Bacterial Lysates Add‐On Therapy to Reduce Postoperative Recurrence in Nasal Polyps

ABSTRACT

Objective

This study aimed to investigate the potential role of OM‐85 in reducing polyp recurrence (PR).

Methods

A single‐center randomized, prospective study was performed to compare the inter‐group PR rate, patient‐reported outcome measures (PROMs), CT and endoscopic scores. Hundred patients were randomized to receive either add‐on OM‐85 (34/50) or control group (43/50); 77 participants completed the 12‐month follow‐up. The OM‐85 group received oral treatment for 10 days, followed by a 20‐day washout (Months 1–3 and 7–9). Primary outcome was the PR rate. Secondary outcomes included PROMs, Lund‐Kennedy (L‐K) scores, Lund‐Mackay (L‐M) scores, and complete blood count (CBC) parameters.

Results

The PR rate was significantly lower in the OM‐85 group (8.82%) than in the control group (27.91%, χ ² = 4.408, p = 0.036). Univariable analysis identified pre‐operative Lund‐Mackay (L‐M) score (p = 0.008) and hyposmia VAS score (p = 0.031) as significant predictors of PR. In multivariable analysis, the L‐M score remained an independent predictor (OR = 1.15, p = 0.012), with an optimal cutoff of 10. The OM‐85 group showed significant improvements in nasal obstruction, olfactory dysfunction, and mucopurulent discharge at 6 and 12 months (p < 0.05). Lund‐Kennedy (L‐K) score and 22‐item Sinonasal Outcome Test (SNOT‐22) score were also significantly improved (p < 0.05). Furthermore, the OM‐85 group exhibited elevated white blood cell counts and lymphocyte percentages from 6 months onward (p < 0.05).

Conclusion

Adjuvant OM‐85 may reduce postoperative PR, with improved endoscopic and symptom scores, potentially mediated by enhanced systemic immune function.

Level of Evidence

2.

Adjuvant therapy with the bacterial lysate OM‐85 significantly reduced postoperative polyp recurrence at 12 months (8.82% vs. 27.91%) and improved symptoms, L‐K endoscopic and SNOT‐22 scores in patients with nasal polyps following endoscopic sinus surgery. These clinical benefits were associated with elevated white blood cell and lymphocyte counts, suggesting that OM‐85 may reduce recurrence through enhanced systemic immune function.

1. Introduction

Chronic rhinosinusitis (CRS) is one of the most prevalent chronic inflammatory respiratory diseases, primarily affecting the nasal and paranasal sinus mucosa, with clinical manifestations including purulent rhinorrhea, nasal obstruction, headache, postnasal drip, hyposmia/anosmia, and facial pressure/pain [1]. Although not life‐threatening, the persistent symptoms severely impair patients' quality of life and productivity [2], resulting in substantial economic burdens [3]. CRS may also contribute to stress‐related disorders such as depression and anxiety [4]. It affects 8% of the Chinese population [5] and 5% to 15% of populations in the United States and Europe [1]. CRS is clinically distinguished as either without (CRSsNP) or with (NP) nasal polyps. Compared to CRSsNP, NP often requires endoscopic sinus surgery (ESS) combined with long‐term pharmacological management. Nevertheless, a proportion of patients still achieve poor symptom control, exhibit persistent mucosal inflammation, and face high recurrence rates, a clinical profile frequently labeled as refractory NP [6, 7]. These refractory cases frequently comorbid with other chronic respiratory inflammatory diseases, including allergic rhinitis (AR), asthma, and chronic obstructive pulmonary disease (COPD) [8]. Studies indicated that approximately 20% of NP patients experience recurrence within 1 year post‐surgery [9], 40% within 1–2 years [10, 11, 12], and up to 80% within 12 years postoperatively [13]. Eosinophilic inflammation and Type 2 (T2) immune responses have been identified as critical risk factors for disease recurrence in NP patients [14, 15].

