Complementary and alternative medicine: Herbs, phytochemicals and vitamins and their immunologic effects

• Abstract
• Use of CAM
• Risks of CAM use
• NCCAM and clinical trials
• Immune impact of specific herbs and vitamins
  • Vitamin D
  • Vitamin E
  • Vitamin A
  • Vitamin C
• Herbal medicines and potential mechanisms of action
  • Magnolol
  • Quercetin
  • Antiasthma herbal medicine interventions
  • Resveratrol
  • Ma huang (Ephedrine sinica)
• Clinical applications for the practicing allergist
  • Asthma
  • Atopic dermatitis
  • Allergic rhinitis
  • Indian Ayurvedic medicine
  • TCM
  • Kampo medicine (Japanese)
  • Conclusions
  • What do we know?
  • What is still unknown?
• Table E1.
• References
• References
• Copyright

Complementary and alternative medicines (CAMs) are used in more than 80% of the world’s population and are becoming an increasing component of the US health care system, with more than 70% of the population using CAM at least once and annual spending reaching as much as $34 billion. Since the inception of the National Center for Complementary and Alternative Medicine, there has been an enormous increase in the number of basic science and therapy-based clinical trials exploring CAM. The subspecialty of allergy and immunology represents a particularly fertile area with a large number of CAM therapies that have been shown to affect the immune system. Recent work has uncovered potential biochemical mechanisms involved in the immunomodulatory pathway of many supplemental vitamins (A, D, and E) that appear to affect the differentiation of CD4⁺ cell T_H1 and T_H2 subsets. Other research has shown that herbs such as resveratrol, quercetin, and magnolol may affect transcription factors such as nuclear factor-κB and the signal transducer and activator of transcription/Janus kinase pathways with resultant changes in cytokines and inflammatory mediators. Clinically, there have been hundreds of trials looking at the effect of CAM on asthma, allergic rhinitis, and atopic dermatitis. This article reviews the history of CAM and its use among patients, paying special attention to new research focusing on herbals, phytochemicals, and vitamins and their potential interaction with the immune system.

Key words: Complementary and alternative medicine, immunology, herbal medicines, vitamin, NIH—National Center for Complementary and Alternative Medicine, asthma, allergic rhinitis, atopic dermatitis

Abbreviations used: CAM, Complementary and alternative medicine, FDA, US Food and Drug Administration, NCCAM, National Center for Complementary and Alternative Medicine, NF-κB, Nuclear factor-κB, STAT, Signal transducer and activator of transcription, TCM, Traditional Chinese medicine

Complementary and alternative medicines (CAMs) represent a diverse group of interventions that exist outside the realm of traditional medical therapeutics in that their efficacy and safety have yet to be determined. In the 1998 editorial accompanying an article on alternative therapies to prostate cancer, Marcia Angell, then editor of the New England Journal of Medicine, stated that what sets alternative medicine apart from conventional medicine “is that it has not been scientifically tested and its advocates largely deny the need for such testing”¹ and that “alternative medicine also distinguishes itself by an ideology that largely ignores biologic mechanisms, [and] often disparages modern science.”¹ (pp 839-40) This is all too often a viewpoint shared by many health care practitioners in the United States, and is also engrained in many medical school curriculums. However, to provide a balance, the US Congress in 1991 enacted funding for the National Institute of Health’s Office of Alternative Medicine, which in 1998 evolved to become the National Center for Complementary and Alternative Medicine (NCCAM). One year later, Dr Stephen Straus was named as its first director. He focused on discovering the biochemical mechanisms and clinical application of a variety of alternative therapies (Fig 1). Being a member of the National Institute of Allergy and Infectious Diseases, Dr Straus had a particular interest in the immunologic mechanisms surrounding complementary and alternative medicine. This article is a review of the recent advances in CAM on the immune system and its clinical relevance.

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• Fig 1.

  National Institutes of Health NCCAM timeline. A graphical timeline of the events surrounding the formation of NCCAM. CDC, Centers for Disease Control and Prevention; HHS, Health and Human Services; NIH, National Institutes of Health; OAM, Office of Alternative Medicine; WHO, World Health Organization.

The number of researchers publishing general CAM articles has exploded with more than 1700 articles cited in PubMed using “complementary medicine” as a keyword for the year 2007, compared with only 355 in 1990. There has been a similar upswing in the number of articles and the general interest in the effect of CAM on allergy and immunology. The number of articles published every year just using the key words immunology and complementary medicine has tripled since 1990 (Fig 2).

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• Fig 2.

  Annual CAM publications related to allergy and immunology. The numbers of articles published and available for search through PubMed using the search terms complementary medicine and immunology, asthma, allergy, autoimmune, hypersensitivity, or inflammation are shown.

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Use of CAM

Complementary and alternative medicine encompasses several major categories: alternative medical systems, biologically based therapies, manipulative therapies, mind-body therapies, and energy therapies (Fig 3). The use of CAM in the United States has been increasing at a substantial rate over the past 2 decades from a total of 34% (427 million) to 42% (628 million), which was in excess of the 385 million visits to a primary care physician visits in both 1990 and 1997 combined.², ³, ⁴ Because the costs of CAM are mostly paid out-of-pocket, the annual spending for CAM is approximately $27 to $34 billion, compared with $29 billion in out-of-pocket expenditures for all other US physician services.⁴, ⁵, ⁶ In a recent report, the use of CAM at least once in a lifetime, including prayer, was as high as 75%. Similarly, the use of CAM in the past 12 months was 62%, with 26% of respondents stating that they used 1 or more CAM modalities at the suggestion of a physician.³ When this is compared to a recent survey of allergists (see letter to the editor by Engler et al in this issue), there are many similarities to the trends noted, except for the large difference among those who have ever used herbal medicines (8% vs 25%; Fig 4).

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• Fig 3.

