broad array of respiratory pathogens [11].Antibiotic-induced microbial disruption in early life can be exacerbated by the vertical transmission of resistance genes from mother to offspring during pregnancy and lactation, and [12], is associated with higher risks of childhood metabolic disorders [13], neurobehavioral conditions including autism spectrum disorder, intellectual disorder, language disorder, epilepsy [14], and Juvenile Idiopathic Arthritis (JIA) [15].Although most recent reviews reveal the variable outcomes, knowledge gaps and insufficient evidence to recommend probiotic for prevention or management of RTi conditions [16][17][18][19], specific formula with consistent positive clinical results should be recommended, and be considered as a possible supportive approach in selected patients to improve their quality of life and reduce the burden of RTIs.Oropharyngeal probiotics, Bactoblis has clinical and real-world evidence for indications of selected Therefore, it is extremely important for healthcare professionals to be properly educated and updated on the knowledge of oropharyngeal probiotics even though their awareness towards gut probiotic has been well-established [21], with the purpose of assisting pediatricians or practitioners who are willing to offer their patients an alternative option to safely and effectively manage their respiratory conditions and appropriately recommend the use of oropharyngeal probiotics. The following professional recommendations are meant to be broadly applicable and should be viewed as the preferred alternative and adjunctive approach. However, they are not meant to replace standard approaches and clinical management strategies depend on individual clinical scenarios. This project aims to support decision-making in respiratory health based on scientific evidence and the daily life of both the pediatric patients with respiratory infections and their care-givers.A meeting of our consensus panal consisting of clinical and scientific experts (with specialties in paediatrics, obstetrician and gynecologist, oncologist, pharmacist, immunology and microbiology scientists) was convened to review, examine, select and synthesize 38 evidence-based publications on oropharyngeal probiotics, and organized them into 2 main topics, which are the existing evidencebased science and the recommendation for future researches, respectively. Participants in the meeting jointly considered key questions and generated and approved the outcomes hereby summarized.We hope that this consensus statement will provide consensus views on the appropriate use of oropharyngeal probiotic, and recommendations for future research associated with oropharyngeal probiotics and human respiratory health. societies and group of experts technically reviewed 10 clinical trials conducted with oropharyngeal probiotics with documented efficacy for management of RRTi published since 2012 with a total of 832 children participating.Oropharyngeal probiotic Bactoblis was given in the form of slowly dissolving oral lozenges, to be administered before bedtime after brushing teeth every evening and subjects were required to suck the lozenge until fully dissolved (approximately 4-5 min) and making sure that the lozenge was not chewed or directly swallowed. They were suggested not to drink or swallow any substance for at least 1 hour 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 two hours 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: Probioticcs and Prebiotics 2024 [22], 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, the 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 intervention. The risk of antibiotic exposure was significantly higher among controls than among subjects administrating oropharyngeal probiotic Bactoblis. Limitation 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, 4 were carried out in Ukraine and published in Ukrainian with the abstract in English and in most cases were publish 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 that represents a significant burden on children, their families, and the healthcare system is the major cause of hearing loss and serious life-long sequelae, such as behavior, attention [34], anxiety, learning and speech-language problems in early and late childhood [35], if left their chronic and recurrent otitis media 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 [36]. antibiotics are generally used empirically for treating chronic suppurative otitis media, which may lead to the emergence of resistant bacterial strains [37]. In addition, official recommendations differ regarding tympanostomy-tube placement that could favoring 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 [38]. Relative abundances of potential pathogens such as Haemophilus influenzae, Streptococcus pneumonia and Moraxella catarrhalis in the upper respiratory tract, might lead to further investigation into new preventive measurements for acute, secretory and recurrent otitis media [39]. 