Treatment of Acute Upper Respiratory Tract Infections in Children With Herbal Preparations

Introduction

Upper respiratory tract infections (URTIs) are common in children. Their incidence increases significantly in the autumn. These infections are important because they substantially increase healthcare costs [2]. According to the latest guidelines for the treatment of respiratory tract infections, antibiotics are not the first-line treatment for URTIs, and clear indications are required for their use [3, 4]. Therefore, unnecessary antibiotic use should be avoided.

Preparations made from plant extracts are among the most suitable options for treating URTIs and are generally very well tolerated [1]. In the medical practice of many countries, Tonsilgon® N (also known as Imupret® N) has been used for more than 50 years [5]. It is an extract of seven medicinal plants, including marshmallow root (Althaeae radix), chamomile flowers (Matricariae flos), yarrow (Millefolii herba), oak bark (Quercus cortex), walnut leaves (Juglandis folium), horsetail (Equiseti herba), and dandelion (Taraxaci herba).

These herbs have pharmacologically demonstrated immunomodulatory, antiseptic, antiviral, antibacterial, and anti-inflammatory effects [5, 6].

The respiratory tract is the main entry point for pathogens. Complex protective mechanisms of the epithelium lining the respiratory tract help prevent pathogen colonization and the development of infection. The effect of Tonsilgon® N on A549 lung epithelial cells was evaluated in vitro [5].

It was found that Tonsilgon® N can suppress respiratory tract inflammation by inhibiting the production of interleukin-8 (IL-8) and human beta-e (hBD-e) [5]. An additional study described the effect of Tonsilgon® N on healthy immune cells in vitro [7]. The results showed that this preparation can affect cells of both innate and acquired immunity.

The antioxidant properties of Tonsilgon® N in the treatment of chronic tonsillitis in children have also been identified [8]. The effectiveness of Tonsilgon® N in the conservative and surgical treatment of acute and chronic upper respiratory tract infections has been evaluated in various clinical trials [9], as has its effectiveness in the treatment of URTIs [11, 12]. A preventive effect of Tonsilgon® N drops has been observed during acute viral respiratory tract infections in children [10, 13].

In a study involving 32 children aged 3–15 years, the effectiveness of Tonsilgon® N in the treatment of chronic tonsillitis was demonstrated. Improvement in symptoms with the drops was observed 6 months after the start of treatment and persisted for 1 year. The study also demonstrated a correlation between clinical findings and immunoglobulin G (IgG) concentrations [12].

In a descriptive study conducted in Germany in 2006–2007, the effectiveness and safety of Tonsilgon® N were confirmed. The study involved children aged 2–17 years with recurrent URTIs. Treatment with this preparation in more than 1,100 children was safe and effective. The study also described the immunomodulatory and antibacterial effects of Tonsilgon® N, an herbal preparation that alleviates inflammation-induced symptoms [6].

Based on the studies conducted, Tonsilgon® N is a well-known herbal therapeutic preparation with a long history of use in the treatment of URTIs [14, 15].

Although this preparation has been used for many years, studies described in the literature confirm its positive clinical and immunological effects. Several reports in the scientific literature suggest that Tonsilgon® N could be considered an evidence-based treatment option for URTIs. This article describes a new study from 2016 aimed at confirming the effectiveness and safety of Tonsilgon® N in the treatment of recurrent URTIs [1].

Study Methodology

A prospective, non-interventional study was conducted at 14 centers in Russia: 6 university hospitals, 5 outpatient clinics, and 3 private healthcare facilities. The study was conducted from March 2013 to February 2014. A total of 516 patients (boys and girls) aged 2–11 years were included in the study. All participants were diagnosed with URTIs. Two age groups were distinguished: children aged 2–5 years (n = 269) and those aged 6–11 years (n = 247).

The study was conducted in accordance with current Good Clinical Practice (GCP) standards and the latest version of the Declaration of Helsinki. Approval was also obtained from local ethics committees. Parents or legal guardians provided written informed consent for their child's participation in the study. Clinical parameters were monitored at authorized clinical trial organizations.