  CAM classifications. The alternative medical system involves whole medical systems that are built on other theories and practices including acupuncture, Ayurveda, homeopathic treatment, and naturopathy. Manipulative therapies include chiropractic care and massage. Mind-body therapies use a variety of techniques designed to enhance the mind’s capacity to affect bodily function and symptoms and include biofeedback, meditation, guided imagery, progressive relaxation, deep breathing, hypnosis, yoga, Tai Chi, Qi-gong, Reiki, and prayer. The biologically based therapies use substances found in nature, such as herbs, foods, and vitamins and include megavitamin therapy, various diet-based therapies, folk medicine, chelation therapy, and herbal medicines.³ Energy therapies are essentially made up of biofield therapies that are intended to affect energy fields that purportedly surround and penetrate the human body, whereas bioelectromagnetic-based therapies involve the unconventional use of electromagnetic fields.

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• Fig 4.

  National versus allergist survey. A comparison of the allergy and immunology (AI) subspecialty survey conducted in 2007 compared with the Centers for Disease Control and Prevention survey³ of the US population use of CAM demonstrates an overall similarity in use except for the US population using more prayer, herbal, and chiropractic interventions, whereas the allergy and immunology subspecialty was more inclined to use special diets.

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Risks of CAM use

When evaluating the potential risk of a medication, one must consider intrinsic risks, which consist of predictable and expected adverse reactions (type A) and idiosyncratic reactions (type B). Type A reactions account for 80% of adverse reactions, whereas type B reactions account for 6% to 10%.⁷ In addition, there are extrinsic risks that are attributed to erroneous handling and manufacturing of the product, resulting in misidentified materials, contamination, substitutions, lack of standardization of the product, adulteration, incorrect preparation of the dose, and incorrect labeling and advertising. Although CAM is viewed as natural, it too runs these same risks.⁸ Unfortunately, unlike pharmacotherapy, there is no comprehensive list of potential or predictable reactions with CAM. Along with the listed intrinsic and extrinsic risks, some additional risks of using CAM involve the interruption of conventional therapies because of to the lack of perceived necessity or direct interference of therapeutic actions and the failure to recognize the precautions of the treatment because of the misassumption that the products are “natural” and hence “safe.”⁹ This misconception is alarming if one considers that 18% of people in the United States (equivalent to 2-4 million people in February 2004) are simultaneously using CAM and conventional medical therapies and are thus at potential risk for a herb-drug interaction. However, some relief is offered if one considers that in 2001, a systematic review of herb-drug interactions included 41 case reports and 17 formal clinical trials relating to 5 herbs that seemed to have the most potential for such an adverse interaction. Of the 17 clinical trials, 10 trials involved St John’s wort (Hypericum perforatum), and the remainder involved garlic (Allium sativum), ginseng (Panax ginseng), ginkgo (Ginkgo biloba), and kava (Piper methysticum). Considering the millions of people using CAM, this would suggest that the real risks from the hundreds of medicinal plants is underreported, hypothetical, or still unknown.⁷

Some examples of adverse reactions with herbs are reviewed in this article’s Table E1 in the Online Repository at www.jacionline.org. Examples of agents commonly used by patients for allergic and immune disorders include ma huang, a Chinese herb containing ephedra previously used to promote weight loss, which has been associated with cardiovascular events¹⁰, ¹¹ that in 2004 resulted in the US Food and Drug Administration (FDA) banning the sale of dietary supplements with ephedrine alkaloids. Vitamin A, which has some immunopotentiating properties (relative risk), was studied in the Beta-Carotene and Retinol Efficacy Trial,¹² which evaluated the effects of β-carotene and vitamin A on the development of lung cancer in smokers and workers exposed to asbestos. The results showed the intervention group had a higher mortality from lung cancer (relative risk, 1.46) and cardiovascular disease (relative risk, 1.26). A meta-analysis of placebo-controlled trials involving vitamin E, vitamin A, and β-carotene demonstrated increased mortality in the intervention groups.¹³ In addition, a recent study of Ayurvedic preparations showed that more than 20% had been found to be contaminated with potentially toxic levels of heavy metals including lead, mercury, and arsenic.¹⁴, ¹⁵ Concerns for the subspecialty of allergy and immunology are the development of allergic responses such as anaphylaxis, asthma, urticaria, contact dermatitis,⁸ and the reports of drug interactions with herbal remedies¹⁶ such as St John’s wort because of its ability to interact with cytochrome oxidases, including CYP3A, resulting in alterations in concentrations of fexofenadine, cyclosporine, and antiretroviral agents such as indinavir.¹⁷, ¹⁸ Despite the 100-fold rise in reported adverse reactions to traditional Chinese medicine (TCM) in the last 20 years, the number of adverse events is still negligible compared with the number of adverse events reported from conventional medical therapies, although are certainly not to be considered without risk.

