Reduction of Viral Load in Patients with Acute Sore Throats: Results from an Observational Clinical Trial with Echinacea/Salvia Lozenges

Abstract

Background

Acute tonsillopharyngitis or sore throat is an initial sign of viral respiratory tract infection (RTI) and an optimal indicator for early antiviral and anti-inflammatory intervention. Both of these actions have been attributed to Echinacea purpurea and Salvia officinalis.

Methods

74 patients (age 13–69 years) with acute sore throat symptoms (<48 h) were treated with five Echinacea/Salvia lozenges per day (4,000 mg Echinacea purpurea extract [Echinaforce^®] and 1,893 mg Salvia officinalis extract [A. Vogel AG, Switzerland] daily) for 4 days. Symptom intensities were recorded in a diary and oropharyngeal swab samples collected for virus detection and quantification via RT-qPCR.

Results

The treatment was exceptionally well tolerated, no complicated RTI developed, and no antibiotic treatment was required. A single lozenge reduced throat pain by 48% (p < 0.001) and tonsillopharyngitis symptoms by 34% (p < 0.001). Eighteen patients tested virus positive at inclusion. Viral loads in these patients was reduced by 62% (p < 0.03) after intake of a single lozenge and by 96% (p < 0.02) after 4 days of treatment compared to pre-treatment.

Conclusions

Echinacea/Salvia lozenges represent a valuable and safe option for the early treatment of acute sore throats capable to alleviate symptoms and contribute to reducing viral loads in the throat.

Background

Viruses account for the vast majority of respiratory tract infections (RTIs) [1, 2]. A scratchy throat sensation is often described as being the earliest and most frequent indicator of viral infection. This irritation quickly develops into sore throat, (naso-) pharyngitis, or tonsillitis, often accompanied with classic symptoms of the common cold or flu-like illness. A proportion of initial viral complaints exacerbate into bacterial superinfection and associated complications, such as streptococcal A angina [3–6]. Sore throat and associated pathologies are responsible for 200 doctor visits per 1,000 individuals annually in the USA [7]. The severity of symptoms rapidly increases together with viral shedding, peaking 2–3 days after infection for the common cold [8]. Therapeutic intervention to control symptoms and contain viral concentration and subsequent shedding optimally starts with the first signs of infection, i.e., by treating the earliest signs of sore throat.

Non-antibiotic treatment is usually recommended, which mostly relies on anti-inflammatories, anaesthetics, or antiseptics that are predominantly administered over the counter. They can be administered locally or systemically [2, 9]. The Echinacea/Salvia lozenge product investigated in this study contains extracts from Echinacea purpurea (Echinaforce^®, EF extract) and Salvia officinalis leaves as active ingredients and was flavoured with Mentha × piperita oil.

EF is a standardized extract from freshly harvested Echinacea purpurea herb and roots (95:5%) in a 65% alcohol solution. The most prominent application of EF is in the prevention and acute therapy of RTIs [10–13]. Although the detailed mechanism of action has not yet been completely elucidated, in vitro and in vivo studies indicate virucidal activity against commonly known and newly emerging causative respiratory agents at physiological concentrations [10, 14–18]. Furthermore, EF extract has been shown to interfere with inflammatory cytokine release, which may help soothing typical symptoms of sore throat, common cold, and flu [16, 19].

Salvia officinalis extracts are traditionally used to relieve inflammation in the oral cavity [20]. In addition to the anti-inflammatory and anaesthetic properties [21], they also exert antimicrobial activity against various pathogenic strains, including Staphylococcus aureus, C. albicans, S. typhi, or S. enteritidis[22, 23].

“Echinacea/Salvia lozenges” are a line extension of EF and Salvia extract-containing products specially designed to increase patient convenience. The fixed combination of Echinacea and Salvia in the lozenge equals the composition of “A. Vogel Sore Throat Spray,” the effectiveness of which has been proven in a clinical study with a chlorhexidine/lidocaine-containing comparator [24]. This clinical study aimed to determine the safety and acute effects of the Echinacea/Salvia lozenges for the treatment of early symptoms of acute sore throat, common cold symptoms, and the virus load in the oropharynx.

Materials and Methods

Study Design and Patients

This observational, prospective, monocentric clinical trial was carried out at the Diagnostics and Consultation Center Convex EOOD in Sofia, Bulgaria, in strict adherence to ICH-GCP guidelines and the Declaration of Helsinki (2013) and reported by adhering to the STROBE statement for observational studies [25]. Patients were referred to the study centre by their GPs, and visited the centre twice, at the inclusion visit (day 1) and for final closeout visit (day 5 ± 1).

