Arizona Advanced Medicine Clinic

Dissipating Pharaoh’s Curse: Thwarting the West Nile Virus

The West Nile virus (WNV) is indigenous to Africa, Asia, Europe and Australia. It was first isolated from the blood of a woman in Uganda in 1937, and reported in 1940 in the medical literature.2 It was found in the United States for the first time in 1999 in New York City.3 It migrated rapidly west, and was found in Arizona by 2003. Since that time, it has become the most frequent cause of epidemic meningoencephalitis in North America. In the State of Arizona there have been 106 cases of West Nile encephalitis, with 4 deaths4. In the country as a whole, 19,710 cases of West Nile virus have been reported, 8,388 of them neuroinvasive, with 785 fatalities, making a 9.3% fatality rate for neuroinvasive West Nile. Birds are the natural reservoir for the virus, and mosquitoes are the transmitting vectors5.

West Nile virus is a member of the flavivirus, a small RNA virus whose family is a member of the Japanese encephalitis serogroup, which also includes the St. Louis encephalitis virus, as well as hemorrhagic fever (mosquito-borne) and tick-borne viruses.6

Eighty percent of infected patients are asymptomatic. Of those who do develop serious infection, most are over the age of 50, with only 4% of cases reported in children under the age of 18.7 Meningoencephalitis is associated with significant muscle weakness, sometimes with an acute flaccid paralysis, sometimes with brachial plexus symptoms. It is estimated that 1 in 150 infections results in serious neurologic illness8,9, encephalitis being reported more commonly than meningitis.

If one in 150 people with infection develop serious neurologic illness, this means that 149 in 150 people develop lesser symptoms, either a flu-like illness, or minimal symptoms. Although less than 1% of people who are infected develop serious neurologic illness, to the person who develops encephalitis, the incidence of serious illness is 100%. Vulnerable populations include the elderly, the very young, those with chronic illness and diminished immune function (e.g. diabetics, patients who have been treated with chemotherapy or who are on immunosuppressive drugs ( eg. for rheu matoid arthritis, lupus, organ transplants, or cancer). In the outbreak reported from Israel in 2000, patients older than 70 years were more likely to have encephali tis. Other associated symptoms were headache, myalgia (muscle aches), chills, and rash, also abdominal pain and diarrhea.10 The Israeli study reported a 14% mortality rate for hospitalized patients during that outbreak, very similar to that reported from the initial outbreak in New York City, raising the possibility that a more virulent form of the virus had evolved since the outbreak in Romania in 1996.

Sequellae of serious neurologic illness are considerable, and persistent weakness is common.11 Outcome is significantly worse in experimental dogs (and presumably, by extension, in humans) treated with corticosteroids.12

In Arizona, 300 samples of mosquitoes are collected every month between March and October, and tested at the Arizona State Health Laboratory for virus infection, including Western Equine Encephalitis virus, St. Louis encephalitis virus, and West Nile virus. Horses and flocks of chickens are also monitored twice a month, and tested to determine whether they have been bitten and infected.

Mosquito-based surveillance seems to provide the earliest evidence of transmission of the West Nile virus, but requires that the collectors wear mosquito repellant, lest they themselves become bitten and infected.13

Diagnosis is through measurement of WNV-specific IgM, with at least a 4-fold rise in titer over a 2-week period.14 Serum may be positive or negative for WNV-specific antibody at initial presentation, therefore acute and convalescent sera should be drawn. The IgM may persist in serum for as long as 12 months, so the presence of IgM in the serum may not be diagnostic of acute infection. However, IgM does not readily cross the blood-brain barrier, so its presence in the cerebro-spinal fluid (CSF) is strongly suggestive of acute WNV infection. IgM levels are commonly positive in the CSF at initial presentation. CSF commonly is positive for WNV culture. Immuno compromised patients may never muster an antibody response. Ideally testing should be by MAC-ELISA of both WNV and St. Louis encephalitis virus, as these may have very similar clinical presentations.11

Laboratory findings are similar to any viral meningoen cephalitis - pleocytosis with a predominance of lymphocytes, high CSF protein and normal CSF glucose, normal to slightly elevated peripheral white count, sometimes hyponatremia (particularly in those with encephalitis).15

Supportive care and pharmaceuticals are the mainstay of allopathic treatment, for fever, headache, nausea, vomiting, hydration, seizures and monitoring for increased intracranial pressure with subsequent development of acute respiratory failure.

