Review paper
Immunotropic activity of Echinacea. Part II. Experimental and clinical data

Experimental data

A number of experimental in vivo and in vitro studies have shown that Echinacea-containing remedies increase immunologic activity and may protect experimental animals against systemic viral, bacterial, parasitic and fungal infections. They also exert antioxidative and anti-inflammatory activity, enhance antibody production, phagocytosis, cellular respiratory activity, and lymphocyte activation through release of various cytokines [1-21]. The mechanism of immunostimulatory effects is not fully understood, but it is probably connected with synergistic action of polyphenols, polysaccharides, glycoproteins and alkamides. There is some evidence, that alkamides present in Echinacea are agonists of cannabinoid receptor type 2 (CB2), and by stimulation of this receptor alkamides upregulate tumor necrosis factor  (TNF-) production. Cannabinoid receptor type 2 is expressed in different types of immune-competent cells. It is well established that cannabinoids (and their agonists) mediate both inhibitory and stimulatory effects on the immune system by modulating cytokine expression [22-24].

Janusz Bany in the Military Institute of Hygiene and Epidemiology conducted his research on infection models with Pseudomonas aeruginosa and Trichinella spiralis in mice. He observed a significant inhibition of bacterial and parasite infection in those mice, which were treated with Echinacea purpurea and Echinacea angustifolia extracts, both separately and in mixtures, both before the actual infection and during the proliferation. Both intestinal and muscular phases of Trichinella spiralis infections were greatly inhibited [20, 21]. With the use of experimental model it has been showed that both Echinacea angustifolia and Echinacea purpurea activate macrophages to produce cytokines, including TNF- and IFN- which play the role of cell-type immune response inducers.

Recently, it was reported, that herbal remedies based on Echinacea increase immunoglobulin production and may regulate antibody production by augmenting both Th1 and Th2 cytokine production [25]. Synergetic effects of oral administration of levamisole and Echinacea purpurea on immune response in rats was also observed [26]. No effectiveness of Echinacea extract on acute and chronic rheumatoid arthritis rat model was observed [27]. In mice, genomic and proteomic analyses revealed stimulatory effect of Echinacea purpurea extract on the trafficking activity of mouse dendritic cells [28]. In fish, dietary administration of Echinacea purpurea exerted positive effects on growth and biochemical and haematological indices in rainbow trout [29].

The activity or the lack of activity of Echinacea preparations depends on several aspects, including the cultivation type, cultivation time and part of the plant that was used to produce the preparation. In our own researches we have observed some differences between the immune-stimulant activity of the preparations sent to us from various producers. Most probably, it was a result of the specificity of cultivation areas, purity and composition of raw-material and technological differences.

In some cases the doses recommended by the producer suppressed the immune response, whereas the actual immune-stimulation was demonstrated while using much lesser doses [30-35].

In therapy one can use liquid extracts: alcohol extracts (in a form of drops), oil extracts (ointments) and aqueous extracts (sirups) from the roots or herbs of Echinacea, as well as dry extracts in a form of tablets.

In Germany and Switzerland, approximately 200 preparations containing such extracts are in sale. In Poland there are also many of Echinacea products, unfortunately some of them occurred as food additives and therefore can avoid the registration process which takes place in case of regular medicines. The possible result of their activity is completely unknown.

However, there are preparations already tested by us and registered. Among them Echinapur (ointment, tablets, Herbapol Poznań), Echinerba (tablets, Labofarm), Lymphosil and Lymphosil Forte (tablets, Cesra), Immunal (drops) and Immunal Forte (tablets, Lek SA), Succus Echinacea (drops, Phytofarm), Echinacea forte (dr Theiss) and many others.

We also tested some complex remedies: Echinasal (sirup with the herb of Echinacea purpurea, Grindelia camporum and Plantago lanceolata, Herbapol Wrocław), Reumaherb (Herbapol Poznań, tablets containing extracts from the herb of Echinacea purpurea, the flowers of Filipendula ulmaria and the roots of Harpagophytum procumbens), Alchinal (sirup, Gemi), apart from Echinacea containing extracts from allium and cacao, and Esberitox (tablets and drops, Zymella), containing additionally the extract from the herb of Thuja occidentalis and Baptisia. We performed experiments on mice for evaluation the in vivo influence of Echinacea-containing remedies on cellular and humoral response of animals immune system on antigens and mitogens [30-35]. We also performed experiments in human volunteers. Experiments on mice revealed that despite some differences observed between immunomodulatory action of various Echinacea-containing remedies, and their liquid and dry formulations, all of them stimulated various parameters of cellular and humoral immunity, without big differences between aqueous and hydro-alcoholic extracts.

Although the therapeutic spectrum of Echinacea is quite broad, it is to be remembered that the extracts from roots and herb have immune-modulating abilities. It means that, depending on the dose and/or initial state of the immune system, Echinacea can either stimulate or inhibit the activity of immune cells [35]. Indeed, we have observed it also in patients with oral candidiasis, receiving Echinapur tablets (300 mg daily for 10 days). An augmented chemiluminescence activity (a result of the oxygen free radical production) was observed only in patients, who had it low initially. It is worth emphasising, that in a proper dose that is exactly how a good immune-modulator should work [31].