Principally healthy patients aged 12–75 years were recruited with acute symptoms of sore throat lasting no longer than 48 h and with a minimum of 6 score points on the tonsillopharyngitis symptom severity (TSS) index at inclusion. They were included upon receipt of informed consent (in the case of adolescents, signed by their parents and optionally by the adolescent; in the case of children, signed by their parents). The following exclusion criteria applied: age <12 years or >75 years; pharyngitis or tonsillitis lasting for longer than 48 h before inclusion; intake of analgesics within the last 12 h prior to inclusion; use of local sore throat medication within the last 4 h prior to inclusion; symptoms of primary bacterial pharyngitis or a bacterial superinfection; severe medical conditions including immunosuppressive diseases; systemic use of corticosteroids; allergies to substances used in the lozenges; pregnancy or lactation; participation in a clinical trial within the last 30 days.

Intervention

One Echinacea/Salvia lozenge contained 800 mg of hydro-ethanolic extract (65% v/v) of freshly harvested Echinacea purpurea (95% aerial parts and 5% root, Echinaforce^®, EF extract) and 378.5 mg of hydro-ethanolic extract (68% v/v) of freshly harvested Salvia officinalis leaves (drug extraction ratio 1:17) and excipients. The lozenges were placed into dark brown glass bottles with a PE-screw closure and sealed. Each bottle contained 20 individual lozenges, sufficient for 4 days of consecutive treatment. GMP-compliant manufacturing was performed by A. Vogel AG (Roggwil, CH, Switzerland).

Each participant received a single dose of the study product (1 lozenge) under medical supervision. Afterwards, they received the rest of the study product sufficient for treatment of sore throat symptoms for 4 consecutive days at a daily dose of 5 times 1 lozenge every 3rd hour a day.

Patients were to record study parameters (visual analogue scale [VAS] throat pain intensity, TSS scores, treatment efficacy in view of the patient, and acceptance of the treatment) and investigators were to assess concomitant medication/conditions, other clinical (adverse) events, treatment efficacy in view of the investigator, and take a blood sample for safety analysis and an oropharyngeal (OP) swab for virus identification and “baseline” measures. Treatment with 5 × 1 Echinacea/Salvia lozenges per day started on day 1 by taking a single lozenge under supervision and recording the acute treatment effects. An OP swab sample was taken again 5 min after the first dose. Patients continued with treatment and self-documentation of symptoms at home for 4 consecutive days. Patients were then requested to return to the study centre on day 5 ± 1 for visit 2. The study staff verified diary entries, inclusion and exclusion criteria, and concomitant medication/conditions. Patients were to provide another OP swab sample and blood sample for safety analysis and to finally assess the study parameters before the final closeout.

Sample Size Calculations and Data Evaluation

This study principally used descriptive biometric approaches to estimate effect sizes. However, the study was conceptualized large enough to confirm a clinically relevant difference in tonsillopharyngitis symptoms (TSS score) and acute throat pain intensity (VAS score) relative to baseline prior to start of treatment with appropriate statistical power (nQuery Advisor, 2017, version 7.0, sample size and power calculation from Statsols-Statistical Solutions Ltd, IRL): a two-group t test with a two-sided significance level (α = 0.05) had 96% power to detect a difference ∆TSS = 1 score point with a standard deviation = 2.5 score points and a difference ∆VAS = 1 cm with a standard deviation = 2.2 cm, when the sample size was at least 70 patients.

Quantitative variables were expressed as means and standard deviations. Binary, categorical, and ordinal parameters were summarized by absolute and relative frequencies. Reverse transcription PCR (RT-PCR) results were calculated as the relative reduction compared to baseline and logarithmically transformed for analysis. Quantitative and qualitative parameters were analysed per time point in comparison to pre-treatment (baseline) values. Kaplan-Meier analysis was performed at the episode level to determine the time to reach a total TSS score <1. All statistical tests were two sided at a 5% level of significance and interpreted in a descriptive exploratory manner using the SAS^® system (version 9.4).

