Evaluation of the efficacy of ultra-fractioned and winterized lentisk oil in reducing symptoms of purulent bacterial overinfection of pediatric rhinitis

Evaluation of the efficacy of ultra-fractioned and winterized lentisk oil in reducing symptoms of purulent bacterial overinfection of pediatric rhinitis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Evaluation of the efficacy of ultra-fractioned and winterized lentisk oil in reducing symptoms of purulent bacterial overinfection of pediatric rhinitis Francesco Di Pierro, Giuseppe De Paolis, Antonio Gallese, Rosanna Palazzi, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7385153/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Acute purulent rhinitis in children has a shorter course and milder symptoms if treated with antibiotics. Antibiotic use, in addition to fueling antibiotic resistance, frequently causes gastrointestinal symptoms. Specific fractions of winterized lentisk oil (Pistacea lentiscus) have demonstrated unique antibiofilm and antibiotic activity against nasal and oropharyngeal pathogens potentially implicated in the symptoms of purulent rhinitis in children. In a randomized, prospective, controlled and no profit trial, the use of a class II medical device, formulated as oil drops for nasal use, containing as active ingredient a ultra-fractioned and winterized lentisk oil (UWLO) and administered for six days, demonstrated the ability to significantly reduce symptoms such as mucous rhinitis, retropharyngeal mucous discharge, halitosis, stuffy nose, and nocturnal catarrhal cough compared to treatment with isotonic saline nasal wash. The use of UWLO also tended to reduce the need for antibiotic therapy and was well tolerated and free of side effects. The data obtained suggest the use of the lentisk derivative to reduce the duration of the clinical course and the main symptoms characterizing pediatric purulent mucosa. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Biological sciences/Microbiology Mucous rhinitis mucous retropharyngeal discharge halitosis stuffy nose nocturnal catarrhal cough Pistacea lentiscus Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Acute purulent rhinitis, defined as a runny nose with coloured discharge, is a common complication of the common cold. Although its duration might vary with the prevalence of specific infecting microorganisms, natural history of purulent rhinitis is described to last about two weeks. 1 Nevertheless, the presence of purulent nasal discharge has repeatedly been shown to be an important determinant of the prescribing of antibiotics for respiratory tract infections for both adults and children, 2–4 and indeed some Authors found that purulent nasal discharge was a stronger predictor of antibiotic prescribing than any other characteristic of patients. 4 Of course, also to avoid the induction of antibiotic restance pattern, 5 most guidelines recommend that antibiotics should not be used for this condition, 6,7 also claiming negative evidence that antibiotics reduce the duration of acute purulent rhinitis. 8 However, a larger study reported that treatment with amoxicillin reduced the duration of purulent rhinitis, although it found no significant improvement in symptoms. 9 A following systematic review on the subject demonstrated a significant benefit of antibiotics, compared to placebo, in reducing the duration of symptoms in about one week following the start of treatment. 10 However, the frequency of adverse reactions, especially gastrointestinal and skin reactions, was also significantly increased with antibiotic use. Cultures from patients with purulent rhinitis grew mainly oral-pharyngeal microorganisms including S. pneumoniae , H. influenzae , and S. pyogenes while nasal crusting was significantly associated with the growth of S. pneumoniae or H. influenzae . 8 Recently, different groups of research have highlighted the effect of ultra-fractioned and winterized lentisk oil (from here on UWLO), got by berries of Pistacea lentiscus , against some nasal and oral-pharyngeal pathogens, 11-12 including its effect in preventing chronic rhinosinusitis recurrence. 13 The aim of this prospective, multicenter, controlled, non-profit study was to evaluate the safety and efficacy of using a class II medical device in the form of oil drops containing UWLO in reducing the duration of the infection and the main rhinitis symptoms. Materials and Methods 2.1. Study ethics All study procedures were conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki. The study was registered on www.clinicaltrials.gov (Registration Number: NCT06758804; First Posted Date; 27.12.2024). The study protocol received ethical approval prior to recruitment from the Ethic Committee of Carlo Bo University of Urbino (Italy) as per the Minutes of Session No. 89 of November 28, 2024. Informed consent was obtained from a parent and/or legal guardian for study participation. 2.2. Study Design Patients considered eligible and enrolled between January and April 2025 according to the inclusion and exclusion criteria, were randomized in a 1:1 ratio to create two study groups. The first was treated with three drops per nostril, three times a day, for six consecutive days, using a Class II medical device containing winterized Pistacia lentiscus oil (Bactorinol® nasal drops, PharmExtracta S.p.A., Pontenure, Italy). The second, serving as a control group, was treated for six consecutive days with nasal irrigation using a NaCl 0.9% physiological solution corresponding to 154 mEq/L of Na + and Cl - , isotonic with an osmolarity of 308 mOsm/L. 2.3. Inclusion and exclusion criteria Inclusion criteria were: (i) male and female, aged 2 to 10 years; (ii) clinical symptoms of dense mucous rhinitis and/or purulent mucus, with an onset of no more than 5 days, including mucous rhinitis, nocturnal catarrhal cough, retropharyngeal discharge, halitosis, and stuffy nose; (iii) parental informed consent. Exclusion criteria were: (i) symptom onset more than 5 days prior; (ii) presence of neurological, malformative, and/or immunological pathology; (iii) suspected or presumed allergy to the active substance; (iv) antibiotic use within 48 hours prior to enrollment; (v) lack of parental consent to participate in the study. 2.4. Primary and secondary endpoints The primary endpoint of the study was the evaluation of the reduction in rhinitis symptoms (mucous rhinitis, nocturnal catarrhal cough, retropharyngeal discharge, halitosis, and stuffy nose) in children treated with the Class II medical device containing lentisk oil compared to that observed in the control group treated with saline solution (NaCl, 0.9%) during the study period. The secondary endpoints of the study were: (i) the need for antibiotic therapy during follow-up; (ii) the need for decongestant and fluidizing preparations during the study; and (iii) the tolerability and safety of the lentisk oil-based preparation. The results (primary and secondary endpoints) were collected using a clinical evaluation form completed by the enrolling physician and a clinical evaluation form completed by the parent of the patient participating in the study, complementing the form completed by the physician. 2.5. Clinical Evaluation Forms To evaluate the study endpoints, two complementary clinical evaluation forms were used, one to be completed by the medical staff and one to be completed by the parent of the enrolled patient. The "Physician" form included the enrolled patient's medical history (age, sex, presence of concomitant medications, previous medications), associated with evaluation fields to be completed at T0 (day of enrollment) and T6 (after 6 days of therapy, end of study), which included: (i) days since symptom onset; (ii) presence of mucous rhinitis and its severity (mild: need to blow the nose 2-3 times a day; moderate: need to blow the nose 4-5 times a day; severe: need to blow the nose 6 or more times a day); (iii) presence of retropharyngeal mucous discharge; (iv) presence of bad breath; (v) presence of nocturnal catarrhal cough with awakening from sleep; (vi) presence of stuffy nose. Furthermore, the "Doctor" form always noted the need for antibiotics at the clinical checkup on day six, and, if so, which antibiotics were prescribed. Finally, the onset of side effects during the study and the patient's tolerability of treatment were reported. In the "Patient" form, using assessment fields that could be filled in by the patient's parent, divided into timepoints from day 1, the day after enrollment, to day 5 of treatment, the day before the next medical visit, the severity of mucous rhinitis symptoms (mild, moderate, and severe), if present, was recorded, as well as the presence of halitosis, a nocturnal, catarrhal cough with awakening, and a stuffy nose. The parameter "presence of retropharyngeal discharge" was the sole responsibility of the enrolling physician and was therefore assessed only at enrollment and at the end of therapy (day 6). 2.6. Sample size calculation Considering in clinical practice a mean resolution of 60% for the primary endpoint in the control group treated with saline solution (NaCl 0.9%) 14 . To detect a further decrease of 25%, and therefore a resolution in 85% of patients in the group treated with the class II medical device, with 80% power and a type I error of 0.05, our analysis required 94 participants. 15 By enrolling 100 patients the type I error became 0.039 and therefore clearly lower than 0.05. By enrolling 105 patients, the type I error dropped further to about 0.034 (Supplementary File S1). 2.7. Satistical analysis Analysis were performed by using the Categorical platform in JMP 14.3.0 (serial number R5GE7G0JOB) of the SAS Institute Inc. (100 SAS Campus Drive, Cary, North Carolina 27513; 2414, USA) considering a "between-subjects" (two treatment groups) and "within-subjects" (seven temporal measurements) experimental design. 15 Two standard Chi-square approaches were applied: 1) Likelihood Ratio Chi-square (LR Chi-square) that evaluates the association between categorical variables by comparing the likelihood of the observed data under the null hypothesis versus the alternative hypothesis. This method is often preferred when expected cell counts are low, as it is based on maximum likelihood estimation; 2) Pearson Chi-square, the traditional Chi-square test comparing observed frequencies with those expected under the null hypothesis, based on squared deviations standardized by the expected counts. For each method, we reported both the test statistic (LR Chi-square or Pearson Chi-square) and the corresponding p-value (LR P-value, Pearson P-value), which quantify the probability of observing the given association by chance under the null hypothesis of independence. Both statistics and p-values were used to confirm the robustness of the results. For the analysis of the main symptom "mucous rhinitis", we also used the Pseudo-Markov Chain. 