Chinese medicinal herbs for influenza
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of Chinese medicinal herbs for treating people of all ages with established diagnosis of influenza.
We are also interested in comparing the effects of various Chinese medicinal herbs for treating influenza with each other and any adverse events.
In comparisons between groups intended for treatment with Chinese medicinal herbs and groups allocated to the placebo or other current treatment regimes, or various Chinese medicinal herbs, the following hypotheses will be tested:
(1) There is no difference in the number of people cured at the end of the third day.
(2) There is no difference between various Chinese medicinal herbs in the treatment of influenza
(3) There is no difference in the number of adverse events.
Background
INTRODUCTION
Influenza is an acute respiratory illness caused by a virus of the Orthrosynovitic family, of which three serotypes are known (A, B and C). Influenza causes an acute febrile illness with myalgia, headache and cough. Uncomplicated influenza generally resolves over a two to five day period. In a significant minority, however, symptoms of weakness and malaise may persist for several weeks, particularly in the elderly. Complications of influenza include otitis media, pneumonia, secondary bacterial pneumonia, exacerbation of chronic respiratory disease, croup and bronchiolitis. Additionally, influenza can cause a range of non‐respiratory complications including febrile convulsions, Reyes's syndrome and myocarditis (Wiselka 1994; Jefferson 2002). The influenza virus is transmitted like a cold i.e through person‐to‐person contact, either by airborne droplets from a sneeze or cough, or by transmission via an object. (CDC 2002).
Influenza viruse types (A, B or C) are based on antigenic characteristics of the nucleoproteins and matrix protein antigens. However, the influenza virus genome is segmented and there is a high frequency for rearrangements of the genes (Ahmed 1996; Buda 2000). Major determination of severity and spread of outbreaks of influenza is the level of immunity present in the population at risk. When an antigenically novel influenza virus emerges to which little or no antibody is present in a community, extensive outbreaks may occur (Claas 1998). Major variations as a result of the re‐assortment of genome segments between viral strains, are referred to as "antigenic shifts" and cause pandemics. Minor variations likely arising from point mutations are called "antigenic drifts" and cause local or more isolated epidemics (Fleming 1999). In the 20 th century, influenza outbreaks have occurred annually and have affected large numbers of people worldwide. Generally, influenza causes about 20,000 deaths per year. However, there have been major outbreaks of the influenza virus that have led to significant losses of life. (HamiltonBaldwin 2000). Pandemics usually arise in China where pigs, ducks and humans live in close proximity and spread westward to the rest of Asia, Europe and America (Bonn 1997).
ROUTINE TREATMENT
The treatment for influenza and colds are similar. Over‐the‐counter (OTC) decongestants, antihistamines, cough suppressants, expectorants, and influenzaids are recommended. Bed rest and analgesics are of more use here due to the fever, muscle aches, and fatigue present in influenza. In addition to OTC drugs, two prescription antiviral drugs, amantadine (Symmetrel) and rimantadine (flumadine) can be prescribed. These drugs inhibit all subtypes of influenza A, but are not active against B or C. Their mechanism of action is thought to be through the inhibition of viral un‐coating, thus stopping viral shedding and replication. These medications must be taken within the first 48 hours of the onset of symptoms to be effective and continued for five to seven days. They have been shown to lessen both the severity and duration of influenza A in adults. Amantadine is recommended for use in children of one year and older. Rimantadine is indicated for treatment and prophylaxis in adults, but only prophylaxis in children. Careful use of both of these products is encouraged because of the emergence of resistant influenza strains to both of these drugs (HamiltonBaldwin 2000; Jefferson 2000 ). Dosing and side effects vary depending on the drug, age, hepatic function and renal function. The major side effects tend to affect the central nervous system (CNS) and gastrointestinal tract. Other side effects include light‐headedness, nervousness, anxiety, difficulty in concentration, diarrhoea, and anorexia. Caution should be used when taking OTC agents and amantadine (HamiltonBaldwin 2000).
CHINESE MEDICINAL HERBS FOR INFLUENZA
When prescribing Chinese traditional medicine, one follows a particular theoretical and methodological pathway of assessing the cause, diagnosis and treatment. Chinese medicinal herbs are made from natural plants and usually incorporate one to several herbs as the basic drug(s) to treat the disease. Depending upon the different symptoms or causes, curative herbs are selected, which are then mixed together following a particular method to form the prescription.