Adverse events (AEs) during study conduct were collected via patient diary and during study visits, classified according to preferred/lowest-level term, severity, and causal relationship by the investigator. AEs were coded according to the MedDRA (version 17.0GE). Concomitant medication use was collected via patient diary and during study visits and classified according to MedDRA, M. S. S. O. [26] (2013). At the final visit, returned study medication was counted to assess compliance. Both the investigator and patient rated the effectiveness and tolerability as 1 (“very good”), 2 (“good”), 3 (“moderate”), or 4 (“poor”). Acceptance was determined by asking patients at visit 2 whether they would like to use the study product again.

Laboratory Procedures and Virus Detection

OP samples were collected using HydraFlock swabs from PURITAN (ME, USA) and transferred to a vial containing the transport storage medium OptiSwab (PURITAN, ME USA). The viral nucleic acids were extracted from 200 μL of each specimen using an AllplexTM Respiratory panel (Seegene Inc., Seoul, Korea) in accordance with the manufacturer’s protocols, including nucleic acid extraction and real-time PCR setup on a robotic workstation Microlab Nimbus IVDTM (Hamilton, Reno, USA) and real-time PCR on CFX96TM (Bio Rad Inc., CA, USA). Data analysis was done with the Seegene viewer (Seegene Inc., Seoul, Korea). The collected specimens were screened for the presence of human rhinovirus, influenza (FluA, A-H1, A-H3, H1-pdm09, FluB), parainfluenza (PIV 1/4), respiratory syncytial virus (RSV A/B), coronavirus (CoV-OC43, CoV-NL63, CoV-229E), metapneumovirus, human bocavirus, enterovirus (HEV), and human adenovirus (AdV) using real-time RT-PCR kit (Seegene, Inc., Seoul, Korea) in accordance with the manufacturer’s protocols.

The number of patients per time point becoming virus free was determined by the presence of a single virus-positive OP sample (baseline and/or 5 min after the first intake) that became virus negative during treatment as per RT-PCR measurements. Relative log10 change in virus load after 5 min/4days of treatment compared to baseline was calculated by approximation from the cycle threshold values (Ct) of RT-qPCR measurements assuming a 100% PCR efficiency in accordance with methods described elsewhere [27, 28] using the following formula:

$${\log }_{10}change=\frac{\left({Ct}_1-{Ct}_2\right)}{{\log }_2\left(10\right)}$$

where Ct₁ is the Ct value at baseline and Ct₂, the Ct value after 5 min/4 days. RT-qPCR measurements falling below the limit of detection were set to the maximal number of cycles run in the respiratory qPCR assay (Ct = 42). For 1 patient with a non-measurable Ct value at baseline, we estimated the initial Ct value using regression.

Assessment of Symptoms Severity

Patients marked throat pain intensity on a 10-cm visual analogue scale (VAS) ranging from 0 (no pain) to 10 (most severe pain) at baseline, every 15 min for 90 min after taking the first lozenge, and twice daily (morning/evening) over 4 days of treatment. A patient was considered “throat pain free” if VAS was <1 cm (responder). The TSS scores for throat pain, difficulty swallowing, salivation, reddening, and fever were rated by the patients at baseline, after the first 90 min, and twice daily (morning/evening) over 4 days of treatment as 3 (“severe”), 2 (“moderate”), 1 (“mild”), or 0 (“absent”). The intensity of common cold symptoms, headache, weakness, fever, sneezing, stuffy nose, runny nose, cough, and throat pain were rated at baseline and after 4 days of treatment. The VAS pain scores, individual and aggregated total sum TSS scores, and common cold symptom scores were analysed. We also determined the number of patients reaching a 50% reduction in total TSS score (responders) per time point and the average time to reach “absence of any complaint” (total TSS <1). The investigator assessed the patient’s throat status (reddening, swelling, and plaque formation on the throat and tonsils, as well as tenderness and enlargement of lymph nodes) at baseline and after 4 days of treatment for confirmation.

Results

Baseline Characteristics

This study was conducted from March 2019 to April 2019. Seventy-five patients with acute sore throat were screened for eligibility. One of the screened patients (1.3%) dropped out (TSS score <6 at inclusion). Thus, a total of 74 patients with acute sore throat completed the study (study collective) and were considered for statistical evaluation. The average included patient was 35.4 ± 14.4 years of age, 5 (6.8%) were below the age of 18 years but none below the age of 12 years. 46% were smokers (Table 1). The included study collective was considered representative for the studied indication. Table 1 provides the demographic characteristics of the patients enrolled in this study.

Table 1.