7 studies with evidence for 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 alter subsequent immune function against secondary bacterial infection or the dynamics of inter-microbial interactions, thereby enhancing the proliferation of potentially pathogenic bacterial species. [45],Increased microbial diversity and growth rates of specific pathogens in upper respiratory tract was observed, oropharyngeal microbiota is type-specifically disrupted by the infection of influenza A virus (FluA), influenza B virus (FluB), respiratory syncytial virus (RSV), and human rhinovirus (HRV) [46], as well as Omicron or other variant of SARS-CoV-2 viruses [47].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 [48]. 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 start of daycare and linked to consecutive development of symptomatic RTIs [49]. In summary, restoring the loss of topography is linked to the prevention of subsequent development of RTi episodes. 4 Studies suggesting the clinical benefit on 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［51］, except recurrent antibiotic prescription, 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［52］, importantly, a cohort study of 1.2 million patients followed for up to 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 [53]. 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 adenoid [54]. Surgical removal of adenoids and tonsils to treat obstructed breathing or recurrent middle-ear infections remain common pediatric procedures, however, meta-analysis of current literature included more than a thousand subjects demonstrated that pediatric sleep apnea is often not cured by tonsillectomy and adenoidectomy [55]. Chronic adenoiditis occurs frequently in children, and it 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 who fail to respond to traditional antibiotic therapy, which may predispose a child to long-term functional sequalae and auditory impairment [56].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 [57]. Further investigation of individual microbiomes in a longitudinal design with implantation of protective oropharyngeal probiotic may have a potential to lead to new strategies as an alternative to adenoidectomy. 4 Studies demonstrating that 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 [61] , further, the 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 [62]. 2 Studies evidencing that oropharyngeal probiotic Bactoblis can provide clinical benefit on PFAPA management is listed in Table 5. To restore the beneficial nasopharyngeal microbiota could be an alternative approach for selfmanagement in pediatric patients with allergic respiratory conditions. Evidence from observational studies of children attending daycare revealed that nasopharyngeal probiotics Bactoblis administration in children was associated with an increased abundance of commensal S. salivarius in saliva and a lower abundance of otopathogens, Moraxella, in nasopharynx which is strongly associated with the exacerbation of asthma [72] . More research on oropharyngeal microflora intervention might will 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 is still not clear. The World Health Organization (WHO) and The International Labour Organization (ILO) have 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 [85] ，a review of cross-sectional studies indicated that occupational rhinitis affects 10~60% of healthcare workers, while the occupational anaphylaxis was most frequently triggered by natural rubber latex, chemicals, disinfectants and medications [86] . 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 and nasal eosinophilia, leading to more serious nasal symptoms, which will reduce the quality of life［71］. 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［87］.It has been reported that the oropharyngeal colonization of Streptococcus pneumoniae and haemophilus influenzae in health care workers working in hospitals is as high as 2 times comparing to non-healthcare workers [88][89] , it was also documented a higher prevalence of Methicillin-resistant S. aureus (MRSA) nasal colonization in healthcare workers [90], medical laboratory staff due to direct and dense contact with the pathogens, and those living with hospital staff, the isolates also appeared more virulent while all isolates were β-lactamases positive [91],another study indicated that the carriage rates of S. aureus and MRSA among surgical HCW (32.4%) and nurses (30.8%) were relatively higher, while the highest MRSA rate was detected in nurses [92].The presence of Staphylococcus spp. was more prevalently on the hands of HCWs working in the internal medicine ward and the surgical ward, which is about 6 times compared to personnel in neonatal unit, while those with multi-drug resistant or extensively drug resistant strains were isolated[93], 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 [94]. The establishment of a balanced and healthier respiratory microflora through the intervention of oropharyngeal probiotics among health care 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. The rise of antibiotic resistance and a dwindling antimicrobial pipeline have been recognized as emerging threats to public health [99]. Enormous therapeutic challenges may present in specific groups of children who have higher risk acquiring