The different ingredients in each plant will work synergistically to balance the body. This prescription rule is similar to western medical systems. It is said that herbal remedies have fewer side effects than orthodox therapies with chemical entities. It is not that there are no toxic effects, but plants are a natural source. Humans have co‐evolved with and are adept at using herbal remidies. The preparation of a remedy from a more toxic plant often discards (unless this is specifically required) the actual toxic component and leaves the useful components (Cezanne 1997).
In traditional Chinese medicine, the aim in treating influenza is not only to cure the respiratory symptoms, but to treat the whole body.
In Chinese medine, influenza is differentiated into two types: Wind‐cold Syndrome and Wind‐heat Syndrome.
The main symptoms of Wind‐cold type are: severe cold, slight fever, absence of sweat, headache, aching pain of extremities, stuffy nose with nasal discharge, cough with thin sputum, thin and whitish coating of tongue, and a floating and tight pulse (Zhao 2001). The treatment principle for this type is to: relieve external symptoms with drugs which are pungent in flavour and warm in property; to ventilate the lung and expell the pathogenic cold. Herba Schizonepetae, Radix Ledebouriellae, Radox Bupleuri, Radix Platycodi, Rhizoma Zingiberis Recens etc, are usually the main components of a prescription for Wind‐cold Syndrome. Moreover, supplementary drugs should be added with emphasis on certain symptoms.
The main symptoms of Wind‐heat type are: a higher fever, slight aversion to cold, headache, sore throat with congestion, expectoration of yellowish sputum, thirst, epistaxis, reddened tongue with thin and yellowish coating, and a floating and rapid pulse (Zhao 2001). The treatment principle for this type is to: relieve external symptoms with drugs which are pungent in flavour and cool in property; to promote the dispersing function of the lungs and clear up pathogenic heat. Flos Lonicerae, Fructus Forsythiae, Radix Isatidis, Radix Puerariae, Folium Mori, Flos Chrysanthemi, Fructus Arctii, Herba Lophatheri, Radix Platycodi are usually the main components of prescription to Wind‐heat Syndrome. Supplementary drugs are sometimes added according to certain symptoms (Zhang 1991; Ou 1992; Hou 1995; Deng 1998; Xu 1998; Liu 2001). (See Additional tables 01 Medicinal herbs for influenza).
A number of clinical trials of Chinese medicinal herbs for influenza have been conducted. The quality and effects of all these trials have not yet been assessed and systematically reviewed. Natural medicinal herbs are potential drug resources and the therapeutic and toxic effects of medicinal herbs needs to be identified through a systematic review. Hundreds of millions of dollars are spent treating influenza annually in China, ensuring that a systematic review on the effectiveness of these medicinal herbs will extremely useful in health policy planning
This protocol aims to summarise the existing evidence of comparative effectiveness and safety of medicinal herbs for treating influenza according to current clinical trials.
Objectives
To assess the effects of Chinese medicinal herbs for treating people of all ages with established diagnosis of influenza.
We are also interested in comparing the effects of various Chinese medicinal herbs for treating influenza with each other and any adverse events.
In comparisons between groups intended for treatment with Chinese medicinal herbs and groups allocated to the placebo or other current treatment regimes, or various Chinese medicinal herbs, the following hypotheses will be tested:
(1) There is no difference in the number of people cured at the end of the third day.
(2) There is no difference between various Chinese medicinal herbs in the treatment of influenza
(3) There is no difference in the number of adverse events.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials and quasi‐randomised controlled trials. We will contact authors of trials that did not report the outcome mesaures will use for these results. Trials not reporting these outcome measures will be excluded. Studies with a high percentage of drop‐outs should also be excluded.
Types of participants
People of all ages with influenza.
Patients with the complications of influenza such as otitis media, pneumonia, secondary bacterial infection, exacerbation of chronic respiratory disease, croup and bronchiolitis, and non‐respiratory complications including febrile convulsions, Reye`s syndrome and myocarditis will be excluded.
Types of interventions
Chinese medicinal herbal therapy (including natural herbs and herbal products extracted from natural herbs) compared with placebo, or various other Chinese medicinal herbs, or with other current regimes normally used in care. Chemical drugs with herbal preparations compared with simple chemical drugs will also be included.