Baseline demographic characteristics of the study population

	Females (N = 36)	Males (N = 38)	Total (N = 74)
Age, years	37.2±15.3	33.7±13.4	35.4±14.4
<18 years, n (%)	4 (11.1)	1 (2.6)	5 (6.8)
Weight, kg	67.4±14.6	82.7±12.1	75.3±15.4
Height, cm	165.4±7.8	180.2±8.3	173.0±11.0
BMI, kg/m2	24.7±5.7	25.5±3.6	25.1±4.7
Regular smoker, n (%)	17 (47.2)	16 (42.1)	33 (44.6)

Data are provided as mean ± standard deviation or n (%).

The average compliance was 95.5 ± 7.7%. Two patients reported minor compliance issues (compliance <80%), one subject reported stop of treatment due to complete resolution of symptoms, and none reported major compliance issues.

Clinical Safety Outcomes

In 73 (98.6%) cases, the physicians rated the tolerability of the treatment as “very good”; in 1 patient (1.4%), the tolerability was rated as “good” (primary parameter). Patients confirmed the physicians’ overall positive rating, with 73 subjects rating tolerability as “(very) good” (98.6%) and 1 patient (1.4%) rating it as “average.”

5 AEs were recorded in 4 of the 74 patients (5.4%): increased erythrocyte sedimentation rate (n = 1) and C-reactive protein (n = 1) due to infection and the known tingling sensation of Echinacea (n = 2). None of the AEs required stop of treatment, medication, or any other countermeasures. Most of the recorded AEs were of mild to moderate intensity. A single case of non-serious pruritus occurred for 30 min after the first intake but resolved spontaneously and did not relapse during continuation of treatment; therefore, it was considered unrelated. No serious AE and no serious unexpected adverse drug reactions were recorded.

Virus Identification and Reduction

RT-PCR analysis identified 20 virus detections from 18 individual samples/patients within the 5-day observation period (detection rate: 24.3%). With n = 11, most tested positive for rhinovirus (61.1%) followed by n = 3 adenovirus (16.7%), n = 2 coronavirus NL63 (11.1%), and n = 1 respiratory syncytial virus A (5.6%), but no influenza, parainfluenza, metapneumovirus, or bocavirus were identified. Two patients tested positive for two virus strains (both CoV-NL63 and rhinovirus). One patient turned virus negative after a single lozenge and 5 patients (27.8%) after 4 days of treatment. The mean Ct values representing virus titres overall were 34.0 ± 4.4 at baseline, 35.8 ± 4.9 5 min after taking a single dose, and 38.6 ± 3.8 after 4 days of treatment. A significant mean log reduction of the viral load relative to baseline was observed both 5 min after taking a single dose (−0.42 ± 0.69, p = 0.0296, t test) and after 4 days of treatment (−1.39 ± 1.92, p = 0.0111, t test) referring to a relative reduction by 62% and 96%, respectively (Fig. 1).

Fig. 1.

Relative log change in viral load compared to baseline. The boxplots convey median ± minimal and maximal values; rhombus icons represent means. *p < 0.05.

Throat Pain and Tonsillopharyngitis Symptoms

The self-reported acute throat pain (VAS) reduced continuously after taking one single lozenge (Fig. 2), reaching 48% reduction (−2.5 ± 1.8 cm, p < 0.0001, t test) after 90 min. Thereafter, the perceived throat pain slightly increased again by the evening of day 1, to 27% reduction (−1.4 ± 1.5 cm, p < 0.0001, t test) compared to baseline. However, after day 1, throat pain decreased steadily by approx. 20% per day, reaching a 91% reduction (−4.8 ± 1.3 cm, p < 0.001, t test) at the end of therapy.

Fig. 2.

Frequency of treatment responders (blue bars) and mean VAS scores over time (solid line). Responders were defined as subjects reaching a VAS score of <1 cm. Mean VAS scores are shown with 95% confidence intervals.

Nineteen patients (25.7%) were recorded as throat pain free (VAS score: <1 cm) 90 min after taking a single lozenge, which dropped again to 4 patients (5.4%) by the evening of day 1. By the end of the treatment, 62 patients (83.8%) became free from throat pain (Fig. 2, blue bars).

