Immunological Response to Mistletoe (Viscum album L.)

in Cancer Patients: A Four-Case Series

Nilo Esvalter Gardin*

Rua Carlos Weber, 601/201-C 05303-000 São Paulo/SP, Brazil

European mistletoe (Viscum album) has been used in complementary cancer treatment, but little is known concerning its effects on immunological parameters, although there is evidence that Viscum may stimulate the immune system. In this study, a trial was conducted with cancer patients to determine whether Viscum album extracts could improve the results of immune tests. These were: white blood cell count (leukocytes, neutrophils, lymphocytes), CD4+ and CD8+ T-lymphocytes, intradermal tests of delayed hypersensitivity (candidin, trichophytin, purified protein derivative-PPD), complement C3 and C4, and immunoglobulin A, G and M. Four patients received seven doses of subcutaneous Viscum album 20 mg, twice weekly. Immunological tests were carried out before and after treatment, and an increase in several parameters of humoral and cellular immunity were shown. Apart from reactions around the injection sites, treatment was well tolerated and all patients benefited from it. These results suggest that Viscum album can enhance humoral and cellular immune responses in cancer patients, but further studies attesting to the possible clinical impact of these immunological effects are necessary. Copyright © 2008 John Wiley & Sons, Ltd.

Keywords: Viscum album; Loranthaceae; mistletoe; cancer; lectins; viscotoxins.

 
 
 
 
 

INTRODUCTION

Viscum album Linnaeus (VA) is a hemiparasitic plant of the Loranthaceae family that grows wild on trees, bushes and other plants, from Northern Europe to Northwest Africa, Southwest and Central Asia and Japan (Becker, 1986). Although it has been used in these regions for decades (Franz, 1986), VA was first used as a treatment for cancer in 1917 by Steiner and Wegman, founders of anthroposophic medicine, a com- plementary medicine system practiced worldwide (Leroi and Leroi, 1987), and since then, more than 100 000 patients have been treated with VA. Within the past 30 years it has become one of the most widely used complementary cancer therapies in Europe (Moschèn et al., 2001). Extracts are made from fresh leafy shoots and berries from VA obtained from different species of host tree such as oak (Quercus, Qu), apple tree (Malus, M), pine (Pinus, P) and others. Dosage and route of application vary individually, depending on the reaction of the patient and the stage of disease. Several studies have assessed its cytotoxic (Siegle et al., 2001; Ribéreau-Gayon et al., 1986; Holtskog et al., 1988; Kuttan et al., 1990; Jung et al., 1990; Jurin et al., 1993) and immunomodulatory (Jurin et al., 1993; Pelletier et al., 2001; Chernyshov et al., 2000; Stein et al., 1999a, 1999b; Büssing et al., 2005; Kovacs, 2000; Rentea et al., 1981; Bloksma et al., 1982; Hajto, 1986) proper- ties. In 2001, a large study with 10 226 cancer patients showed that VA prolonged overall survival of patients with colon, rectum, breast and lung (small-cell) cancer (Grossarth-Maticek et al., 2001). However, to date, no

* Correspondence to: Nilo Esvalter Gardin, Rua Luminarias 154-05439- 000 São Paulo/SP, Brazil.
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

clinical trials evaluating immunological indices before and after the use of VA that could attest to its stimulat- ing effects on cellular and humoral immune system have been reported. Understanding immunosurveillance is important for developing efficient antitumor immuno- logical treatments. Antitumor responses of the immune system include T lymphocytes, B lymphocytes, natural killer cells, macrophages, dendritic cells and granulocytic cells (Boon et al., 2000). These immune mechanisms, if stimulated, can enhance tumor destruction or reduction.

Impairment in immune antitumor function, which has been seen in cancer patients, can help to explain tumor appearance and spread. In addition, cancer treatment with chemotherapy and radiotherapy generally leads to further immunosuppression, so prevention of this would be beneficial for these patients. For this reason a small trial with cancer patients was conducted to deter- mine whether VA can improve immune tests that had previously been altered. There is also a special signifi- cance for patients with malignant neoplasia affecting the immune system, for example lymphoma and multi- ple myeloma: in these disorders, immune parameters generally have great impact on clinical outcome.

