Category: Allergy

By Joan Lewis, MD
Otorhinolaryngologist

Introduction

Disorders of the ear, nose, and throat (ENT) are the cause of many patient visits to a primary care physician. Some of the common ENT disorders include acute and recurrent otitis media (OM); acute, chronic, and recurrent tonsillitis; and allergic and recurrent rhinitis and chronic rhinosinusitis (CRS). However, the common cold remains one of the most frequent upper respiratory tract infections (URIs). Approximately half of the cases of colds in children can be attributed to a wide variety of up to 200 different viruses that are seasonally active, such as rhinoviruses in the early fall, spring, and summer. Other viruses that might cause URIs include coronavirus, parainfluenza virus, adenovirus, enterovirus, and respiratory syncytial virus.¹

The subsequent development of recurrent sinusitis²–³ and OM⁴ commonly has been related to viral URIs that last longer than a week. A child can be expected to have 6 to 10 colds annually, whereas adolescents may have only 2 to 4 colds per year. In developing countries, URIs tend to be more severe, such as pneumonia and influenza, with a higher risk of complications. Therefore, URIs can be a leading cause of death for children younger than 5 years.⁵

An increased understanding of the pharmacoeconomic incidence, relevance of antibiotic resistance, physician involvement, and anatomical and physiological features of each of the common ENT disorders will improve clinical outcomes. An integrative medical approach that uses complementary and alternative therapies, such as antihomotoxic medications, in addition to mainstream medical therapies is a therapeutic strategy that shows much promise in reducing the current disease burden and preventing further recurrences.

Pharmacoeconomic Incidence

The annual cost of time lost from school for adolescents and from work for adults because of URIs is substantial and is estimated to be as high as $15 billion in direct treatment costs by practitioners, with more than half of that amount being for ambulatory care centers in hospitals. The indirect cost of wages from URIs is estimated at $9 billion.⁶

The over‑the‑counter cough and cold remedy market was identified as being the “most competitive category in North America,” with sinusitis showing the most potential growth. Figures extrapolated from a survey of 4,000 US residents suggested that a total economic burden of $40 billion, including income lost from time off for these occurrences, was related to noninfluenza viral URIs alone.

Antibiotic Resistance

In 2007, prudent antibiotic use was not correlated with appropriate knowledge of microbial resistance;⁷ thus, the reduction of unnecessary antibiotics as treatment options for the virally associated common cold was identified in 2008 as a public health priority.⁸

Recent public opinion polls show an increased understanding of the relationship between the development of resistant bacterial strains and inappropriate antibiotic use and also report a significantly higher level of trust in physicians who did not prescribe antibiotics for the common cold.⁹ However, 45% of respondents in the United States in 2008 and 41% of a population in Belgium in 2001 still did not understand the lack of efficacy of antibiotics in treating viral illnesses.¹⁰ These data suggest that there is still a considerable opportunity to better educate patients and health care providers.

Environmental Impact

In the pediatric population, the close proximity of children in day‑care centers contributes to the transmission of respiratory tract disease.¹¹ Childhood exposure to common environmental pollutants, such as firsthand or secondhand smoke, and common household allergens, such as aerosolized cleaning products, in persons with a genetic predisposition might be associated with later development of asthma and allergic conditions through inappropriate sensitization.¹² Furthermore, asthmatic children have URIs more frequently than their nonasthmatic classmates. The polycyclic aromatic hydrocarbons present in diesel exhaust particles have recently been shown to stimulate the release of interleukin (IL)‑4, IL‑8, and histamine from basophil cells,¹³ suggesting that other common environmental pollutants also can play a role in the development of asthma and allergic rhinitis.

Physician Involvement

Most persons with ENT disorders visit their health care practitioners early in the disease process because the associated signs and symptoms are readily apparent to both the patient and practitioner and frequently affect activities of daily living. The mechanical and physical appearances of structures (e.g., teeth, palate, gingiva, and tongue) indicate a variety of physiological states and can be used diagnostically with a minimal investment of time. For example, fasciculations of the tongue might indicate neural disorders; a glossy tongue is associated with nutritional deficiencies, such as a deficiency in vitamin B12. Dental caries or loss correlates with impaired immune systems, smoking or tobacco use or exposure,¹⁴ and poor nutritional status. Xerostomias are linked to poor hygiene, and temporomandibular joint disorders can be attributed to trauma or articular disorders.¹⁵

Relevant Anatomical and Physiological Features

Lymphatic tissue in the Waldeyer ring is designed to protect the body from pathogens and toxins encountered in this vulnerable area; therefore, it is strategically placed to protect critical respiratory and digestive functions. It is the first protective barrier encountered by orally ingested and inhaled toxins, viruses, and bacteria. An interaction with the body’s lymphatic tissues provokes a reaction that includes copious nasal discharge, sneezing, coughing, and mucosal engorgement as a mechanism to remove the offending substance. The resultant reaction, with its associated signs and symptoms, is diagnosed as the common cold or rhinitis. Further progression to include fever and exhaustion, and the presence of clusters of similar infections in the community and a documented influenza virus infection, would lead to a diagnosis of the flu.