Subjective symptoms at home were also monitored and recorded by parents (guardians) or the patients themselves for 2 weeks after the first visit to the physician by completing symptom diaries.

Inclusion criteria: children aged 2–11 years with URTIs and a physician's decision to use Tonsilgon® N for treatment. Informed consent had to be signed by the parents or legal guardians. The study included children diagnosed with acute pharyngitis, acute nasopharyngitis, acute tonsillitis, acute laryngitis, acute tracheitis, acute laryngotracheitis, or acute laryngopharyngitis who had at least 2 previously documented episodes of acute respiratory tract infections (ARTIs) during the preceding 6 months. Previous episodes had to be documented in the patient's medical records.

Exclusion criteria: absence of written informed consent, bacterial origin of ARTIs, antibiotic use at the time of the first visit or a need for antibiotic therapy, and onset of initial symptoms more than 3 days previously.

Tonsilgon® N was administered to children aged 2–5 years at a dose of 10 drops 5–6 times daily and to children aged 6–11 years at a dose of 15 drops 5–6 times daily or 1 coated tablet 5–6 times daily.

The medication was prescribed for 14 days. At the second visit, 15 days after the first visit, treatment effectiveness was assessed, and the patients were monitored for an additional 30 days after the second visit, for a total follow-up period of 45 days.

The first visit was considered the first day of the physician visit or telephone consultation. An in-person physician visit was required for the second visit (day 15). The third visit could consist of either a physician visit or a telephone consultation.

Study criteria included objective and subjective symptoms, recovery time (determined from data recorded by parents [guardians] or patients in the child's observation diary), the need for additional medication, occurrence of adverse events, overall effectiveness (number of patients responding to treatment), and assessment of tolerability.

Effectiveness was assessed based on changes in 2 objective and 7 subjective symptoms between the first and second visits. Physicians assessed the two objective symptoms: mucosal hyperemia and tonsillar swelling. Parents or patients themselves recorded changes in subjective symptoms. These included fatigue and general weakness, loss of appetite, sore throat, cough, headache, hoarseness, and limb pain.

The severity and changes in symptoms during treatment were assessed using the categories "none," "mild," "moderate," "severe," and "very severe."

Recovery time was expressed as the duration of each symptom in days, as recorded by parents or patients in the child's observation diary.

Patients who met at least one of the following criteria were assigned to the non-responder group: need for antibiotics because of insufficient therapeutic effectiveness, worsening of symptoms, or no change in condition during treatment.

Response to treatment was defined as the absence of a need for antibiotic therapy together with a reduction in disease symptoms. The number of patients responding to treatment was calculated.

The number of doses of the investigational product taken was recorded in the patients' diaries. The use of additional medications was also documented.

Tolerability was assessed based on the occurrence of adverse events while taking the investigational product. Adverse events were evaluated by physicians during the second and third visits and on the basis of data recorded by parents (guardians) or patients in the child's observation diary.

As the study was non-interventional, no statistical hypotheses were formulated. Descriptive statistical analyses were performed and frequencies were calculated. To determine possible associations between parameters, the Cox proportional hazards model was used. Age, sex, adherence to the prescribed regimen, and dosage form of the drug were analyzed in relation to the time to symptom resolution. SAS/STAT software (version 9.2) [16] was used for statistical analysis.

Results

A total of 518 patients participated in the study, but 516 were included in the final analysis. The excluded patients did not meet the age criteria: one patient was too young (1.8 years old), while the other was older than the upper age limit (12 years old).

The younger age group (2–5 years) accounted for 52.1% of the total study population, while the older age group (6–11 years) accounted for 47.9%. A similar distribution of boys and girls was observed in both age groups: in the 2–5-year group, there were 131 girls (48.7%) and 138 boys (51.3%), while in the 6–11-year group, there were 120 girls (48.6%) and 127 boys (51.4%).

During the previous 6 months, children most commonly experienced 2 episodes of ARTIs (79.8% of participants). Three episodes were reported in 16.1% of patients, while 3.5% had experienced 4 or 5 episodes. A similar distribution of initial ARTI diagnoses was observed in both age groups. The most common diagnoses were acute nasopharyngitis, acute pharyngitis, and acute tonsillitis.

