Children are frequently affected by upper respiratory tract infections (URTI) or common colds, causing a lot of missed days from kindergarten or school,¹ as well as missed days off work for parents who have to take leave to take care of their child.^2,3 Each year young children may have as many as 6 to 8 or even more episodes.^4–6 The German Health Interview and Examination Survey for Children and Adolescents found that the 1-year average prevalence of URTI among children and adolescents amounts to 88.5%, with the highest prevalence of almost 94% among children aged 3 to 6 years.⁷ Symptoms usually include sore throat, runny nose, general malaise, and low-grade fever at onset, followed by nasal congestion and cough, and peak at around day 3 or 4 after the onset of symptoms. Recovery is typically complete after about 7 to 10 days.^1,8 Viral pathogens like rhinoviruses,^6,9–11 and also influenza viruses,¹² are the major causes of URTI.

Since no universally accepted specific therapy for URTI exists, treatment is mainly symptomatic.¹³ Antiviral drugs are only recommended in confirmed influenza cases in children under 2 years of age, immunocompromised and chronically ill children, and in cases with severe symptoms.¹⁴ In all other cases antipyretics, anti-inflammatory drugs, expectorants, decongestants, and cough suppressants either alone or in combination can be used.¹³ In Germany, medicines are used to treat the common cold and URTI in about 14% of children (7% prescribed and 7% over-the-counter), and about 12% of the prescribed medicines are antibiotics.¹⁵ In general, antibiotics are widely prescribed.^16,17 Since URTI are mainly caused by viruses,⁶ an antibiotic treatment is often inappropriate, and only indicated if there is a bacterial infection or to prevent superinfections.^13,18 Overuse further spreads the problem of antibiotics resistance, which is of significant concern from a public health point of view.^19,20

Homeopathy is increasingly popular.²¹ For instance in Germany, 60% of the population has used homeopathy. The great majority (87%) of these users report positive experiences, and the common cold and flu is the most frequently mentioned indication.²² Homeopathy is the most commonly used complementary medicinal treatment in German children. It is estimated that around 16% of all homeopathic medicines used in children are for flu or rhinopharyngeal complaints.²³ One homeopathic preparation for the treatment of flu-like infections with fever and other acute viral URTI is Influcid^® (IFC), which was marketed in its first form as a solution in Germany in 1928, and is currently available in 26 countries worldwide. Preliminary studies indicate that IFC is an effective and safe treatment of typical cold-related symptoms in both adults and children.^24,25

Since there is no approved specific therapy for URTI and because conventional medicines sometimes lead to side-effects and inappropriate use of antibiotics, there is an interest in the identification and evaluation of alternative therapies with a beneficial risk-benefit profile. We therefore evaluated the effectiveness and safety of IFC as an add-on to symptomatic standard treatment in a randomized controlled trial in adult and pediatric URTI with fever. The primary outcome measure in this trial, “symptom and fever resolution” at day 4, was significantly superior in the IFC-group compared to the standard treatment group. For full results of this trial, see the publication by Thinesse-Mallwitz et al.²⁶ Given the wide use of homeopathy in children, we aimed to better distinguish and differentiate the effects in preadolescent children. This article reports the findings in this subpopulation.

Materials and Methods

We conducted a subgroup analysis of a randomized, symptomatic standard treatment controlled, parallel groups, open, multicenter, multinational clinical trial. This analysis of preadolescent children was planned in the protocol. The methods of the trial are summarized below and described in detail in the publication by Thinesse-Mallwitz et al.²⁶ Participants were recruited in the Ukraine and in Germany. Preadolescent children (1 to 11 years of age) with clinical signs and symptoms of an URTI with a duration of up to 24 hours, accompanied by fever ≥37.5°C (axillary body temperature), with at least 1 of 3 types of URTI symptoms (nasal, pharyngeal, cough) and at least 1 of 5 general symptoms (feeling tired, weakness, body aches, irritable/whiney, or less active), were eligible.

The children were randomized to receive either on-demand symptomatic standard treatment (paracetamol, ambroxol, and/or oxymetazoline; ST-group) or IFC tablets in addition to the same symptomatic standard treatment (IFC-group) as an add-on treatment.

IFC tablets, containing a fixed combination of 6 homeopathic single substances (Aconitum D3, Bryonia D2, Eupatorium perfoliatum D1, Gelsemium D3, Ipecacuanha D3, and Phosphorus D5), were administered to children in the IFC-group for a period of 7 days (8 tablets/day during the first 72 hours, 3 tablets/day during the following 96 hours). Paracetamol syrup, ambroxol syrup, and oxymetazoline nasal spray were offered as symptomatic standard medication to all children on an “as-needed” basis.

Parents completed a diary (child’s axillary body temperature, symptoms, symptomatic standard medication intake), and the children were followed-up by the investigator for 14 days (baseline visit (day 1), follow-up visits on days 4 ± 1 and 8 ± 1, termination visit on day 15 ± 2, additional follow-up calls on days 2 and 3).

URTI symptoms were assessed using the Wisconsin Upper Respiratory Symptom Survey–21 (WURSS-21), which is a 21-item illness-specific symptom and health-related quality-of-life questionnaire containing 1 global severity item, 10 symptom-based items, 9 functional quality-of-life items, and 1 global change item, each of which are rated on a 0 to 7 Likert-type scale.²⁷ Six additional complaints questions were asked, whereof 2 questions (irritable/whiny; less active) were specifically applicable to children.

Symptom and fever resolution was defined as a combination of the following criteria: (a) WURSS-21 item 1 “How sick do you feel today?” being graded as 0 (“not sick”) or 1 (“very mildly”) in both the morning and evening and (b) mean daily axillary body temperature ≤37.2°C.

Further outcome measures were the time to the resolution of individual symptoms; the global severity and course of the infection; the absence of fever; the amount and duration of paracetamol, ambroxol, and oxymetazoline consumption; treatment outcome as assessed by both the investigator and the children’s parents, on the Integrative Medicine Outcome Scale (IMOS; complete recovery, major improvement, slight to moderate improvement, no change, deterioration); satisfaction with treatment on the Integrative Medicine Patient Satisfaction Scale (IMPSS; very satisfied, satisfied, neutral, dissatisfied, very dissatisfied) as assessed by the parents at the termination visit on day 15.

The safety assessment took place by analyzing the occurrence and nature of adverse events (AEs).

The statistical analysis was based on the intention-to-treat (ITT) principle. The analyzed population consisted of those children who started the treatment plan and had at least one postbaseline outcome assessment. Safety analysis included all randomized children who started the treatment plan. Since the analyses reported in this article are explorative, no type 1 error adjustment took place. The between-group difference in days until symptom resolution, as assessed with the WURSS-21 item 1, was quantified via the median of all pairwise differences, calculated from each groups’ individuals’ data values, that is, via the Hodges-Lehmann (HL) estimate of location shift²⁸ and its 95% confidence intervals (CIs); fever resolution was analyzed via calculation of the between-group difference in the proportion of children with absence of fever; global severity during the course of the URTI was analyzed by calculating the area under the curve (AUC) of the WURSS-21 total score (WURSS-21 items 2 to 20) as well as separately for the WURSS symptom subscores (WURSS-21 items 2 to 11) and quality-of-life subscores (WURSS-21 items 12 to 20), plus for the 2 additional children-specific questions. Missing fever and/or WURSS data were imputed based on the “last observation carried forward” method.