16,17 A Markov chain is a process in which the probability of moving from one “state” to another (known as the transition probability) depends solely on the state reached in the previous event. In other words, the process is memoryless. The technique presented here, aimed at generating new information, draws from Markov theory only the concepts of “state” (Baseline or T6) and “transition” (the change from one to the other). For this reason, we refer to it as a pseudo-Markov chain (Martino Recchia (2023)-Obtaining More Information from a Contingency Table: Pseudo Markov Chain Analysis - Journal of Medical – Clinical Research & Reviews). Results 3.1. Descriptive features of the analyzed patients of the two groups As shown in Figure 1, after assessing for eligibility 135 patients, 30 of the them were excluded according to the inclusion and exclusion criteria. After randomization and allocation, none abandoned the study during its course. Therefore, all the results shown refers to the 105 patients completing the study. According to Table 1, the main features, including age, sex, number of patients who were subjected to therapies in the 15 days before the enrolment, and days spent from the onset of the symptoms to the enrolment day, were not significantly different between the two. Also, type of drugs and length of treatment before the enrolment day were not significantly different (Supplementary File 2). Table 1. Main features of the enrolled patients of the two groups of treatment. UWLO-treated group (N=53) NaCl-treated group (N=52) p Age (years) 4.60 ± 1.96 4.73 ± 2.01 n. s. Sex (M/F) 27/26 29/23 n. s. Previous therapies* 4 patients 3 patients n. s. Days from onset 3.15 ±1.35 2.88 ± 1.25 n. s. UWLO: Ultra-fractionated and winterized lentisk oil. M: males; F: females. n. s.: not significant. *Further details are given in Supplementary File 2. 3.2. Treatment effect on mucous rhinitis Results on mucous rhinitis are graphically shown in Figure 2. At enrollment, no patients in the UWLO group had mild mucous rhinitis, 49.1% had moderate mucous rhinitis, and 50.9% had severe mucous rhinitis. In the NaCl group, 7.7% had mild mucous rhinitis, 59.6% had moderate mucous rhinitis, and 32.7% had severe mucous rhinitis. Therefore, at enrollment, both groups had moderate or severe symptoms, indicating a significant clinical condition, with the UWLO group showing a slightly higher percentage of severe cases than the NaCl group. At day 1, 5.7% of patients treated with UWLO had mild symptoms, 50.9% had moderate symptoms, and 43.4% had severe symptoms. In the NaCl group, 5.8% showed mild symptoms, 59.6% moderate, and 34.6% severe. A slight improvement was then observed in the UWLO-treated group, with a small increase in mild cases and a decrease in severe cases. The majority of patients of both groups continued to exhibit signs of moderate or severe rhinitis. At day 2, 9.4% of patients treated with UWLO showed mild symptoms, 66.0% moderate, and 24.5% severe. In the NaCl-treated group, the values were 3.8%, 67.3%, and 28.8%, respectively. Therefore, the UWLO-treated group continued to show a positive trend with an increase in mild cases and a decrease in severe cases. The NaCl group also showed a decrease in severe cases, but with a lower number of mild cases than the UWLO group. On day three, a significant improvement was observed in the UWLO group, with 28.3% of patients having mild symptoms, 67.9% moderate symptoms, and only 3.8% severe symptoms. In the NaCl group, 19.2% of patients had mild symptoms, 71.2% moderate symptoms, and 9.6% severe symptoms. Both treatments therefore showed a marked reduction in severe cases. However, in the UWLO group, severe cases were reduced to a lower percentage and mild cases to a higher percentage than in the NaCl group. On day four, in the UWLO group, 47.2% of patients had mild rhinitis, 52.8% moderate symptoms, and no patients had severe symptoms. In the NaCl group, 42.3% of patients had mild symptoms, 57.7% moderate, and no patients had severe symptoms. In both groups, there were no longer any cases of severe rhinitis, and most patients had mild or moderate symptoms, with a higher percentage of mild cases in the UWLO group. On day 5, 79.2% of patients in the UWLO group had mild symptoms and 20.8% had moderate symptoms, compared to 61.5% of patients with mild symptoms and 38.5% with moderate symptoms in the NaCl group. Also at this stage, treatment with UWLO demonstrated a higher percentage of mild cases compared to NaCl. At the end of the study (day 6), 86.8% of patients in the UWLO group had mild symptoms and 13.2% had moderate symptoms, compared to 61.5% of mild patients and 38.5% of moderate patients in the NaCl group. Both treatments were effective in reducing the severity of mucous rhinitis over the 6 days of therapy, and by day 4, none of the patients in either group had severe mucous rhinitis. However, treatment with UWLO apparently demonstrated greater efficacy in converting cases from moderate to mild, especially in the later stages of the study (days 3 to 6), consistently surpassing treatment with NaCl in the percentage of patients with mild rhinitis. This apparently suggests that treatment with UWLO may offer greater benefit in achieving minimal severity for mucous rhinitis. To determine whether the distribution of responses, expressed as severity of mucous rhinitis, was statistically similar/homogeneous between the two treatment groups (UWLO versus NaCl) at each observation time point (days 0–6), we measured the discordance between the observed frequencies and those that would be expected if there were no difference between the groups (that is, if the two groups were homogeneous). By evaluating the severity of mucous rhinitis in relation to treatment for each time point using the Likelihood Ratio Chi-square and Pearson Chi-square tests (Supplementary File 3), we found that, despite randomization, at enrollment, there was a statistically significant difference (p<0.05) in the distribution of rhinitis severity between the UWLO group and the NaCl group. This finding was consistent with the previous observation that on day 0, the UWLO group had a slightly higher percentage of severe cases (50.9%) than the NaCl group (32.7%). The samples were therefore not perfectly balanced in terms of initial severity, to the detriment of the UWLO-treated group. The same comparative analysis, carried out between the results obtained in the two groups between days 1 and 4, did not highlight significant differences. On day 5, the distribution of mucous rhinitis severity between the two groups was again significant (p<0.05). The difference in this case was due to a significantly higher percentage of patients with mild symptoms observed in the UWLO group (79.2%) compared to that observed in the NaCl group (61.5%). At the end of treatment (day 6), the distribution of mucous rhinitis grade between the two groups was highly significant (p<0.01) and in favor of the UWLO group, in which mucous rhinitis was mild in 86.8% of cases compared to 61.5% of cases in the NaCl group. Patient-by-patient analysis using a Markov chain 16,17 to observe transitions in symptom severity showed that, in the NaCl-treated group, of the four patients who had mild symptoms at enrollment, none changed their symptoms by day 6. Of the 31 patients with moderate symptoms at enrollment, 25 improved their symptom severity by day 6, transforming them to mild symptoms, while six remained stable. Of the 17 patients who had severe symptoms at enrollment, three transitioned to mild symptoms at the end of therapy, and 14 to moderate symptoms. Conversely, the case study observed for the group treated with UWLO shows that of the 26 patients who presented a moderate severity at enrollment, 24 reduced the severity to mild, while 2 maintained the same level of severity found on day 0. Of the 27 patients who presented a severe severity at enrollment, 22 showed a mild severity at the end of therapy, while 5 recorded a transition to moderate severity (Supplementary File 4). We therefore developed new categories of subjects based on state migrations: (i) improved (patients who on day 6 show a symptom severity lower than that revealed on day 0); (ii) immune (patients who do not show, between the two periods, any variation in their symptom severity); worsened (patients who at the end of therapy show a severity higher than that shown on day 0). The results of the Markovian analysis show that of the 53 patients in the UWLO group, 96.2% improved, 3.8% remained unchanged, and none worsened between the beginning and the end of the study. Conversely, of the 52 patients in the NaCl group, 80.8% improved, 19.2% remained unchanged, while none worsened between the beginning and the end of the study. The difference in efficacy between the two treatments appears evident when the previous data are subjected to statistical analysis with the Likelihood Ratio (p = 0.0097) and Pearson tests. (p=0.0128) which demonstrate the greater efficacy of treatment with UWLO (Table 2 and Supplementary File 5). A Markov chain is a process in which the probability of moving from one state to another (called the transition probability) depends only on the state reached in the previous event. The table 2 shows data on the symptomatology of mucous rhinitis, a transition matrix relating to the patient's symptom, which can be in three different states, identified as mild, moderate, and severe. The table therefore illustrates the changes in symptom severity that each patient in the two groups exhibited at the end of therapy. Table 2 Markovian analysis of the state transition of patients in the two treatment groups Patient condition UWLO-treated group (N=53) NaCl-treated group (N=52) Improved N=51 N=42 Unchanged N=2 N=10 Worsened N=0 N=0 Likelihood ratio and Pearson chi-square were 6.685 and 6.195 with, respectively, p=0.0097 and p=0.0128. 3.3. Treatment effect on stuffy nose Regarding stuffy nose symptoms, both groups, although with some differences, showed a reduction over the course of treatment (Figure 3). In the UWLO group, the presence of the symptom decreased dramatically from 100.0% at baseline to 47.2% on the third day and further to 17.0% on the fifth and sixth days of therapy. In the NaCl group, the symptom decreased from 94.2% at baseline to 71.2% on the third day, and then to 32.7% and 34.6% on the fifth and sixth days. The comparison between the two groups also showed that starting from the third day, the percentage of patients with a stuffy nose was considerably lower in the UWLO group than in the group treated with 0.9% NaCl solution. In fact, on the fourth day, only 22.6% of patients treated with UWLO showed a stuffy nose symptom compared to 53.8% in the NaCl group. This difference suggested a virtually greater efficacy of UWLO treatment in resolving the symptom. Analyzing the presence of symptom in relation to treatment for each time point by the Likelihood Ratio Chi-square and Pearson Chi-square tests (Supplementary File 6), we found that the slight difference in percentages between the two groups at enrollment (100% vs. 94.2%) was statistically significant (p<0.05) to the detriment of the UWLO-treated group. On the first and second days of therapy no significant differences were observed between the groups. On the third day, the UWLO group had a significantly (p<0.05) lower percentage (47.2%) than that observed in the NaCl group (71.2%). On day 4, the analysis indicated a highly significant difference (p<0.01) between the groups, with symptom presence at 22.6% in the UWLO group and 53.8% in the NaCl group. On day 5, the symptom frequency was not significantly different between the two groups. Conversely, at the end of therapy, the symptom was again significant (p<0.05) with a frequency of. 17.0% in the UWLO group versus 34.6% in the NaCl group. 