No generally accepted diagnostic definition for AOM existed at the time of our study. We defined AOM as an acute illness with at least one symptom (fever, rhinorrhea, cough, otalgia, irritability, lethargy, anorexia, vomiting, or diarrhea) and at least two otoscopic findings of middle-ear inflammation (injection, opacity, fullness, or impaired mobility) or purulent otorrhea. This definition is consistent with the later 2004 American Academy of Pediatrics guidelines on otitis media. Recurrent otitis media was defined as at least 3 separate episodes of AOM within a 6-month period, or 4 episodes in one year. In order for episodes to be considered separate, the protocol required otoscopic documentation of resolution of one episode, or at least two weeks without symptoms following completion of antibiotic therapy, prior to onset of the subsequent episode.
Children aged 12–60 months with recurrent otitis media (as documented in their medical records) were recruited from the Arizona Health Sciences Center Pediatric Clinic and from private pediatric offices in Tucson, Arizona. Children were excluded for unwillingness to participate, congenital malformations of the ears, nose, or throat (e.g., cleft palate), known or suspected allergy to echinacea, immune deficiency including HIV infection, or tuberculosis. Children taking prophylactic antibiotics or who had tympanostomy tubes in place were excluded from enrollment. The Arizona Health Sciences Center Pediatric Clinic serves an urban population, of which approximately 75% are covered by Medicaid.
Randomization was done in blocks of eight using a random number table by a clinical pharmacist (KLG) having no contact with participants. Children were randomly assigned to one of four groups in a two-by-two factorial design. The first group received placebo extract orally and sham manipulation. The second group received Echinacea purpurea extract and sham manipulation. The third group received placebo extract and true OMT. The last group received Echinacea purpurea extract and true OMT. Sequentially numbered, indistinguishable bottles of echinacea or placebo were provided in advance. After informed consent was obtained, the parent was given the next bottle in sequence, and the pharmacist was telephoned to determine which of two osteopathic physicians was assigned (also determined randomly). The osteopathic physician independently contacted the pharmacist to learn whether a child was to receive sham or true osteopathic manipulative treatment. Children, families, and pediatricians were blinded to the group assignment of each subject.
Children assigned to echinacea treatment received a 1:1 weight-to-volume 50% ethanol liquid extract of the fresh roots and dried mature seeds of Echinacea purpurea manufactured by Eclectic Institute, Inc. (Sandy, Oregon). All echinacea came from the same lot number, with an analysis by the manufacturer confirming 50% root and seed extract of Echinacea purpurea. A similar, identically labeled placebo prepared by Eclectic Institute contained 50% ethanol, 45% filtered water, food coloring and thickeners. Parents were instructed to give 0.5 ml orally 3 times daily for 3 days at the onset of cold symptoms, followed by 0.25 ml orally 3 times daily for 7 more days.
All children were scheduled for osteopathic sessions as soon as possible after entry, then 2, 4, 8, and 12 weeks later. At each visit, children assigned to OMT received diagnostic examinations and concurrent treatments as deemed necessary by the treating physician. Treatment modalities were limited to cranial osteopathy, balanced membranous/ligamentous tension, and/or myofascial release (applied directly or indirectly). These treatments consist of gentle manipulations of the cranium, pelvis, diaphragm, and other structures. No high velocity or thrusting maneuvers were performed. At the discretion of the osteopathic physician, an osteopathic percussion hammer could also be used for treatment, which allowed gentle vibration in tissues at variable frequencies. Children assigned to sham manipulation received an osteopathic examination only (palpation of the cranial bones and muscles and other structures) without treatment maneuvers.
The osteopathic physicians were well-respected members of the Tucson osteopathic community with practices restricted to manipulative treatment. All were members of the American Academy of Osteopathy and the Cranial Academy.
In addition to the study interventions, all parents received educational materials regarding otitis risk factors. If after enrollment a child received prophylactic antibiotics, otolaryngology referral, or tympanostomy tubes (usually for further recurrences of AOM), this information was recorded, but the child was allowed to remain in the study. Such decisions were made on clinical grounds by the treating clinician and were not influenced by the child's participation in the study.
After enrollment, children were prospectively followed for 6 months, with monthly telephone contact, and availability for evaluation 5 days per week by study pediatricians (MBA and RAW) if AOM was suspected. Children diagnosed with ear infection during weekends were asked to see one of the study physicians early the following week to confirm the diagnosis. In addition, children received otoscopic and physical examinations at entry, at 3 months, and at 6 months by study pediatricians, who were blinded to the treatment assignment of subjects.
At enrollment, a questionnaire was used to collect information about the child's previous episodes of AOM, past medical history, cigarette smoke exposure, previous use of study alternative interventions, family history of allergy, and recurrent otitis media. The results of otoscopic and physical examinations were recorded at entry, 3, and 6 months, and at the time of any evaluation for possible AOM. At monthly telephone contacts, parents were asked if the child had any suspected or diagnosed ear problems during the previous month, and whether any side effects of the interventions were suspected. Parents were also asked at the 3- and 6-month visits whether they believed their child was receiving placebo for each study intervention.
Main outcome measures
The primary study outcome was the occurrence of a first episode of AOM during the study period as defined above. The final analysis was performed using only episodes of AOM that were sufficiently well documented in the medical record to meet the definition as described in the paper. A secondary outcome was the number of episodes of AOM. For this secondary outcome measure, all physician-diagnosed episodes of AOM were included, without respect to the case definition for AOM.
Children were analyzed in the groups into which they were randomized. An initial analysis was done to determine if there was any important interaction between the effects of echinacea and OMT on the occurrence of AOM. Since none was found, the two interventions were considered independently. For each intervention, the cumulative incidence of AOM during follow-up was compared between treatment and placebo groups using chi-square analysis and the relative risk (RR) with 95% confidence interval (CI). P was considered significant at P < 0.05. The time to first episode of AOM was compared between groups using Kaplan-Meier analysis and the log rank test. Kaplan-Meier curves were truncated at 200 days of follow-up. Cox regression was used to estimate the relative risk of AOM during follow-up with adjustment for confounding effects of other factors. The median number of episodes of AOM during follow-up was compared using the Mann-Whitney nonparametric test. Analyses were performed using SPSS for Windows (Version 11.5.0, SPSS Inc., Chicago, IL) and EpiInfo (Version 5.01b, CDC and USD, Inc., Stone Mountain, GA).
We assumed the risk of having at least one episode of AOM during 6 months of observation among children with recurrent otitis media to be 60%. With no effect modification between echinacea and osteopathic treatment, a final sample of 100 children (50 subjects per group for each analysis), was needed to provide 80% power to detect a 50% reduction in the risk of AOM associated with the treatment being analyzed (alpha = 0.05). This magnitude of risk reduction is comparable to that observed with antibiotic prophylaxis .
The study was conducted with the approval of the University of Arizona Human Subjects Committee, and informed consent was obtained from a parent or guardian of each subject.