No specific pharmaceutical therapy is available as of 2005.17 No studies have been reported as yet, although a few therapeutic trials are in progress.

• Immunoglobulins - associated with risk of anaphy laxis, neutropenia, secondary infection, secondary malignancy. IgG from pooled plasma has been used therapeutically in Israel, with good results.18 Trials of IVIg are under way. In Arizona, to enroll a patient contact Dr. Eskild Petersen, University of Arizona (1-800-777-7552) or Dr. Janis Blair at Mayo Clinic, Scottsdale (480-342-0115).

• Antiviral medications - Ribavirin, a synthetic nucleoside analogue and RNA mutagen with in vitro activity against WNV. This drug has low lipid solubility and does not cross the blood-brain barrier well. Thirty-seven Israeli patients, of whom 14% eventually died, received Ribavirin in 2000.

• Interferons19 - associated with risk of anaphylaxis, depression, pancytopenia, seizures, liver failure, kidney failure. Cornell University has an interferon alpha-3n study. Efficacy of interferon is markedly diminished when treatments are delayed beyond 4-6 hours before viral challenge, making this a somewhat less than useful therapeutic tool, although it might have some effect prophylactically.

• Vaccines are currently in the initial stages of clinical trials.

• Monoclonal antibodies - One group has developed a humanized monoclonal antibody against WNV, which has been tested in mice with excellent results.20 It has not yet been tested in humans.

Many other forms of supportive and helpful treat ments are available. Herbal remedies include Humic acid extract (e.g. Ultimate Viral Defense, Perfect Solutions),21,22 Yin Qiao (Chinese herbal formulation) to relieve heat symptoms,23 formulae containing Coptis chinensis and Scutellaria baicalensis to relieve heat and toxicity.24

Orthomolecular treatments can be extremely helpful, both in the acute phase, and in the chronic recovery phase - these substances can all be given intravenously, bypassing the intestinal tract. Their function is to restore cellular health and to enable the body to deal with the viral infestation.

Supportive nutrients may include IV minerals - (magnesium & zinc especially are required for multiple enzymes, and are rapidly depleted with any physical stress), IV vitamins - especially Vitamin C in high dose, since Vitamin C is markedly depleted in severe infection and/or stress.25,26,27,28 Vitamin C is known to be viricidal in sufficiently high con centrations (serum levels over 400 mg%).29 Phospholipids given intravenously can to help heal the cell membranes whose damage leads to unnecessary cell death.30 Glycero phosphocholine is used for neuroproctsion,31 and lipoic acid for liver protection.

Homeopathic treatments are often used in conjunction with standard allopathic treatments as necessary. These may include things like Oscillococcinum - for flu-like symptoms without encephalitis, available in most health food stores.

The HEEL homotoxicology approach is two pronged:32 one arm treats the acute symptoms.The other is aimed at supporting the immune system, so that it can fight off the viral infection.

Among the remedies used acutely are encephalitis remedies like Belladonna Homaccord or Apis Homac cord,33 combination remedies which work well in conjunction with standard allopathic treatments. Practitioners may also choose to use more specific viral remedies like Gripp Heel and Engystol. They may also choose to use auto-sanguis therapy - blood (or other body fluid) is diluted with the appropriate Heel remedy and given by injection or ingestion. This serves to boost the body's immune system and helps to relieve the tox icity of infections.

Another homeopathic company approaches a patient with acute infections somewhat differently. The GUNA homeopathic approach uses remedies like GUNA-flu to mitigate the acute symptoms, drainage remedies to support detoxification mechanisms at the lymphatic, extra-cellular matrix and cell level, and specific organ remedies to support the major organs of detoxification - kidney and liver.