PATIENTS AND METHODS

The Ethical Committee of Edmundo Vasconcelos Hospi- tal in São Paulo, Brazil approved the study, and all parti- cipants provided written informed consent before enrolling in the study according to institutional guidelines.

Patients. Patients were recruited from the Hematology and Oncology ambulatory of Edmundo Vasconcelos Hospital. Eligibility was limited to those above 18 years old, with a diagnosis of malignant neoplasia confirmed

 
 
 
 

Received 20 June 2006

Copyright © 2008 John Wiley & Sons, Ltd. Phytother. Res. 23, 407–411 (2009)

Accepted 16 June 2008

Copyright © 2008 John Wiley & Sons, Ltd.

DOI: 10.1002/ptr

408 N. E. GARDIN

by histological or cytological tests, with a deficit of cellular or humoral immunity demonstrated by laboratory tests, and with adequate renal and hepatic function values (respectively: serum creatinine 1.5 mg/dL or lower, serum bilirubin 2 mg/dL or lower). Other inclusion criteria were the absence of chemotherapy, radiotherapy, immuno- therapy with corticosteroids or other immunosuppres- sive drugs, or any other experimental treatment in the 30 days before study entry, and the absence of granulocyte or granulocyte-macrophage colony-stimulating factors given in the previous 10 days. Patients were ineligible if they had had a recent positive pregnancy test, were breast-feeding, there was a possibility of a future preg- nancy, or if they had a psychiatric or neurological disor- der including dementia that could affect the compliance with the protocol.

Laboratory evaluation. Patients underwent laboratory analysis after clinical evaluation. Tests included white blood cell count, T lymphocyte count, CD4+ and CD8+ T cell subsets, plasma concentration of complement com- ponent C3 and C4, measurement of serum immunoglobulin (Ig) A, IgG and IgM, and then intradermal tests of delayed hypersensitivity with antigens inoculation (candidin, trichophytin and purified protein derivative – PPD). Skin test indurations were measured 48 to 72 h after inoculation, and after this VA treatment began. All the tests were performed before the VA treatment and 2 or 3 days after. Then 4 weeks after the last dose of VA, blood tests were performed again. Skin tests were made only twice because of sensitization risks.

VA treatment. Ampoules of 20 mg of VA Qu were sup- plied by Weleda do Brasil Laboratório & Farmácia Ltda (São Paulo, Brazil). The mistletoe extract Viscum album Qu (Quercus) 20 mg is an aqueous sterile preparation derived from Viscum album L. grown on oak and fermented with Lactobacillus plantarum. VA was subcutaneously injected in the abdominal or gluteal region, twice a week, with an interval of 3 or 4 days; a total of seven injections. All patients were monitored weekly by the responsible investigator and adverse events were checked closely at each visit. Common terminology criteria for adverse events were used to classify reactions associated with the use of VA (National Cancer Institute, 2003).

RESULTS

Four patients were enrolled in this study and their char- acteristics are shown in Table 1. The first patient was also diagnosed with squamous cell carcinoma of the epiglottis, stage II, treated with surgery and radiotherapy

24 months before the VA tests; and basal cell carci- noma of the nose and upper limb, treated with surgery 2 months before the VA tests.

The second patient was the only smoker (8 cigarettes/ day for 20 years), and the fourth patient was the only one taking other drugs during the VA tests (atenolol 100 mg and nifedipine 40 mg daily for hypertension). This patient had to be admitted to the hospital 2 weeks after the second test because of a new chemotherapy cycle and was not submitted to the third test.

Immunological response

Tables 2–5 show all laboratory parameters examined before the VA use (‘before’), 2 or 3 days after the VA treatment (‘second tests’) and 4 weeks after the last dose of VA (‘third tests’). Values out of the normal range are in bold type. The fourth patient was not submitted to PPD for a second test because he had a strong posi- tive reaction to the first. The first patient showed the best response, resulting in the enhancement of all analysed parameters apart from the intradermal tests. Similarly, the fourth patient showed an increase in all indices except trichophytin inoculation. All parameters, which were initially below the normal range, had increased by the final tests, except for some intradermal reactions (three skin tests of the first and second patients and one of the third and fourth patients).