The total reported TSS scores decreased similarly to VAS-scale throat pain, reaching 34% reduction (−2.5 ± 1.9 score points; p < 0.0001, t test) 90 min after taking a single lozenge (Fig. 3). In contrast to VAS-throat pain, the average TSS plateaued until the evening of the first day. Thereafter, the TSS continuously decreased by about 23% each day, reaching a 93% reduction (−6.8 ± 1.4 score points, p < 0.0001, t test) at the end of the therapy. Eighteen patients (24.3%) experienced a 50% reduction in symptom intensity 90 min after taking a single lozenge and with 73 (98.6%) almost all patients by the end of therapy. Complete symptom relief (total TSS score: <1) was reached by the majority of 49 patients (66.2%) at the end of the treatment.

Fig. 3.

Frequency of patients reaching ≥50% total TSS reduction (blue bars) and mean total TSS score (solid line) over time. Mean TSS score is shown with 95% confidence intervals.

Common Cold Symptoms and Throat Status

All patients experienced throat pain (inclusion criterion), and most reported additional common cold symptoms upon inclusion, i.e., nasal symptoms such as stuffy nose (93.2%), sneezing (90.5%), and runny nose (68.9%) or cough (90.5%). Other symptoms such as headache (40.1%), weakness (32.4%), and fever (9.2%) were reported less frequently. In consistence with VAS and TSS scores assessments, throat pain completely resolved in 88% of patients, nasal complaints in 83%, and other complaints in 93% after 4 days of treatment. Cough completely resolved in 60% of cases.

Assessment of the throat tissue pathology by the investigator after 4 days of treatment confirmed remission of the throat and tonsil conditions, in the vast majority of cases (84%). On the other hand, remission of lymph node conditions occurred in 39.3% of cases reported at inclusion.

Subject and Investigator Assessment

In all cases (100%), physicians rated the treatment effectiveness as “(very) good.” Patients mostly confirmed these positive ratings with 70 (94.6%) giving “(very) good” ratings. Four patients (5.4%) rated the effectiveness as “average.” Seventy-three patients (98.6%) stated that they would take the Echinacea/Salvia lozenges again to treat acute sore throat symptoms.

Concomitant medication was documented for 3 patients (4.1%): expectorants, mucolytics, or other nasal preparations. No antibiotics were applied in the frame of this study, and no RTI and/or sore throat-associated exacerbations were detected.

Discussion

Early treatment of RTIs is essential for controlling symptomatic progression, as well as viral transmission. Sore throat represents an optimal indicator for starting treatment as one of the earliest and most bothersome symptom. We found that the Echinacea/Salvia lozenges had an excellent safety profile for the treatment of acute sore throat and common cold symptoms. They received exceptionally positive tolerability ratings from both the physicians (primary parameter) and patients. This matched well with the low rate of AEs and absence of any serious AEs or unexpected adverse drug reactions, exacerbation, or antibiotic treatment.

The viral load more than halved within 5 min after taking a single lozenge. Potent and broad antiviral effects were observed for Echinacea preparations in previous in vitro and in vivo studies whereas development of resistance was not observed [10, 14–18]. The observed reduction in viral load by 96% after 4 days of treatment in this study was comparable to recent randomized, blinded, placebo-controlled studies that reported a 90% reduction after a maximum 4 days of treatment with an iota-carrageenan nasal spray compared to placebo [29] and a 98.5% reduction during symptomatic coronavirus infections in children treated with a proprietary Echinacea formulation (Echinaforce^® Junior tablets) in comparison to vitamin C as placebo [18]. Although limited in the number of samples, the rate of responders turning virus negative was superior to previous reports (27.8% vs. 13%, respectively, at the same time point) [29]. Given the relevance of the results shown, the reduction in viral load under treatment, we recommend further controlled studies that should quantify and compare explicit virus copy numbers using validated virus-strain qPCR reference standards and determine residual infectivity in clinical samples taken pre- and post-treatment.

Lindbaek et al. [30] reported that approximately half (51%) of patients suffering from non-streptococcal sore throat recovered from throat pain (VAS score <1 cm) by day 6 of illness in a cohort of 148 placebo- or bovine colostrum tablets-treated patients (young adults). In this regard, the lozenges were highly efficient in alleviating VAS-reported throat pain, halving complaints after 90 min and with 19 patients (26%) considered pain free (VAS pain <1 cm). We then observed an increase in the average throat pain intensity until the evening of day 1. We hypothesize that the analgesic effect was transient and speculate that the next dosing time on day 1 may have been too close or too far from the assessment time for the lozenges to exert or maintain their immediate analgesic effect. Despite this, throat pain reduced continuously from day 2 onwards. These observations indicate that the lozenges really need to be taken regularly, especially at the onset of symptoms, to maintain an efficient reduction of throat pain.