Single homeopathic remedies can also be used in treatment, for mild to moderate cases. Most of these are available at health food stores.

• Sulphur - for patients who are thirsty for cold drinks, with offensive body odor and sensations of great heat

• Calcaria carbonica - for patients who are cold and clammy, despairing of recovery

• Hyoscyamus - for patients who are manic, with significant muscle weakness, restlessness and delusions

• Nux vomica - for patients with seizures and vomiting

• Phosphorus - for patients who are cold, with salt cravings and anxiety

• Aconite - for patients with sensation of impending death, restlessness, facial weakness

Any of the orthomolecular and homeopathic treat ments may be used as post-infection treatments as well, to help restore the individual to full metabolic and brain function and excellent health. Their aim is not necessarily specifically to kill the virus. Anti-viral pharmaceuticals, as we have already seen, are ineffective against the West Nile virus. The aim of the orthomolecular and homeopathic remedies is to restore the body's function to health, by strengthening the immune system, neutralizing the effects of acute infection, and normalizing the hormonal-endo crine-neurotransmitter balance.

Preventive treatment can be either active or passive. With active treatment, we look to get rid of the pests. With passive treatment, our goal is to keep ourselves from being bitten by the pests.

Official governmental websites recommend DEET-containing insecticides, and also include some informa tion on Lemon Eucalyptus.

The biggest problem with chemical insecticides is that they not only kill mosquitoes, but also the mosquito hawks that eat mosquitoes, the bees that pollinate fruit trees and flowers, and ladybugs that eat many insects, as well as the frogs and other reptiles which eat the bugs. Doris Rapp, MD, a wellknown pediatric allergist, wrote about this issue in 2004.34 The venerable journal Science, and even the popular press, are now commenting on the impending extinction of the entire reptile family, due to environmental toxicity.35

Toxicity of insecticides is rated by measuring acute toxicity, the lethal dose being given in a single bolus. This author was unable to locate any studies which measure the toxicity of low doses of insecticide poisons absorbed over a period of time.

Topical conventional insect repellants for the most part contain DEET (N,N-diethyl-m-toluamide). This compound was invented in 1953. According to Science, “it smells evil, melts plastic, and is perceived by many people to be poisonous.”36 Toluene is a well known carcinogen which should probably be applied very sparingly, if at all, and not to small children, especially those with already-compromised immune and detoxification systems (like our autistic population).

Many products are available. Those containing 7% DEET will repel mosquitoes for about 5 hours. Those containing 12% DEET will repel them for a little over 7 hours.37 A much quoted article in the New England Journal of Medicine states: “Until a better repellant becomes available, DEET-based repellants remain the gold standard of protection...”38 In the same article, we find the following statement about repellents containing oil of lemon eucalyptus: “The repellent had a mean ... complete-protection time of 120 ... minutes.” If the goal is to repel mosquitoes for up to 8 hours without reapplication of product, then clearly the DEET based products are the most effective. If the need is only for one or two hours of protection, then the oil of lemon eucalyptus products would be equally effective and significantly less toxic. The issue may not be so much the DEET itself, as the DEET as it affects the Cytochrome P450 system. Concern has been voiced about the role of DEET in the Gulf War Syndrome. “DEET in combinations with pyridostigmine bromide or permethrin can lead to significant neurobehavioral deficits associated with significant inhibition of brainstem acetylcholinesterase activities.”39

Some other less toxic repellants appear to be less potent than DEET.40,41 Nevertheless, several remedies, some of which have been in use for hundreds of years with little or no known toxicity, are also effective.42,43

NoBite XF contains Neem Oil, Karanja Oil, Catnip Oil and Lemon Eucalyptus Oil. This compound requires more frequent application than DEET but has no known toxicity and is effective in repelling mosquitoes.44

Lemon Eucalyptus Oil is recommended by the CDC and discussed in the New England Journal of Medicine.45 This product seems to be effective for about two hours, before it must be reapplied.