Broncho‐vaxom (OM‐85) is a kind of bacterial lysates containing the extracts of some common pathogens, including Branhamella catarrhalis , Streptococcus pyogenes , Klebsiella pneumoniae , Klebsiella ozaenae , Streptococcus pneumoniae , Streptococcus viridans, and Staphylococcus aureus . Mechanistically, OM‐85 stimulates key components of both innate and adaptive immunity. It activates monocytes, macrophages, natural killer (NK) cells, and dendritic cells, thereby enhancing antigen presentation and phagocytic activity. In the adaptive immune response, it promotes B‐cell activation and antibody production, shifts the Th1/Th2 balance toward Th1 dominance via increased IFN‐γ secretion, and amplifies T‐cell proliferation [16, 17, 18, 19]. Previous study further revealed that OM‐85 enhanced superoxide production in macrophages, indicating potentiated respiratory burst activity without inducing systemic inflammation [20].

Since the 1980s, OM‐85 has been used in adults and children to prevent recurring respiratory tract infections [21]. Nowadays, it has demonstrated efficacy in AR by alleviating nasal itching, rhinorrhea, and sneezing, while reducing medication use and acute exacerbations [22, 23]. In CRS management, it lowered recurrence risk and improved radiological outcomes [24], with additional evidence supporting its cost‐effectiveness through decreased sinusitis episodes [25]. However, no studies have yet investigated its role in preventing postoperative recurrence in refractory NP. This single‐center prospective study aims to evaluate the therapeutic potential of OM‐85 in reducing recurrence following ESS in refractory NP patients.

2. Methods

2.1. Sample Size Calculation

So far, there is no literature on the use of OM‐85 for postoperative recurrence prevention in NP. However, multiple randomized controlled trials have demonstrated that prophylactic administration of OM‐85 achieves a 30% to 50% decrease in the rate of infection‐triggered exacerbations and wheezing episodes among children with recurrent wheezing episodes or asthma [26, 27]. Sample size calculation (α = 0.05, two‐tailed; power = 95%; 35% recurrence difference) gave 40/group. Accounting for 20% dropout, this was adjusted to 50/group (Supporting Information).

2.2. Participants

A total of 100 participants were recruited between 2023 and 2024, and only 77 participants completed the full 1‐year follow‐up period (Figure S1). The study received approval from the Ethical Committee of the Third Affiliated Hospital of Sun Yat‐sen University, Guangzhou, China (Approval No. II2023‐067‐03). This clinical registration number was ChiCTR2300075072. The detailed inclusion and exclusion criteria are provided in Table S1 (Additional information is provided in Supporting Information). Demographic characteristics are summarized in Table 1. The two groups were well‐balanced and showed no statistically significant differences in baseline demographic and clinical characteristics, including history, age, gender, L‐M score, L‐K endoscopic score, SNOT‐22, and VAS scores (all p > 0.05).

TABLE 1.

Baseline characteristics of participants.

Items	OM‐85 group N = 34	Control group N = 43
Dropping out rate (%)	16/50	7/50 a
Gender n (%)
Female	10 (29.41)	12 (27.91)
Male	24 (70.59)	31 (72.09)
BMI	22.99 ± 2.27	23.80 ± 3.59
History (year)	3.00 (1.00, 10.00)	4.00 (1.00, 8.00)
Age	39.77 ± 11.41	38.91 ± 11.74
Allergic comorbidities n (%)
No	28 (82.35)	33 (76.74)
Yes	6 (17.65)	10 (23.26)
Eosinophilic NP n (%)
No	19 (55.88)	22 (51.16)
Yes	15 (44.12)	21 (48.84)
tIgE > 100 IU/mL n (%)
No	23 (67.65)	32 (74.42)
Yes	11 (32.35)	11 (25.58)
L‐M CT score	14.71 ± 5.77	14.93 ± 6.07
L‐K score	11.00 (8.00, 12.00)	9.00 (6.00, 12.00)
SNOT‐22 score	33.00 (19.00, 41.00)	32.00 (19.00, 44.00)
Total VAS score	19.50 (12.75, 26.25)	23.00 (13.00, 28.00)

Note: Data shown in mean ± SD or median [25th, 75th] or absolute n (%) counts. Eosinophilic NP was defined when the average histologic count of eosinophils exceeded 10 at high power magnification (HPF, × 400) after hematoxylin–eosin (HE) staining.

Abbreviations: L‐K score, Lund‐Kennedy score; L‐M CT score, Lund‐Mackay CT score; SNOT‐22 score, 22‐item Sinonasal Outcome Test; VAS, Visual Analog Scale; WB, White blood cells.