antibiotic resistant genes. For example, major proportion of pneumococci isolated from the nasopharyngeal aspirates of the inpatient children with The panel conducted a technical review of evidence-based clinical review and completed the first expert consensus on the adjuvant use of oropharyngeal probiotics for the management of pediatric respiratory tract infections and otitis media based on the clinical studies that explicitly labeled the use of evidence-based finished formulas rather than formula with only strains described of which the clinical benefit is undefined.The consensus process aims to help more doctors understand how to use the evidence-based oropharyngeal probiotic Bactoblis as dietary supplement, an assistive tool, to be adjunctively used with standard treatment and help their patients better manage their respiratory health, especially for the refractory pediatric recurrent and chronic respiratory tract infections, such as recurrent and suppurative otitis media, recurrent tonsillitis, chronic adenoiditis, etc., adjuvant or prophylactically supplemented with oropharyngeal probiotics can safely reduce the incidence of respiratory tract infections and shorten the course of infectious episodes. Meanwhile, children and parents or their caregivers can also be benefited from the reduced absence from school due to illness, absence due to care-giving, and reduced need for prescriptions of antibiotics and antiviral drugs. This expert consensus can be considered as a widely applicable strategy for self-health management that is accepted according to the patient's active will. The recommendation of oropharyngeal probiotics is not intended to replace any standard treatment. The expert consensus provided by this panel serves only as a reference to best practice, and the diagnosis and treatment of the disease is determined by the physician on a case-by-case basis. The ［15］ KINDGREN E，LUDVIGSSON J.Infections and antibiotics during fetal life and childhood and their relationship to juvenile idiopathic arthritis：a prospective cohort study［J］.Pediatr Rheumatol，2021，19(1)：145. [23] . 3-12 Among 65 children with a history of recurrent streptococcal respiratory infections, 45 were treated with oropharymgeal probiotics for 90 days, and the remaining 20 subjects that did not take any probiotics served as recurrent control group. Another 17 children without recurrent respiratory infections were served as healthy control group. The incidence of streptococcal pharyngotonsil infection decreased by 92% (p<0.0001) compared to that of previous year during the 90-day oropharyngeal probiotic administration, while it increased by 39% (p<0.001) in children of recurrent control group, in contrast, there was a non-significant increase of 29% in the incidence of streptococcal pharyngotonsil infection among healthy control children compared to that of previous year. During the 6-month follow-up period, children with recurrent streptococcal respiratory infections who received oropharyngeal probiotics experienced a significant reduction of 66% (p=0.0278) in the incidence of pharyngeal tonsillitis compared to children in the recurrent control group. Pierro et al [24] .2013 40 18-65 20 adult patients with streptococcal recurrent pharyngitis or tonsillitis were treated with oropharyngeal probiotics for 90 days as probiotic group and 20 of whom did not take probiotics as a control group. The incidence of pharyngeal tonsillitis in adults during oropharyngeal probiotic administration decreased by 84% (p<0.001) comparing with that of previous year, while it increased slightly by 14% (p<0.001) in control patients; During the 6 months of follow-up period, the incidence of pharyngeal tonsillitis in probiotic group was 62% lower than that in the control group (p=0.0389). Pierro et 2014 b 60 3-13 The prevalence of streptococcal pharyngotonsillitis decreased significantly by 96.8% (p<0.001) during 90 days of oropharyngeal probiotics administration compared with the same quarter of the previous year in children with al [25] .recurrent streptococcal pharyngotonsillitis, while the prevalence of viral pharyngeal tonsillitis was significantly reduced by 80% (p<0.01), the prevalence of streptococcal pharyngotonsillitis and viral pharyngotonsillitis in the control group was not significantly different from that in the previous year. Further, the days of medication, absent from school for children, and absent from work for parents due to caregiving to their children were reduced during the study. Pierro et al [26] . 