Does additional antimicrobial treatment have a better effect on URTI cough resolution than homeopathic symptomatic therapy alone? A real-life preliminary observational study in a pediatric population

Alessandro Zanasi1*, Salvatore Cazzato2, Massimiliano Mazzolini3, Carla Maria Sofia Ierna3, Marianna Mastroroberto4, Elena Nardi4 and Antonio Maria Morselli-Labate4

* Corresponding author: Alessandro Zanasi [email protected]

Author Affiliations
1 Italian Association for Cough Study (AIST), Via Mazzini, 12, Bologna, 40138, Italy

2 Department of Pediatrics, Alma Mater Studiorum – University of Bologna, Bologna, Italy

3 Respiratory Medicine and Intensive Care Unit, Sant’Orsola Malpighi Hospital, Alma Mater Studiorum – University of Bologna, Bologna, Italy

4 Department of Medical and Surgical Sciences, Alma Mater Studiorum – University of Bologna, Bologna, Italy

The electronic version of this article is the complete one and can be found online here.

Abstract
Background
The effectiveness of a homeopathic syrup on cough has been demonstrated in an adult population in a previous double-blind randomized study. The present prospective observational study investigated children affected by wet acute cough caused by non-complicated URTIs, comparing those who received the homeopathic syrup versus those treated with the homeopathic syrup plus antibiotic.

Objectives
The aims were: 1) to assess whether the addition of antibiotics to a symptomatic treatment had a role in reducing the severity and duration of acute cough in a pediatric population, as well as in improving cough resolution; 2) to verify the safety of the two treatments.

Methods
Eighty-five children were enrolled in an open study: 46 children received homeopathic syrup alone for 10 days and 39 children received homeopathic syrup for 10 days plus oral antibiotic treatment (amoxicillin/clavulanate, clarithromycin, and erythromycin) for 7 days. To assess cough severity we used a subjective verbal category-descriptive (VCD) scale.

Results
Cough VCD score was significantly (P Table 1. Characteristics of the studied children affected by wet acute cough caused by non-complicated URTI. Data are shown as frequencies or mean ± standard deviation
Ethics
The research was promoted by the Italian Association for Cough Study (AIST) and was conducted according to the Helsinki declaration. The protocol was approved by the Institutional Review Board and the informed consent was obtained by the legal guardians of the enrolled children.

Sample size and power analysis
To evaluate sample size, we hypothesized–for this study performed on children–the same results obtained previously in adults after 7 days of administering the same homeopathic syrup [17] (i.e., a difference between groups of VCD equal to 0.7 and a within-group standard deviation of 1.0). Based on these values, we needed to study a total of at least 76 subjects (i.e., 38 subjects in each group, hypothesizing an equal distribution of patients among the two groups) to be able to reject the null hypothesis with probability (power) equal to 0.90 at a significance level of 0.05. The sample size was estimated by means of the “PS Power and Sample Size Calculations” software (Version 3.0.43; Department of Statistics of the Vanderbilt University, Nashville, TN, USA; http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize) according to the Dupont and Plummer procedure [19], [20].

Statistical analysis
Frequencies and mean values ± standard deviation were used as descriptive statistics. The two groups of children were compared by means of the Fisher’s exact and the Kruskal-Wallis tests, while the Wilcoxon matched-pairs signed-rank test was used to test the changes of the VCD scale observed versus the basal values. The IBM SPSS Statistics package (Version 21; IBM Co., Armonk, NY, USA) was used to analyze the data. Two-tailed P values less than 0.05 were considered statistically significant.

Results
Cough severity
s40248-015-0022-3-1
Figure 1 shows the behavior of the verbal category-descriptive (VCD) scale of cough during the entire observational period. Cough severity was comparable between the two groups at baseline (Day 1; P = 0.763) as well as on all other days of the study. We found a highly significant (P s40248-015-0022-3-2
Fig. 2. Cough resolution during the whole observational period in children affected by wet acute cough caused by non-complicated URTI. The Fisher’s exact test was applied
Safety
We observed a total of 11 adverse events with a significantly (P = 0.020) higher frequency in patients who received syrup plus antibiotic treatment than in those who took syrup alone. In fact, two patients in Group 1 (4.3 %) reported insomnia (n = 1) and vomit (n = 1) while nine patients in Group 2 (23.1 %) reported diarrhea (n = 4), vomit (n = 3) and skin rash (n = 2).