3.4. Nocturnal catarrhal cough As shown in Figure 4, the use of UWLO resulted in a more marked progressive improvement than the effect due to NaCl therapy, with an increasing percentage of patients without symptoms at each time point. The NaCl group improved more slowly and maintained higher percentages of patients with symptoms, especially from day 3 onwards. The statistical analysis of homogeneity, aimed at determining the existence of a significant difference in symptom distribution between the UWLO group and the NaCl group at each time point (Supplementary File 7), demonstrated that at enrollment, despite randomization, there was a small but significant difference (p<0.05) between the two groups to the disadvantage of the NaCl group. In the initial phases (days 1 and 2), treatment with UWLO significantly improved cough compared to the NaCl group. On the third day, the difference, in favor of the UWLO group, was no longer statistically significant, but in the more advanced phases of the study (days 4-6). the efficacy of UWLO became clear and highly significant (p<0.01) and by day 6 almost 80% of patients treated with UWLO were no longer coughing, compared to just over 40% in the NaCl group. 3.5. Halitosis As shown in Figure 5, treatment with UWLO reduced the presence of the symptom more rapidly and significantly than that seen in the NaCl group, with differences particularly evident from the third day onward. Statistical analysis aimed at identifying differences in homogeneity of response (Supplementary File 8) demonstrated significant differences, always favoring treatment with UWLO, at days 2 and 4 of therapy (p<0.05) and highly significant differences (p<0.01) on days 3 and 6. On day 5, although graphically evident, the difference was not significant, with a p=0.0558 in the Likelihood Ratio test (Supplementary File 8). 3.6. Mucous retropharyngeal discharge Differently from previous endpoints, the presence of retropharyngeal mucous discharge was detected, in both treatment groups, only at enrollment and at the end of therapy. As shown in Figure 6, and statistically demonstrated by the Likelihood Ratio and Pearson tests in Supplementary File 9, at enrollment, despite randomization, 44 (83%) patients in the ULWO group and 32 (61.5%) in the NaCl group demonstrated the presence of the symptom (p<0.05). At the end of therapy, only 2 (3.8%) patients in the UWLO group, compared to 26 (50%) in the NaCl group, still presented the symptom (p<0.01). 3.7. Need for antibiotics at follow-up and use of other drugs during treatment As detailed in Supplementary File 10, at the follow-up one patient in the UWLO group was treated with amoxicillin and clavulanic acid and three patients in the NaCl group were treated with amoxicillin (2 patients) and clarithromycin (1 patient). Thus, 52 patients (98.1%) in the UWLO group and 49 (94.2%) in the NaCl group did not require antibiotic therapy. Although the result tended to favor treatment with UWLO, analysis revealed no significant differences between the two groups. Regarding the need for other therapies during treatment with UWLO or NaCl, almost all patients did not take other medications during the study. Some patients took paracetamol (two children in the UWLO group, a 5-year-old male and a 7-year-old female, took it for 24 hours due to a sore throat; one child in the NaCl group, a 5-year-old male, took it for 24 hours due to a mild fever below 38°C) or acetylcysteine-based fluidizing syrup (one child in the NaCl group, a 2-year-old male, took it from day 3 to day 5 inclusive). Again, the difference between the two groups was not significant. 3.8. Tolerability and treatment-related side effects Treatment tolerability (Supplementary File 11) was very good in both groups, with a slight, though non-significant, trend favoring the UWLO group. No treatment-related side effects were reported in either group, confirming the excellent safety profile of the two treatments. Discussion The underlying idea of the study was to verify whether it was possible to improve the overall symptomatic picture in pediatric patients diagnosed with purulent rhinitis simply by applying UWLO from Pistacea lentiscus berries, formulated as oil drops for nasal administration. This effectively replicates the antibacterial action typically achieved by antibiotics, but without the same adverse effects, especially gastrointestinal ones. Comparing the results with those obtained in a control group treated with nasal irrigation using 0.9% isotonic saline solution, the results were significantly better, at least considering the symptoms and signs examined. Specifically, in mucous rhinitis, the mastic oil preparation demonstrated greater efficacy in converting cases from moderate to mild, especially in the later stages of the study (days 3 to 6), consistently and significantly outperforming the saline preparation in the percentage of patients with mild symptoms. Regarding the "stuffy nose" symptom, mastic oil showed a more rapid and stable trend of improvement, with a consistent and significant reduction in symptomatic patients as early as the third day. At the end of therapy, 83% of patients treated with mastic oil no longer had symptoms, while in the control group, the symptom persisted in approximately one-third of patients. Regarding nocturnal catarrhal cough, mastic oil proved superior to the control, with significant improvements, especially in the later stages of treatment. Halitosis was treated more rapidly and more markedly, with statistically significant results from day 2 onward. Finally, regarding retropharyngeal mucous discharge, despite initial heterogeneity in favor of the saline rinse, at the end of the study (day 6), mastic oil produced significantly superior results, with a highly significant difference between the two treatments. Noteworthy, not only was a reduced need for antibiotics observed at follow-up, but these results were achieved with very good tolerability for the young patients (and better than that observed in the control group), with no side effects specifically attributable to the preparation. The results obtained, thanks also to an appropriate sample size, therefore allow us to state that the intranasal administration of UWLO proved to be a significantly better option than nasal rinses with saline in pediatric purulent rhinitis. Other studies, 11-13 pharmacological (both in vitro and in vivo) and clinical (in chronic recurrent sinusitis), had in some ways prompted this assessment and may also help us understand the reasons for the findings in our study. These investigations had demonstrated the specific antibacterial action of some fractions of lentisk oil, effect in all likelihood caused by the specific antibiofilm role exerted by preparation, against certain nasal and oropharyngeal pathogens, an action so specific that it does not affect commensal and non-pathogenic bacteria present in the same microbiota, such as the species S. salivarius . 18-20 This unique antibacterial role may have influenced the potential for nasal and oropharyngeal dysbiosis, perhaps limiting it. Indeed, the dysbiosis hypothesis, the alteration of microbiota associated with perturbation of the local ecological landscape, has been suggested as a mechanism involved in most pathologies, including those occurring in the respiratory tract. 21,22 Recent advancements in culture-independent molecular techniques have enhanced understanding of bacterial interactions inside the microbiota of upper airway microenvironment demonstrating that, for instance in case of chronic sinusitis, during infection global bacterial load does not change in comparison with healthy controls, while biodiversity reduces. 23 Differences have been also demonstrated from a taxonomical perspective. Versus healthy controls acute bacterial sinusitis is mostly characterized by the presence of microorganisms like S. pneumoniae , H. influenzae , M. catarrhalis , and S. pyogenes ; while S. aureus and anaerobic organisms ( Prevotella and Porphyromonas , Fusobacterium , and Peptostreptococcus spp.) are the commonest isolates in chronic rhinosinusitis. 24 While it is not possible to translate with certainty what has been observed in acute sinusitis and chronic sinusitis in purulent pediatric rhinitis, it is impossible not to highlight that the active fractions of lentisk oil behave in an antibiotic-like manner precisely against those bacterial taxa involved in the acute disorder, preserving the eubiotic fraction, with already demonstrated favorable clinical consequences. 12,13 The observed safety profile, fundamental for our trial which was a "first" in pediatrics, is also in line with what has been reported in studies aimed at evaluating also its anti-inflammatory and non-toxic effect. 12,13 According to validated methods and ISO (International Organization for Standardization) documents, 25-28 the fractionated and winterized lentisk oil has been subjected to an important series of verification tests whose results have demonstrated that: (i) it is not absorbed by human mucosa; (ii) it does not exhibit skin sensitization potential; (iii) it is not irritant for nasal mucosa; and (iv) it is not cytotoxic for human cells. Our study presents some limitations and potential biases: (i) the sample size chosen, although in line with statistical requirements, is not high; (ii) the study design does not allow for the evaluation of a possible additive effect deriving from the use of saline and UWLO; (iii) the study design, although randomized, controlled and prospective, lacks elements such as being double-blind and measuring the placebo effect; (iv) no analytical and/or instrumental approach aimed at understanding the possible mechanism of action was foreseen (previous publications have however demonstrated the anti-biofilm effect of the preparation) 12,13 ; (v) and no real prolonged follow-up investigation was foreseen, beyond the sixth day of vision, and therefore it is not possible to know whether the preparation used once, therefore for a week, reduces possible recurrences. Despite these limitations, our study demonstrates that the use of a class II medical device containing ultra-fractionated and winterized lentisk oil as its sole active ingredient, used as the sole medication for pediatric purulent rhinitis, is safe and significantly more effective in controlling symptoms than the daily use of a saline solution (0.9% NaCl) for nasal irrigation, perhaps also resulting in a reduced need for antibiotics. Further, larger, double-blind studies should confirm our observations. Declarations Data Availability Statement All data generated or analyzed during this study are included in this published article. Funding This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author contributions Conceptualization: AAN, GDP, AG, RP, AMR, DP, TM, AAM FDP; Methodology, Investigation, Validation, and Formal analysis: GDP, AG, RP, AMR, DP, TM, AAM,; FDP, AK, FR, NMM Resources; FDP, CMP, AB, MLT, NZ; Data curation; FDP, MR, AAM; Writing–original draft preparation; FDP, AAN, NZ; Writing–review and editing; FDP, AAN, CMP, NZ; Visualization; FDP, AAN, NZ; Supervision; FDP, AAN, MLT, NZ, MR; Project administration: AAN. All authors have read and agreed to the published version of the manuscript. Competing interests FDP is the Scientific & Research Director in Pharmextracta SpA. FDP is also the main author of the European patent describing the fractionated lentisk oil (N° 20205961.4 deposited on November 5th, 2020). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AB is a Pharmextracta consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Steinweg KK. Natural history and prognostic significance of purulent rhinitis. J Fam Pract. 