3-10 48 children with recurrent streptococcal adenoiditis were given oropharyngeal probiotics for 90 days, and another 76 children without recurrent adenoiditis were enrolled as healthy controls. The prevalence of adenoiditis in children was significantly reduced by 89.6% (P<0.01) during oropharyngeal probiotic administration compared to that in the previous year, while it increased by 33.3% non-significantly in healthy controls. Prevalence of various respiratory tract infections in children was significantly lower during oropharyngeal probiotics administration compared with that of healthy controls, including a 93% (P<0.01) reduction in bronchitis, a 76% (P<0.01) reduction in viral pharyngitis, a 69% (P<0.05) reduction in rhinitis, a 95% (P<0.01) reduction in influenza, a 93% (P<0.01) reduction in laryngitis, and a 100% (P<0.01) reduction in acute otitis media.Grego ri et al [27] .2016 b 130 3-776 children with recurrent streptococcal pharyngotonsil were treated with oropharyngeal probiotics for 90 days, and 54 children took no probiotics as a control group, and were followed up for 9 months. During the one-year observation period, administration of oropharyngeal probiotics for 3 months significantly reduced the prevalence of streptococcal pharyngotonsil infection by 82% compared to children in the control group (p<0.001).Kryuc hko et al [28] .2017 66 3-10 Pediatric outpatients were classified as three subgroups according to the diagnosis, including 26 in the recurrent pharyngotonsil infection group, 22 in chronic adenoid or tonsil hypertrophy group, and 18 in beta-Hemolytic Group A Streptococcus (BHSGA) infection group, and children in each subgroup were further assigned to take oropharyngeal probiotics for 30 days or to take no probiotic as controls, and then been followed up for 5 months. In the BHSGA subgroup, the prevalence of BHSGA pharyngotonsil infection in children taking oropharyngeal probiotics during the study period was 90% lower than that in the previous year (p<0.001), was 86% less than that in control children (p< 0.001); In chronic adenoid or tonsil hypertrophy subgroup, oropharyngeal probiotics in combination with medication significantly improved the severity of chronic adenoiditis-associated symptoms, such as nasal dyspnea, mouth breathing and snoring during sleep, cough (mainly at night and in the morning), nasal congestion, and hearing loss by about 2 times, compared with children using only a drug prescription; In recurrent pharyngotonsil infection subgroup, significant changes in the pharyngeal microbiome composition were observed during oropharyngeal probiotic administration, especially the decrease in the detection rates of pathogenic haemophilus, staphylococcus aureus, Streptococcus pneumoniae, and streptococcus pyogenes, whether been compared to the time before the study started or been compared with the control group, while the risk of various respiratory infections was lower than that in the control group, including a 75% reduction in the incidence of viral pharyngitis (p<0.01), a 92% reduction in the incidence of bronchitis (p<0.01), a 65% reduction in the incidence of rhinitis (p<0.05), a 86% reduction in the incidence of laryngitis (p<0.01), and a 100% reduction in the incidence of otitis media (p<0.01). During the entire six-month study period, it was observed that the protective effect of 30-day oropharyngeal probiotics administration may lasted for a few months after cessation of oropharyngeal probiotics administration, while this protective benefit decreased during the fourth month.Kryuc hko et al [29] .2018 c 48 3-14 Pediatric outpatients diagnosed with recurrent adenoiditis or recurrent respiratory infections were treated with two adjuvant courses of oropharyngeal probiotics for 30 days in each course with a 90-day interval, and were followed-up for 6 months of clinical observation. Compared to the same time of previous year, the incidence of streptococcal adenoiditis in children treated with two adjuvant courses oropharyngeal probiotics decreased by 87% during the study period compared to that in the previous year (P<0.001), the incidence of non-streptococcal caused adenoiditis was reduced by 90% (P<0.001), the incidence of acute otitis media was reduced by 70% (P<0.001), the incidence of viral pharyngitis was reduced by 67% (P<0.01), the incidence of bronchitis was reduced by 94% (P<0.01), the incidence of rhinitis was reduced by 61% (P<0.05), the incidence of influenza was reduced by 81% (P<0.01), the incidence of laryngitis was reduced by 81% (P<0.01), and the incidence of stomatitis was reduced by 83% (P<0.01). In addition, the number of days taking antibiotics decreased by 86% (P<0.01), the number of days taking antipyretics decreased by 80% (P<0.01), children missed 81% fewer days of school (P<0.01), and 77% fewer days of parental absence from work due to caregiving (P<0.01) were observed.Marini et al [30] .2019 100 5-10 Children diagnosed with recurrent streptococcal tonsillitis and recommended by thier doctor to receive adenotonsillectomy were recruited, 50 were given oropharyngeal probiotics for 90 days as probiotic group, while 50 did not take any probiotics in a control group, they were followed-up for one year for clinical observation since the start of oropharyngeal probiotic administration. All children received medication at the onset of tonsillitis during the study period according to standard clinical practice. Supplementation with oropharyngeal probiotics reduced the needs for adenotonsillectomy in children by 72%. Despite the lower prevalence of adenotonsillectomy in probiotic group during the study period, a lower incidence of pharyngeal tonsils, fewer days receiving antibiotics and fewer days of school absence were observed in children in the probiotic group compared to the controls.Ilchen ko et al [31] . Puhlik et al [32] . 