Adverse events

The VA treatment was well tolerated and were adminis- tered in the outpatient setting. Systemic symptoms did not occur. All patients reported mild induration on the injection site (Table 6). Only one patient had moderate pain and erythema. All toxicities reversed spontaneously without sequela, generally after one day. There was no need to use symptomatic medication, interrupting VA, or changing VA dose or frequency.

DISCUSSION

The present study investigated immune stimulation by VA in four cancer patients who had immune impairment. These patients, who received seven subcutaneous doses of VA 20 mg, showed improvement in several laboratory parameters, confirming that VA can improve the immune response and restore suppressed cellular and humoral immunity to some extent. There is evidence, supported by clinical studies, that VA has positive benefits for

 
 
 
 

Table 1. Patient characteristics

Age Patient Gender (years)

  1. 1 Male 57

  2. 2 Male 18

  3. 3 Female 44

  4. 4 Male 46

Cancer diagnosis

Hodgkin disease (nodular sclerosis) Hodgkin disease (mixed cellularity) Breast (infiltrative ductal)
Multiple myeloma (IgG)

Stage

III-B II-A II III-A

Months from diagnosisa

43 50 30 16

Months from Treatment end of treatmenta

CT+RT 31 CT+RT 33 SR+RT+CT 20 CT4

Phytother. Res. 23, 407–411 (2009) DOI: 10.1002/ptr

 
 
 

a To VA tests.
CT, chemotherapy; RT, radiotherapy; SR, surgery.

Copyright © 2008 John Wiley & Sons, Ltd.

Table 2. Results of patient 1

Parameter

Before VA

1670 868 701 109 244 0.45 66 21 188 882 63 0 0 0 Normal/Evaluatedb 4/14

a Due to a technical problem.
b Number of normal parameters/number of parameters evaluated.

2–3 days after VA

Conclusion

Improvement Improvement Improvement Improvement Kept normal Improvement Normal

Kept normal Kept normal Improvement Improvement Unaltered Unaltered Unaltered Improvement

Conclusion

Improvement Kept normal Kept normal Kept normal Kept normal Improvement Kept normal Kept normal Kept normal Kept normal Kept normal Unaltered Unaltered Unaltered Improvement

Conclusion

Kept normal Kept normal Kept normal Kept normal Kept normal Kept high Kept normal Kept normal Kept high Kept normal Kept normal Unaltered Improvement Improvement Improvement

Leucocytes × 109/L Neutrophils × 109/L Lymphocytes × 109/L CD4 (cells/μL)

4000–11000 1800–7700 800–4950 240–1800 120–1110 0.9–2.2

2280 1254 889 Not donea Not donea Not donea 84 26 227 963 63
0
0
0
5/11

2–3 days after

3600

2160 1116 234 333 0.7 98 21 216 1430 119 0 0 0 8/14

2–3 days after

      9360
      5616
      2433
      1166

521

2.24 128 32 478 1490

3440

2476

791 126 249 0.51

94

26 210 968 78



– 7/11

4 weeks after VA

     4730
     2606
     1466

408

522

0.78

76

       20
      211
     1250
      128



– 10/11

4 weeks after VA

     8230
     4608
     2798
     1556

585

2.66

89

26

449

CD8 (cells/μL) CD4/CD8 ratio
C3 (mg/dL)
C4 (mg/dL)
IgA (mg/dL)
IgG (mg/dL)
IgM (mg/dL) Candidin (mm) PPD (mm) Trichophytin (mm)

50–120 10–40 60–400

Normal range

4 weeks after VA

900–1500 70–320 5–10 5–10 5–10

IMMUNE RESPONSE TO MISTLETOE

409

 
 
 

Table 3. Results of patient 2

Parameter

Leucocytes × 109/L Neutrophils × 109/L Lymphocytes × 109/L CD4 (cells/μL)

CD8 (cells/μL)
CD4/CD8 ratio
C3 (mg/dL)
C4 (mg/dL)
IgA (mg/dL)
IgG (mg/dL)
IgM (mg/dL)
Candidin (mm)
PPD (mm)
Trichophytin (mm)
Normal/Evaluateda 9/14

a Number of normal parameters/number of parameters evaluated.