1983;17(1):61-4. Arroll B, Goodyear-Smith F. General practitioner management of upper respiratory tract infections: when are antibiotics prescribed? N Z Med J. 2000; 113(1122):493-6. Mainous AG 3rd, Hueston WJ, Eberlein C. Colour of respiratory discharge and antibiotic use. Lancet. 1997; 350(9084):1077. doi: 10.1016/S0140-6736(05)70457-8. Gonzales R, Barrett PH Jr, Steiner JF. The relation between purulent manifestations and antibiotic treatment of upper respiratory tract infections. J Gen Intern Med. 1999; 14(3):151-6. doi: 10.1046/j.1525-1497.1999.00306.x. Huemer M, Mairpady Shambat S, Brugger SD, Zinkernagel AS. Antibiotic resistance and persistence-Implications for human health and treatment perspectives. EMBO Rep. 2020; 21(12):e51034. doi: 10.15252/embr.202051034. Snow V, Mottur-Pilson C, Hickner JM; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine; Centers for Disease Control; Infectious Diseases Society of America. Principles of appropriate antibiotic use for acute sinusitis in adults. Ann Intern Med. 2001; 134(6):495-7. doi: 10.7326/0003-4819-134-6-200103200-00016. Rosenstein N, Phillips WR, Gerber MA, Marcy SM, Schwartz B, Dowell SF. The common cold, principles of judicious use of antimicrobial agents. Pediatrics. 1998; 101(1): 181-184. Todd JK, Todd N, Damato J, Todd WA. Bacteriology and treatment of purulent nasopharyngitis: a double blind, placebo-controlled evaluation. Pediatr Infect Dis. 1984; 3(3):226-32. doi: 10.1097/00006454-198405000-00009. De Sutter AI, De Meyere MJ, Christiaens TC, Van Driel ML, Peersman W, De Maeseneer JM. Does amoxicillin improve outcomes in patients with purulent rhinorrhea? A pragmatic randomized double-blind controlled trial in family practice. J Fam Pract. 2002; 51(4):317-23. Arroll B, Kenealy T. Are antibiotics effective for acute purulent rhinitis? Systematic review and meta-analysis of placebo controlled randomised trials. BMJ. 2006; 333(7562):279. doi: 10.1136/bmj.38891.681215.AE. Orrù G, Demontis C, Mameli A, Tuveri E, Coni P, Pichiri G, Coghe F, Rosa A, Rossi P, D'hallewin G. The Selective Interaction of Pistacia lentiscus Oil vs. Human Streptococci, an Old Functional Food Revisited with New Tools. Front Microbiol. 2017 Oct 24;8:2067. doi: 10.3389/fmicb.2017.02067. Di Pierro F, Sagheddu V, Galletti S, Forti M, Elli M, Bertuccioli A, Gaeta S. Antibacterial Activity of a Fractionated Pistacia lentiscus Oil Against Pharyngeal and Ear Pathogens, Alone or in Combination With Antibiotics. Front Microbiol. 2021; 12:686942. doi: 10.3389/fmicb.2021.686942. PMID: 34220777; PMCID: PMC8247648. DI Pierro F, Zerbinati N, Tanda ML, Monti G, Macchi A. Fractionated lentisk oil as add-on therapy for preventing chronic rhinosinusitis recurrence. Minerva Med. 2025 Mar 6. doi: 10.23736/S0026-4806.25.09683-1. Yata K, Srivanitchapoom C. The comparison of nasal irrigation outcome between 3% NaCl and 0.9% NaCl in adults majority with intermittent allergic rhinitis: A randomized double-blind study. Asian Pac J Allergy Immunol. 2021; 39(1):9-14. doi: 10.12932/AP-140520-0844. Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions. 2003. Third Edition. John Wiley & Sons. New York. Recchia M. Obtaining More Information from a Contingency Table: Pseudo Markov Chain Analysis. J Med - Clin Res & Rev. 2023; 7(5): 1-3. Mazzi MA, Del Piccolo L, Zimmermann C. Event-based categorical sequential analyses of the medical interview: a review. Epidemiol Psichiatr Soc. 2003; 12(2):81-5. doi: 10.1017/s1121189x00006126. Baker JL, Mark Welch JL, Kauffman KM, McLean JS, He X. The oral microbiome: diversity, biogeography and human health. Nat Rev Microbiol. 2024 Feb;22(2):89-104. doi: 10.1038/s41579-023-00963-6. Epub 2023 Sep 12. PMID: 37700024; PMCID: PMC11084736. Abranches J, Zeng L, Kajfasz JK, Palmer SR, Chakraborty B, Wen ZT, Richards VP, Brady LJ, Lemos JA. Biology of Oral Streptococci. Microbiol Spectr. 2018; 6(5):10.1128/microbiolspec.gpp3-0042-2018. doi: 10.1128/microbiolspec.GPP3-0042-2018. Delorme C, Abraham AL, Renault P, Guédon E. Genomics of Streptococcus salivarius, a major human commensal. Infect Genet Evol. 2015; 33: 381-92. doi: 10.1016/j.meegid.2014.10.001. Manos J. The human microbiome in disease and pathology. APMIS. 2022; 130(12):690-705. doi: 10.1111/apm.13225. Faner R, Sibila O, Agustí A, Bernasconi E, Chalmers JD, Huffnagle GB, Manichanh C, Molyneaux PL, Paredes R, Pérez Brocal V, Ponomarenko J, Sethi S, Dorca J, Monsó E. The microbiome in respiratory medicine: current challenges and future perspectives. Eur Respir J. 2017; 49(4):1602086. doi: 10.1183/13993003.02086-2016. Cho DY, Hunter RC, Ramakrishnan VR. The Microbiome and Chronic Rhinosinusitis. Immunol Allergy Clin North Am. 2020; 40(2):251-263. doi: 10.1016/j.iac.2019.12.009. Brook I. Microbiology of chronic rhinosinusitis. Eur J Clin Microbiol Infect Dis. 2016; 35(7):1059-68. doi: 10.1007/s10096-016-2640-x. Koschier F, Kostrubsky V, Toole C, Gallo MA. In vitro effects of ethanol and mouthrinse on permeability in an oral buccal mucosal tissue construct. Food Chem Toxicol. 2011; 49(10):2524-9. doi: 10.1016/j.fct.2011.06.018. Erratum in: Food Chem Toxicol. 2012; 50(5):1815. Gibbs S, Kosten I, Veldhuizen R, Spiekstra S, Corsini E, Roggen E, Rustemeyer T, Feilzer AJ, Kleverlaan CJ. Assessment of metal sensitizer potency with the reconstructed human epidermis IL-18 assay. Toxicology. 2018; 393:62-72. doi: 10.1016/j.tox.2017.10.014. https://www.iso.org/obp/ui/en/#iso:std:iso:10993:-23:ed-1:v1:en (visited on June 11th, 2025). https://www.iso.org/obp/ui/en/#iso:std:iso:10993:-5:ed-3:v1:en (visited on July 9th, 2025). Additional Declarations Competing interest reported. FDP is the Scientific & Research Director in Pharmextracta SpA. FDP is also the main author of the European patent describing the fractionated lentisk oil (N° 20205961.4 deposited on November 5th, 2020). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AB is a Pharmextracta consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Supplementary Files SupplementaryFiles.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 25 Jan, 2026 Reviewers agreed at journal 14 Jan, 2026 Reviewers invited by journal 07 Jan, 2026 Editor assigned by journal 01 Dec, 2025 Editor invited by journal 25 Aug, 2025 Submission checks completed at journal 22 Aug, 2025 First submitted to journal 22 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7385153","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":571279402,"identity":"c6c6027b-b7b6-48f3-bcfe-c7cb6cd7b4a8","order_by":0,"name":"Francesco Di Pierro","email":"","orcid":"","institution":"Microbiota International Clinical Society","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"Di","lastName":"Pierro","suffix":""},{"id":571279403,"identity":"549b876d-7010-45c9-8214-76e6c4924772","order_by":1,"name":"Giuseppe De Paolis","email":"","orcid":"","institution":"ASL Roma 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Palazzi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYFACHoYDEAZjA8MHIMXGTooWxhkgLcxEaIEDZjCbkBZz9rMHD/zcYxfNP/tw42ebX9vk+ZgZGD98zMGtxbInL+Fgz7Pk3BnnEpulc/tuG7YxMzBLztyGW4vBDR6DAzwHmHMbzjA2SOf23GYEamFj5iWg5eCfA/W5888wNv+27LltT5SWwzwHDuduOMPYJs3w43YiQS2WPTkGh2UOHM/dCNRi2dtwO7mNmbEZr1/M2c8Yf3xzoDp33hn2xzd+/LltO7+9+eCHj/gchsJjbAOTDbjVY2hh+INX8SgYBaNgFIxQAABsLFXKuwmYuQAAAABJRU5ErkJggg==","orcid":"","institution":"Microbiota International Clinical Society","correspondingAuthor":true,"prefix":"","firstName":"Chiara","middleName":"Maria","lastName":"Palazzi","suffix":""},{"id":571279410,"identity":"5fa5589c-453b-4236-bd30-1df7d00c8e87","order_by":8,"name":"Alexander Bertuccioli","email":"","orcid":"","institution":"University of Urbino Carlo Bo","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Bertuccioli","suffix":""},{"id":571279411,"identity":"7b14f9da-56d1-4e7f-a075-ce5c0ab4d303","order_by":9,"name":"Martino Recchia","email":"","orcid":"","institution":"Mario Negri Institute Alumni Association (MNIAA)","correspondingAuthor":false,"prefix":"","firstName":"Martino","middleName":"","lastName":"Recchia","suffix":""},{"id":571279412,"identity":"0fa724b0-f63c-4ffb-b05c-4a50962817ce","order_by":10,"name":"Maria Laura Tanda","email":"","orcid":"","institution":"University of Insubria","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Laura","lastName":"Tanda","suffix":""},{"id":571279413,"identity":"d72e5458-0e02-4508-996d-5e558b2113c8","order_by":11,"name":"Nicola Zerbinati","email":"","orcid":"","institution":"University of Insubria","correspondingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"","lastName":"Zerbinati","suffix":""},{"id":571279414,"identity":"468d43f9-d37f-4d65-b8b3-95306478673d","order_by":12,"name":"Antonio Augusto Niccoli","email":"","orcid":"","institution":"UOC Pediatria, Fabrizio Spaziani Hospital","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Augusto","lastName":"Niccoli","suffix":""}],"badges":[],"createdAt":"2025-08-16 05:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7385153/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7385153/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100009331,"identity":"4d912596-9feb-41aa-a795-9559cacb8d89","added_by":"auto","created_at":"2026-01-12 06:01:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":267090,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow Chart of the study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/f8b81233f7fc087cf720976f.png"},{"id":100361772,"identity":"c10823c7-ce12-45a8-b7cc-8f9baf02c457","added_by":"auto","created_at":"2026-01-16 07:45:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":395333,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMucous rhinitis in Ultrafractionated and Winterized Lentisk Oil (1) and NaCl 0.9% (2) treated groups. \u003c/strong\u003eThe statistical analysis by percent trend of the symptom (mild: A; moderate: B; severe: C) and number of subjects (shown in the upper part of each graph) has shown that both treatments reduced the severity of the symptom, but significant differences were observed only at day 0 (p\u0026lt;0.05) where the UWLO group present a higher number of patients with severe symptom, and at day 5 (p\u0026lt;0.05) and day 6 (p\u0026lt;0.01) where the UWLO group presented a higher number of patients with mild symptom. In the other days, the results are not differently significant between the two groups.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/98f556ef65606840b1416163.png"},{"id":100361704,"identity":"56ea8644-8e70-4345-b784-3905f8b16fb4","added_by":"auto","created_at":"2026-01-16 07:45:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":114950,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStuffy nose in (A) Ultrafractionated and Winterized Lentisk Oil- and (B) NaCl-treated groups. \u003c/strong\u003eBoth groups, although with some differences, showed a reduction over the course of treatment. The slight difference in percentages between the two groups at enrollment (100% vs. 94.2%) was statistically significant (p\u0026lt;0.05) to the detriment of the UWLO-treated group. Results were significantly different between the two groups in favor of the treatment with UWLO the third (p\u0026lt;0.05), the fourth (p\u0026lt;0.01) and at the end of therapy, where the symptom was again significant lower (p\u0026lt;0.05) in the UWLO group.