^a p < 0.05 (Chi² test) for dropping out rate, and there were no differences among the other groups, with p > 0.05.

2.3. Interventions

The bacterial lysate used was OM‐85 (Broncho‐Vaxom, manufactured by OM Pharma SA, Switzerland). According to the usage from a previous study [28], for the OM‐85 group, the treatment was administered orally for 10 consecutive days, followed by a 20‐day washout interval, at the beginning of each month. This 10‐days‐on/20‐days‐off cycle was repeated for three consecutive months (Months 1–3), followed by a three‐month treatment‐free period (Months 4–6). The cycle was then repeated for a second three‐month period (Months 7–9), followed by a final three‐month treatment‐free period (Months 10–12). The control group received no additional treatment beyond the standard care (Figure 1).

FIGURE 1.

Study outline. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

2.4. Study Protocol

All the participants underwent ESS performed by the same surgeon. Then, they received a standardized postoperative medical regimen. This included a one‐week course of macrolide antibiotics post‐surgery. Intranasal corticosteroid sprays (Mometasone furoate, 100 μg per nostril twice daily) were initiated for all patients 1 week after surgery and continued throughout the 12‐month follow‐up period. Oral glucocorticoids were not routinely administered but were permitted as rescue medication for significant disease exacerbation; their use was recorded and will be analyzed. Postoperative outcomes were assessed during five visits using Lund‐Kennedy endoscopic scores, two patient‐reported outcome measures (PROMs). It is worth mentioning that L‐K endoscopic scoring was performed by two independent otolaryngologists who were blinded to the patient's treatment group allocation evaluated by the same researcher. During postoperative 6 and 12 months, participants also performed a complete blood count (CBC) (Figure 1). Additional information is provided (Supporting Information).

2.5. Study Outcomes

The primary study outcome was endoscopic evaluation for PR, which was defined as the presence of any NPs on endoscopy [29]. Polyp size was further graded using the Lund‐Kennedy scoring system (range 0–2 for polyps) as part of the overall endoscopic assessment.

2.6. Randomization and Treatment Allocation

Randomization was performed by allocating the first consecutive number to the participant. Investigators and assessing physicians were blinded to the allocation during the study.

2.7. Statistical Analysis

Recurrence comparisons between groups were performed using Chi² tests. Univariate analysis of factors associated with recurrence was performed using the chi‐square test, Kruskal‐Wallis test, or Student's t‐test. Multivariate analysis was conducted via binary logistic regression to identify independent predictors of recurrence. Between‐group comparisons of postoperative outcomes were analyzed using the Kruskal‐Wallis test. Statistical significance was set at p < 0.05. Analyses were performed using SPSS version 27 (Supporting Information).

3. Results

3.1. Bacterial Lysates Reduces Postoperative Recurrence and L‐M CT Score as a Predicative Recurrent Biomarker in Nasal Polyp

Of 100 eligible patients participated in this study and 77 patients completed the 1‐year follow‐up (OM‐85 = 34 vs. Control = 43) (Figure S1). The two groups showed comparable history, age, gender, Lund‐Mackay (L‐M) score, L‐K endoscopic score, SNOT‐22, and VAS score (Table 1). The dropout rate was significantly higher in the OM‐85 group (32.0%, 16/50) than in the control group (14.0%, 7/50, χ ² = 4.57, p = 0.032). Primary reasons for discontinuation in the OM‐85 group included failure to take their medications at the prescribed times (n = 6, 37.5%), pregnancy, cancer (n = 3, 18.7%), and loss to follow‐up (n = 7, 43.8%). In contrast, control group dropouts were mainly due to loss to follow‐up (n = 5, 71.4%) and relocation (n = 2, 28.6%).