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NCCAM and clinical trials

In the world of scientific research, randomized controlled trials are accepted as the gold standard when defining the methodologic quality of a clinical trial, especially a double-blind trial. When a clinical trial is designed, attempts are made to minimize bias (placebo effects, observational bias, sampling bias), exclude effects of cointerventions, and prevent the progression of the natural disease course to obtain reliable, reproducible, and generalizable results worthy of recognition. However, some barriers exist that make such scientific designs difficult to achieve and in some cases impossible for researchers investigating complementary and alternative medical therapies. Examples include finding and randomizing representative CAM sample populations into equal comparison groups. This is challenging as a result of the differing world views regarding CAM, because the motivation to follow the treatment regimen is influenced by the patient’s preference. Some have alluded to allocating patients to their preference group and randomizing those who have no preference; however, this suggestion has the potential for biased reporting of a positive response. In another example resulting from ethical implications, some institutions are hesitant to approve clinical trials using CAM when conventional therapies exist that are both effective and evidence-based. As a result, many clinical trials are designed using the CAM intervention as an adjuvant to the conventional therapy, as opposed to being the primary treatment under investigation. Blinding in some CAM therapies is also difficult, especially in mind-body therapies such as tai chi, acupuncture, biofeedback, and other manipulative therapies, because the investigator is critical to the treatment intervention. Similarly, finding a suitable control or placebo for comparison is a hurdle that researchers have tried to overcome using sham interventions, as in the case of acupuncture; however, this attempt has received scrutiny by many, because some claim that sham acupuncture offers some benefits through the process of needling. Because the mechanism of action for most CAM therapies is yet unknown, standardized diagnostic criteria and endpoint measurements to determine the treatment efficacy are lacking, making it difficult to compare multiple study results accurately. Also, some CAM regimens, such as TCM, are individualized and cannot always be standardized for the large groups preferred in conventional randomized controlled trials, which decreases the external validity of the results and increases the likelihood of type II error in these studies. In addition, this form of therapy yields results with less internal validity than orthodox medical trials because the formulations are often polyherbal and the effectiveness cannot be attributed to any 1 ingredient but rather is a product of the synergistic effect of the formulation as a whole. By the same token, the efficacious results of some Chinese herbal remedies have been linked to contamination by steroids, as in 1 case of atopic dermatitis treated with a topical herbal formula.¹⁹ However, despite the potential for the surreptitious inclusion of glucocorticoids in polyherbal formulations, which can explain the positive outcome, some herbal remedies have withstood rigorous tests disproving the presence of glucocorticoid contamination while demonstrating efficacy.²⁰, ²¹ Considering all the obstacles in making a well designed clinical trial, it seems that the best approach is to allow the question under investigation to dictate the methodology of the study design and to take an interdisciplinary approach when determining the therapeutic effectiveness, considering both the qualitative and quantitative data before defining the clinical significance of the results.²² NCCAM has developed a scientifically appropriate support mechanism that has resulted in funding for more than 228 general CAM clinical trials. Many of the initial trials have shown enough promise to warrant further investigations, with several investigating CAM and immunity.

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Immune impact of specific herbs and vitamins

Vitamin D

1α-25-Dihydroxyvitamin D₃ (vitamin D) is a fat-soluble vitamin necessary in the human diet whose affects include not only calcium homeostasis and bone metabolism but also immune function. Vitamin D has its actions promoted through binding to the vitamin D receptor (VDR) and translocating to the nucleus. A variety of immune cells express VDR and are under investigation into the effect of vitamin D on autoimmune or infectious diseases.²³ Early studies demonstrated²⁴ that the addition of vitamin D interrupted mitogenesis of T cells because vitamin D appears to suppress preferentially the differentiation of CD4⁺ cells to the T_H1 subtype, with subsequent shifting of the CD4⁺ cells to the T_H2 subtype,²⁵, ²⁶ and lower levels of vitamin D showing negative effects in both multiple sclerosis and inflammatory bowel disease.²⁷, ²⁸

Vitamin E

Vitamin E is a lipid soluble molecule that is known to have at least 8 different isoforms (α, β, γ, and δ-tocopherols and α, β, γ, and δ-tocotrienols), all with a chromanol nucleus surrounded by different lipophilic side chains. Vitamin E intercalates itself into lipid membranes of cells, and it can help in halting peroxidation of lipid molecules. The activity of vitamin E in gene expression and transcription in mast cells has been described recently as affecting the activation of protein kinase C, protein phosphatase 2A, and protein kinase B in mast cells,²⁹ with inhibition of protein kinase C halting the proliferation of mast cells in vitro,³⁰ and other studies showing inhibition of eosinophilic infiltration of mucosal surfaces.³¹

Vitamin A

Using the theory that high levels of vitamin A shift the immune system from a predominantly T_H1 to a T_H2 paradigm,³² vitamin A deficiency appears potentially to ameliorate experimental asthma, whereas supplementation with vitamin A increases bronchial hyperreactivity, levels of IL-4 and IL-5, and pulmonary eosinophilia. The effect of vitamin A on shifting the immune response toward a T_H2 phenotype and increasing antibody production has also been demonstrated in the successful seroconversion of children vaccinated in areas known to be vitamin A–deficient with vitamin supplementation.³³ The effect of vitamin A on cytokine production and shifting the body to a T_H2 state has implications in common variable immunodeficiency. Two studies have shown that supplementation with vitamin A improved antibody production.³⁴, ³⁵

Vitamin C

Vitamin C is an antioxidant necessary in some species that have lost the ability to synthesize it on their own. The implication that vitamin C is an important mediator of the immune response with an effect on ameliorating the common cold is an idea that stretches back decades, although early studies³⁶, ³⁷ never demonstrated an effect on the duration or intensity of the common cold in patients supplemented with vitamin C. The connection between vitamin C and asthma has also been of interest to researchers; however, the results have not shown much effect of vitamin C on the pathogenesis of asthma.³⁸, ³⁹ In a large study by Fogarty et al,⁴⁰ supplementation with vitamin C and magnesium had no effect on asthma symptoms. This was borne out by a recent review⁴¹ of clinical trials looking at vitamin C supplementation and asthma, with most trials showing no benefit.

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Herbal medicines and potential mechanisms of action

The potency of different herbal remedies will ultimately be related to their individual mechanisms of action that have been scrupulously explored over the past decade. A primary focus has been on their ability to interact with transcription factors: the nuclear factor-κB (NF-κB) pathway, the JAK/signal transducer and activator of transcription (STAT) pathway, and the GATA-3 pathway (Fig 5).

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• Fig 5.

