ARTICLE

Effectiveness of an Herbal Preparation Containing

Echinacea, Propolis, and Vitamin C in Preventing
Respiratory Tract Infections in Children
A Randomized, Double-blind, Placebo-Controlled, Multicenter Study
Herman A. Cohen, MD; Itzchak Varsano, MD; Ernesto Kahan, MD, MPH; E. Michael Sarrell, MD; Yosef Uziel, MD

Objective: To evaluate the effectiveness and safety of a Results: Significant mean ± SD reductions of illnesses
preparation containing echinacea, propolis, and vita- were seen in the Chizukit group in the number of ill-
min C in the prevention of respiratory tract infections ness episodes, 138 vs 308 (55% reduction); number of
in children during a 12-week winter period. episodes per child, 0.9±1.1 vs 1.8±1.3 (50% reduction,
P⬍.001); and number of days with fever per child,
Design: Randomized, double-blind, placebo-controlled 2.1 ± 2.9 vs 5.4 ± 4.4) (62% reduction, P⬍.001). The
study. total number of illness days and duration of individual
episodes were also significantly lower in the Chizukit
Subjects: Four hundred thirty children, aged 1 to 5 years, group. Adverse drug reactions were rare, mild, and
were randomized to an herbal extract preparation (n=215) transient.
or a placebo elixir (n = 215).
Conclusion: A preventive effect of a product contain-
Intervention: Administration of an herbal prepara- ing echinacea, propolis, and vitamin C on the incidence
tion (Chizukit) containing 50 mg/mL of echinacea, 50 of respiratory tract infections was observed.
mg/mL of propolis, and 10 mg/mL of vitamin C, or pla-
cebo (5.0 mL and 7.5 mL twice daily for ages 1 to 3 years
and 4 to 5 years, respectively) for 12 weeks. Arch Pediatr Adolesc Med. 2004;158:217-221

A
T THE TIME OF THE PAS - ing preparations may differ according to the
sage of the Dietary Supple- species (Echinacea purpurea, Echinacea pal-
ments Health and Educa- lida, or Echinacea angustifolia) and plant
tion Act in 1994, the parts (roots, leaves, or whole plants) used,
annual expenditures for the method of extraction, and the pres-
herbal medicines in Europe, Japan, and the ence of other plant extracts. Propolis is a
United States and Canada were $6 bil- natural resinous product collected by hon-
From the Pediatric and lion, $2.1 billion, and $1.5 billion, respec- eybees from various plant sources and is
Adolescent Ambulatory tively.1 In the United Kingdom, the amount also used for the management of respira-
Community Clinic (Drs Cohen exceeds £40 million.2 Since then, con- tory infections. After the resin is masti-
and Sarrell) and Schneider sumer sales of herbal products have grown cated and salivary enzymes are added, the
Children’s Medical Center of by about 10% to 15% per year. partially digested material is mixed with
Israel and Sackler Faculty of Some herbal or natural products are
Medicine (Dr Varsano), Petach
beeswax and used in the hives.12,13 Propo-
Tikva; Department of Family
believed to affect certain immunological fac- lis is composed of 50% resin and veg-
Medicine, Sackler Faculty of tors. Echinacea, one of the most popular etable balsam, 30% wax, 10% essential and
Medicine, Tel Aviv University, herbal medicines in Europe and the United aromatic oils, 5% pollen, and 5% other sub-
Tel Aviv (Drs Cohen and stances (minerals).14 Its putative antimi-
Kahan); Israel Pediatric See also page 222 crobial activities have been attributed to fla-
Research in Office Setting vones14,15 and its anticancerous activities to
Network of the Israel States, is considered an immune stimu- caffeic acid phenethyl ester.16 Propolis has
Ambulatory Pediatrics lant and is usually used for the prevention also been shown to have a general anti-
Association, Tel Aviv
and treatment of upper respiratory tract in- inflammatory activity, an antiviral effect on
(Drs Cohen, Varsano, Kahan,
Sarrell, and Uziel); and fection. Several researchers have demon- herpes simplex virus type 117,18 and influ-
Department of Pediatrics, Sapir strated its cytokine-modulating and mac- enza virus,19 and a suppressive effect on the
Medical Center, Kfar Saba, and rophage and natural killer cell activity in replication of human immunodeficiency vi-
Sackler Faculty of Medicine vitro and in animal studies.3-11 However, the rus type 1.20 Experimental studies indi-
(Dr Uziel), Israel. chemical properties of echinacea contain- cate that vitamin C may have effects on the