Soybean Oil repellant is as effective as lemon eucalyptus oil, also providing about 2 hours of repellant activity, similar to the lower concentrations of DEET.46 One example of such a product is Bite Blocker which contains soybean oil, geranium oil, and vanillin.47

Catnip Oil has significant mosquito repelling properties, being initially as active as DEET. The effect diminishes after 30 minutes, and wears off within 3 hours48, thus it requires frequent reapplication. Your cats will certainly love you.

Neem Oil is known for its larvicidal properties.49,50,51 as well as its anti-viral properties.52 In a 1993 study,53 Neem Oil provided complete protection from mosquito bites for 12 hours.

The least toxic way to treat the environment is to destroy mosquito breeding grounds - all standing water, puddles, containers, old tires, ponds which have no active circulation, bird baths... It is possible to do this without toxic chemicals, simply by emptying containers and cleaning up ponds, but most municipalities choose the chemical route.

Adulticides are typically sprayed over a large area, organophosphates, pyrethrins and synthetic pyrethroids typically are used. Piperonyl butoxide is commonly used as a synergist, to eliminate the competitive advantage of those mosquitoes which are resistant to the insecticides. Phoenix and its environs use both Anvil and piperonyl butoxide in their spraying program, according to a position paper dated August 2004.54

Adult dragonflies happily eat mosquitoes, and are available through or by calling 1-616-677-2850.

The Vector Control office provides a source of Gambusia, mosquito larvae eating fish, free to the public.55

Maricopa County posts a fogging schedule on the Vector Control website, so that those who are allergic or sensitive to the compounds used may stay indoors or leave the area for a time. Theoretically the compounds are safe for pets, according to the Center for Disease Control (CDC).

Larvicides may be synthetic or organic. Bacillus thuringensis israelensis is a bacterium which eats mosquito larvae, found in some garden stores and through the Artistic Arborist, among other sources.56 DEET based products which are larvicidal (kill mosquito larvae) include the following: 87-100% larvicidal - Vaseline Mosquito Repellent, Amway Hour Guard, Off! Skintastic, Cutter Unscented, Sawyer Controlled-Release. Off! Skintastic with Sunguard was not effective.

Biological products which are larvicidal and which could be used for widespread spraying at 0.1% concentration include:

• 100% larvicidal - Bite Blocker, MosquitoSafe, Neem Aura, SunSwat
• >69% larvicidal - Ballet, Natrapel, Quwenling, Sketolene, Avon Skin-So-Soft Bug Guard
• Not significantly larvicidal - GonE!, Bygone, Alfresco

Organophosphate insecticides may persist for several months after application indoors,57 Chlorphyrifos and other organophosphates are thought to be neurodevelopment toxicants, and prenatal exposure to these agents is thought to cause biochemical and functional abnormalities in fetal neurons which may be related to subsequent behavioral abnormalities.58

Pyrethrins and synthetic pyrethroids may cause liver damage, may harm the thyroid, and disrupt the endocrine system by mimicking the effects of estrogen. This can lower the sperm count in men, and result in growth of abnormal breast cells in women.59 They can be highly toxic to bees and to fish.

These are biological products which reduce oviposition (i.e. laying of eggs) - excellent alternatives to organophosphates:

• >91% oviposition deterrence - Alfresco, Ballet, Bite Blocker, Bygone, MosquitoSafe, Natrapel, Quwenling, Sketolene, SunSqat
• 79-88% oviposition deterrence - GonE!, Avon Skin-so-soft Bug Guard, Neem Aura

Other sources for safe mosquito control can be found on the website: http://www.safesolutionsinc.com/resources.htm

In the final analysis, the best preventive treatment is a healthy body, fueled with nutritious foods, with an adequate supply of vitamins and nutrients so that there is significant functional reserve. When an infection threatens, this body can martial its defenses and throw off the infection with very little disruption to its normal every day function.

6 Solomon T. Flavivirus Encephalitis. NEJM 2004;351:370-8.

7 Centers for Disease Control. Epidemic/epizootic West Nile Virus in the United States: Guidelines for Surveillance, Prevention and Control. US Department of Health 2003, page 18.