  Herbal medicines and potential mechanisms of action. NF-κB is an enzyme that is at the center of an evolutionarily conserved proinflammatory cascade. Initiation of the NF-κB system begins through receptors such as TNF-α and TLR4. The inactivated NF-κB is complexed with an inhibitory protein, IκB, which, after activation of cell membrane receptor, is a target of phosphorylation and ubiquitination. This allows NF-κB to translocate to the nucleus and bind to DNA. This allows transcription of proinflammatory genes for such proteins as TNF-α, IL-1, MMP-9, IL-8, monocyte chemoattractant protein 1 (MCP), macrophage inflammatory protein 1α (MIP), and inducible NOS. The JAK pathway is initiated with cytokine binding to its receptor, particularly the IFN-γ cytokine. The receptor then dimerizes and turns on a member of the STAT family, of which 7 have been described in human beings. This enzyme then translocates to the nucleus and begins transcribing proteins such as IFNs, IL-2, IL-4, and IL-12. Of interest, one of the regulators of the STAT pathway is the suppressor of cytokine signaling family (SOCS), and the SOCS3 enzyme has been implicated in the propagation of allergic responses with increased expression of SOCS3, resulting in greater T_H2 differentiation.¹⁰⁵, ¹⁰⁶, ¹⁰⁷ A final biochemical pathway for the JAK/STAT pathway includes the GATA transcription family. Activation of STAT6 leads to expression of GATA-3, which in turn will transform naive CD4⁺ T cells into the T_H2 subtype. This activation of the GATA-3 pathways has been implicated in asthma and other allergic disorders independent of the SOCS pathway.¹⁰⁸, ¹⁰⁹ ASHMI, Antiasthma herbal medicine intervention; EGCG, epigallocatechin gallate; TRAD, TNF-α recepter associated death domain; TRAF, TNF-α receptor associated factor; RelA, reticuloendotheliosis viral oncogene homolog A; STAT, signal transducers and activators of transcription protein; NOS, nitric oxide synthase.

Magnolol

One of the many plant polyphenols that are present in herbal remedies and have been shown to have action against NF-κB is magnolol, a constituent of the Chinese herb Hou p’u (Magnolia officinalis).⁴², ⁴³ By using an elegant assay that monitors the production of NF-κB transcriptional products through activation via TNF-α, Chen et al⁴² have shown that magnolol suppresses inhibitor of nuclear factor-κB kinase β subunit activity, and thus decreases degradation of the inhibitor of κβ enzyme. In another study, the researchers showed that magnolol has effects beyond the IKKB activity and in fact can inhibit activation of the STAT3/JAK pathway in IL-6–treated cells.

Quercetin

Quercetin is a ubiquitous flavonoid found in a variety of foods, from raspberries and apples to onions and capers. In a 2003 article, Cho et al⁴⁴ showed that Quercetin reduces LPS-mediated cytokine production through NF-κB and in particular in the IKB degradation pathway. This is similar in nature to the cascade suppression previously shown in curcumin and magnolol.⁴⁵ Of interest, Quercetin has also been shown to have antiangiogenic effects in vitro,⁴⁶ as well as effects in preventing IL-1–mediated mast cell release of IL-6 without degranulation.

Antiasthma herbal medicine interventions

As opposed to a single herbal intervention, antiasthma herbal medicine interventions Mt Sinai School of Medicine formula 02 and food allergy herbal formula, refined 2, are proprietary formulas containing anywhere from 3 to 14 different herbs. In a randomized clinical trial published in 2005, Wen et al⁴⁷ showed that antiasthma herbal medicine interventions produced significant improvement in FEV₁, peak expiratory flow, self-reported symptoms, and β-agonist use, and was not associated with either adrenal dysfunction or IFN-γ suppression. In a study in 2004,⁴⁸ a group studying Mt Sinai School of Medicine formula 02 showed similar results with a decrease in IL-4 and IL-5 production, without a decrease in IFN-γ, thus suggesting that these herbal formulas can help switch individuals from a predominantly T_H2 to a T_H1 phenotype through the potential suppression of GATA-3.

Resveratrol

Resveratrol is a phytoalexin found in large amounts in the traditional Japanese and Chinese medicinal herb Polygonum cuspidatum, as well as in grape skin extracts and red wine. Resveratrol is synthesized in plant cells whenever stress (particularly fungal invasion) or nutrient depletion occurs. Interest in resveratrol as a nutritional supplement grew when an article published in Science in 1997⁴⁹ showed that resveratrol has potent cancer chemoprotective activity with remarkable ability to inhibit COX-1 and COX-2. Two later studies published in Nature⁵⁰, ⁵¹ further increased interest because resveratrol supplementation demonstrated an increased lifespan in Caenorhabditis elegans and Drosophila melanogaster. In 2000, the activity of resveratrol at NF-κB was discovered to block NF-κB reporter gene activation through inhibition of phosphorylation of p65.⁵² No activity at inhibitor of κβ subunit α was found. Subsequent studies have shown that resveratrol blocks the TIR-domain–containing adapter-inducing INF-β (TRIF) pathway, not the MyD88 pathway, in Toll-like receptor (TLR)–dependent NF-κB activation.⁵³

Ma huang (Ephedrine sinica)

Ephedrine sinica has been used for >5000 years in the form of teas in TCM to treat respiratory conditions such as asthma. In the United States, however, it was being used for weight reduction, energy boosting, and enhancement of physical performance by athletes. Because of its sympathomimetic properties on α-adrenergic and β-adrenergic receptors, it became popular as an illicit street drug with amphetamine-like effects and was abused in the form of “ecstasy.” Ma huang is composed of 6 ephedrine alkaloids, although the indications for its use in the United States were not described in TCM, despite a meta-analysis in 2003 by the FDA demonstrating its short-term effectiveness in promoting weight loss. In 2003, this agent was removed from the market after r>3000 cases were reported to the FDA, of which 30% resulted in serious adverse events (chest pain, hypertension, myocardial infarctions, strokes, arrhythmia, psychiatric disturbances, and death), and many involved young healthy individuals. The safe use of this herb for decades in Chinese medicine compared with its use in the United States was thought to be a result of the differences in the indications for its use and the careful combination of ma huang with synergistic herbs in Chinese herbal concoctions, namely licorice, ginger, honey, cinnamon, and apricot seeds, which also act to reduce its side effects. Others have proposed that extrinsic factors including inadequate chemical analysis of extracts, inconsistent herbal compositions, variations in herb sources, and other idiosyncratic reactions resulted in toxicity despite use at recommended doses, which were determined on the basis of ephedrine content without accounting for the other undefined potent ingredients.⁵⁴ A new assay has since been established that uses reverse-phase HPLC to determine the exact species of Ephedra present in a herbal extract.⁵⁵ By chemically fingerprinting in this manner, one can now authenticate ground plant materials and ensure that the active component is the plant extract expected. In this manner, one can prevent surreptitious inclusion of ephedra in unexpected herbal remedies. Because several other herbal remedies have gained popularity in the treatment of atopic diseases, many options are available for those seeking CAM discussed in the Clinical Applications for the Practicing Allergist section below.