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immune system. Ascorbic acid has been reported to in- each. The boxes and bottles were identical, and the Chizukit
crease the proliferative responses of T lymphocytes in and placebo extracts were indistinguishable by appearance, color,
vitro21,22 and to induce the production of interferon in cell or flavor. The Chizukit and the placebo were supplied directly
culture.23,24 Vitamin C concentrations are up to 100 times by the manufacturer, and all randomization lots were stored
in a sealed envelope at the pharmacy of the company, to be
greater in phagocytes and lymphocytes than in plasma, sug-
opened only in the event of an emergency.
gesting a physiological role in these immune system cells.25 At the outset of the study, the parents were given the first
Despite the widespread use of echinacea and propo- box of Chizukit or placebo and were instructed to administer
lis, their efficacy remains controversial.26,27 Clinical re- it according to schedule. They also received a diary card to rec-
sults supporting their effectiveness in the treatment and ord any acute episodes of respiratory tract illness, specific symp-
prevention of upper respiratory tract infection have been toms (fever, runny nose, and nighttime and daytime cough, if
published primarily in German and only from trials among more than usual), use of antipyretic or antibiotic agents, ab-
adults.27 The objective of the present study was to inves- sence from day care or kindergarten, and physician office vis-
tigate the effectiveness of a preparation containing echi- its (other than those scheduled). Follow-up visits were con-
nacea extract, propolis, and vitamin C (Chizukit; Hadas ducted at 4, 8, and 12 weeks to hand out new medication, collect
data on respiratory morbidity and adverse drug reaction, and
Corp Ltd, Yokneam, Israel) in preventing upper respi-
monitor compliance. All other visits because of respiratory symp-
ratory tract infections in children. toms were considered unscheduled physician visits. The partici-
pants were asked to contact the study physicians in the event
METHODS of symptoms of upper respiratory tract infection to confirm the
existence of the acute episode of respiratory illness. The final
SUBJECTS registration of an illness episode was made only if such a con-
firmation was done. We define an adverse drug reaction as an
A randomized, double-blind, placebo-controlled design was appreciably harmful or unpleasant reaction, resulting from an
used. The study was performed during the winter between No- intervention related to the use of a medicinal product, that pre-
vember 1, 1999, and March 30, 2000. It took place at 10 pri- dicts hazard from future administration and warrants preven-
mary care pediatric community clinics in Israel. The study tion or specific treatment, alteration of the dosage regimen, or
sample consisted of 430 children aged 1 to 5 years, 215 each withdrawal of the product.29 In addition, a study coordinator
randomized to placebo elixir or active Chizukit groups. The weekly telephoned the parents to obtain information regard-
sample size calculation was based on a previous study28 that ing the occurrence of acute respiratory episodes, symptoms, and
showed a crude rate of 17.8% reports of flulike and acute res- use of additional prescribed medication (antipyretics, antibi-
piratory symptoms during a winter period. Although that popu- otics, and decongestants). An episode of acute illness was de-
lation (mean age, 28 years) was not restricted to children, other fined as the appearance after at least 5 symptom-free days of 1
characteristics, such as membership in the Israeli Health In- or more major signs together with at least 1 minor sign, as fol-
surance System, seasonality, and 12 weeks’ observation, were lows: major signs, fever greater than 38°C, acute otitis media,
similar to those among the population of the present study. As- tonsillopharyngitis with severe redness or exudates, and aus-
sumptions for the calculation were based on a 0.18 probabil- cultatory finding compatible with pneumonia; and minor signs,
ity of colds in the placebo group, estimating that we had 90% hoarseness or stridor, conjunctivitis, cough, and runny nose
power with ␣ = .05 to detect a relative risk of 0.5. (significantly more than usual). The duration of an episode was
Under these conditions, the minimum sample size for each measured from the onset of symptoms to the return to the ba-
group is 134 subjects. Adding 50% to accommodate probable sic condition, based on parental assessment.
dropouts, the sample size increased to 201. Although it is ex- The local ethics committee of the Schneider Children’s
pected that a population of children in a clinical trial will re- Medical Center of Israel approved the study. All parents gave
port more events than the general population, reducing the informed consent to participate before starting the study.
sample size needs, we added an extra 10% (13.4 subjects) in
case the reported rate in children was lower. Therefore, the fi- STATISTICAL ANALYSIS
nal calculated sample size was 215 subjects for each trial group.
Exclusion criteria were presence of acute upper respiratory tract Statistical analysis was performed with SPSS for Windows, ver-
infection or other infections within the 7 days before consid- sion 10.0 (SPSS Inc, Chicago, Ill). The differences between pro-
eration for the study, cystic fibrosis, immunodeficiency syn- portions test was used to determine the significance of differ-
dromes (acquired or congenital), anatomic abnormalities of the ences in nominal variables (number [percentage] of children
respiratory tract (acquired or congenital), malabsorption, or use with ⱖ1 episodes in Table 1, and incidence of respiratory sys-
of immunostimulating or immunosuppressive drugs within 4 tem infection in Table 2) between the groups, and a t test was
weeks before inclusion in the study. Eligible patients were ran- used to compare the mean number of days with symptoms and
domly assigned to receive 12 weeks’ treatment with placebo elixir means of the other variables. For the relevant variables,
or active Chizukit, a preparation containing an extract of 50 mean ± SD and 95% confidence intervals were calculated.
mg/mL of echinacea (upper plant parts of E purpurea and roots
of E angustifolia), 50 mg/mL of propolis, and 10 mg/mL of vi- RESULTS
tamin C. Chizukit is a standard combination widely used in
Israel as an over-the-counter drug. Group allocation was done Three hundred twenty-eight children completed the study,
according to a computer-generated randomization list in blocks 160 (82 boys) in the Chizukit group and 168 (91 boys)
of 4. The medication or placebo was administered following
the company recommendations, twice daily, in a dosage of 5.0
in the placebo group. The mean ages of the groups were
mL for children aged 1 to 3 years and 7.5 mL for children aged 38.3 ± 18.6 months and 38.9 ± 20.6 months, respec-
4 to 5 years. If an episode of acute illness occurred during the tively. Ninety-nine children (23%) dropped out, 55 from
study, the dosage was increased to 5.0 mL and 7.5 mL, respec- the Chizukit group and 44 from the placebo group. Among
tively, 4 times daily during the episode only. The medication all dropouts, the reasons for withdrawal from the study
or placebo was packed in boxes containing 5 bottles of 250 mL were unpleasant taste (27 subjects and 22 subjects from