 

Normal range

Before VA

3840

VA

 

4000–11000 1800–7700 800–4950 240–1800 120–1110 0.9–2.2

1958 1612 324 555 0.58 65 24 213 1460 109 0 0 0

50–120 10–40 60–400

900–1500 70–320 5–10 5–10 5–10

 

Table 4. Results of patient 3

Parameter

Leucocytes × 109/L Neutrophils × 109/L Lymphocytes × 109/L CD4 (cells/μL)

CD8 (cells/μL)
CD4/CD8 ratio
C3 (mg/dL)
C4 (mg/dL)
IgA (mg/dL)
IgG (mg/dL)
IgM (mg/dL)
Candidin (mm)
PPD (mm)
Trichophytin (mm)
Normal/Evaluateda 9/14

a Number of normal parameters/number of parameters evaluated.

Copyright © 2008 John Wiley & Sons, Ltd.

VA

 

Normal range

Before VA

  9670
  6285
  2417
  1184
 

4000–11000 1800–7700 800–4950 240–1800 120–1110 0.9–2.2

491

2.41

89

30

455

50–120 10–40 60–400

900–1500 70–320 5–10 5–10 5–10

1103 131 0 2 2

1310 135 125

0– 9– 9–

10/14 9/11

 

Phytother. Res. 23, 407–411 (2009) DOI: 10.1002/ptr

410

N. E. GARDIN

Table 5. Results of patient 4

Parameter

Leucocytes × 109/L Neutrophils × 109/L Lymphocytes × 109/L CD4 (cells/μL)

CD8 (cells/μL)
CD4/CD8 ratio
C3 (mg/dL)
C4 (mg/dL)
IgA (mg/dL)
IgG (mg/dL)
IgM (mg/dL)
Candidin (mm)
PPD (mm)
Trichophytin (mm)
Normal/Evaluateda 8/14

a Number of normal parameters/number of parameters evaluated.

Table 6. Adverse events associated with the use of VA

 

Normal range

Before VA

  4210
  2273
  1599

427

2–3 days after VA

Conclusion

 

4000–11000 1800–7700 800–4950 240–1800 120–1110 0.9–2.2

677

0.63

  4570
  2467
  1965

662

792

0.84 131 16 72 7590 36 5

Not done

0

8/13

Kept normal Kept normal Kept normal Kept normal Kept normal Improvement Become high Kept normal Kept normal Kept high Improvement Improvement –

Unaltered Improvement

50–120 10–40 60–400

117 15 63 7380 31 0 30 0

900–1500 70–320 5–10 5–10 5–10

 
 

Patient Adverse event

  1. 1 Induration and erythema

  2. 2 Pain and erythema

    Pain Induration Itching

  3. 3 Pain and erythema Induration

  4. 4 Pain Induration

some cancer patients although efficacy is still not con- sidered to have been conclusively demonstrated (Ernst et al., 2003). In 1989, Kiene published the first meta- analysis about VA clinical studies (Kiene, 1989), which included 46 studies and trials of VA therapy for carci- nomatous diseases. There were 35 controlled studies, of which 12 were considered conclusive, and all of these showed an advantage of the mistletoe group in survival time and survival rate. Nine of those 12 studies were statistically significant. Kleijnen and Kipschild (1994) also analysed VA clinical studies, but were more criti- cal about methodological aspects. They uncovered 11 controlled trials, four of which showed significance with a positive result for mistletoe as a treatment for cancer, six trials showed a positive trend and one with no benefit. Finally, in 2007 Kienle and Kiene evaluated only prospective clinical trials on the effectiveness of anthroposophic mistletoe therapy for cancer (Kienle and Kiene, 2007). Thirty seven studies were identified: 16 randomized, nine non-randomized and 12 single-arm cohort studies. Among 25 controlled trials evaluated for clinically relevant outcome measures, a statistically sig- nificant benefit for survival was reported in eight of 17 trials, for remission of tumor and malignant effusion in two of four controlled trials, for quality of life in three of five studies, and for quality of life and reduction of side effects of cytoreductive therapies (chemotherapy, radiation or surgery) in five of seven trials. Among 12 single-arm cohort studies, five of seven studies found substantial tumor remission, one study reported remis- sion of carcinoma in intra-epithelial neoplasm, and four

Copyright © 2008 John Wiley & Sons, Ltd.