In healthy human volunteers another Echinacea purpurea-containing remedy (Immunal forte tablets) administered for seven days in 160 mg daily doses, have stimulated granulocyte metabolic activity, have increased the incidence of CD16+ and CD56+ NK lymphocytes and have stimulated production of angiogenic growth factors by blood mononuclear cells, in comparison to placebo group. Also liquid form of Echinacea purpurea (Immunal drops) administered for 7 days in 6 ml daily dose, have stimulated the following parameters of immunologic reactivity of healthy humans blood leukocytes: release of angiogenic growth factors by mononuclear cells and their response to mitogen PHA (phytohaemagglutinin). Increase of chemiluminescent activity of granulocytes, and lymphocytes CD4/CD8 ratio, were also observed [36–38].

Schwarz et al. (2005) in a double-blind, placebo controlled, cross-over study, observed modulatory effect of oral administration of freshly pressed juice of Echinacea purpurea on the number of various subpopulations of B- and T-lymphocytes in healthy volunteers [39]. In Ritchie et al. study (2011) treatment with ethanolic extract of fresh Echinacea purpurea (Echinaforce) healthy volunteers for 8 days, reduced blood pro-inflammatory mediators TNF- and IL-1, and increased anti-inflammatory IL-10 levels. An analysis of a subgroup of volunteers who showed low pre-treatment levels of the cytokines MCP-1, IL-8, IL-10 or IFN- showed significant stimulation of these factors upon Echinaforce treatment, whereas the levels in subjects with higher pre-treatment levels remained unaffected. This is another example demonstrating immune-modulating ability of Echinacea [40].

Clinical data

The immune system relies on numerous feedback, strictly correlated between each other and therefore, in case of its excessively long and intense stimulation, the suppression mechanism starts to counteract, thereby limiting the immune response.

The very same regulation applies to the preparations made from Echinacea. It is already known for quite a long time, since the classic publication of Wagner [1], and supported by Coeugniet and Elek in 1987 [2]. In their study extracts of Viscum album (Plenosol) and Echinacea purpurea (Echinacin) were used clinically for their non-specific action on cell-mediated immunity. In vitro they proved that these two extracts have a stimulating effect on the production of lymphokines by lymphocytes and in the transformation test. A toxic effect on cells was produced only with very high, clinically irrelevant concentrations. Clinical application of these extracts produced a stimulation of cell-mediated immunity (one therapeutic administration followed by a free interval of one week) or had a depressive action (daily administrations of high doses). These observations were confirmed by lymphokine production and 3H-thymidine incorporation and a skin test with recall antigens (Multitest Merieux).

Regrettably, this knowledge rarely reaches the clinicians, which during the trials administer excessive doses of Echinacea, exceeding the proper time period. It is exactly the reason why there are so many negative outcomes in the trials of Echinacea-based preparations [41-45].

There are however numerous information about the benefits stemming from the use of Echinacea in infections. In 2004 Goel et al. [46] observed the reduction of symptoms in patients suffering from upper respiratory tract infections (URTIs) after a 7-day-long administration of Echinilin, a preparation produced from the herb of Echinacea purpurea. In his review Awang [3] refers to the researches of Braunig and his colleagues from 1992 [4], where one can find descriptions of beneficial effects, in comparison to placebo group, of an administration of 450-900 mg of the Echinacea purpurea roots to patients with URTIs.

Similar outcomes were published in 1992 by Schoneberger, who conducted the double-blind trials of fresh Echinacea purpurea succus [47]. Earlier in 1988 Baetgen described positive effects of Echinacea purpurea in paediatric patients with bronchitis [48]. Recently, the herbal compound of Echinacea angustifolia, -glucan, vitamin C, arabinogalactan and zinc was presented as improving the quality of life in paediatric patients affected by recurrent pharyngotonsillitis and otitis media without contralateral effects [49]. Yakoot and Salem confirmed in adults efficacy of multiherbal formula Immumax (Echinacea, garlic, Nigella sativa, Panax ginseng, vitamin C, zinc) in reducing the duration and severity of common cold symptoms [50].

In the fifties and sixties of the past century one can find out that Echinacea extracts were used as an additive medicine in psoriasis. With their use 90% of the patients experienced the remission of their disease. Extracts were also administered intramuscularly to children suffering from whooping-couch and during a 3-day treatment the frequency and severity of couch attacks was diminished. Patients with tuberculosis who did not respond well to the conventional therapy were also given the Echinacea extracts.

Given that the immunity to tuberculosis is a result of the ability of immune system cells to produce TNF- and noting that the Echinacea extracts stimulate its production – it seems quite logical to use them as an auxillary agents in the treatment of tuberculosis, instead of regarding tuberculosis as a counter-indication to the use of Echinacea preparations.

In another review of Schimmel and Werner [51], the authors describe the results of Sprockhoff’s researches (1964), who stated the beneficial effect of the Echinacea extracts treatment in children with tonsilitis, otitis media, whooping-couch and bronchitis. In some cases Echinacea even replaced the antibiotic [52]. Echinacea was also used in osteoarthritis of bones and joints.

