key: cord-343941-nfdplszh authors: Wong, Lai-yi; Leung, Ping-chung; Pang, Suet-yee; Cheng, King-fai; Wong, Chun-kwok; Lam, Wai-kei; Fung, Kwok-pui; Lau, Tak-fai; Tse, Yee-kit; Kwok, Chi-yui title: A herbal formula for prevention of influenza-like syndrome: A double-blind randomized clinical trial date: 2013-04-02 journal: Chin J Integr Med DOI: 10.1007/s11655-012-1269-6 sha: doc_id: 343941 cord_uid: nfdplszh OBJECTIVE: To investigate the efficacy of a herbal formula in the prevention of influenza or influenza-like syndrome among elderies residing in old-people’s home in Hong Kong. The secondary objectives are to investigate the quality of life (QOL) and symptomology changes among the herbal users and to evaluate the safety of this formula. METHODS: In ten old people’s home or community centres in New Territories, Hong Kong, 740 eligible subjects agreed to join the study and were randomized to receive a herbal formula or a placebo on alternate days over 8 weeks. Among those 740 participants, 113 had provided blood samples for immunological assessments before and after the study drug. Assessments were done at 0, 4, 8 and 12 weeks. Participants were instructed to keep a daily record of body temperature and any symptoms as sore throat, myalgia, running nose or cough, and to report to assessor accordingly. Those reporting body temperature of 37.8 °C and above would be visited and a proper nasopharyngeal swab be taken for viral study. RESULTS: Seventy-two participants developed influenza-like-symptoms but none of them was proven influenza in their nasopharyngeal swabs, 40 of these patients belonged to the herbal group and 32 to the placebo group, without significant differences between groups. The difference on the changes in QOL between the two groups was not statistically significant. However, in the immunological study, the natural killer cell absolute count was significantly increased in the herbal group compared with the placebo group (463±253 vs 413±198, P<0.05). CONCLUSIONS: The herbal preparation was not effective compared with placebo in the prevention of influenza-like syndrome. It was however safe and possibly supporting immunological responses. infection. (4) The results of evaluation were encouraging: none of those using the herbal preparation contracted SARS while 0.4% of other health workers were infected. Improvement of influenza-like symptoms and quality of life (QOL) measurements were also observed. Only less than 2% reported minor adverse events. (4) The observation did not allow conclusive deductions since the trial was neither randomized nor placebo-controlled; and during the chaotic period of the deadly epidemic, measures to ensure a proper conduction of a trial were simply lacking. Nevertheless, a study of the immunological state of 40% the herbal consumers indicated that there was objective evidence of improvement of body defense system after two weeks of treatment. Interestingly, the boostering effect subsided two weeks later. (5) We therefore consider that further exploration on the efficacy of the herbal preparation is justified and a plan for a proper randomized controlled trial is thus constructed. Since the annual record of the Department of Health in Hong Kong, indicated that an endemic of influenza is likely to appear from February to April every year, a preventive program could be organized within this period accordingly. The primary objective of the study was to investigate the efficacy of the herbal preparation previously used for the prevention of SARS against endemic influenza among a group of at risk elderly people. If unpredictabley, the annual endemic did not happen, the primary objective would have to be changed to the control of influenza like syndrome. The secondary objectives included the safety of using the preparation and the changes in the QOL among the users. The study was designed as a double-blind, placebo-controlled, and randomized trial. The target participants were dwellers of old-age homes or attendance of elderly centre, aged 60 or above. A total of 10 elderly centres and old age homes were randomly selected from New Territories, Hong Kong. The inclusion criteria included those enjoying stable health and had no influenza-like symptoms on enrollment. Written informed consents were obtained from all the participants before entry into the study and the study protocol was approved properly by the Clinical Research Ethics Committee of the Prince of Wales Hospital. Exclusion criteria included history of hypersensitivity to herbs, regular consumers of other herbal preparations, medications that were known to upset the immuno-modulating function, e.g. steroids, and severe cognitive dysfunctions. Only those who did not receive influenza vaccination in the past six months would be asked to join the blood sample group. The eligible participants were allocated randomly in a double-blind way to one of the two treatment groups according to a computer generated stratification randomized block design. The stratification was made on old-age home/elderly centre and vaccination status. In each old-age home or elderly centre the participants were randomized separately within the vaccinated group or non-vaccinated group to receive either herbal preparation or placebo. Participants received the 4 g sachet of herbal preparation or placebo