Thus, it can be seen that dropout was the primary reason for two groups. No side effects, such as gastrointestinal side effects, a known effect of OM‐85, and other significant adverse events were recorded in both groups. Thus OM‐85 is a highly safe medication. The recurrence rate was significantly lower in the OM‐85 group (8.82%, 3/34) compared to the control group (27.91%, 12/43), as demonstrated by chi‐square test (χ ² = 4.408, p = 0.036). A subgroup analysis of patients with eosinophilic NP (eNP) revealed a numerically lower recurrence rate in the OM‐85 group (1/14, 7.14%) compared to the non‐eNP subgroup (2/20, 10%), although the interaction was not statistically significant (χ ² = 0.087, p > 0.05). Given the small sample size and exploratory nature of this subgroup analysis, this finding requires validation in larger, adequately powered studies. Univariate logistic regression identified L‐M score (t = −2.718, p = 0.008) and olfactory dysfunction VAS score (Z = −2.161, p = 0.031) for postoperative recurrence in nasal polyp patients as significant predictors of recurrence (Table S2). Multivariable analysis confirmed L‐M score as an independent predictor after adjusting for confounders, with each 1‐point increase elevating the odds of recurrence by 15.5% (OR = 1.155, 95% CI: 1.032–1.292, p = 0.012). Receiver operating characteristic (ROC) curve analysis revealed moderate diagnostic accuracy for L‐M score in predicting recurrence (Figure 2, AUC = 0.704, 95% CI: 0.567–0.842, p = 0.015). The optimal cutoff value was determined as 10 score (sensitivity 68.4%, specificity 72.3%).

FIGURE 2.

ROC curve of L‐M score for predicting recurrence. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

3.2. OM‐85 Ameliorates Postoperative Clinical Symptoms for NP Patients

During the follow‐up period, significant intergroup differences in symptom severity were observed (Figure 3). At 6 months postoperatively, the OM‐85 group demonstrated markedly lower nasal obstruction VAS scores (median [IQR]: 0.000 [0.000, 0.000] vs. 0.000 [0.000, 2.000], p = 0.015), which persisted through 12 months (0.000 [0.000, 0.000] vs. 0.000 [0.000, 1.000], p = 0.027). Similar patterns were observed for mucopurulent discharge (6‐month: 0.000 [0.000, 0.000] vs. 0.000 [0.000, 2.000], p = 0.020; 12‐month: 0.000 [0.000, 0.000] vs. 0.000 [0.000, 1.000], p = 0.005) and olfactory dysfunction (6‐months: 0.000 [0.000, 0.000] vs. 0.000 [0.000, 2.000], p = 0.009; 12‐months: 0.000 [0.000, 0.000] vs. 0.000 [0.000, 1.000], p = 0.011).

FIGURE 3.

Adjuvant therapy with the bacterial lysate OM‐85 significantly reduced postoperative polyp recurrence at 12 months (8.82% vs. 27.91%) and improved symptoms, L‐K endoscopic and SNOT‐22 scores in patients with nasal polyps following endoscopic sinus surgery. These clinical benefits were associated with elevated white blood cell and lymphocyte counts, suggesting that OM‐85 may reduce recurrence through enhanced systemic immune function. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

The total VAS composite scores further confirmed treatment efficacy, with the OM‐85 group showing superior outcomes at both 6 months (0.000 [0.000, 2.000] vs. 2.000 [0.000, 8.000], p = 0.019) and 12 months (0.000 [0.000, 1.000] vs. 2.000 [0.000, 5.000], p = 0.002). Endoscopic evaluation via L‐K scoring revealed a significant between‐group difference (6‐month: 0.000 [0.000, 4.000] vs. 3.000 [0.000, 6.000], p = 0.008; 12‐month: 0.000 [0.000, 2.000] vs. 3.000 [0.000, 6.000], p = 0.006). The SNOT‐22 scores similarly favored the OM‐85 group (6‐month: 2.000 [0.000, 5.000] vs. 3.000 [0.000, 14.000], p = 0.017; 12‐month: 2.000 [0.000, 5.000] vs. 3.000 [0.000, 14.000], p = 0.017). Collectively, these data indicate that OM‐85 initiated statistically from 6 months post‐surgery onward.