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/3b16231ea6014f0cdb9ab20f.png"},{"id":100361659,"identity":"6bcf1f05-bedf-4e1e-9ef2-9a48175cde0f","added_by":"auto","created_at":"2026-01-16 07:45:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":117412,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNocturnal catarrhal cough in (A) Ultrafractionated and Winterized Lentisk Oil- and (B) NaCl-treated groups. \u003c/strong\u003eBoth groups, although with some differences, showed a reduction over the course of treatment. The slight difference in percentages between the two groups at enrollment (94.3% vs. 100%) was statistically significant (p\u0026lt;0.05) to the detriment of the NaCl-treated group. From day 1 onward, but day 3, results were significantly different between the two groups in favor of the treatment with UWLO with p\u0026lt;0.05 on days 1 and 2 and p\u0026lt;0.01 on days 4-6. At the end of the treatment, about 80% of the patients of the UWLO group were free of symptom versus over 40% of the NaCl group.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/52172d548d3a9ed074c4e936.png"},{"id":100361632,"identity":"927a2dd9-3d9c-48b0-af2d-b239bf660b87","added_by":"auto","created_at":"2026-01-16 07:45:25","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":121892,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHalitosis in (A) Ultrafractionated and Winterized Lentisk Oil- and (B) NaCl-treated groups. \u003c/strong\u003eBoth groups, although with some differences, showed a reduction over the course of treatment. The slight difference in percentages between the two groups at enrollment (94.3% vs. 100%) was statistically significant (p\u0026lt;0.05) to the detriment of the NaCl-treated group. From day 1 onward, but day 3, results were significantly different between the two groups in favor of the treatment with UWLO with p\u0026lt;0.05 on days 1 and 2 and p\u0026lt;0.01 on days 4-6. At the end of the treatment, about 80% of the patients of the UWLO group were free of symptom versus over 40% of the NaCl group.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/32bcc4a0d3e719f8edb6c301.png"},{"id":100009330,"identity":"2dfb8d5d-b79f-4bc2-95de-b194b2a811ec","added_by":"auto","created_at":"2026-01-12 06:01:52","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":67887,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMucous retropharyngeal discharge in Ultrafractionated and Winterized Lentisk Oil- and NaCl-treated groups.\u003c/strong\u003e Both groups, although with some differences, showed a reduction over the course of treatment. At enrollment, despite randomization, 44 (83%) patients in the ULWO group and 32 (61.5%) in the NaCl group demonstrated the presence of the symptom (p\u0026lt;0.05). At the end of therapy, only 2 (3.8%) patients in the UWLO group, compared to 26 (50%) in the NaCl group, still presented the symptom (p\u0026lt;0.01).\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/62df8894f778927480922943.png"},{"id":100380845,"identity":"23aa5f50-9840-4f21-8b8f-423f43cb281f","added_by":"auto","created_at":"2026-01-16 10:35:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2066526,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/30519b87-7315-483f-aaa7-4a907b7f1229.pdf"},{"id":100009325,"identity":"7462be1c-564c-4eaa-a768-f994f4705790","added_by":"auto","created_at":"2026-01-12 06:01:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":725068,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFiles.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7385153/v1/8733be83971c5ecfa71eaa24.pdf"}],"financialInterests":"Competing interest reported. FDP is the Scientific \u0026 Research Director in Pharmextracta SpA. FDP is also the main author of the European patent describing the fractionated lentisk oil (N° 20205961.4 deposited on November 5th, 2020). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AB is a Pharmextracta consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","formattedTitle":"Evaluation of the efficacy of ultra-fractioned and winterized lentisk oil in reducing symptoms of purulent bacterial overinfection of pediatric rhinitis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute purulent rhinitis, defined as a runny nose with coloured discharge, is a common complication of the common cold. Although its duration might vary with the prevalence of specific infecting microorganisms, natural history of purulent rhinitis is described to last about two weeks.\u003csup\u003e1\u003c/sup\u003e Nevertheless, the presence of purulent nasal discharge has repeatedly been shown to be an important determinant of the prescribing of antibiotics for respiratory tract infections for both adults and children,\u003csup\u003e2\u0026ndash;4\u003c/sup\u003e and indeed some Authors found that purulent nasal discharge was a stronger predictor of antibiotic prescribing than any other characteristic of patients.\u003csup\u003e4\u003c/sup\u003e Of course, also to avoid the induction of antibiotic restance pattern,\u003csup\u003e5\u003c/sup\u003e most guidelines recommend that antibiotics should not be used for this condition,\u003csup\u003e6,7\u003c/sup\u003e also claiming negative evidence that antibiotics reduce the duration of acute purulent rhinitis.\u003csup\u003e8\u003c/sup\u003e However, a larger study reported that treatment with amoxicillin reduced the duration of purulent rhinitis, although it found no significant improvement in symptoms.\u003csup\u003e9\u003c/sup\u003e A following systematic review on the subject demonstrated a significant benefit of antibiotics, compared to placebo, in reducing the duration of symptoms in about one week following the start of treatment.\u003csup\u003e10\u003c/sup\u003e However, the frequency of adverse reactions, especially gastrointestinal and skin reactions, was also significantly increased with antibiotic use. Cultures from patients with purulent rhinitis grew mainly oral-pharyngeal microorganisms including \u003cem\u003eS. pneumoniae\u003c/em\u003e, \u003cem\u003eH. influenzae\u003c/em\u003e, and \u003cem\u003eS. pyogenes\u003c/em\u003e while nasal crusting was significantly associated with the growth of\u003cem\u003e\u0026nbsp;S. pneumoniae\u003c/em\u003e or \u003cem\u003eH. influenzae\u003c/em\u003e.\u003csup\u003e8\u003c/sup\u003e Recently, different groups of research have highlighted the effect of ultra-fractioned and winterized lentisk oil (from here on UWLO), got by berries of \u003cem\u003ePistacea lentiscus\u003c/em\u003e, against some nasal and oral-pharyngeal pathogens,\u003csup\u003e11-12\u003c/sup\u003e including its effect in preventing chronic rhinosinusitis recurrence.\u003csup\u003e13\u003c/sup\u003e The aim of this prospective, multicenter, controlled, non-profit study was to evaluate the safety and efficacy of using a class II medical device in the form of oil drops containing UWLO in reducing the duration of the infection and the main rhinitis symptoms.\u003c/p\u003e\n"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1. Study ethics \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study procedures were conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki. The study was registered on www.clinicaltrials.gov (Registration Number: NCT06758804; First Posted Date; 27.12.2024). The study protocol received ethical approval prior to recruitment from the Ethic Committee of Carlo Bo University of Urbino (Italy) as per the Minutes of Session No. 89 of November 28, 2024. Informed consent was obtained from a parent and/or legal guardian for study participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2. Study Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients considered eligible and enrolled between January and April 2025 according to the inclusion and exclusion criteria, were randomized in a 1:1 ratio to create two study groups. The first was treated with three drops per nostril, three times a day, for six consecutive days, using a Class II medical device containing winterized Pistacia lentiscus oil (Bactorinol\u0026reg; nasal drops, PharmExtracta S.p.A., Pontenure, Italy). The second, serving as a control group, was treated for six consecutive days with nasal irrigation using a NaCl 0.9% physiological solution corresponding to 154 mEq/L of Na\u003csup\u003e+\u003c/sup\u003e and Cl\u003csup\u003e-\u003c/sup\u003e, isotonic with an osmolarity of 308 mOsm/L.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3. Inclusion and exclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria were: (i) male and female, aged 2 to 10 years; (ii) clinical symptoms of dense mucous rhinitis and/or purulent mucus, with an onset of no more than 5 days, including mucous rhinitis, nocturnal catarrhal cough, retropharyngeal discharge, halitosis, and stuffy nose; (iii) parental informed consent. Exclusion criteria were: (i) symptom onset more than 5 days prior; (ii) presence of neurological, malformative, and/or immunological pathology; (iii) suspected or presumed allergy to the active substance; (iv) antibiotic use within 48 hours prior to enrollment; (v) lack of parental consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4. Primary and secondary endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of the study was the evaluation of the reduction in rhinitis symptoms (mucous rhinitis, nocturnal catarrhal cough, retropharyngeal discharge, halitosis, and stuffy nose) in children treated with the Class II medical device containing lentisk oil compared to that observed in the control group treated with saline solution (NaCl, 0.9%) during the study period. The secondary endpoints of the study were: (i) the need for antibiotic therapy during follow-up; (ii) the need for decongestant and fluidizing preparations during the study; and (iii) the tolerability and safety of the lentisk oil-based preparation. The results (primary and secondary endpoints) were collected using a clinical evaluation form completed by the enrolling physician and a clinical evaluation form completed by the parent of the patient participating in the study, complementing the form completed by the physician.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5. Clinical Evaluation Forms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the study endpoints, two complementary clinical evaluation forms were used, one to be completed by the medical staff and one to be completed by the parent of the enrolled patient. The \u0026quot;Physician\u0026quot; form included the enrolled patient\u0026apos;s medical history (age, sex, presence of concomitant medications, previous medications), associated with evaluation fields to be completed at T0 (day of enrollment) and T6 (after 6 days of therapy, end of study), which included: (i) days since symptom onset; (ii) presence of mucous rhinitis and its severity (mild: need to blow the nose 2-3 times a day; moderate: need to blow the nose 4-5 times a day; severe: need to blow the nose 6 or more times a day); (iii) presence of retropharyngeal mucous discharge; (iv) presence of bad breath; (v) presence of nocturnal catarrhal cough with awakening from sleep; (vi) presence of stuffy nose. Furthermore, the \u0026quot;Doctor\u0026quot; form always noted the need for antibiotics at the clinical checkup on day six, and, if so, which antibiotics were prescribed. Finally, the onset of side effects during the study and the patient\u0026apos;s tolerability of treatment were reported. In the \u0026quot;Patient\u0026quot; form, using assessment fields that could be filled in by the patient\u0026apos;s parent, divided into timepoints from day 1, the day after enrollment, to day 5 of treatment, the day before the next medical visit, the severity of mucous rhinitis symptoms (mild, moderate, and severe), if present, was recorded, as well as the presence of halitosis, a nocturnal, catarrhal cough with awakening, and a stuffy nose. The parameter \u0026quot;presence of retropharyngeal discharge\u0026quot; was the sole responsibility of the enrolling physician and was therefore assessed only at enrollment and at the end of therapy (day 6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6. Sample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsidering in clinical practice a mean resolution of 60% for the primary endpoint in the control group treated with saline solution (NaCl 0.9%)\u003csup\u003e14\u003c/sup\u003e. To detect a further decrease of 25%, and therefore a resolution in 85% of patients in the group treated with the class II medical device, with 80% power and a type I error of 0.05, our analysis required 94 participants.