A review of the collected data identified 96 protocol violations. These were attributed to the following criteria: age <2 years (n = 1), age >11 years (n = 1), antibiotic use at the first visit (n = 13), fewer than 2 ARTI episodes during the previous 6 months (n = 1), non-compliance with the prescribed dosage of the product (n = 55), failure to comply with additional treatment (n = 23), and improper combined use of the investigational product and additional treatment (n = 3). A total of 422 patients complied with the study protocol. This subset of the study population was used to calculate treatment response and drug tolerability.

Objective Symptoms

During the first and second visits, physicians evaluated objective symptoms: hyperemia of the nasal mucosa and tonsillar swelling. At the first visit, 99% of patients had reddened mucosa and 83% had enlarged tonsils. After 14 days of treatment with Tonsilgon® N, these symptoms had significantly decreased: at the second examination, 93% of patients no longer had hyperemia of the nasal mucosa, and 98% had tonsils of normal size (n = 516 patients). These results indicate the effectiveness of this herbal preparation.

When mucosal hyperemia and tonsillar swelling were evaluated, a clear tendency toward a reduction in these symptoms was observed in patients with nasopharyngitis, pharyngitis, and tonsillitis.

For example, among 339 children with nasopharyngitis and hyperemic mucosa, symptoms ranged from moderate to severe at the first examination. By the second visit, 93.2% (316 of 339) no longer had hyperemic mucosa.

A similar pattern was observed for tonsillar swelling: 282 of 339 patients (83%) had slightly, moderately, significantly, or very significantly enlarged tonsils at the first examination. By the second visit, 97.6% (331 of 339) had tonsils of normal size, indicating that patients diagnosed with nasopharyngitis had recovered.

Patients with pharyngitis had reddened nasal mucosa and swollen tonsils. By the second visit, most of these patients no longer had these symptoms: 90.7% (n = 137) no longer had reddened mucosa, and 98.7% (n = 149) had tonsils of normal size.

The same symptoms were observed in patients with tonsillitis (n = 106). All had reddened mucosa at the first examination, and 91 patients (85.8%) had completely recovered by the second visit. Initially, 106 patients had swollen tonsils, but after 14 days of treatment, 103 patients (97.2%) had recovered.

Therefore, in patients with nasopharyngitis, pharyngitis, and tonsillitis, objective symptoms such as reddened nasal mucosa and swollen tonsils had disappeared in almost all patients by the second examination. Symptoms resolved in 93.2% to 98.7% of patients.

Subjective Symptoms

Parents (guardians) or the patients themselves were asked to report the subjective symptoms experienced by the child during the study: fatigue, loss of appetite, sore throat, cough, headache, stuffiness, and limb pain. Symptom severity was classified as "none," "mild," "moderate," "severe," or "very severe."

At the first examination, fatigue of varying severity was observed in the majority of patients (approximately 89%).

Loss of appetite (approximately 86%) and sore throat (approximately 85%) were also common. Cough of varying severity was less frequent, occurring in 79% of patients. Headache was reported by 60% of participants and was mostly mild to moderate, while 4% experienced severe or very severe headaches.

The least common symptoms were stuffiness (approximately 25%) and limb pain (21%). These symptoms varied in severity, but only 1.4–3.3% were severe or very severe.

After 14 days of treatment, at the time of the second examination, a significant reduction in subjective symptoms was observed, with symptoms disappearing in almost all patients. A small percentage of patients still experienced mild fatigue and sore throat (approximately 0.78%), loss of appetite (approximately 3%), cough of mild or moderate severity (approximately 3%), and stuffiness of mild or moderate severity (approximately 0.4%). None of the 516 patients reported headache or limb pain at the second examination.

Duration of Illness

The duration of illness was assessed based on entries made by parents or patients in the diary. There was no continuous monitoring by physicians between the first and second examinations. The duration of previous episodes of illness was determined retrospectively; therefore, this parameter should be interpreted with caution.