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 Table 1. Primary Outcome Data* 500 Assessed for Eligibility; Age, 1-5 y

Chizukit Placebo P 14 Excluded

Variable (n = 160) (n = 168) Reduction, % Value 56 Refused to Participate

Total No. of episodes 138 308 55 ...

Total No. of illness days 423 1040 59 ...
430 Randomized
No. (%) of children with 85 (53.1) 150 (89.3) 43 ⬍.001†
ⱖ1 episodes
No. of episodes per child 0.9 ± 1.1 1.8 ± 1.3 50 ⬍.001‡
215 Allocated to Chizukit 215 Allocated to Placebo
Days of illness per child 2.6 ± 4.2 6.2 ± 5.0 58 ⬍.001‡ 215 Received Allocated 215 Received Allocated
Duration of individual 1.6 ± 1.9 2.9 ± 1.6 45 ⬍.001‡ Intervention Intervention
episodes

55 Dropped Out 44 Dropped Out

*Data are mean ± SD unless otherwise indicated. Chizukit is an herbal 27 Unpleasant Taste 22 Unpleasant Taste
preparation. See text for detail. 24 Noncompliance Without 21 Noncompliance Without
†Difference between proportions test. Any Explanation Any Explanation
‡t Test. 4 Lack of Confidence in the 1 Lack of Confidence in the
Treatment Treatment