\u003csup\u003e15\u003c/sup\u003e By enrolling 100 patients the type I error became 0.039 and therefore clearly lower than 0.05. By enrolling 105 patients, the type I error dropped further to about 0.034 (Supplementary File S1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.7. Satistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis were performed by using the Categorical platform in JMP 14.3.0 (serial number R5GE7G0JOB) of the SAS Institute Inc. (100 SAS Campus Drive, Cary, North Carolina 27513; 2414, USA) considering a \u0026quot;between-subjects\u0026quot; (two treatment groups) and \u0026quot;within-subjects\u0026quot; (seven temporal measurements) experimental design.\u003csup\u003e15\u003c/sup\u003e Two standard Chi-square approaches were applied: 1) Likelihood Ratio Chi-square (LR Chi-square) that evaluates the association between categorical variables by comparing the likelihood of the observed data under the null hypothesis versus the alternative hypothesis. This method is often preferred when expected cell counts are low, as it is based on maximum likelihood estimation; 2) Pearson Chi-square, the traditional Chi-square test comparing observed frequencies with those expected under the null hypothesis, based on squared deviations standardized by the expected counts. For each method, we reported both the test statistic (LR Chi-square or Pearson Chi-square) and the corresponding p-value (LR P-value, Pearson P-value), which quantify the probability of observing the given association by chance under the null hypothesis of independence. Both statistics and p-values were used to confirm the robustness of the results. For the analysis of the main symptom \u0026quot;mucous rhinitis\u0026quot;, we also used the Pseudo-Markov Chain.\u003csup\u003e16,17\u003c/sup\u003e A Markov chain is a process in which the probability of moving from one \u0026ldquo;state\u0026rdquo; to another (known as the transition probability) depends solely on the state reached in the previous event. In other words, the process is memoryless. The technique presented here, aimed at generating new information, draws from Markov theory only the concepts of \u0026ldquo;state\u0026rdquo; (Baseline or T6) and \u0026ldquo;transition\u0026rdquo; (the change from one to the other). For this reason, we refer to it as a pseudo-Markov chain (Martino Recchia (2023)-Obtaining More Information from a Contingency Table: Pseudo Markov Chain Analysis - Journal of Medical \u0026ndash; Clinical Research \u0026amp; Reviews).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e3.1.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Descriptive features of the analyzed patients of the two groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in Figure 1, after assessing for eligibility 135 patients, 30 of the them were excluded according to the inclusion and exclusion criteria. After randomization and allocation, none abandoned the study during its course. Therefore, all the results shown refers to the 105 patients completing the study. According to Table 1, the main features, including age, sex, number of patients who were subjected to therapies in the 15 days before the enrolment, and days spent from the onset of the symptoms to the enrolment day, \u0026nbsp;were not significantly different between the two. Also, type of drugs and length of treatment before the enrolment day were not significantly different (Supplementary File 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain features of the enrolled patients of the two groups of treatment.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUWLO-treated\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003egroup (N=53)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNaCl-treated\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003egroup (N=52)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.60 ± 1.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.73 ± 2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en. s.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex (M/F)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27/26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en. s.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious therapies*\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en. s.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDays from onset\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.15 ±1.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.88 ± 1.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en. s.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eUWLO: Ultra-fractionated and winterized lentisk oil. M: males; F: females. n. s.: not significant. *Further details are given in Supplementary File 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. \u0026nbsp; \u0026nbsp; \u0026nbsp; Treatment effect on mucous rhinitis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults on mucous rhinitis are graphically shown in Figure 2. At enrollment, no patients in the UWLO group had mild mucous rhinitis, 49.1% had moderate mucous rhinitis, and 50.9% had severe mucous rhinitis. In the NaCl group, 7.7% had mild mucous rhinitis, 59.6% had moderate mucous rhinitis, and 32.7% had severe mucous rhinitis. Therefore, at enrollment, both groups had moderate or severe symptoms, indicating a significant clinical condition, with the UWLO group showing a slightly higher percentage of severe cases than the NaCl group. At day 1, 5.7% of patients treated with UWLO had mild symptoms, 50.9% had moderate symptoms, and 43.4% had severe symptoms. In the NaCl group, 5.8% showed mild symptoms, 59.6% moderate, and 34.6% severe. A slight improvement was then observed in the UWLO-treated group, with a small increase in mild cases and a decrease in severe cases. The majority of patients of both groups continued to exhibit signs of moderate or severe rhinitis. At day 2, 9.4% of patients treated with UWLO showed mild symptoms, 66.0% moderate, and 24.5% severe. In the NaCl-treated group, the values were 3.8%, 67.3%, and 28.8%, respectively. Therefore, the UWLO-treated group continued to show a positive trend with an increase in mild cases and a decrease in severe cases. The NaCl group also showed a decrease in severe cases, but with a lower number of mild cases than the UWLO group. On day three, a significant improvement was observed in the UWLO group, with 28.3% of patients having mild symptoms, 67.9% moderate symptoms, and only 3.8% severe symptoms. In the NaCl group, 19.2% of patients had mild symptoms, 71.2% moderate symptoms, and 9.6% severe symptoms. Both treatments therefore showed a marked reduction in severe cases. However, in the UWLO group, severe cases were reduced to a lower percentage and mild cases to a higher percentage than in the NaCl group. On day four, in the UWLO group, 47.2% of patients had mild rhinitis, 52.8% moderate symptoms, and no patients had severe symptoms. In the NaCl group, 42.3% of patients had mild symptoms, 57.7% moderate, and no patients had severe symptoms. In both groups, there were no longer any cases of severe rhinitis, and most patients had mild or moderate symptoms, with a higher percentage of mild cases in the UWLO group. On day 5, 79.2% of patients in the UWLO group had mild symptoms and 20.8% had moderate symptoms, compared to 61.5% of patients with mild symptoms and 38.5% with moderate symptoms in the NaCl group. Also at this stage, treatment with UWLO demonstrated a higher percentage of mild cases compared to NaCl. At the end of the study (day 6), 86.8% of patients in the UWLO group had mild symptoms and 13.2% had moderate symptoms, compared to 61.5% of mild patients and 38.5% of moderate patients in the NaCl group. Both treatments were effective in reducing the severity of mucous rhinitis over the 6 days of therapy, and by day 4, none of the patients in either group had severe mucous rhinitis. However, treatment with UWLO apparently demonstrated greater efficacy in converting cases from moderate to mild, especially in the later stages of the study (days 3 to 6), consistently surpassing treatment with NaCl in the percentage of patients with mild rhinitis. This apparently suggests that treatment with UWLO may offer greater benefit in achieving minimal severity for mucous rhinitis.\u003c/p\u003e\n\u003cp\u003eTo determine whether the distribution of responses, expressed as severity of mucous rhinitis, was statistically similar/homogeneous between the two treatment groups (UWLO versus NaCl) at each observation time point (days 0–6), we measured the discordance between the observed frequencies and those that would be expected if there were no difference between the groups (that is, if the two groups were homogeneous). By evaluating the severity of mucous rhinitis in relation to treatment for each time point using the Likelihood Ratio Chi-square and Pearson Chi-square tests (Supplementary File 3), we found that, despite randomization, at enrollment, there was a statistically significant difference (p\u0026lt;0.05) in the distribution of rhinitis severity between the UWLO group and the NaCl group. This finding was consistent with the previous observation that on day 0, the UWLO group had a slightly higher percentage of severe cases (50.9%) than the NaCl group (32.7%). The samples were therefore not perfectly balanced in terms of initial severity, to the detriment of the UWLO-treated group. The same comparative analysis, carried out between the results obtained in the two groups between days 1 and 4, did not highlight significant differences. On day 5, the distribution of mucous rhinitis severity between the two groups was again significant (p\u0026lt;0.05). The difference in this case was due to a significantly higher percentage of patients with mild symptoms observed in the UWLO group (79.2%) compared to that observed in the NaCl group (61.5%). At the end of treatment (day 6), the distribution of mucous rhinitis grade between the two groups was highly significant (p\u0026lt;0.01) and in favor of the UWLO group, in which mucous rhinitis was mild in 86.8% of cases compared to 61.5% of cases in the NaCl group. Patient-by-patient analysis using a Markov chain\u003csup\u003e16,17\u003c/sup\u003e to observe transitions in symptom severity showed that, in the NaCl-treated group, of the four patients who had mild symptoms at enrollment, none changed their symptoms by day 6. Of the 31 patients with moderate symptoms at enrollment, 25 improved their symptom severity by day 6, transforming them to mild symptoms, while six remained stable. Of the 17 patients who had severe symptoms at enrollment, three transitioned to mild symptoms at the end of therapy, and 14 to moderate symptoms. Conversely, the case study observed for the group treated with UWLO