Discussion
Our group recently published a controlled randomized trial demonstrating the favorable effect of a homeopathic syrup on the resolution of acute cough in adults compared to placebo. [17]. Our data suggest an antitussive efficacy of this homeopathic syrup in children since the time-courses of the VCD severity score in the syrup treated children of this study resulted overlapping to that obtained in syrup treated adults in a randomized, double-blind placebo-controlled trail [17]. In fact, after 4 days the mean VCD score was a bit more than 2 both in children (present study) and in adults [17]versus a mean VDC score of more than 3 observed in adults treated with placebo [17].

The data of the present study also indicate that adding antimicrobial agents to the homeopathic syrup does not in any way benefit the symptomatic treatment–so adding to the weight of evidence against prescribing antibiotics to patients with acute cough due to uncomplicated URTI. The differences in VCD scale between the homeopathic syrup group and the group that also received antibiotics are not statistically significant on any observation day, and the cough resolution trend was comparable week after week for both groups (Table 2).

At the end of the second week of observation, cough was resolved in 74 % of children treated with syrup alone and in 72 % of children who received syrup plus antibiotic, while at the end of the 28-day observation period about 10–20 % of children still presented cough, without any significant difference between the two treatment groups. These data are consistent with a recent review on the duration of symptoms of respiratory tract infections in children [3]. The percentage of children still presenting cough at the end of the study confirms that acute cough associated with URTI continues for several weeks, thus suggesting that it is necessary to educate people and the medical community about this natural history.

For the assessment of cough severity we did not use a complete parent-compiled quality of life quality (PC-QoL) questionnaire but instead we adopted a subjective verbal category-descriptive (VCD) scale [18]. Although this scale was validated against an objective cough meter measure in children slightly older (6–17 year-old) than our population (4–15 year-old), it can be considered reliable also for our study since it is a parent-assisted card. The VCD was found to be easier to use than the PC-QoL and so assures better compliance; in fact, we have made a preliminary test on the correct compilation of the VCD scale and the PC-QoL questionnaire, conducted on 20 patients for 28 consecutive days, and we obtained a compliance of 95 % for VCD but just 35 % for PC-QoL. It should also be pointed out that VCD has been proven to have a high correlation with domain variations of the PC-QoL questionnaire in children [21], [22]. Furthermore, since the VCD scale was used in our previous study on the same homeopathic syrup in adults, applying the same validated assessment tool in this study on a child population enabled us to obtain standardized and comparable data between children and adults [17].

As far as safety is concerned, it is worth noting that a significant difference was found between the two groups of children: only two children in the group treated with syrup alone reported adverse effects, versus nine children in the group treated with the syrup plus antibiotics.

As far as the limitations of the research are concerned, a major weakness of our study arises from the observational design that we applied in this appraisal. Thus we did not considered a placebo group since the main goal of our research was not the effectiveness of homeopatic syrup but it was to evaluate the role of additional antibiotic. It should be pointed out that this research was a pilot study conducted before starting a larger trial on the role of antitussive and mucolytic drugs in children; however, the results of this preliminary study can provide valuable information for the sizing of future rigorous controlled studies, to be planned with a random allocation of patients to study groups.

Conclusion
In conclusion, our data confirm that the studied homeopathic treatment has potential benefits on cough in children, as well as highlighting the good safety profile of this treatment. Supplementing the syrup with antibiotics did not improve cough resolution and was associated with more adverse events than the homeopathic syrup alone. These results indicate that antibiotics should not be routinely prescribed for uncomplicated acute cough secondary to URTI, as they are inappropriate for this condition and might be even dangerous– leading to increased antimicrobial resistances and adverse events, without evidence of benefit [23]–[27].

Abbreviations
PC-QoL: Parent-compiled quality of life

URTI: Upper respiratory tract infection

VCD: Verbal category-descriptive

Competing interests
The authors declare that they have no competing interests.

Authors’ contributions
AZ contributed to conception, design and interpretation of data, as well as in drafting and revising the manuscript. SC supported the pediatric practitioners in the management of patients and in drafting the manuscript. MM made the acquisition of data and supported the pediatric practitioners in themanagement of patients. CMSI made the acquisition of data and supported the pediatric practitioners in the management of patients. MM contributed to the interpretation of data, helped to draft the manuscript and revised the manuscript critically. EN performed the statistical analysis. AMML contributed to the design, analysis and interpretation of data, as well as in drafting and revising the manuscript. All authors read and approved the final manuscript.

Acknowledgements
We thank Boiron SA, Messimy, France for a non-binding financial contribution.

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Received: 18 June 2015
Accepted: 27 July 2015
Published: 7 August 2015
© 2015 Zanasi et al.
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