3.3. Postoperative OM‐85 Administration Enhances WBC and Lymphocyte Counts

This prospective clinical study incorporated a 12‐month follow‐up protocol, with hematological evaluations performed at 6‐month and 12‐month postoperative intervals to assess immunomodulatory effects of OM‐85 through CBC profiling. Comparative analysis revealed statistically significant intergroup differences in key immune parameters. A significant between‐group increase in WBC counts was observed at the 6‐months visit for the OM‐85‐add patients (5.88 [5.56, 8.39] vs. 6.52 [5.26, 7.98], p = 0.016). This differential persisted at the 12‐month follow‐up, with the OM‐85 cohort maintaining higher WBC levels (6.65 [5.57, 7.91] vs. 7.42 [6.32, 8.70], p = 0.007). Similarly, at the 6‐month postoperative assessment, the OM‐85 group exhibited elevated lymphocyte percentage (29.5% [26.40%, 32.60%] vs. 21.0% [13.9%, 36.6%], p = 0.004) compared to controls. These differentials remained clinically and statistically significant at 12‐month follow‐up (32.9% [25.0%, 37.7%] vs. 28.7% [24.3, 34.4%], p = 0.012, Figure 4). The sustained elevations in both WBC count and percentage of lymphoid suggest OM‐85 may enhance systemic immune surveillance through hematopoiesis modulation. No significant between‐group differences were observed in both neutrophils (NEUT) and eosinophils (EOS) during the follow‐up.

FIGURE 4.

Variations in CBC parameters. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

4. Discussion

To our knowledge, this represents the first study investigating the bacterial lysate OM‐85 as an add‐on therapy for preventing postoperative recurrence in NP. OM‐85, a lysate from eight pathogenic bacterial species, is known for its protective efficacy against respiratory infections [30]. Our results confirmed that over 12 months, adjunct OM‐85 treatment following ESS yielded a significantly lower recurrence rate (8.82%, 3/34) compared to the control group (27.91%, 12/43), corresponding to a 68.4% relative risk reduction. Notably, the robust efficacy of OM‐85 in reducing postoperative recurrence was accompanied by sustained clinical benefits that emerged early in the treatment course. Significant improvements in key patient‐reported symptoms—including nasal obstruction, mucopurulent discharge, and olfactory dysfunction—were observed as early as 6 months post‐surgery and were consistently maintained throughout the entire 12‐month follow‐up period. Crucially, these subjective symptomatic benefits were strongly supported by objective endoscopic evidence, as demonstrated by significant and parallel reductions in L‐K scores.

Corresponding to this is, a study found that high sphenoid/posterior ethmoid L‐M scores are linked to smell loss, while high maxillary scores are associated with thick nasal discharge [31]. Another study demonstrated a significant positive correlation between the L‐M score and the severity of both clinical symptoms and sinusitis, supporting its utility as a reliable criterion for diagnostic and therapeutic evaluation [32]. Our analysis identified the pre‐operative L‐M score as a robust, independent predictor of recurrence, with an optimal cutoff of 10. This underscores the high‐risk nature of our cohort. The significant reduction in recurrence achieved with OM‐85 in this context is therefore particularly notable, suggesting that OM‐85 may be effective in modifying the disease course even in patients predisposed to a more aggressive disease phenotype.

Moreover, a critical temporal correlation was observed between the onset of clinical improvement at 6 months and the concurrent enhancement in systemic immune parameters, specifically increased white blood cell (WBC) counts and lymphocyte percentages, in the OM‐85 cohort, suggesting a systemic immunomodulatory mechanism of action. This finding is consistent with previous reports in adult sinusitis, where OM‐85 significantly reduced reinfection rates by the 6th month and rapidly alleviated purulent discharge, with effects sustained until study end [33]. Mechanistically, the 6‐month delay before significant symptom reduction corresponds to the established timeline for adaptive immune maturation, since the memory T‐cell pool establishes till 3–6 months post‐antigen exposure typically [34]. Our findings align with prior clinical evidence demonstrating that the OM‐85 cohort exhibited significantly fewer sinusitis reinfection episodes at the 6‐month [24]. However, purulent discharge relieved in the first month of treatment with OM‐85 and continued to decrease significantly. The according rapid clinical improvement may be mediated through its targeted modulation of innate immune mechanisms, through enhancing phagocytic activity of macrophages and cytotoxic function of NK cells [17], optimizing antigen presentation and up‐regulating maturation and antigen‐presenting capacity of dendritic cells (DCs¹⁶) [16]. Similarly, blood‐derived human phagocytes can express adhesion molecules (LFA‐1, MAC‐1, p150, 95, ICAM‐1) to develop a NK activity [35]. These findings indicate that OM‐85 is capable of stimulating both cellular and humoral components of the immune response [33]. To sum up, OM‐85 promotes plasma cell differentiation and antigen‐specific antibody production (IgA/IgG) [18], enhances Treg cell expansion in the airways [36, 37], reduces Th2‐related cytokine levels (IL‐4, IL‐13) while increasing Th1‐related cytokine levels (IFN‐γ) [17], ultimately restoring the type 1 helper T (Th1)/Th2 balance [16, 38, 39].