Table 2. Incidence of Respiratory System Infection 160 Analyzed 168 Analyzed

No. (%) Flow diagram of subject progress through the phases of the trial. Chizukit is
an herbal preparation. See text for details.
Chizukit* Placebo Reduction, P
Diagnosis (n = 160) (n = 168) % Value†
Upper respiratory 79 (47.4) 158 (94.0) 50 ⬍.001 nitis and daytime and nighttime cough (more than usual),
tract infection according to parental report, was lower by 22%, 30%, and
Acute otitis media 31 (19.4) 73 (43.5) 68 ⬍.001 36%, respectively, in the Chizukit group, but these differ-
Pneumonia 13 (8.1) 38 (22.6) 66 ⬍.001 ences did not reach statistical significance, except for night-
Tonsillopharyngitis 10 (6.3) 25 (14.9) 60 .01 time cough (P=.03). The respiratory system diseases di-
agnosed during the study are summarized in Table 2. Upper
*Chizukit is an herbal preparation. See text for details.
†Difference between proportions test. respiratory tract infection was the most frequent, fol-
lowed by acute otitis media. There were few cases of pneu-
monia and tonsillopharyngitis. The incidence of each of
the Chizukit and placebo groups, respectively), lack of the diseases was significantly lower in the Chizukit group.
confidence in the treatment (4 subjects and 1 subject), Adverse drug reactions were observed in 9 patients
and noncompliance without any explanation (24 sub- (5.6%) in the Chizukit group and 7 (4.2%) in the pla-
jects and 21 subjects). Because all of the differences be- cebo group (P=.54). All were mild gastrointestinal and
tween the Chizukit and placebo groups (rate of with- palatability symptoms that were transient and did not re-
drawal and reasons for it) were not significant (P quire discontinuation of treatment.
approaching 1.00 for all) and because all dropouts oc-
curred during the first week of the study, we performed COMMENT
an efficacy study instead of an intention-to-treat analy-
sis. The Figure shows the subject progress through the The results of the present study demonstrate, for the
phases of the trial. first time, that an herbal preparation containing an ex-
The primary outcome data are presented in Table tract of echinacea, propolis, and vitamin C has a signifi-
1. The number of children who experienced 1 or more cant beneficial effect on the incidence and severity of
respiratory tract illness episodes during the 12 weeks of respiratory tract infections in young children (as in
the study, the total number of episodes, and the mean adults). Recently, Mark et al8 reviewed the use of echi-
number of episodes per child were significantly lower in nacea in the pediatric population and described their
the Chizukit than the placebo group (by 43%, 55%, and trial evaluating the effect of echinacea in preventing re-
50%, respectively). The total number of illness days and current otitis media.
duration of individual episodes were also significantly Several studies3,6,30,31 have investigated the effective-
lower in the Chizukit group. Similar findings were noted ness of various preparations of echinacea extracts for the
when the children 3 years and younger and those older treatment and prevention of respiratory tract infection
than 3 years were analyzed separately (data not shown). in adults. Barret et al31 reviewed the evidence on orally
The secondary outcome data are presented in administered echinacea extracts for acute upper respi-
Table 3. The number of days of fever and of use of an- ratory tract infections and concluded that they may be
tipyretics (acetaminophen) and antibiotics, the number of beneficial for the early treatment of existing illness but
unscheduled visits to the physician’s office for respira- not for prevention. The same conclusion was reached by
tory tract illnesses, and the number of days absent from Melchart6 and Gunning32 and their colleagues. How-
day care or kindergarten were significantly lower in the ever, Schoneberger,33 in an 8-week trial, noted a shorter
Chizukit than the placebo group (by 62%, 53%, 50%, 36%, duration of illness and a trend toward fewer study par-
and 49%, respectively). In addition, the incidence of rhi- ticipants with infection, indicating a possible preven-

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 What This Study Adds
Table 3. Secondary Outcome Data*