Grade

I II I I I I I I I

Period

Duration

1 day
2 days
1 day
1 day
1 day
1 day 8–10 days 1 day
1 day

 

After dose 4 After dose 1 After dose 2 After dose 3 After dose 5 After all 7 doses After all 7 doses After all 7 doses After dose 1

 

studies reported remission of malignant pleural effusion or ascites.

In the present study, almost all immune indices improved after VA therapy. This supports the work of Chernyshov et al. who showed previously that VA therapy reduced recurrent respiratory infections and improved immune parameters in more than 70% of 92 children living in areas exposed to the radioactive fallout from Chernobyl (Chernyshov et al., 2000). The immunomodu- lating and anticancer activities of VA are attributed to its three main classes of biologically active components: lectins, viscotoxins and polysaccharides (Romagnoli et al., 2003; Stein et al., 1999b; Coulon et al., 2003; Frantz et al., 2000). The lectins especially have well recognized antitumor and immunomodulating activities.

The incidence of adverse effects was small, most of them transient and mild, and none systemic. Previous clinical studies showed the same results (Gorter et al., 1999, Stein and Berg, 2000), consequently, complemen- tary treatment with VA has been considered safe.

In conclusion, although this study has had only four cases, the VA therapy showed immune benefits in labo- ratory tests and suggests that VA can enhance humoral and cellular immune responses. However, new studies attesting to the clinical impact of these immunological effects in cancer patients are needed.

Acknowledgement

The author is grateful to Dr José Roberto Lazzarini Neves and Dr Bernardo Kaliks Litvak and Dr Ricardo Caponero for their scientific support.

Phytother. Res. 23, 407–411 (2009) DOI: 10.1002/ptr

IMMUNE RESPONSE TO MISTLETOE 411

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                      ADD/ADHD/ASPERGERS

Dr. Johnson D.O. has 17 years  of experience working with ADD, ADHD.  Aspergers and related brain disorders and will accept a limited number of patients for consultation.  He has been a consultant for several remedial programs and has lectured frequently on the topic of sensory integration and early childhood education.  He can employ an in depth knowledge of nutritional, cranio- sacral/osteopathic anthroposophic/homeopathic, holistic and botanical therapies as well as extensive functional  and nutritional testing. These includw food sensitivities, organic acids. methylation and functional gastrointestinal evaluations if necessary. Our nurse practioner Tanya Geraci can also see children for primary care issues as needed.

Dr. Johnson also does osteopathic manipulation and cranial sacral therapy for  musculoskeletal problems which can also be related to many health issues as well. This concept is known as somatic dysfunction which teaches that via the nervous system internal health problems are often reflected in the musculoskeletal system and vice versa.

 

                                           Lab Testing

At the clinic we offer disounted lab fee's from Labcorp for pt's with high deductibles or no insurance including allergy panels, thyroid panels, and individualized health screenings. We can duplicate most Life Extension testing panels and costs are discounted significantly similar to Life Extensions or "Any Lab Now".We specialize in preventative testing and healthcare.  Our labs are interpreted by clinicains who have years of training to do this correctly and accurately and combine this understanding with a "holistic and functional" eye.  Many inaccurate interpretations are performed by undertrained practitioners.