Types of outcome measures
Types of outcome measures of interest include the rate of recovery; effectiveness of the drug (marked improvement, general improvement, no improvement) and any side effects. We are interested in comparing the outcome measures between the different medicinal administrations by using a statistical analysis to determine whether Chinese medicinal herbs for influenza is more effective.
Rate of recovery: By this we mean that the symptoms and clinical manifestations are completely cleared and body temperature returns to normal within one to three days after administration.
Marked improvement: Most of the clinical symptoms have cleared within one to three days.
General improvement: Partial symptoms or manifestations of influenza neither lightened nor deteriorated within 3 days.
No improvement: Symptoms or manifestations of influenza are not imrpoved or may even have deteriorated (e.g. complications may occur) after three days.
Side effects: Any adverse events resulting from the treatment (eg (1) mortality, (2) life threatening, (3) toxic response, (4) anaphylaxis, and (5) result in the discontinuation of treatment).
Search methods for identification of studies
The following electronic databases will be searched:
1. The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue), which includes the Cochrane Acute Respiratory Infections Review Group specialised register
2. MEDLINE (1966 to present)
3. EMBASE (1988 to present)
4. CBM (Chinese Biomedical Database) (1980 to present)
5. The Chinese Cochrane Centre's Controlled Trials Register (latest issue)
A comprehensive and exhaustive search strategy will be formulated in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress), using the following terms in combination with the search strategy defined by the Cochrane Collaboration and detailed in Appendix 5c of the Cochrane Reviewer's Handbook (Edition 4.0) (Clarke 2003).
MeSH Headings:'Medicine‐Chinese‐Traditional', 'Drugs‐Chinese‐Herbal', ' therapy', 'Influenza'
Text/title words:'medicinal herb* ', 'Chinese herb* ', 'Chinese medic* ', 'therap* ', 'influenza'
We will also search databases of ongoing trials:
Current Controlled Trials (www.controlled‐trials.com)
The National Research Register (http://www.update‐software.com/National/)
We will attempt to identify additional studies by searching the reference lists of relevant trials, reviews, conference proceedings, and journals. In particular, with respect to journals, we will search those not indexed in the electronic databases. Authors will be contacted to obtain full details and if these cannot be obtained, the trial should probably be excluded.
OTHER SEARCH STRATEGIES:
Organisations (including the World Health Organization), individual researchers working in the field, and medicinal herbs manufacturers will be contacted in order to obtain additional references if needed, unpublished trials, or ongoing trials, confidential reports and raw data of published trials. Additional key words of relevance may be identified during any of the electronic or other searches. If this is the case, electronic search strategies will be modified to incorporate these terms.
Data collection and analysis
1. TRIALS SELECTION:
To determine the studies to be assessed further, we will scan the titles, abstract sections and keywords of every record retrieved. Full articles will be retrieved for further assessment if the information given suggests that the study: (1) Includes patients with influenza; (2) Compares medicinal herbs with placebo or any other active intervention; (3) Assesses one or more relevant clinical outcome measures; (4) Uses random allocation to the comparison groups.
If there is any doubt regarding these criteria from the information given in the title and abstract, the full article will be retrieved for clarification. Interrater agreement for study selection will be measured using the kappa statistic (Cohen 1960). Where differences in opinion exist, they will be resolved by discussion. If resolving a disagreement is not possible, the article will be added to those 'awaiting assessment' and the authors will be contacted for clarification. If no clarification is provided, the Review Group editorial base will be consulted.
2. QUALITY ASSESSMENT OF TRIALS:
The quality of reporting each trial will be assessed based largely on the quality criteria specified by Schulz and by Jadad (Schulz 1995; Jadad 1996). In particular, the following factors will be studied:
(1). Minimisation of selection bias ‐ a) was the randomisation procedure adequate? b) was the allocation concealment adequate?
(2). Minimisation of performance bias ‐ were the patients and people administering the treatment blind to the intervention?
(3). Minimisation of attrition bias ‐ a) were withdrawals and dropouts completely described? b) was analysis by intention‐to‐treat?
(4). Minimisation of detection bias ‐ were outcome assessors blind to the intervention?
Based on these criteria, studies will be broadly subdivided into the following three categories:
A ‐ all quality criteria met: low risk of bias.