In 1990 Mowrey described the positive results of the persistent vaginal candidiasis treatment using Echinacea in a form of vaginal ointment and parallel administration per os. In 1978 in Germany a multi-directional trial on 4598 patients with various skin afflictions were conducted [53]. 538 clinicians reported that the ointment containing 16% of a fresh Echinacea purpurea succus demonstrated very good results in the treatment of skin inflammation (85.4% of patients), chronic wound healings (91.5%), eczema (82.3%), burns (96.3%), Herpes simplex infections (91.4%) and leg ulcers with varicose veins (71.1%).

These results were confirmed on other group in 1979 [54] and in 1994 with regard to leg ulcers [55].

In the literature there were also descriptions of the antibacterial and antiviral activity of Echinacea, especially against the Herpes group and VSV, which cause herpes and viral stomatitis, as well as against influenza virus, that has been recently confirmed [10–14].

Professor Jerzy Lutomski (2002) informed that a German E commission tested 50 clinically verified herbal preparations for skin problems, out of which 26 were marked as positive, including Echinacea purpurea. In his paper, he stated that „There is much hope for the treatment of atopic dermatitis with Echinacea purpurea. ECHINAPUR, made of standardised Echinacea purpurea extract, seems to be a perfect example as it accelerates the healing of surface wounds” [56].

Beneficial effect of short therapeutic treatment was also reported by Brinkeborn [57], Scaglione and Lund [58], Heinen-Kammerer [59], Cohen (composite herbal product in children aged 1-5 years) [60], Lindenmuth [61] and others [62, 63]. Schoop et al. performed a meta-analysis of three studies of Echinacea use in the prevention of induced Rhinovirus colds. This meta-analysis suggests that standardized extracts of Echinacea were effective in the prevention of symptoms of the common cold after clinical inoculation, compared with placebo [64].

In conclusion, Echinacea administered in low doses, within short periods of time should be widely used in prevention and treatment of numerous infections, as it is a powerful stimulator of antiviral, antibacterial and antifungal response [65].

There are also some papers, presenting other effects of Echinacea on health. Hou et al. (2011) suggest a new application of Echinacea as a hepatoprotective agent [66]. Isbaniah et al. show (2011) that the combination of Echinacea purpurea, zinc, selenium and vitamin c may alleviate exacerbation symptoms caused by URTI in chronic obstructive pulmonary disease [67]. In other study Echinaforce readily killed Propionibacterium acnes, and in cell culture models inhibited Propionibacterium acnes – induced the secretion of several pro-inflammatory cytokines, what could provide a benefit to acne individuals [68].

There are some papers suggesting a role of Echinacea and its phenolic components in tumors treatment [69-75]. We reported inhibitory effect of various Echinacea-containing remedies on neovascular reaction induced in murine skin after intradermal grafting of murine L-1 sarcoma cells or human lung and kidney cancer cells and cells homogenates [37, 76-78].

Benefits aside, it is also necessary to list the counter-indications for the use of Echinacea.

Above all those are: hypersensitivity, autoimmune and auto-aggression disease, leukaemia, AIDS and HIV infection. Now we know, that tuberculosis doesn’t seem to count among them.

As AIDS is concerned, opinions vary. Kligler, in 2003 estimated the risk of the use of Echinacea in these patients to be theoretical, as it is not validated by any scientific reports. He shared the same point of view as the autoimmune diseases were discussed. Due to the possible interactions, Echinacea should be carefully administered to patients taking Itraconazole, Fexofenadine and Lovastatin. Recently, it was shown that co-administration of Echinacea purpurea with darunavir-ritonavir was safe and well tolerated in HIV-infected patients [79-83].

The problem of Echinacea use during pregnancy remains open. There is some evidence from human studies that Echinacea is not teratogenic. However, there are no formal studies, which may exclude the possibility that the absence of malformations in the living births resulted from the fact that consuming Echinacea may promote spontaneous abortion. In pregnant mice Echinacea reduced the number of viable fetuses, interfered with embrional angiogenesis, and negatively influenced maternal lympho- and hemopoiesis [84].

Summarily, herbal remedies with Echinacea purpurea extracts exhibit immune-stimulation of numerous immune system parameters, which leads to the assumption that it could be highly beneficial in various types of infections, wound healing, bed sores, ulcerations and many others. They can be also effective used as a prevention in all situations of epidemiological risk such as: airway travel, massive public transportation, crowded events or current infections in close surroundings. Supplementation with standardized Echinacea tablets, if taken before and during travel, may have preventive effects against the development of respiratory symptoms during travel involving long-haul flights [85]. Yet, both the recommended dosage and intervals of administration (7-14 days) are to not be exceeded, in view of contradictory effects which may occur. That means immune-suppression, instead of immune-stimulation. It is essential to test all available preparations on the market, measuring their immunomodulatory properties and the influence on both immune and tumour angiogenesis process activity, in order to determine the proper dosage and therapeutic intervals.

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