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Clinical applications for the practicing allergist

To explain the biological mechanisms and provide clinical evidence of the effectiveness of CAM remedies, 3 common atopic disease processes are reviewed.

Asthma

Asthma is a chronic inflammatory disease characterized by bronchial inflammation, bronchial constriction, and increased mucus production. Although effective conventional remedies are available, a large population (as high as 65% among black subjects, poor subjects, less educated parents, and children with persistent symptoms) exists that uses complementary medicines adjunctively to minimize the need for conventional therapies and hence avoid the profound side-effect profiles.⁵⁶, ⁵⁷ These complementary treatments for asthma fall into 1 of 5 main categories: herbal, antioxidants, vitamins, fatty acids, and probiotics.

Although several herbs have reportedly been used for the treatment of asthma, a Cochrane Review recently conducted with 21 herbs showed mixed benefits. For instance, Tylophora indica produced improvements in symptom scores >50% from baseline after 1 week⁵⁸, ⁵⁹ and decreased the frequency of attacks by 50%.⁵⁹, ⁶⁰, ⁶¹ Unfortunately, these effects were short-lived and were no longer evidenced after 12 weeks of treatment. Similarly, ginger improved symptoms by providing relief from chest tightness,⁶² whereas pulmoflex, an Ayurvedic polyherbal formulation, provided relief to “patients experiencing deterioration.”⁶³ Eucalyptol demonstrated a steroid-sparing effect in a single case, although its mucolytic effect has been known for many years.⁶⁴ Contrary to limited subjective reports, objective measures of improvement have been clearly reported with boswellia, a gummy resin of the Boswellia tree with a long history of use in Indian herbal medicine, improving FEV₁⁶⁵ and peak expiratory flow rate (PEFR)⁶⁶ in adults; propolis, a resinous mixture collected by bees from various botanical sources, improved PEFR in adults.⁶⁷ Pycnogenol (Horphag Research, Geneva, Switzerland), a water extract of the bark of the French maritime pine (Pinus pinaster ssp Atlantica) containing oligomeric proanthocyanidins and bioflavonoids, had similar effects in children.⁶⁸ However, because of the measurements in percent of predicted FEV₁ and PEFR, these improvements equate to only minimal changes in actual FEV₁ and PEFR, and hence their clinical benefit remains undetermined.

The majority of CAM literature associated with allergy and asthma (Fig 2) seems to focus on the effects of antioxidants and probiotics. However, 1 study⁶⁹ on fatty acids reported a 30% to 50% reduction in childhood asthma just by incorporating fish, which is high in ω-3, into the child’s regular diet. Although anecdotal, such dramatic results warrant further studies because it is from these anecdotal reports that many of the current studies have found their origin.⁷⁰ As for the antioxidants, although the list is mostly made up of vitamins and minerals (Table E1), there are some vitamins, such as vitamins A and D, that have no antioxidant affects but rather affect immune function. A recent animal model⁷¹ reported that contrary to previous claims that vitamin A negatively correlated with asthma severity,⁷² the excessive intake of vitamin A demonstrated a shift toward T_H2, resulting in pulmonary hyperresponsiveness and more deaths from asthma in the United States compared with Third World countries, where vitamin A deficiency resulted in death from infection.⁷¹ This observation was supported by the decreased IL-4 and IL-5 levels in bronchoalveolar lavage fluid, pulmonary eosinophilia, and suppressed IgE and IgG₁ responses measured in deficient patients. Of the vitamins that have antioxidant properties, vitamin C is the most recognized in regard to asthma. A bivariable analysis of children noted that despite controlling for several potential confounding variables, of the antioxidants, children with asthma lacked vitamin C and α-carotene.⁷³ It is proposed that perhaps the oxidative stress from the generation of reactive oxygen and free radicals causes bronchial inflammation and hyperreactivity, which results in a decrease in the cell’s reducing capacity, leading to the development of asthma.⁷⁴, ⁷⁵ Moreover, it seems that although introducing fresh fruits and vegetables after age 1 year reduced the risk of developing asthma, early supplementation within the first 6 months actually increased the child’s allergic sensitization to house dust mite on skin prick testing and thereby increased the risk of developing asthma.⁷⁶ This effect was most prevalent among black children.⁷⁷ Finally, in 2007, Lactobacillus gained interest as a probiotic with effective therapeutic potential in allergic diseases. Because there are several strains of Lactobacillus, conflicting reports of its efficacy exist. Two groups found no objective evidence of beneficial effects with Lactobacillus GG given to marathon runners during pollen season⁷⁸ or with Lactobacillus casei given to preschool children to decrease the frequency of attacks. However, 2 other groups used mouse models and found significant improvements with live oral Lactobacillus reuteri, Lactobacillus rhamnosus GG, and Bifidobacterium lactis (Bb-12). With such mixed data on the subject, further studies are needed to distinguish the mechanisms of action and efficacy of the various probiotic strains before any definitive conclusions can be made. However, one thing is clear: probiotics are vital to the healthy maturation of the immune system after birth,⁷⁹ as has been demonstrated in patients with atopic dermatitis.⁸⁰, ⁸¹

Atopic dermatitis

Atopic dermatitis is an inflammatory cutaneous disease characterized by atopic eczema and pruritus and is occasionally complicated by superimposed bacterial skin infections. Like asthma, although many complementary therapies exist for the treatment of atopic dermatitis, only a few have been researched in terms of their efficacy, safety, and mechanism of action. In Table E1, an extensive list of complementary treatments associated with this disease process is presented. However, even with such limited knowledge about these alternative treatments, their popularity is worldwide, and they are being used without inhibition.