on alternate days over 8 weeks. After 8 weeks, participants stopped taking either the herbal preparation or placebo but were followed up by research interviewers at the end of another 4 weeks. The placebo was made of starch that was coloured to resemble herbal tea. In the 8-weeks study period, participants were instructed to keep a daily record of body temperature and any symptoms such as sore throat, myalgia, running nose and cough, which resembled symptoms of influenza. A research interviewer telephoned each participant twice a week to gather the update data, while individual participants was required to report to the interviewers any time when they suspected contraction of influenza-like illness. When the body temperature was more than 37.8 ℃, a naso-pharyngeal swab would be taken from the individual by the research nurse, and sent for viral investigation. Influenza-like symptoms and adverse reactions were observed and QOL was evaluated at the 0, 4th, 8th and 12th week. A subgroup was recruited for examination of the blood for immunological markers. Total of 133 participants who did not receive influenza vaccination within 6 months before the study were recruited and consent on voluntary basis. They were required to give 12 mL of blood each before and 8 weeks after the administration of either herbal or placebo intervention. Every herbal component was tested for heavy metals, microbial and pesticide contaminations and all test results met the safety requirements in Hong Kong. The formula was prepared as granules ready for consumption as a drink in a qualified laboratory licensed for Good Manufacturing Practice in Hong Kong (Chinese Medicine Industry Development Centre, Hong Kong Institute of Vocational Education, Hong Kong, China). The formula contained 12 commonly used herbs: Morus alba L. 8.2%, Chrysanthemum morifolium Ramat. 3.3%, Prunus armeniaca L. 6.6%, Forsythia suspense Vahl 5.5%, Mentha haplocalyx Briq. 2.7%, Platycodon grandi florum (Jacq.) A. DC. 6.6%, Glycyrrhiza glabra L. 2.7%, Phragmites communis Trin. 6.6%, Scutellaria baicalensis Georgi 13.1%, Isatis indigotica Fort. 17.5%, Astragalus membranaceus (Fisch.) Bge. 16.4%, Saposhnikovia divaricata (Turcz.) Schischk. 10.9%. The placebo was manufactured in the same laboratory and the preparation matched the herbal drink satisfactorily in both colour and taste. The primary outcome was the number of episodes of influenza and influenza-like illnesses detected in the two different groups (incidence). Influenza-like illness was defined by a fever over 37.8 ℃, plus presence of at least one of the influenza symptoms, e.g. sore throat, cough, running nose, or myalgia. For cases with fever, a nasopharyngeal swab was collected for the laboratory detection of influenza pathogens. The QOL was evaluated using SF-36 questionnaire (Vitality and Mental Health Sub-scales) (6,7) and the immunological state was read from blood samples. Immunological parameters included B lymphocytes, T lymphocytes, T-helper lymphocytes (CD4), T-suppressor lymphocytes (CD8) and natural killer (NK) cells. Basic hematology (complete blood count and white blood cell), and biochemistry for renal and liver functions were included for safety studies. All data was managed using SPSS 11.0 software. The participants' demographics were first presented descriptively in overall and subgroups aspects. Then parametric and non-parametric statistical analysis methods were used to test the change of health status, flu-like syndrome, immunological status, and safety profile before and after taking study drinks. Intention-totreat analysis was applied. From Dec 2003 to July 2004, a total of 1,483 subjects were screened in 10 elderly homes and elderly centres, and 872 subjects met the inclusion and 740 subjects agreed to join the study with the response rate of 85%. Among the 740 subjects, 133 subjects agreed to provide blood samples for immunology assessments. Before randomization, 740 participants were randomly allocated into either the herbal or placebo group after recruitment and written consent signing. Sixty-six participants drop out shortly after commencement, another 58 participants drop out in the following visit and a total of 124 participants (16.8%) declined participation with 16.5% and 17% respectively belonging to the herbal and placebo groups. Reasons for withdrawals were related to personal preference and mild adverse events which are listed in the flow chart (Figure 1 ). At baseline, there were no significant differences between the herbal and the placebo groups. Material including age, gender, habits of herb/dietary supplement intake and medical conditions are shown in Table 1 . Also, the renal and liver functions of all 133 participants who volunteered to provide blood sample for immunological assessment were within normal ranges. During the study period, for the first time in five years in the record of the Department of Health in Hong Kong, there was no outbreak of influenza endemic, either in the general family clinics of the Department of Health, or in the Private Sector. Our protocol that was designed to meet the endemic therefore the study had to be modified to target on control of influenza-like syndrome, 72 of 740 participants (9.7%) reported to us about fever and symptoms resembling influenza, however, their nasopharyngeal swabs