shows that of the 26 patients who presented a moderate severity at enrollment, 24 reduced the severity to mild, while 2 maintained the same level of severity found on day 0. Of the 27 patients who presented a severe severity at enrollment, 22 showed a mild severity at the end of therapy, while 5 recorded a transition to moderate severity (Supplementary File 4). We therefore developed new categories of subjects based on state migrations: (i) improved (patients who on day 6 show a symptom severity lower than that revealed on day 0); (ii) immune (patients who do not show, between the two periods, any variation in their symptom severity); worsened (patients who at the end of therapy show a severity higher than that shown on day 0). The results of the Markovian analysis show that of the 53 patients in the UWLO group, 96.2% improved, 3.8% remained unchanged, and none worsened between the beginning and the end of the study. Conversely, of the 52 patients in the NaCl group, 80.8% improved, 19.2% remained unchanged, while none worsened between the beginning and the end of the study. The difference in efficacy between the two treatments appears evident when the previous data are subjected to statistical analysis with the Likelihood Ratio (p = 0.0097) and Pearson tests. (p=0.0128) which demonstrate the greater efficacy of treatment with UWLO (Table 2 and Supplementary File 5). A Markov chain is a process in which the probability of moving from one state to another (called the transition probability) depends only on the state reached in the previous event. The table 2 shows data on the symptomatology of mucous rhinitis, a transition matrix relating to the patient's symptom, which can be in three different states, identified as mild, moderate, and severe. The table therefore illustrates the changes in symptom severity that each patient in the two groups exhibited at the end of therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMarkovian analysis of the state transition of patients in the two treatment groups\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient condition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUWLO-treated group (N=53)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNaCl-treated group (N=52)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eImproved\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN=51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN=42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnchanged\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN=2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN=10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWorsened\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN=0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eN=0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eLikelihood ratio and Pearson chi-square were 6.685 and 6.195 with, respectively, p=0.0097 and p=0.0128.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. \u0026nbsp; \u0026nbsp; \u0026nbsp; Treatment effect on stuffy nose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding stuffy nose symptoms, both groups, although with some differences, showed a reduction over the course of treatment (Figure 3). In the UWLO group, the presence of the symptom decreased dramatically from 100.0% at baseline to 47.2% on the third day and further to 17.0% on the fifth and sixth days of therapy. In the NaCl group, the symptom decreased from 94.2% at baseline to 71.2% on the third day, and then to 32.7% and 34.6% on the fifth and sixth days. The comparison between the two groups also showed that starting from the third day, the percentage of patients with a stuffy nose was considerably lower in the UWLO group than in the group treated with 0.9% NaCl solution. In fact, on the fourth day, only 22.6% of patients treated with UWLO showed a stuffy nose symptom compared to 53.8% in the NaCl group. This difference suggested a virtually greater efficacy of UWLO treatment in resolving the symptom. Analyzing the presence of symptom in relation to treatment for each time point by the Likelihood Ratio Chi-square and Pearson Chi-square tests (Supplementary File 6), we found that the slight difference in percentages between the two groups at enrollment (100% vs. 94.2%) was statistically significant (p\u0026lt;0.05) to the detriment of the UWLO-treated group. On the first and second days of therapy no significant differences were observed between the groups. On the third day, the UWLO group had a significantly (p\u0026lt;0.05) lower percentage (47.2%) than that observed in the NaCl group (71.2%). On day 4, the analysis indicated a highly significant difference (p\u0026lt;0.01) between the groups, with symptom presence at 22.6% in the UWLO group and 53.8% in the NaCl group. On day 5, the symptom frequency was not significantly different between the two groups. Conversely, at the end of therapy, the symptom was again significant (p\u0026lt;0.05) with a frequency of. 17.0% in the UWLO group versus 34.6% in the NaCl group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Nocturnal catarrhal cough\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in Figure 4, the use of UWLO resulted in a more marked progressive improvement than the effect due to NaCl therapy, with an increasing percentage of patients without symptoms at each time point. The NaCl group improved more slowly and maintained higher percentages of patients with symptoms, especially from day 3 onwards. The statistical analysis of homogeneity, aimed at determining the existence of a significant difference in symptom distribution between the UWLO group and the NaCl group at each time point (Supplementary File 7), demonstrated that at enrollment, despite randomization, there was a small but significant difference (p\u0026lt;0.05) between the two groups to the disadvantage of the NaCl group. In the initial phases (days 1 and 2), treatment with UWLO significantly improved cough compared to the NaCl group. On the third day, the difference, in favor of the UWLO group, was no longer statistically significant, but in the more advanced phases of the study (days 4-6). the efficacy of UWLO became clear and highly significant (p\u0026lt;0.01) and by day 6 almost 80% of patients treated with UWLO were no longer coughing, compared to just over 40% in the NaCl group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Halitosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in Figure 5, treatment with UWLO reduced the presence of the symptom more rapidly and significantly than that seen in the NaCl group, with differences particularly evident from the third day onward. Statistical analysis aimed at identifying differences in homogeneity of response (Supplementary File 8) demonstrated significant differences, always favoring treatment with UWLO, at days 2 and 4 of therapy (p\u0026lt;0.05) and highly significant differences (p\u0026lt;0.01) on days 3 and 6. On day 5, although graphically evident, the difference was not significant, with a p=0.0558 in the Likelihood Ratio test (Supplementary File 8).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Mucous retropharyngeal discharge\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDifferently from previous endpoints, the presence of retropharyngeal mucous discharge was detected, in both treatment groups, only at enrollment and at the end of therapy. As shown in Figure 6, and statistically demonstrated by the Likelihood Ratio and Pearson tests in Supplementary File 9, at enrollment, despite randomization, 44 (83%) patients in the ULWO group and 32 (61.5%) in the NaCl group demonstrated the presence of the symptom (p\u0026lt;0.05). At the end of therapy, only 2 (3.8%) patients in the UWLO group, compared to 26 (50%) in the NaCl group, still presented the symptom (p\u0026lt;0.01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.7. \u0026nbsp; \u0026nbsp; \u0026nbsp; Need for antibiotics at follow-up and use of other drugs during treatment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in Supplementary File 10, at the follow-up one patient in the UWLO group was treated with amoxicillin and clavulanic acid and three patients in the NaCl group were treated with amoxicillin (2 patients) and clarithromycin (1 patient). Thus, 52 patients (98.1%) in the UWLO group and 49 (94.2%) in the NaCl group did not require antibiotic therapy. Although the result tended to favor treatment with UWLO, analysis revealed no significant differences between the two groups. Regarding the need for other therapies during treatment with UWLO or NaCl, almost all patients did not take other medications during the study. Some patients took paracetamol (two children in the UWLO group, a 5-year-old male and a 7-year-old female, took it for 24 hours due to a sore throat; one child in the NaCl group, a 5-year-old male, took it for 24 hours due to a mild fever below 38°C) or acetylcysteine-based fluidizing syrup (one child in the NaCl group, a 2-year-old male, took it from day 3 to day 5 inclusive). Again, the difference between the two groups was not significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.8. \u0026nbsp; \u0026nbsp; \u0026nbsp; Tolerability and treatment-related side effects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment tolerability (Supplementary File 11) was very good in both groups, with a slight, though non-significant, trend favoring the UWLO group. No treatment-related side effects were reported in either group, confirming the excellent safety profile of the two treatments.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe underlying idea of the study was to verify whether it was possible to improve the overall symptomatic picture in pediatric patients diagnosed with purulent rhinitis simply by applying UWLO from \u003cem\u003ePistacea lentiscus\u003c/em\u003e berries, formulated as oil drops for nasal administration. This effectively replicates the antibacterial action typically achieved by antibiotics, but without the same adverse effects, especially gastrointestinal ones. Comparing the results with those obtained in a control group treated with nasal irrigation using 0.9% isotonic saline solution, the results were significantly better, at least considering the symptoms and signs examined. Specifically, in mucous rhinitis, the mastic oil preparation demonstrated greater efficacy in converting cases from moderate to mild, especially in the later stages of the study (days 3 to 6), consistently and significantly outperforming the saline preparation in the percentage of patients with mild symptoms. Regarding the \u0026quot;stuffy nose\u0026quot; symptom, mastic oil showed a more rapid and stable trend of improvement, with a consistent and significant reduction in symptomatic patients as early as the third day. At the end of therapy, 83% of patients treated with mastic oil no longer had symptoms, while in the control group, the symptom persisted in approximately one-third of patients. Regarding nocturnal catarrhal cough, mastic oil proved superior to the control, with significant improvements, especially in the later stages of treatment. Halitosis was treated more rapidly and more markedly, with statistically significant results from day 2 onward. Finally, regarding retropharyngeal mucous discharge, despite initial heterogeneity in favor of the saline rinse, at the end of the study (day 6), mastic oil produced significantly superior results, with a highly significant difference between the two treatments. Noteworthy, not only was a reduced need for antibiotics observed at follow-up, but these results were achieved with very good tolerability for the young patients (and better than that observed in the control group), with no side effects specifically attributable to the preparation. The results obtained, thanks also to an appropriate sample size, therefore allow us to state that the intranasal administration of UWLO proved to be a significantly better option than nasal rinses with saline in pediatric purulent rhinitis. Other studies,\u003csup\u003e11-13\u003c/sup\u003e pharmacological (both in vitro and in vivo) and clinical (in chronic recurrent sinusitis), had in some ways prompted this assessment and may also help us understand the reasons for the findings in our study. These investigations had demonstrated the specific antibacterial action of some fractions of lentisk oil, effect in all likelihood caused by the specific antibiofilm role exerted by preparation, against certain nasal and oropharyngeal pathogens, an action so specific that it does not affect commensal and non-pathogenic bacteria present in the same microbiota, such as the species \u003cem\u003eS. salivarius\u003c/em\u003e.