The therapeutic mechanisms of OM‐85 extend beyond synergistic immune enhancement to encompass additional pathways. For instance, evidence suggests that OM‐85 may remodel the gut and lung microbiota, thereby promoting immune crosstalk and sustaining homeostasis [40]. Furthermore, it can reinforce epithelial barrier integrity and foster antigen‐specific immunological memory, which collectively help prevent microbial colonization and infection [30]. This role in barrier fortification is directly relevant to the pathogenesis of CRS, which is characterized by a compromised nasal epithelial barrier due to pathogen‐ or allergen‐induced downregulation of tight junction proteins like occludin and claudin [41]. In the postoperative phase, the nasal epithelium plays a critical role in the natural renewal process [42], a function that is supported by immune potentiation [30]. Therefore, strategies aimed at promoting epithelial regeneration and barrier reconstruction represent a promising therapeutic avenue for reducing recurrence. Given that epithelial dysfunction is a key contributor to the pathogenesis of NP, the significant reduction in recurrence rates observed with OM‐85 provides compelling evidence for its use as a postoperative add‐on treatment that targets this fundamental pathological mechanism. Previous studies have demonstrated the immunomodulatory effects of OM‐85 on allergic inflammation in murine models. Prolonged treatment with a low, clinically equivalent dose of OM‐85 significantly attenuated nasal eosinophil infiltration, and reduced serum levels of IgE and IgG1 antibodies [43]. Furthermore, our subgroup analysis suggested a trend toward a greater treatment effect of OM‐85 in patients with eNP, a subgroup typically driven by type 2 inflammation. This observation, while preliminary, aligns with the proposed mechanism of OM‐85 in restoring Th1/Th2 balance [22, 39] and warrants further investigation in larger studies. Consistent with our result, OM‐85 may reduce postoperative recurrence rates by suppressing subepithelial eosinophil infiltration.

Additionally, some studies discovered the preventive use of OM‐85 can reduce the use of antibiotics, contributing to antibiotic dependency [28, 40]. But it is regrettable that in this study the use of antibiotics wasn't included in the analysis because patients in both groups routinely received macrolide antibiotics for 1 week postoperatively.

5. Conclusion

The immunomodulatory properties of OM‐85 stem from its dual capacity to potentiate both innate and adaptive immune responses. This clinical study positions OM‐85 as a unique postoperative adjuvant that modifies the CRSwNP recurrence trajectory through fundamental immune recalibration rather than transient symptom suppression. OM‐85 may reduce postoperative recurrence in NP.

5.1. Limitations and Future Directions

This study has several limitations. First, the sample size, though calculated a priori, may still be underpowered for certain subgroup analyses and makes the study susceptible to type II errors. Further studies with a larger sample size and involving multiple centers will be necessary for validation. Second, the significantly higher dropout rate in the OM‐85 group (32.0% vs. 14.0%) is a primary concern for potential bias. This attrition was largely driven by challenges with medication adherence to the intermittent dosing protocol (10 days on, 20 days off). Third, this study did not specifically analyze outcomes in patients with comorbid asthma or hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs), populations that are known to have a higher risk of postoperative recurrence and more severe type 2 inflammation. Future studies should investigate the efficacy of OM‐85 in these specific subgroups.

Funding

This work was supported by the National Natural Science Foundation of China, (82000957, 82271148, and 82401331).

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1: Flowchart of inclusion and dropout.

Table S1: Inclusion and Exclusion Criteria.

Table S2: Results of univariate Analysis on factors influencing postoperative recurrence (baseline).

Data S1: lary70581‐sup‐0003‐Supinfo.docx.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.