Similarly, in line with the observed effects on throat pain, the treatment appeared to be effective to resolve other typical sore throat symptoms as assessed by the more extended TSS score, including difficulty swallowing, salivation, throat pain, and reddening/fever, and even common cold symptoms, such as headache, weakness, nasal complaints, or cough. The average TSS score reduced significantly after 90 min, but the effect was weaker than reported for the VAS-throat pain score at the same time point, which could be a further indication of a specific and fast “analgesic” effect of the treatment at the beginning. The more than 83% reduction in TSS score and other cold complaints except for cough were in line with the reduction observed for throat pain.

After 4 days of consecutive treatment, 66% of patients had an absence of any tonsillopharyngitis complaint (total TSS <1). This was slightly superior to previous reports [30], in which 49% of patients treated with placebo or bovine colostrum tablets had persisting symptoms by day 6 with a mean duration of 5–6 days.

Almost 3 quarters of patients (74.3%) achieved a min 50% reduction of their TSS scores after 3 days of treatment and in 66% TSS-reported complaints became absent (TSS <1). This finding is in line with observations by Schapowal et al. [24] (2009), who compared an Echinacea/Saliva spray formulation (verum) identical to the lozenges in this study with a chlorhexidine/lidocaine spray (comparator) in a double-blinded, randomized comparative study. With 63.8% (verum) and 57.8% (comparator) of patients after 3 days of treatment, a similar number of patients experienced a 50%-TSS score reduction as compared with the lozenges.

The physicians ultimately confirmed the observed treatment effects described above by documenting pronounced remission of the throat status in up to 90% of cases after 4 days of treatment. This finding was highly consistent with the 94.6% (very) good subjective effectiveness ratings by both physicians and patients, as well as the fact that 73 of the 74 patients (98.6%) would take the lozenges again.

This study did not employ an internal comparator or reference treatment and was limited in sample size. Therefore, the causal relationship between the observed treatment effects derived from the comparison with baseline prior to treatment is limited and should be interpreted with caution until further confirmation in a distinctively larger sample following a controlled study setup.

Conclusion

In conclusion, the data presented here indicate that the Echinacea/Salvia lozenge product is safe and well tolerated. The treatment of patients suffering from acute sore throat in this observational cohort was associated with a fast and significant reduction in the intensity of typical symptoms within minutes and over 4 days of treatment compared to the condition pre-treatment. The viral load reduced under treatment, which could contribute to reducing viral shedding and transmission. Patients and physicians may consider the “Echinacea/Salvia lozenges” as a safe and convenient over-the-counter option for the treatment of acute sore throat and common cold symptoms in children and adults.

Acknowledgments

The authors thank Dr. Andy Suter and Dr. Dimitar Mirchev for scientific input in the discussion of the results.

Statements of Ethics

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of the Ethics Committee at Diagnostics and Consultation Center Convex Ltd., Sofia (registration No.: 20/14.12.2018), for protocol (version 1.0, 12 December 2018). The clinical study is registered at ClinicalTrials.gov (identifier: NCT04139681).

Written informed consent was obtained from all parents/children, adolescents, and adults before they participated in the study. Accordance with the ethical principles of the Declaration of Helsinki/Good Clinical Practice guidelines, adherence to national/regional regulatory requirements and data protection were ensured permanently.

Conflict of Interest Statement

R.W. and A.S. are employees of A. Vogel AG, the study sponsor. A.B., E.K., and P.K. received honorarium funds from the study sponsor. The authors indicated that they have no other competing interests to declare regarding the content of this article.

Funding Sources

This study was sponsored by A. Vogel AG, Roggwil, Switzerland. The sponsor covered the funding of the article and publication fees. The role of the funder was to supply the study medication, which was the Echinacea/Salvia lozenge.

Author Contributions

Alexandar Buchkov and Emil Kolev collected clinical data and conducted data analysis. Peter Klein conducted the statistical analysis and data analysis. Ramon Weishaupt and Roland Schoop designed the study and contributed to the data analysis. All authors contributed to data interpretation, discussion, writing of the manuscript, and read and approved the final manuscript for submission.

Funding Statement

This study was sponsored by A. Vogel AG, Roggwil, Switzerland. The sponsor covered the funding of the article and publication fees. The role of the funder was to supply the study medication, which was the Echinacea/Salvia lozenge.

Data Availability Statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. A preprint version of this article is available as preprint on ResearchSquare [31].