8 Petersen LR, Marfin AA. West Nile Virus: A Primer for the Clinician. Ann Int Med 137;3:E173-179.

9 Mostashari F, Bunning ML. Epidemic west Nile encephalitis, New York, 1999: results of a household-based seroepidemiological survey. The Lancet 358 (July 28, 2001):261-264.

10 Chowers MY, Lang R. Clinical Characteristics of the West Nile Fever Outbreak, Israel, 2000. Emerg Infect Dis (Jul-Aug 2001)7;4:675- 78)

11 Sejvar JJ, Bode AB. West Nile Virus-associated flaccid paralysis outcome. Emerg Infect Dis. 2006 Mar;12(3):514-6.

12 Bowen RA, Rouge MM. Pathogenesis of West Nile virus infection in dogs treated with glucocorticoids. Am J Trop Med Hyg. 2006 Apr;74(4):670-3.

13 Centers for Disease Control. Epidemic/epizootic West Nile Virus in the United States: Guidelines for Surveillance, Prevention and Control. US Department of Health 2003, page 18.

14 West Nile Virus (WNV) Infection: Information for Clinicians. CDC website. 11 Sejvar JJ, Bode AB. West Nile Virus-associated flaccid paralysis outcome. Emerg Infect Dis. 2006 Mar;12(3):514-6.

15 West Nile Virus (WNV) Infection: Information for Clinicians. CDC website.

16 Jackson AC. Therapy of West Nile Virus Infection. Can J Neurol Sci 2004;31:131-34.

17 DeBiasi RL, Tyler KL. West Nile Virus meningoencephalitis. Nat Clin Pract Neurol May 2006;2:5(264-275).

18 Haley M et al. The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis. Clin Infect Dis 37:e88-e90.

19 Sayao AL, Suchowersky O. Calgary experience with West Nile virus neurological yndrome during the late summer of 2003. Can J Neurol Sci. 2004 May;31(2):194-203.

20 Oliphant T, Engle M. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med May 2005;11:5(522-30).

21 Lu FJ, Tseng SN. In vitro anti-influenza virus activity of synthetic humate analogues derived from protocatechuic acid. Arch Virol. 2002;147(2):273-84.

22 Anesio AM, Hollas C. Influence of Humic Substances on Bacterial and Viral Dynamics in Freshwaters. Appl Env Microbiol August 2004;70:8(4848-54).

23 Bensky D, Barolet R. Chinese herbal medicine: formulas and strategies. ©1990 Eastland Press

24 Bensky D, Gamble A. Chinese herbal medicine: materia medica. ©1993 Eastland Press.

25 Iqbal K, Khan A. Biological Significance of Ascorbic Acid (Vitamin C) in Human Health. Pakistan J. Nutri 3(1):5-13, 2004.

26 Vojdani A, Namatalla G. Enhancement of Human Natural Killer Cytotoxic Activity by Vitamin C in Pure and Augmented Formulations. J Nutr Env Med (1997)7:187-95.

27 Heuser G, Vojdani A. Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C. Immunopharmacol Immunotoxicol. 1997 Aug;19(3):291-312.

28 Stephensen CB, Marquis GS. Vitamins C and E in adolescents and young adults with HIV infection. Am J Clin Nutr. 2006 Apr;83(4):870-9.

30 Klunk WE, Xu CJ et al. Aggregation of beta-amyloid peptide is promoted by membrane phospholipid metabolites elevated in Alzheimer’s disease brain. J Neurochem. 1997 Jul;69(1):266-72.

31 Kidd PM. GPC (GlyceroPhosphoCholine), Orthomolecule For Active Living and Healthy Aging. Townsend Letter for Doctors and Patients, April 2004.

32 Heel, Inc. Routine Therapy - the Practitioner’s Handbook of Homotoxicology. Bruce Shelton, MD, MD(H), medical director. shelton@ drbruceshelton.com

33 Remedies are available from Heel Inc,

34 Rapp D. Our Toxic World, a Wake Up Call. Environmental Medical Research Foundation, Buffalo NY, © 2004.

35 Mendelson JR, Lips KR. Biodiversity - Confronting Amphibian Declines and Extinctions. Science (7 July 2006) 313;5783:48.