Herbal remedies predominate in the literature, whereas of the fatty acids, ω-6 fatty acid and γ-linolenic acid, found in evening primrose (Oenothera biennis), is the primary agent to have therapeutic and prophylactic effects in atopic dermatitis,⁸² associated with decreasing the redness, scaling, and itching from the lesions and preventing future exacerbations. Likewise, Rumex japonicus Houtt⁸³ has been shown to have some efficacy in a hapten-induced mouse model of atopic dermatitis. This herb demonstrated anti-inflammatory, antioxidant, and antibacterial properties. By inhibiting the histological changes in the skin (decreasing the hypertrophy, hyperkeratosis, and infiltration of inflammatory cells in the skin), R japonicus Houtt decreased the development of eczematous skin lesions, and by decreasing the colonization of the skin by Staphylococcus aureus, it decreased scratching behavior and the frequency of exacerbations as well.

A more detailed review of 12 herbs has demonstrated some effect in atopic skin disorders. Butterbur, like montelukast, had no significant effect on either the histamine or allergen-induced cutaneous wheal and flare response compared with fexofenadine.⁸⁴ In an animal model, Actinidia arguta improved dermatitis skin lesions in magnesium-deficient hairless rats by decreasing infiltration of the skin by inflammatory cells and preventing histopathological remodeling of the dermis and epidermis while preventing transepidermal water loss.⁸⁵ Saururus chinensis, described by the same group,⁸⁶ demonstrated similar anti-inflammatory effects to A arguta, resulting in decreased hypertrophy and hyperkeratosis of the dermis and epidermis and decreased itching behavior in the atopic subjects. In addition, they demonstrated a shift toward the T_H1 cell pathway with no effect demonstrated on T_H2. Mahonia aquifolium demonstrated contrasting results: in an open-label trial in adults, significant improvements were reported in eczema area, severity index scores, and patient satisfaction on the basis of a posttreatment questionnaire,⁸⁷ whereas a randomized, double-blind, vehicle-controlled, half-side comparison with an herbal ointment containing M aquifolium, Viola tricolor, and Centella asiatica reported no statistical improvement compared with placebo in either primary skin symptoms or secondary assessment of pruritus, effectiveness, and tolerability.⁸⁸ Lyophyllum decastes extracted from Hatakeshimeji mushrooms effectively lowered total skin severity scores and serum IgE levels through its inhibitory action on the T_H2 immune response.⁸⁹ Konjac ceramide orally administered favored a shift toward the T_H1 pathway and demonstrated improvements in the Score of Atopic Dermatitis for skin symptoms, decreased skin responses to skin prick testing, and decreased dust mite specific IgE production.⁹⁰ A randomized, double-blind, placebo-controlled monocentric trial of St John’s wort cream containing 1.5% hyperforin (the main active ingredient) showed effective anti-inflammatory properties resulting in an improved appearance of the skin in patients with mild-moderate atopic dermatitis in addition to antibacterial effects with decreased skin colonization by S aureus.⁹¹ Persimmon leaf extract was evaluated over a period of 4 weeks by administering 1.5 mg/kg/day of its major flavonoid astragalin. Results showed both prophylactic and therapeutic efficacy in decreasing severity of exacerbations of atopic dermatitis with decreased scratching behavior, decreased transepidermal water loss, and decreased serum IgE, and with prophylactic daily dosing there was a demonstrable decrease in the onset and progression of exacerbations.⁹²

TCM polyherbal remedies have been implicated for the treatment of atopic dermatitis. One such formula containing 5 different herbs was investigated²¹ in children with moderate-severe atopic dermatitis and demonstrated a significant decrease in corticosteroid use by one third and an improvement in the dermatology quality of life score, although no significant difference was noted in the allergic rhinitis score or the Score of Atopic Dermatitis. Zemaphyte (Phytofarm Plc, London, United Kingdom), a Chinese herb, also demonstrated clinical improvements in atopic dermatitis with decreased erythema, decreased surface damage, and decreased itching of the skin with few minor gastrointestinal side effects. Bhu-zong-yi-qi-tang is a polyherbal compound made up of 10 herbs with effectiveness as a prophylactic agent in allergic rhinitis and also therapeutic potential in atopic dermatitis because it decreased serum IgE levels in a mouse model. Finally, BSASM is also a multicompound preparation with anti-inflammatory effects in atopic dermatitis demonstrated by improvements in pruritus, transepidermal water loss, and eczema area severity index scores. It is thought to act by inducing NF-κB activation, reducing IL-8 and TNF-α production, and inhibiting IL-2 production in Jurkat T cells, although the true mechanism is still under investigation. One thing is clear: the effectiveness of such polyherbal formulas, whether it is BSASM or bu-zhong-yi-qi-tang, is attributed to the synergistic effects of their individual components, which exemplifies the tenet that the whole exceeds sum of the parts—that is, the synergistic effects of these components, although they are a strong force together (the whole), have only a fraction of the efficacy when tried individually (the parts).

Allergic rhinitis

A large proportion of the literature in CAM and allergy clinical studies has been focused on the impact of multiple herbal remedies on allergic rhinitis² (Table E1).