We also offer the following specialized labs: ZRT saliva and blood spot hormone tests, Genova nutritional evaluations, epigenetic/methylation testing by Younique genomics and XRMD (see video section),  GI panels for bowel flora, leaky gut, parasites and candida, Urine hormone analysis, IgG-E Food sensitivity tests, Cerex specialized metabolic labs, Corus coronary artery disease blood test: Heart Disease Screening Berkely Heart labs (Genetic), Heavy Metals testing (hair and urine challenge testing), Iodine and selenium testing, Specialized Lyme and Tic Bourne dz Tests, Clifford Compatibility tests (tests sensitivity to dental materials), EKG and Holter Monitoring, musculoskeletal ultrasound.

 

The GAPS DIET for Autism, ADD, Irritable Bowel, Neurological Disorders and Chronic Food Intolerances:  (Also consider Fodmap diet)

The GAPS diet is a comprehensive healing protocol developed by Dr. Natasha Campbell-McBride, a neurologist and nutritionist who specializes in healing of issues like autism spectrum disorders, ADD/ADHD, dyspraxia, dyslexia and schizophrenia by treating the root cause of many of these disorders: compromised gut health.

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Resources for the GAPS Diet

GAPS Book & GAPS Guide

In Gut & Psychology Syndrome, by Dr. Campbell-McBride, she not only describes how and why the GAPS diet works with our digestive tracts to enable optimal healing, but she explains just how schizophrenia, autism spectrum disorders and other illnesses with neurological components can be attributed, at least in part, to compromised gut health. The book helps you to understand the science behind GAPS, and it’s that understanding that helps to motivate you – keeping you going through the strict elimination and slow reintroduction phases of the GAPS intro diet.

 

GAPS Guide is a simple guidebook that can be used side-by-side with Gut & Psychology Syndrome. Written by Baden Lashkov, a mother who saw her own son healed through GAPS and has since taken on the calling to help other families work their way through GAPS, the GAPS Guide provides real world advice on the practical application of the GAPS diet. You’ll see tips for managing the introduction, information on how to work with friends and family who disapprove of the diet and information on troubleshooting your progress.

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30 Days on the GAPS Intro E-Book

 
 
 
 

30 Days on the GAPS Intro is a comprehensive e-book that provides a clear, step- by-step guide to surviving the individual stages of the GAPS introduction. From information on what to pick up before starting the introduction (like good quality knives and grass-fed beef) to recipes organized by stage, this e-book offers 57 pages of a very comprehensive and practical look at GAPS. It is approved by Dr. Natasha Campbell-McBride for use with the GAPS diet.

You can download this e-book here: http://www.healthhomehappy.com/grain-free- 2/30-days-on-gaps-intro-e-book

Also research Fodmap diets.

The La Crosse Method™ Protocol

At Allergy Associates of La Crosse, our sublingual immunotherapy treatment approach is based on the available international research and our more than 40 year history of clinical application in treating more than 125,000 patients with a wide variety of allergic conditions.

As sublingual immunotherapy treatment continues to gain momentum around the United States, it is important to note that all methods of sublingual immunotherapy are not following the same protocol nor have the same results. According to our La Crosse Method™ Practice Protocol, sublingual immunotherapy dosing is determined based on the individual's skin and/or blood test results; doses are administered multiple times a day; and allergens are preserved in high glycerin content. We believe this approach is the safest and most cost-effective option for the wide variety of allergic patients. Your allergy drop treatment is customized exactly to your needs; not too little antigen and not too much. We also believe it is best to address all of your allergies comprehensively. More than 99.9% of our active patient population has more than one allergy. By mixing allergens in a 50% glycerin solution, a preservative, we are able to treat multiple allergies at the same time without the allergens degrading or interacting with one another as they can with multi-allergen shot therapy.

We also find it important to take multiple daily doses. Studies show that once drops are placed under the tongue, the allergen stays in the sublingual area for up to 48 hours. From a technical standpoint, this allows for the specialized dendritic cells to interact with T cells—an important step for allergen desensitization. Multiple dosing is necessary in order to secure constant, uninterrupted exposure over time. Without multiple doses each day, the amount of antigen drops off until you deliver the next dose, similar to a peak and valley effect. Studies have also confirmed this effect. Bordignon et al. stated that, "the allergen persistence in the oral mucosa may be a far more relevant factor for gaining efficacy than allergen concentration." 1