2021 90 15-40Adolescents and adults diagnosed with Streptococcus pyogenes-associated recurrent pharyngotonsillitis were recruited, 30 were adjuvantly treated with oropharyngeal probiotics for 30 days in addition to standard medication, 30 were adjuvantly treated with oropharyngeal probiotics for 30 days in addition to standard medication and vacuum aspiration to remove nasal and tonsil secretions, and the other 30 only received standard medication as a control group. Follow-up was continued up to 9 months. During the 9 months study period, oropharyngeal probiotics combined with tonsil vacuum aspiration had the best effect on preventing pharyngotonsil infections. The prevalence of pharyngotonsillitis in both groups receiving oropharyngeal probiotics was lower than that in the control group, while the pharyngeal detection rate for pathogenic streptococcal bacteria in swab was lower in patients adjuvantly treated with oropharyngeal probiotics comparing to those who were not.Guo et al [33] .2022 973-10 Children with recurrent respiratory infections were recruited and randomly assigned to probiotic group to adjuvantly treatment with oropharyngeal probiotics for 30 days in addition to standard medication, or to the control group managed with standard treatment alone. Compared to children in the control group, adjuvant administration of oropharyngeal probiotics effectively protected children from new episodes of respiratory infections during both the 30-day intervention period and the 30-day follow-up period. Specifically, a 56% reduction in the prevalence of respiratory infections (p<0.05), the duration of disease was shortened by 27% (p<0.05), the average days of respiratory infection decreased by 68% (p<0.05), the number of days taking antibiotics decreased by 97% (p<0.05), and the number of days taking antiviral drugs decreased by 90% (p<0.05). It is worth noting that, during the clinical observation period, no new respiratory infections were observed among children in the probiotic group since the day-10 of initiation to the end of the study (p=0.002), while no antibiotic courses were prescribed among children in the probiotic group from the day-6 of initiation to the end of the study (p=0.001). This observation suggests the protective effects of oropharyngeal probiotics for children with history of recurrent respiratory infections. al [23] .2012 82 3-12 Among 65 children diagnosed with recurrent streptococcal respiratory tract infections, 45 were assigned to take oropharyngeal probiotics for 90 days as probiotic group and 20 did not take any probiotics as a recurrent control group, while another 17 children without recurrent respiratory tract infection were considered as a healthy control group, they were followed up for six months. The incidence of acute otitis media was reduced by 40% (p<0.01) in children during oropharyngeal probiotic treatment compared with that in the previous year, while the incidence of acute otitis media was 2.16 times (p<0.05) higher than that of the previous year in the recurrent control group and 1.95 times (p<0.05) higher in healthy control group. during the study period was 1.95 times higher than in the previous year (p<0.05). During the 6-month follow-up period, the incidence of acute otitis media in children receiving oropharyngeal probiotics was 82% lower than that in the recurrent control group (p=0.0278). al [40] .2015 22 3-9Children diagnosed with recurrent otitis media with unilateral or bilateral middle ear effusion for more than two months were given oropharyngeal probiotics for 90 days, the incidence of acute otitis media episodes was reduced by 42.5% (p<0.01) during probiotic administration compared with that in the previous year, while the left and right ear tone audiometry scores decreased by 55% and 66%, respectively (p<0.01); Endoscopic scores for left and right ear decreased by 39% and 40%, respectively (p<0.05); Nasal endoscopy score decreased by 28.6% (p<0.01); Tonsil test scores decreased by 36.8% (p<0.01).In addition, the middle ear effusion was significantly improved in about 80% of children with recurrent otitis media after 90 days of oropharyngeal probiotic administration. al [41] .2016 222 3 Healthy children who attended kindergarten for the first year were given oropharyngeal probiotic for six months, compared with the control group who did not take any probiotics, the incidence of acute otitis media decreased by 45% (p<0.01) during the six months of oropharyngeal probiotic administration, and decreased by 67% (p<0.05) during the three months of follow-up period. et al [28] .2017 b 66 3-10 No incidence of otitis media infection was observed among children with recurrent otitis media during the oropharyngeal probiotic administration for 30 days, while the incidence was 18% in children who did not take oropharyngeal probiotics during the same period. al [42] .2018 b 133 3-14 Compared with the previous year, the incidence of acute otitis media in healthy children without recurrent otitis media reduced by 71% (P<0.001) during the 1 year study period while oropharyngeal probiotics were