36 Krajick K. Keeping the Bugs at Bay. Science (7 July 2006) 313:36-38.

37 Barnard DH, Xue RD. Laboratory Evaluation of Mosquito Repellents Against Aedes Albopictus, Culex nigripalpus, and Ochlerotatus triseriatus (Diptera: Culicidae). J Med Entomol 41;4(726-30).

38 Fradin MS, Day JF. Comparative Efficacy of Insect Repellents against Mosquito Bites. NEJM July 4, 2002; 347;1:13-18.

39 Abou-Donia MB, Goldstein LB et al. Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination. Drug Metab Dis 30;3:289-294 (March 2002).

40 Chauhan KR, Klun JA. Feeding deterrent effects of catnip oil components compared with two synthetic amides against Aedes aegypti. J Med Entomol. 2005 Jul;42(4):643-6.

41 Bernier UR, Furman KD. Comparison of contact and spatial repellency of catnip oil and N,N-diethyl-3- methylbenzamide (deet) against mosquitoes. J Med Entomol. 2005 May;42(3):306-11.

42 Amer A, Mehlhorn H. Repellency effect of forty-one essential oils against Aedes, Anopheles, and Culex mosquitoes. Parasitol Res. 2006 Apr 27.

43 Xue RD, Barnard DR. Laboratory evaluation of 21 insect repellents as larvicides and as oviposition deterrents of Aedes albopictus (Diptera: Culicidae). J Am Mosquito Control Assn 22(1):126-30 (2006).

44 http://www.oasisadvancedwellness.com/products/ nobite.html

45 Fraydin MS, Day JF. Comparative Efficacy of Insect Repellents against Mosquito Bites. NEJM July 4, 2002;347:13-18.

46 Ibid

47 http://www.biteblocker.com/intro.html

48 Rimando AM, Duke SO. Natural Products for Pest Management. ACS Symposium series 927, chapter 13. Published by the American Chemical Society, 2006.

49 Awad OM, Shimaila A. Operational use of neem oil as an alternative anopheline larvicide. Part A: Laboratory and field efficacy. East Mediterr Health J. 2003 Jul;9(4):637-45.

50 Awad OM. Operational use of neem oil as an alternative anopheline larvicide. Part B: Environmental impact and toxicological potential. East Mediterr Health J. 2003 Jul;9(4):646-58.

51 Vatandoost H, Vaziri VM. Larvicidal activity of a neem tree extract (Neemarin) against mosquito larvae in the Islamic Republic of Iran. East Mediterr Health J. 2004 Jul-Sep;10(4-5):573-81.

52 Parida MM, Upadhyay C. Inhibitory potential of neem (Azadirachta indica Juss) leaves on dengue virus type-2 replication. J Ethnopharmacol. 2002 Feb;79(2):273-8.

53 Sharma VP, Ansari MA et al. Mosquito repellent action of neem (Azadirachta indica) oil. J Am Mosquito Control Assn, 9(3):359-360.

54 http://www.maricopa.gov/ENVSVC/BUSINESS/NEWS/pesticides.pdf#search=%22Maricopa%20mosquito%20control%22

55 https://maricopa.gov/ENVSVC/WATER/VECTOR.ASP 3343 W. Durango, #3911, Phoenix, Arizona 85009, tel (602) 506-0700 (Office)

56 http://www.artisticarborist.com/august_2004.htm

57 Berger-preiess E, Preiess A et al. The Behaviour of Pyrethroids Indoors: A Model Study. Indoor Air 7:248 (December 1997).

58 Landrigan PJ, Claudio L et al. Pesticides and Inner-City Children: Exposures, Risks, and Prevention . EHP 7;suppl 3(June 1999).

59 Cox C. Sumithrin (D-Phenothrin). J Pesticide Reform (summer 2003) 23;2:10-14)

60 Xue RD, Barnard DR. Laboratory evaluation of 21 insect repellents as larvicides and as oviposition deterrents of Aedes albopictus (Diptera: Culicidae). J Am Mosq Control Assoc. 2006 Mar;22(1):126-30.

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