Butterbur is a perennial shrub whose root contains the active compound petasins. Adult studies showed butterbur proved efficacious compared with placebo in sustaining nasal inspiratory flow while being challenged with a potent nasal congestant, adenosine monophosphate,⁹³ and when compared with fexofenadine, it provided equally significant effective relief from intermittent allergic rhinitis both by subjective patient ratings and by the physician’s global assessment.⁹⁴ Urtica dioica is a plant whose leaf, flower, seed, and root each contain different chemical constituents, including histamine, thus the common name stinging nettle. Medicinal extracts contain polysaccharides and caffeic malic acid, found in all parts of nettle, which relieved most of the rhinoconjunctivitis symptoms in 58% of subjects and provided greater efficacy than over-the-counter remedies in 48%.⁹⁵ Citrus unshiu powder demonstrated relief from seasonal allergic rhinitis to Japanese cedar pollen with dose-dependent inhibition of histamine and β-hexosaminidase, a marker for mast cell degranulation.⁹⁶ The 3 flavonoids credited for these effects are hesperetin, hesperidin, and nobiletin. Both Lycopus lucidus plant extract⁹⁷ and Amomum xanthiodes⁹⁸ have demonstrated antihistamine and anti-inflammatory potential to prevent fatal systemic allergic reactions and IgE-induced passive cutaneous anaphylaxis in mice. Although the objective data are significantly favorable for CAM, one must consider the data in context, keeping in mind that the study of U dioica is an open-trial study, and no quantitative data were measured. As for citrus unshiu powder, L lucidus, and A xanthiodes, in vivo trials are needed to determine whether the findings from the rat models can be accurately extrapolated to real clinical practices.

Likewise, dietary products like grape seed extract, tomato extract, dietary spirulina, and cellulose powder have been suggested for the treatment of allergic rhinitis. Unfortunately, no evidence was found to support the efficacy of grape seed extract,⁹⁹ and only an insignificant downward trend in serum-measured eosinophil cationic protein concentrations was seen with tomato extract.¹⁰⁰ However, dietary Spirulina, a filamentous blue-green alga, with its main active ingredient C-phycocyanin, did demonstrate antiallergic effects by inhibiting histamine release from mast cell–mediated allergic reactions and by suppressing IL-4, thereby inhibiting the T_H2 synthesis of IgE.¹⁰¹ Likewise, cellulose powder administered to the nasal mucosa proved beneficial in enhancing the filtration of allergens and irritants from inhaled air, similar to one’s normal mucus providing complete resolution of rhinoconjunctivitis in 77% of subjects.¹⁰² Although the trials investigating dietary supplements are designed in a randomized double-blind manner, the data are qualitative, measuring subjective symptom scores and quality of life questionnaires. More objective endpoint measurements and large-scale studies are needed to lend internal and external validity to the conclusions drawn.

Indian Ayurvedic medicine

The 2 most studied regimens in this group include a polyherbal formula called Aller-7 and Tinospora cordifolia. Aller-7 has demonstrated anti-inflammatory properties in rat models and has shown improvement in rhinitis and total nasal symptom scores that correlate with objective measurements.¹⁰³ Similarly, T cordifolia provided significant relief from sneezing, nasal discharge, nasal obstruction, and nasal pruritus compared with placebo with consistent improvements on examination of the nasal smears and nasal mucosa.¹⁰⁴

TCM

As mentioned, Bhu-zong-yi-qi-tang has shown proven effects in both allergic rhinitis¹⁰⁵ and atopic dermatitis. Another polyherbal formula important to the treatment of allergic rhinitis is biminne, made of 11 constituents, each with anti-inflammatory, antioxidant, and antiallergic properties. Although the mechanism of action is unclear, there are subjective reports of improvement in symptoms that correlate with total serum IgE levels, physician evaluations, and sustained effects after 1 year.¹⁰⁶ Last, Shi-Bi-Lin, a modified form of Cang Er Zi San, has proven to be an effective therapeutic choice with its anti-inflammatory effects on the suppression of IL-4, TNF-α, and IL-6 production.¹⁰⁷ No effect was demonstrated on the messenger RNA sequence for these cytokines, so the mechanism of cytokine modulation remains unknown.

Kampo medicine (Japanese)

Kampo agents Sho-seiryu-to and rosmarinic acid are the main CAM agents used in Japanese culture. Sho-seiryu-to is a polyherbal formula with evidence of shifting toward a T_H2 response, resulting in decreased IL-4 and allergen-specific IgE production consistent with the improvement in allergen-specific sneezing in mice. No effect was seen on IFN-α.¹⁰⁸ Rosmarinic acid, on the other hand, decreased leukocyte infiltration in the nostrils, demonstrated by subjective improvements in symptoms that correlate with improvements seen by nasal lavage. Polyherbal preparations as seen with Ayurvedic, Kampo, and TCM require carefully designed intricate studies to understand the mechanism of action and the active ingredients responsible for their efficacy. The polyherbal formulas reviewed in this article are all investigated via high-quality randomized trials with reliable reproducible results. Future studies should build on the results of these trials with the aim to follow long-term outcomes via prospective trials.

In conclusion, the data on complementary remedies are extensive but as of yet remain scientifically unclear because there are conflicting results about efficacy, and well controlled trials with reliable data are limited. More independently funded replications of the isolated randomized controlled trials published are needed to confirm the accuracy and validity of the study findings. The National Institutes of Health establishing the National Center for Alternative and Complementary Medicine is a major step forward to unraveling the science of CAM and assisting in integrating those interventions that have passed not just the test of time but also the test of validation. Future trials should include larger studies to account for the subject variations in the extent of allergen exposure and sensitization and disease severity to avoid any confounding variables. Also, better documentation of the methods of randomization and blinding to ensure appropriate allocation concealment will lend strength to the conclusions drawn. Last, reliable subjective and valid objective measurement outcomes are key to confirm the data and conclusions of any study design are trustworthy, even more so in the study of medicine.

Conclusions

What do we know?

What is still unknown?

Back to Article Outline

Table E1.

Clinical evidence of CAM safety and efficacy in asthma and allergy

ECP, Eosinophil cationic protein.