A review of patients’ previous medical records showed that the mean duration of previous upper respiratory tract infections (URTIs) was 7.65 days (median, 7 days), regardless of age and sex. According to patient diaries, most subjective symptoms disappeared within 4 days, compared with 7 days during previous URTIs.

The only exceptions were cough (median, 6 days) and headache (median, 3 days). The time to disappearance of subjective symptoms was compared according to sex, age, adherence to the treatment regimen, and dosage form of the medication. These factors had little influence on symptom duration. Only limb pain was associated with sex (p = 0.0363), lasting longer in boys. The duration of cough (p = 0.0038) and loss of appetite (p = 0.0024) was also associated with age, with symptoms lasting longer in older children.

Adherence to the Treatment Regimen

During this non-interventional study, adherence to the treatment regimen could be observed under real-world conditions. Of the 516 patients, 455 (88.2%) adhered to the treatment regimen. Data on adherence were unavailable in 6 cases. Another 55 patients were assigned to the non-adherent group because of changes in drug dosage, irregular medication intake, or both. Younger patients (2–5 years) were more likely not to follow the treatment regimen. Of the 55 non-adherent patients, 29 were in the younger age group (2–5 years) and 26 were in the older age group (6–11 years).

Despite 10.5% of patients being non-adherent to the treatment regimen, the majority followed the physician’s instructions. Based on the fact that 88.2% of patients were classified as adherent, it can be concluded that physicians’ instructions and prescribed treatment regimens were followed very well during the study. It is also possible that, as the children’s condition improved, parents decided to reduce the frequency of drug administration to 3 times daily, as indicated in the drug information leaflet. Taking this into account, the proportion of patients adhering to the regimen may have been even higher.

Patient groups (n = 422)	Responders to treatment (n)	No response to treatment (n)	Total (n)	Responders to treatment (%)
Total	420	2	422	99.5
Age group 2–5 years	204	2	206	99.0
Age group 6–11 years	216	–	216	100.0
Girls	210	1	211	99.5
Boys	210	1	211	99.5

Additional Medications

According to the WHO/DDD classification, information on concomitant medications was to be documented by the investigators and by parents, guardians, or the patients themselves in the patient diaries.

Along with the investigational product, medications commonly used concomitantly to relieve respiratory symptoms were prescribed, including antihistamines, nasal and throat preparations, medications to relieve respiratory tract obstruction, and treatments for cough and cold symptoms.

Overall Effectiveness Assessment

Frequency of treatment response. Patients whose symptoms completely disappeared or decreased were considered to have responded to treatment. Patients whose symptoms remained unchanged, worsened, or who switched to antibiotic therapy were classified as having no response to treatment. According to these definitions, almost all patients (99.5%), regardless of age and sex, were classified as treatment responders. Distribution data for the patient sample that complied with the study protocol are presented in Table 1. During the study, symptoms worsened in 2 patients who received drops, symptoms remained unchanged in 1 patient, and 4 patients required antibiotics.

Tolerance assessment. Analysis of drug tolerance showed that, according to assessments by investigators, patients, and parents, treatment was mostly well or very well tolerated. Only one patient experienced an adverse drug reaction: hives on the legs. This was found to be related to a previously undiagnosed allergy to chamomile. Treatment was discontinued, and no additional therapeutic measures were required; the patient recovered completely. In addition, allergy to a member of the plant family is considered a contraindication to Tonsilgon® N, as stated in the package insert [17].

Conclusions

The study published in 2016 states that the duration of illness was shortened by 3 days with Tonsilgon® N compared with previous episodes of upper respiratory tract infections. It was also noted that the product was well tolerated and easy to dose in both tablet and drop forms. Furthermore, because of its simple dosing, it is suitable for young children.

Based on the study results, it can be concluded that the complex herbal product Tonsilgon® N is safe and effective in the treatment of upper respiratory tract infections in children aged 2–11 years. The product shortens the duration of upper respiratory tract infection symptoms, while adverse effects are rare.

Source: Pediatrics, 2016 / 3 (75).