showed negative results in the viral cultures. There was no statistical difference in fever occurrence between the herbal and placebo groups [40 (10.6%) vs 32 (8.8%), Table 2 ]. And the symptoms such as running nose was less in the herbal group than in the placebo group (P=0.03, Table 2 ). The QOL on mental health and vitality health were improved in both herbal and placebo groups during the treatment period and washout period (P<0.01, Table 3) , with no significant difference between the two groups. Notes: Student's t-test was used on continuous variable, χ 2 test or Fisher's exact test was used on categorical variable, twotailed, α=0.05; : any fever in last 4 weeks of treatment start; △ : 4 missing cases (vaccinated 551/non-vaccinated 189 cases). The vaccinated and non-vaccinated groups were compared for symptoms and improvement of symptoms after herbal drink. No significant difference was found between the two groups. There were 287 participants in the herbal group and 253 in the placebo group who were reported mild adverse effect. Dizziness, headache, sputum, and diarrhea were the most common mild adverse effects. Thirty-one (8.2%) and 35 (9.6%) participants withdrew from the herbal and the placebo group respectively due to the mild adverse events. All mild adverse events subsided 2-3 days either in the dropout group and study groups probably because the reported symptoms were not directly related to the herbal preparation (Table 5 ). The anti-viral formula was created from the combination of two popular classic formulae, Sangju Decoction (桑菊饮) and Yupingfeng Powder (玉屏风 散) modified and supplemented with two other herbal items known to be anti-viral. This trial was designed according to the annual expectation of an influenza endemic which happened for 5 consecutive years from 1999-2003. For some uncertain reasons, the In 133 participants who volunteered to have their blood checked before and after treatment, 20 participants were lost to follow-up due to their personal reasons. Thus, there were 113 subjects providing baseline and post-study blood sample. In the immunological state, there were no different between groups at baseline. After 8-week-treatment, the NK absolute count was significantly enhanced in the herbal group (P<0.05, Table 4 ). Other immunological parameters had no significant difference. The majority of subjects had received influenza vaccination within 3 months before the study expected endemic did not occur during the trial. Instead, the clinical trial had to shift the target from influenza prevention to the investigation on preventing influenza-like syndrome with herbal preparation. There is no apparent efficacy of the herbal preparation on the prevention of influenza like symptoms, the preparation showed only better effect than the placebo on nasal discharge. Similar to the results from our previous study using the same herbal preparation during the SARS crisis, objective data on immunological modulation showed clear superiority of the herbal preparation over placebo. In another trial on healthy volunteers aiming at the behavior of immunomodulating indicators, i.e., T cells and B cells in the lymphocyte series, the results were also positive. (5) The series of objective data supporting the immuno-modulating efficacy of the herbal preparation threw optimism on the further research of using herbal preparations for the prevention or treatment of influenza or influenza-like upper respiratory viral infection. The direction would include the optimization of the herbal formula, by varying the components of the formula, or better still, by identifying the effective fraction from the gross extraction of the formula. The concept of disease prevention in herbal medicine is not one that follows the logic of immunization, which initiates a prolonged state of positive immuno-defense. Instead, the mechanism of action could be very much of a short term boostering of the immunological sensitivity which would be beneficial for the early control of an invading viral infection at its early stage. While seasonal Influenza vaccination was highly recommended to prevent influenza and its complications, especially to high risk groups, such as healthcare workers, chronic illness, pregnant women, children less than 6 years, elderly persons aged above 65 years. (8) The cost-effectiveness analysis and reports pronounced the vaccination program could reduce both health-care costs and productivity losses associated with influenza illness. (9,10) While most developed country and area like United States, United Kingdom, Canadian, Australia, including Hong Kong had implemented national vaccination programs against influenza annually in the form of free or subsidized offer to the high risk groups, the community acceptance of pre-pandemic influenza vaccination was rather low. (11) (12) (13) (14) In the 2009/2010 swine Influenza vaccination program among developed countries, due to the low take-up rate, the over abundance of unused vaccine ended up with inevitable destruction. (15, 16) With the rising popularity of herbal medicine, some of the known antiviral activities, immuno-supportive and symptom relieving effects, our herbal formula could be offered as a viable option by itself or as an adjuvant to the vaccination program. 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