administrated at intervals in the spring and autumn of the year.Havrylenko et al [43] .2019 b 22 2-6The incidence of acute otitis media decreased by 71% (P< 0.01) during 30 days of oropharyngeal probiotic administration in children diagnosed with secretory otitis media, compared to that of the previous year, while both the left and right otoscopy scores significantly decreased by 68% and 62%, respectively (p<0.05), nasal endoscopy score decreased by 59% (p<0.01), and both left and right middle ear effusion was significantly improved by 86% and 78%, respectively (p<0.05). et al [44] .2021 58 2-4 In the first year of kindergarten, healthy children who were given oropharyngeal probiotics had a reduced incidence of otitis media by 90% (p<0.01) during the 90 days of probiotic administration comparing to those who did not take any probiotics, while a reduced incidence of otitis media by 91% (p<0.01) was observed during the followed up period of six months compared with those who did not take probiotics. Pierro et al [41] . Healthy children who entered kindergarten in the first year were assigned to take oropharyngeal probiotic for six months, while the others did not take any probiotic as control group were followed up for three months. The incidence of pharyngeal tonsillitis decreased by 67% (p<0.01) during the 6 months of oropharyngeal probiotic administration comparing to control group, the incidence of pharyngeal tonsillitis showed a decreasing trend during the follow-up period. et al [42] .2018 b 133 3-14 Healthy children were given oropharyngeal probiotics for three months in the spring and autumn of the year, and followed up for a year, the prevalence of streptococcal pharyngotonsil infection in children during the 1 year study period decreased by 89% compared with that of the previous year (p< 0.001), the prevalence of non-streptococcal pharyngotonsil infection decreased by 94% (p< 0.001), days of antibiotic use decreased by 88% (p< 0.01), days of antipyretic drug use decreased by 85% (p< 0.01), days absent from school due to illness decreased by 85% (p< 0.01), days of parental absence from work due to care-giving decreased by 75% (p< 0.01) compared with those of the previous year. al [44] . 2021 58 2-4 In the first year of kindergarten, healthy children were given oropharyngeal probiotics for 90 days and were followed up for six months. Compared to those who did not take any probiotics as control group, the prevalence of pharyngeal tonsillitis decreased by 92% (p< 0.01), bronchitis decreased by 63% (p< 0.01), rhinitis decreased by 61% (p< 0.01) and laryngitis decreased by 79% (p< 0.01) in children during oropharyngeal probiotic administration. During the 6 months follow-up period, the prevalence of pharyngeal tonsillitis decreased by 82% (p< 0.01), bronchitis decreased by 65% (p< 0.01), rhinitis decreased by 63% (p< 0.01) and laryngitis decreased by 71% (p< 0.01) among children in probiotic group compared to those in control group. Throughout the study period, children in the probiotics group were significantly less likely to be prescribed medications and absent from school than those in the control group, of which 65% (p< 0.01) fewer days of antibiotic use, 73% (p< 0.01) fewer days of antipyretic drug use, and 61% (p< 0.01) fewer days of absent from school were observed. al [50] . 2021 62 0.5-2 Healthy infants and toddlers were randomly assigned into probiotic group to take oropharyngeal probiotics for 30 days and control group to not taking any probiotics as control group and were followed up for 3 months. Healthy infants and toddlers who took oropharyngeal probiotics were better protected from respiratory infections throughout the study period compared to controls, with a 65% (p< 0.01) reduction in the prevalence of viral acute respiratory infections, a 76% (p< 0.01) reduction in the prevalence of secondary bacterial respiratory infections, a 86% (p< 0.01) reduction in the number of otorhinolaryngologic outpatient visits, a 81% (p< 0.01) reduction in days of antibiotic use, and a 55% (p< 0.01) reduction in days of antipyretic drug use. Karpo va et al [58] .2015 219 6-7The incidence of acute adenoiditis decreased by 44% in children diagnosed with chronic adenoiditis during the 30 days of oropharyngeal probiotics administration along with nasal irrigation, compared to those only treated with nasal irrigation as conservative treatment, while it decreased by 74% during the 90 days follow-up period. The incidence of acute otitis media, a common complication of chronic adenoiditis in children receiving oropharyngeal probiotics, also decreased by 62%.Maru shko et al [59] . Children with chronic tonsillitis manifestinged symptoms more than twice a year and treated with conservative nasal irrigation, of whom 70% had symptoms of enlarged tonsils, were treated with oropharyngeal probiotics for 30 days in May and 30 days in September respectively. During the observation period of 30 and 180 consecutive days from the beginning of probiotic administration, various clinical symptoms related to chronic tonsillitis improved over time, including a 14% and 52% reduction in the prevalence of enlarged tonsils