\u003csup\u003e18-20\u003c/sup\u003e This unique antibacterial role may have influenced the potential for nasal and oropharyngeal dysbiosis, perhaps limiting it. Indeed, the dysbiosis hypothesis, the alteration of microbiota associated with perturbation of the local ecological landscape, has been suggested as a mechanism involved in most pathologies, including those occurring in the respiratory tract.\u003csup\u003e21,22\u003c/sup\u003e Recent advancements in culture-independent molecular techniques have enhanced understanding of bacterial interactions inside the microbiota of upper airway microenvironment demonstrating that, for instance in case of chronic sinusitis, during infection global bacterial load does not change in comparison with healthy controls, while biodiversity reduces.\u003csup\u003e23\u003c/sup\u003e Differences have been also demonstrated from a taxonomical perspective. Versus healthy controls acute bacterial sinusitis is mostly characterized by the presence of microorganisms like \u003cem\u003eS. pneumoniae\u003c/em\u003e, \u003cem\u003eH. influenzae\u003c/em\u003e, \u003cem\u003eM. catarrhalis\u003c/em\u003e, and \u003cem\u003eS. pyogenes\u003c/em\u003e; while \u003cem\u003eS. aureus\u003c/em\u003e and anaerobic organisms (\u003cem\u003ePrevotella\u003c/em\u003e and \u003cem\u003ePorphyromonas\u003c/em\u003e, \u003cem\u003eFusobacterium\u003c/em\u003e, and \u003cem\u003ePeptostreptococcus\u003c/em\u003e spp.) are the commonest isolates in chronic rhinosinusitis.\u003csup\u003e24\u003c/sup\u003e While it is not possible to translate with certainty what has been observed in acute sinusitis and chronic sinusitis in purulent pediatric rhinitis, it is impossible not to highlight that the active fractions of lentisk oil behave in an antibiotic-like manner precisely against those bacterial \u003cem\u003etaxa\u003c/em\u003e involved in the acute disorder, preserving the eubiotic fraction, with already demonstrated favorable clinical consequences.\u003csup\u003e12,13\u003c/sup\u003e The observed safety profile, fundamental for our trial which was a \u0026quot;first\u0026quot; in pediatrics, is also in line with what has been reported in studies aimed at evaluating also its anti-inflammatory and non-toxic effect.\u003csup\u003e12,13\u003c/sup\u003e According to validated methods and ISO (International Organization for Standardization) documents,\u003csup\u003e25-28\u003c/sup\u003e the fractionated and winterized lentisk oil has been subjected to an important series of verification tests whose results have demonstrated that: (i) it is not absorbed by human mucosa; (ii) it does not exhibit skin sensitization potential; (iii) it is not irritant for nasal mucosa; and (iv) it is not cytotoxic for human cells. Our study presents some limitations and potential biases: (i) the sample size chosen, although in line with statistical requirements, is not high; (ii) the study design does not allow for the evaluation of a possible additive effect deriving from the use of saline and UWLO; (iii) the study design, although randomized, controlled and prospective, lacks elements such as being double-blind and measuring the placebo effect; (iv) no analytical and/or instrumental approach aimed at understanding the possible mechanism of action was foreseen (previous publications have however demonstrated the anti-biofilm effect of the preparation)\u003csup\u003e12,13\u003c/sup\u003e; (v) and no real prolonged follow-up investigation was foreseen, beyond the sixth day of vision, and therefore it is not possible to know whether the preparation used once, therefore for a week, reduces possible recurrences. Despite these limitations, our study demonstrates that the use of a class II medical device containing ultra-fractionated and winterized lentisk oil as its sole active ingredient, used as the sole medication for pediatric purulent rhinitis, is safe and significantly more effective in controlling symptoms than the daily use of a saline solution (0.9% NaCl) for nasal irrigation, perhaps also resulting in a reduced need for antibiotics. Further, larger, double-blind studies should confirm our observations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: AAN, GDP, AG, RP, AMR, DP, TM, AAM FDP; Methodology, Investigation, Validation, and \u0026nbsp;Formal analysis: GDP, AG, RP, AMR, DP, TM, AAM,; FDP, AK, FR, NMM Resources; FDP, CMP, AB, MLT, NZ; Data curation; FDP, MR, AAM; Writing\u0026ndash;original draft preparation; FDP, AAN, NZ; \u0026nbsp;Writing\u0026ndash;review and editing; FDP, AAN, CMP, NZ; Visualization; FDP, AAN, NZ; Supervision; FDP, AAN, MLT, NZ, MR; Project administration: AAN. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFDP is the Scientific \u0026amp; Research Director in Pharmextracta SpA. FDP is also the main author of the European patent describing the fractionated lentisk oil (N\u0026deg; 20205961.4 deposited on November 5th, 2020). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AB is a Pharmextracta consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSteinweg KK. Natural history and prognostic significance of purulent rhinitis. 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Front Microbiol. 2017 Oct 24;8:2067. doi: 10.3389/fmicb.2017.02067. \u003c/li\u003e\n\u003cli\u003eDi Pierro F, Sagheddu V, Galletti S, Forti M, Elli M, Bertuccioli A, Gaeta S. Antibacterial Activity of a Fractionated Pistacia lentiscus Oil Against Pharyngeal and Ear Pathogens, Alone or in Combination With Antibiotics. Front Microbiol. 2021; 12:686942. doi: 10.3389/fmicb.2021.686942. PMID: 34220777; PMCID: PMC8247648.\u003c/li\u003e\n\u003cli\u003eDI Pierro F, Zerbinati N, Tanda ML, Monti G, Macchi A. Fractionated lentisk oil as add-on therapy for preventing chronic rhinosinusitis recurrence. Minerva Med. 2025 Mar 6. doi: 10.23736/S0026-4806.25.09683-1.\u003c/li\u003e\n\u003cli\u003eYata K, Srivanitchapoom C. The comparison of nasal irrigation outcome between 3% NaCl and 0.9% NaCl in adults majority with intermittent allergic rhinitis: A randomized double-blind study. 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Eur Respir J. 2017; 49(4):1602086. doi: 10.1183/13993003.02086-2016. \u003c/li\u003e\n\u003cli\u003eCho DY, Hunter RC, Ramakrishnan VR. The Microbiome and Chronic Rhinosinusitis. Immunol Allergy Clin North Am. 2020; 40(2):251-263. doi: 10.1016/j.iac.2019.12.009. \u003c/li\u003e\n\u003cli\u003eBrook I. Microbiology of chronic rhinosinusitis. Eur J Clin Microbiol Infect Dis. 2016; 35(7):1059-68. doi: 10.1007/s10096-016-2640-x. \u003c/li\u003e\n\u003cli\u003eKoschier F, Kostrubsky V, Toole C, Gallo MA. In vitro effects of ethanol and mouthrinse on permeability in an oral buccal mucosal tissue construct. Food Chem Toxicol. 2011; 49(10):2524-9. doi: 10.1016/j.fct.2011.06.018. Erratum in: Food Chem Toxicol. 2012; 50(5):1815. \u003c/li\u003e\n\u003cli\u003eGibbs S, Kosten I, Veldhuizen R, Spiekstra S, Corsini E, Roggen E, Rustemeyer T, Feilzer AJ, Kleverlaan CJ. Assessment of metal sensitizer potency with the reconstructed human epidermis IL-18 assay. Toxicology. 2018; 393:62-72. doi: 10.1016/j.tox.2017.10.014. \u003c/li\u003e\n\u003cli\u003ehttps://www.iso.org/obp/ui/en/#iso:std:iso:10993:-23:ed-1:v1:en (visited on June 11th, 2025).\u003c/li\u003e\n\u003cli\u003ehttps://www.iso.org/obp/ui/en/#iso:std:iso:10993:-5:ed-3:v1:en (visited on July 9th, 2025).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mucous rhinitis, mucous retropharyngeal discharge, halitosis, stuffy nose nocturnal catarrhal cough, Pistacea lentiscus","lastPublishedDoi":"10.21203/rs.3.rs-7385153/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7385153/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Acute purulent rhinitis in children has a shorter course and milder symptoms if treated with antibiotics. Antibiotic use, in addition to fueling antibiotic resistance, frequently causes gastrointestinal symptoms. Specific fractions of winterized lentisk oil (Pistacea lentiscus) have demonstrated unique antibiofilm and antibiotic activity against nasal and oropharyngeal pathogens potentially implicated in the symptoms of purulent rhinitis in children. In a randomized, prospective, controlled and no profit trial, the use of a class II medical device, formulated as oil drops for nasal use, containing as active ingredient a ultra-fractioned and winterized lentisk oil (UWLO) and administered for six days, demonstrated the ability to significantly reduce symptoms such as mucous rhinitis, retropharyngeal mucous discharge, halitosis, stuffy nose, and nocturnal catarrhal cough compared to treatment with isotonic saline nasal wash. The use of UWLO also tended to reduce the need for antibiotic therapy and was well tolerated and free of side effects. The data obtained suggest the use of the lentisk derivative to reduce the duration of the clinical course and the main symptoms characterizing pediatric purulent mucosa.","manuscriptTitle":"Evaluation of the efficacy of ultra-fractioned and winterized lentisk oil in reducing symptoms of purulent bacterial overinfection of pediatric rhinitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 06:01:47","doi":"10.21203/rs.3.rs-7385153/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-01-25T13:49:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"268211866858950103122784112432835371815","date":"2026-01-14T07:43:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T06:41:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-02T04:48:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-25T07:02:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-22T10:29:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-22T10:26:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"952829da-4037-425f-a42f-2ed60379fb1d","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":60793011,"name":"Health sciences/Diseases"},{"id":60793012,"name":"Health sciences/Health care"},{"id":60793013,"name":"Health sciences/Medical research"},{"id":60793014,"name":"Biological sciences/Microbiology"}],"tags":[],"updatedAt":"2026-01-12T06:01:47+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 06:01:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7385153","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7385153","identity":"rs-7385153","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}