B ‐ one or more of the quality criteria only partly met: moderate risk of bias.
C ‐ one or more criteria not met: high risk of bias.
This classification will be used as the basis of a sensitivity analysis. Additionally, we will explore the influence of individual quality criteria in a sensitivity analysis.
Each trial will be assessed by two reviewers independently (Chen and Wu). Internal agreement will be calculated using the kappa statistic, and disagreements will be resolved, while necessary, by recourse to a third reviewer (Liu). In cases of disagreement, the rest of the group will be consulted and a judgement will be made based on consensus.
3. DATA EXTRACTION
Data concerning details of study population, intervention and outcomes will be extracted independently by two reviewers (Chen and Wu) using a standard data extraction form. A data abstraction form will by specifically designed for this review. Data on participants, interventions, and outcomes, as described above, will be abstracted. The data extraction form will include the following items:
(1). General information: published/unpublished, title, authors, reference/source, contact address, country, urban/rural etc., language of publication, year of publication, duplicate publications, sponsor, setting.
(2). Trial characteristics: design, duration of follow up, method of randomisation, allocation concealment, blinding (patients, people administering treatment, outcome assessors), check of blinding.
(3). Intervention(s): placebo included, interventions(s) (dose, route, timing), comparison intervention(s) (dose, route, timing), co‐medication(s) (contents,dose, route, timing).
(4). Patients: sampling (random/convenience), exclusion criteria, total number and number in comparison groups, sex, age (children/adults), baseline characteristics, duration of influenza, diagnostic criteria, similarity of groups at baseline (including any co‐morbidity), assessment of compliance, withdrawals/losses to follow‐up (reasons/description), subgroups.
(5). Outcomes: outcomes specified above, any other outcomes assessed, other events, length of follow‐up, quality of reporting of outcomes.
(6). Results: for outcomes and times of assessment (including a measure of variation), if necessary converted to measures of effect specified below, intention‐to‐treat analysis.
Differences in data extraction will be resolved by consensus, referring back to the original article. When necessary, information will be sought from the authors of the primary studies. We will contact authors by letter or by telephone about missing information and confusing points such as methods of randomisation and allocation concealment, separate information for certain patient subgroups, information about complications, number of dropouts, etc. Statements referring to certain types of data not being available will be acceptable by contacting the authors. We will also contact the manufactures for the components of a processed Chinese medicine if it is not clear.
Original reports of trial results will be independently abstracted by Chen and Wu. Disagreement will be resolved by discussion and, where necessary, in consultation with a third reviewer (Liu). For binary outcomes, number of events and total number in each group will be extracted. For continuous outcomes, mean, standard deviation and sample size of each group will be abstracted or imputed.
4. DATA ANALYSIS
Data of same medicinal herbs will be included in meta‐analysis if they are available, of sufficient quality and sufficiently similar.
The data should be dichotomous and will be expressed as odds ratio (OR). The relative risk (RR) may be used as an alternative to the OR as interpretation is easier, especially if the outcome is a negative event.
Overall results will be calculated based on the random effects model. Heterogeneity will be tested for using the Z score and the Chi square statistic with significance being set at p < 0.1. Possible sources of heterogeneity will be assessed by sensitivity and subgroup analyses as described below. Publication bias will be tested for using the funnel plot or other corrective analytical methods depending on the number of clinical trials included in the systematic review.Summarise for each comparison group the number randomised to treatment, the number of drop‐outs, and the number of subjects who were lost to follow‐up, using intention‐to‐treat analysis.
5. SUBGROUP ANALYSES
We will aim to perform subgroup analyses of patients with an established diagnoses of influenza in order to explore effect size differences as follows:
(1). Adults versus children
(2). Various Chinese medicinal herbs versus placebo or other current treatment regime
(3). One kind of Chinese medicinal herbs versus others
(4). Drugs with herbal preparations versus placebo or simply chemical drug prescription.
6. SENSITIVITY ANALYSES
We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:
(1). Repeating the analysis excluding unpublished studies (if there are any)
(2). Repeating the analysis taking account of study quality, as specified above.
(3). Repeating the analysis excluding any very long or large studies to establish how much they dominate the results.
(4). Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.
The robustness of the results will also be tested by repeating the analysis using different measures of effects size (risk difference, odds ratio etc.) and different statistic models (fixed and random effects models).