at 30 and 180 days, respectively (p<0.05), the prevalence of general discomfort decreased by 57% and 74%, respectively (p< 0.05), low-grade fever decreased by 88% and 80%, respectively (p<0.05), arthralgias decreased by 65% and 55%, respectively (p<0.05), palpated lymph node enlargement decreased by 23% and 47%, respectively (p<0.05), leucocytosis decreased by 89% and 87%, respectively (p<0.05), leukemia-like reactions decreased by 43% and 91%, respectively (p<0.05), C-reactive protein both increased by 97% (p<0.05), and allergic manifestations caused by aggravation of tonsillitis decreased by 82% and 100%, respectively (p<0.05). During the study period, the detection rate of pathogenic bacteria on the pharyngeal tonsillar mucosa also decreased with time, including a reduction of Beta-Hemolytic Group A Streptococcus (BHSGA) by 82% and 67% at 30 and 180 days, respectively (p< 0.05), BHSGA associated with Staphylococcus aureus decreased by 100% and 71% at 30 and 180 days, respectively (p< 0.05).Gavril enko et al [60] .2018 57 6-10Children diagnosed with recurrent pharyngeal tonsillitis were divided into three subgroups, including ones of chronic tonsillitis, hemolytic streptococcal infection, and swollen pharyngeal tonsillitis. Children in the three subgroups were further randomly assigned to probiotic group to take oropharyngeal probiotics for 30 days while the others not to serve as control group. Children received oropharyngeal probiotics for 30 days had an 85% (p< 0.05) reduction in the incidence of hemolytic streptococcal respiratory infections throughout the clinical observation period of 5 months comparing to the same period in previous year, while there was no significant difference in the control group. Chronic tonsillitis-related symptoms, such as shortness of breath, mouth breathing during sleep, snoring, cough (mainly during the night and in the morning), nasal congestion, and hearing loss, showed significant improvement since day 10 after the start of the study. There was a decreased trend of detection rate for Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, pneumococcus and other pathogenic bacteria in the throat samples among children in the chronic tonsillitis subgroup during the 30 days of oropharyngeal probiotics administration compared with those in the control group.Mari ni et al [30].2019 100 5-10Children diagnosed with chronic streptococcal tonsillitis who were recommended to receive adenotonsillectomy were randomly assigned to take oropharyngeal probiotics for 3 month while the others did not take probiotics as a control group, and been followed-up for another three quarters. 72% less of children taking oropharyngeal probiotics underwent adenotonsillectomy throughout the study period comparing those in the control group. Further, comparing to those in control group, a reduction of 64%, 50%, 39% and 43% (p< 0.01), respectively, in the incidence of tonsillitis during each querter of the study period was observed in children taking oropharyngeal probiotics, the number of days receiving antibiotic also decreased by 81%, 60%, 58% and 53% (p< 0.01) during each quarter, respectively, in children taking oropharyngeal probiotic comparing with control group, while the days absent from school was 54% fewer in probiotic group comparing with control group during the study period. Franc esco et al [63] . The first study showing clinical evidence that significant improvement in PFAPA clinical symptoms was observed during both the 90 days of Bactoblis administration and 30 days of follow-up period, including fever, oral ulcers, the frequency and days of pharyngitis and adenoid enlargement, resulting in not only a decrease in the use of medications, such as Cortisone and Ibuprofen, but also a significantly improved life and sleep quality during the four-month study period.Torre et al [64] .2023 c 85 1-8 85 children with PFAPA at mean age of 2 years who had taken Bactoblis at mean age of 4.58 years were selected from the International Auto-Inflammatory Diseases Alliance Registry (AIDA), the mean duration of Bactoblis administration was 6 months, and the median age of PFAPA illness before starting Bactoblis administration was 19 months. During the period of taking oropharyngeal probiotics, children with PFAPA experienced significantly less episodes of febrile (85% of children had a reduced febrile episodes from a median of 13 episodes to 5 episodes; p<0.001), significantly less days of febrile (77.6% of the children experienced less days of febrile reduced from a median of 4 days to 2 days; p<0.001), while their body temperature during febrile significantly decreased by an average of 1 degree (40℃ vs. 39℃; p<0.001), the incidence of symptoms during PFAPA episodes was significantly improved, including headache (p<0.05), pharyngitis (p<0.001), oral ulcer (p<0.001), adenoid enlargement (p<0.001), abdominal pain (p<0.001), joint and muscle pain (p<0.001), resulting to a significant reduction in the needs for drugs, such as a 60% reduction in the use of the antiinflammatory betamethasone or other equivalent steroid drugs (p<0.001), no adverse reactions were reported throughout the study period.