Back to Article Outline

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78. Moreira A, Kekkonen R, Korpela R, Delgado L, Haahtela T. Allergy in marathon runners and effect of Lactobacillus GG supplementation on allergic inflammatory markers. Respir Med. 2007;101:1123–1131
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83. Lee HS, Kim SK, Han JB, Choi HM, Park JH, Kim EC, et al. Inhibitory effects of Rumex japonicus Houtt on the development of atopic dermatitis-like skin lesions in NC/Nga mice. Br J Dermatol. 2006;155:33–38
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84. Jackson CM, Lee DK, Lipworth BJ. The effects of butterbur on the histamine and allergen cutaneous response. Ann Allergy Asthma Immunol. 2004;92:250–254
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85. Choi JJ, Park B, Kim DH, Pyo M-Y, Choi S, Son M, et al. Blockade of atopic dermatitis-like skin lesions by DA-9102, a natural medicine isolated from Actinidia arguta, in the Mg-deficiency induced dermatitis model of hairless rats. Exp Biol Med. 2008;233:1026–1034
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86. Choi MS, Kim EC, Lee HS, Kim SK, Choi HM, Park JH, et al. Inhibitory effects of Saururus chinensis (LOUR.) BAILL on the development of atopic dermatitis-like skin lesions in NC/Nga mice. Biol Pharm Bull. 2008;31:51–56
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87. Donsky H, Clarke D. Relieva, a Mahonia aquifolium extract for the treatment of adult patients with atopic dermatitis. Am J Ther. 2007;14:442–446
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88. Klovekorn W, Tepe A, Danesch U. A randomized, double-blind, vehicle-controlled, half-side comparison with a herbal ointment containing Mahonia aquifolium, Viola tricolor and Centella asiatica for the treatment of mild-to-moderate atopic dermatitis. Int J Clin Pharmacol Ther. 2007;45:583–591
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89. Ukawa Y, Izumi Y, Ohbuchi T, Takahashi T, Ikemizu S, Kojima Y. Oral administration of the extract from Hatakeshimeji (Lyophyllum decastes sing.) mushroom inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice. J Nutr Sci Vitaminol. 2007;53:293–296
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90. Kimata H. Improvement of atopic dermatitis and reduction of skin allergic responses by oral intake of konjac ceramide. Pediatr Dermatol. 2006;23:386–389
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91. Schempp CM, Windeck T, Hezel S, Simon JC. Topical treatment of atopic dermatitis with St. John’s wort cream—a randomized, placebo controlled, double blind half-side comparison. Phytomedicine. 2003;10(suppl 4):31–37
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92. Matsumoto T, Shibata T. The ex vivo effect of the herbal medicine sho-saiko-to on histamine release from rat mast cells. Eur Arch Otorhinolaryngol. 1998;255:359–364
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94. Schapowal A. Treating intermittent allergic rhinitis: a prospective, randomized, placebo and antihistamine-controlled study of Butterbur extract Ze 339. Phytother Res. 2005;19:530–537
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95. Urtica dioica; Urtica urens (nettle). [monograph] Alt Med Rev. 2007;12:280–284
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96. Kobayashi S, Tanabe S. Evaluation of the anti-allergic activity of Citrus unshiu using rat basophilic leukemia RBL-2H3 cells as well as basophils of patients with seasonal allergic rhinitis to pollen. Int J Mol Med. 2006;17:511–515
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97. Shin TY, Kim SH, Suk K, Ha JH, Kim I, Lee MG, et al. Anti-allergic effects of Lycopus lucidus on mast cell-mediated allergy model. Toxicol Appl Pharmacol. 2005;209:255–262
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98. Kim S-H, Lee S, Kim IK, Kwon TK, Moon J-Y, Park W-H, et al. Suppression of mast cell-mediated allergic reaction by Amomum xanthiodes. Food Chem Toxicol. 2007;45:2138–2144
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    • CrossRef
99. Bernstein DI, Bernstein CK, Deng C, Murphy KJ, Bernstein IL, Bernstein JA, et al. Evaluation of the clinical efficacy and safety of grapeseed extract in the treatment of fall seasonal allergic rhinitis: a pilot study. Ann Allergy Asthma Immunol. 2002;88:272–278
    • View In Article
    • Abstract
    • Full-Text PDF (173 KB)
    • CrossRef
100. Yoshimura M, Enomoto T, Dake Y, Okuno Y, Ikeda H, Cheng L, et al. An evaluation of the clinical efficacy of tomato extract for perennial allergic rhinitis. Allergol Int. 2007;56:225–230
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101. Mao TK, Van de Water J, Gershwin ME. Effects of a spirulina-based dietary supplement on cytokine production from allergic rhinitis patients. J Med Food. 2005;8:27–30
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102. Josling P, Steadman S. Use of cellulose powder for the treatment of seasonal allergic rhinitis. Adv Ther. 2003;20:213–219
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104. Badar VA, Thawani VR, Wakode PT, Shrivastava MP, Gharpure KJ, Hingorani LL, et al. Efficacy of Tinospora cordifolia in allergic rhinitis. J Ethnopharmacol. 2005;96:445–449
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105. Yang SH, Yu CL. Antiinflammatory effects of Bu-zhong-yi-qi-tang in patients with perennial allergic rhinitis. J Ethnopharmacol. 2008;115:104–109
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106. Hu G, Walls RS, Bass D, Ramon B, Grayson D, Jones M, et al. The Chinese herbal formulation biminne in management of perennial allergic rhinitis: a randomized, double-blind, placebo-controlled, 12-week clinical trial. Ann Allergy Asthma Immunol. 2002;88:478–487
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107. Zhao Y, van Hasselt CA, Woo JK, Chen GG, Wong YO, Wang LH, et al. Effects of the Chinese herbal formula Shi-Bi-Lin on cytokine release from the human mast cell line. Ann Allergy Asthma Immunol. 2005;95:79–85
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108. Ikeda Y, Kaneko A, Yamamoto M, Ishige A, Sasaki H. Possible involvement of suppression of Th2 differentiation in the anti-allergic effect of sho-seiryu-to in mice. Jpn J Pharmacol. 2002;90:328–336
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Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

PII: S0091-6749(08)02439-1

doi:10.1016/j.jaci.2008.12.023

© 2009 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.