Chizukit Placebo Reduction, P Complementary therapies are commonly used and have
Variable (n = 160) (n = 168) % Value† increased in popularity. Echinacea and propolis are widely
used for the treatment and prevention of upper respira-
Fever
tory tract infection in adults and children.
Total No. of days with 340 902 62 ...
The present study demonstrates that an herbal ex-
Days per child 2.1 ± 2.9 5.4 ± 4.4 ... ⬍.001
tract preparation containing echinacea, propolis, and vi-
Antipyretics
Total No. of days used 380 815 53 ...
tamin C may be beneficial for the prevention of respi-
Days used per child 2.4 ± 3.5 4.9 ± 3.9 ... ⬍.001
ratory tract infections in children. Advice regarding the
Antibiotics use of herbal extracts, especially for children, is
Total No. of days used 541 1084 50 ... recommended.
Days used per child 3.4 ± 5.6 6.5 ± 8.0 ... ⬍.001
Unscheduled visits to
physician
Total No. of visits 333 519 36 ... iting, abdominal pain, and diarrhea.42 This was also ob-
Visits per child 2.1 ± 2.1 3.1 ± 2.8 ... ⬍.001 served in the present study. However, serious allergic or
Absence from day care anaphylactic events have been reported in rare cases,43,44
or kindergarten so caution is advised for patients with a history of hy-
Total days 367 718 49 ...
Days per child 2.3 ± 4.6 4.3 ± 5.6 ... ⬍.001
persensitivity to products from the daisy family (sun-
Rhinitis flower seeds and ragweed).
Total No. of days with 771 993 22 ... Melchart et al5 suggested that echinacea may be ben-
Days per child 4.8 ± 8.6 5.6 ± 8.1 ... .43 eficial for individuals who already have an immune dis-
Daytime cough, more order but that it has little or no effect on a healthy im-
than usual mune system. The use of immunostimulants in the
Total No. of days 642 914 30 ...
Days per child 4.0 ± 7.0 5.4 ± 7.6 ... .08
prevention of upper respiratory tract infection is contro-
Nighttime cough, more versial.45 Berber and Del-Rio-Navarro46 conducted a meta-
than usual analysis study and reported that immunostimulants can
Total No. of nights 424 667 36 ... reduce the incidence of acute upper respiratory tract in-
Nights per child 2.7 ± 5.1 4.0 ± 6.0 ... .03 fection in children but cannot prevent all these infec-
tions. Therefore, they suggest that the use of immuno-
*Data are mean ± SD unless otherwise indicated. Chizukit is an herbal stimulants for prevention must be limited to children with
preparation. See text for details.
†t Test. high susceptibility to these kinds of infections or to over-
exposed children attending day care centers, kindergar-
tens, or elementary schools. We assume that the benefi-
tive effect. In other placebo-controlled trials, Schmidt and cial effect of the Chizukit preparation in this study was
colleagues34 found a 15% lower frequency of infection due to the immunomodulatory action of its compo-
in subjects given echinacea (P = .08), Forth and Beu- nents. The immunostimulating properties of echinacea
scher35 reported a relative risk reduction of 38% in nasal may decline with continued use. Therefore, some au-
symptoms (P<.005), and Henneicke-von Zepelin et al36 thors suggest that preparations containing echinacea not
reported a superiority of echinacea preparation over pla- be taken for longer than 8 to 12 consecutive weeks.47-49
cebo in the treatment of the common cold. On the other After a drug holiday, it may be restarted.
hand, Turner et al37 found no significant difference in the One limitation of the present study is the lack of ap-
occurrence of infection or severity of illness in a group propriate quality control and standardization, because the
of 92 volunteers challenged with rhinovirus type 23 and active components of the preparations are not known.
treated with echinacea for 5 days compared with con- In addition, the safety of long-term prophylactic use was
trol subjects. not tested.
Propolis has been shown to have anti-inflammato- The present study suggests that an herbal extract
ry14 and antiviral17-20 activity. Crisan et al38 reported a lower preparation containing echinacea, propolis, and vita-
incidence of rhinopharyngeal infection and symptoms in min C is beneficial for the prevention of respiratory tract
a group of preschool children treated with a propolis prepa- infections in children. However, considering that this is
ration for 5 months. The authors suggest that the de- the first trial conducted in young children, conclusions
crease in the local virus and bacterial carriage rate in the must be made with caution. Additional studies are needed
nasopharynx was attributable to the anti-inflammatory and in larger samples to confirm our findings and to rule out
decongestive properties of the product. potential adverse effects in general or specific popula-
We do not believe that the low dose of vitamin C in tions at risk, such as allergic children or those receiving
the Chizukit preparation by itself plays a role in the pre- cotherapy or having different morbidities, before the
vention of respiratory tract illness. However, some ad- preparation can be recommended for routine clinical use.
ditive effects to echinacea and propolis immunomodu-
lation cannot be ruled out. Accepted for publication August 7, 2003.
The safety data on echinacea are relatively strong.39-41 We thank Dorit Karsh for the statistical analysis,
It also appears to be well tolerated, with a low frequency and Phyllis Curchack Kornspan, Gloria Ginzach, and
of adverse effects, such as unpleasant taste, nausea or vom- Charlotte Sachs for their assistance.

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 Hadas Corp Ltd was not involved in the design, con- 23. Dahl H, Degre M. The effect of ascorbic acid on production of human interferon
and antiviral activity in vitro. Acta Pathol Microbiol Scand B. 1976;84B:280-284.
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24. Siegel BV. Enhancement of interferon production by poly(rI)-poly(rC) in mouse
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atric and Adolescent Ambulatory Community Clinic, Ha- J Biol Chem. 1993;268:5531-5535.
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