Treatment for these uncomfortable reactions is largely symptomatic.

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Pathological Conditions

A short review of the relevant pathological features of each of the common ENT disorders is included to provide further insight into potential therapeutic strategies.

Otitis Media

Acute OM
Acute OM is the most frequent ailment encountered by pediatricians. Persistent middle ear effusion from a failure of the mucus and microbial and immune system debris in the middle ear to drain via the Eustachian tube to the pharynx is associated with recurrent OM.¹⁶ Implicated factors include functional obstruction of the Eustachian tube, anatomical differences in the infant’s Eustachian tube, and a more horizontal position when bottle feeding an infant in a supine position, favoring a retrograde flow of milk. Furthermore, passive smoke environments impair normal ciliary movement that sweeps away debris, and immune system disorders are associated with increased mucus production.

Recurrent OM
Preexisting antibiotic treatment is associated with an increased rate of recurrent OM in young children, supporting the hygiene hypothesis, in which interruption of a normal inflammatory response during childhood leads to an imbalance in Th1/Th2 cell regulation, predisposing a child toward allergy.¹⁷ Novel otopathogens can be cultured in those with recurrent OM after a month‑long course of antibiotics for acute OM.¹⁸ Long‑term morbidity, with recurrent OM occurring before the age of 3 years, might affect the child’s subsequent decreased comprehension when reading.¹⁹

Bioregulatory Treatment
For acute OM, use the basic/symptomatic approach as follows: prescribe Belladonna-Homaccord (8–10 drops twice daily) and Traumeel (8–10 drops or 1 ampoule warmed and instilled into the affected ear twice daily). If resolution does not occur within a reasonable time, individualize therapy:

• With confirmed bacterial etiology and significant inflammation, prescribe Echinacea compositum: 1 tablet every 30–60 minutes up to 12 tablets per day for acute conditions; for chronic conditions, 1 tablet dissolved in the mouth three times daily. Injectable route (IM, SC, ID, or IV) 1–3 times per week may be used if within regulatory framework.†
• With confirmed viral etiology, prescribe Engystol: 1 tablet three times daily or 1 ampoule daily (injectable routes as above for acute situations).
• For marked restlessness, fever, and agitation, prescribe Viburcol suppositories: adults, 1 suppository 2–3 times daily; infants under 6 months, half a suppository up to one per day.

If signs and symptoms persist, consider the 3‑pillar regulation approach (detoxification and drainage; immunomodulation; cell and organ support).† During latent phases, Mucosa compositum (± Coenzyme compositum, Ubichinon compositum) supports cells and organs; Traumeel for immunomodulation; and the Detox‑Kit (comprising Lymphomyosot, Nux vomica-Homaccord, and Berberis-Homaccord) for detoxification and drainage. Persistent effusion may require referral for myringotomy.

Tonsillitis

Acute Tonsillitis
Tonsils are antigen‑presenting lymphatic tissue in the Waldeyer ring, mounting an appropriate B‑cell response. Acute tonsillitis presents as erythematous, swollen tonsils with stertorous breathing. Hypertrophied tonsils can cause sleep disorders and daytime inattentiveness in children. Microbiological evaluation (culture or rapid antigen tests) is required to exclude streptococcal pharyngitis, which necessitates antibiotics to prevent cardiovascular or renal complications.²⁰

Chronic Tonsillitis
Generally bacterial in etiology and more prevalent in adults. Crypts containing pus can form; surgical excision is controversial due to postoperative pharyngitis despite no visible recurrent infection. Post‑tonsillectomy changes in oral flora suggest the chronically infected tonsil may harbor anaerobic bacteria, and removal may restore normal flora.²¹

Recurrent Tonsillitis
In children, recurrent tonsillitis differs from adult chronic forms by higher antigen presence in acute stages. If peritonsillar abscess occurs, immediate tonsillectomy may be first‑line.²² Antigen presentation and B‑cell function remain intact; if possible, avoid tonsillectomy to preserve natural killer cell maturation.

Bioregulatory Treatment
For acute tonsillitis: prescribe Angin-Heel (initial: 1 tablet every 15 minutes for 2 hours; then 1 tablet three times daily), Vinceel spray (once daily), and Mercurius-Heel (1 tablet three times daily). If unresponsive:

• Bacterial etiology: Echinacea compositum as above.
• †Regulation approach: use detoxification, immunomodulation, and organ support as outlined for OM.

References

1. Common cold viruses and URIs; rate in children and adults.
2. Recurrent sinusitis etiology overview.
3. Recurrent sinusitis pathophysiology.
4. Otitis media linkage to viral URI.
5. URI mortality in children <5 years.
6. Dixon RE. Economic costs of respiratory tract infections in the United States. Am J Med. 1985;78(6B):45‑51.
7. McNulty CA, et al. Public’s knowledge and attitudes to antibiotic use. J Antimicrob Chemother. 2007;59(4):727‑738.
8. Earnshaw S, et al. European Antibiotic Awareness Day survey. Euro Surveill. 2009;14(30):19280.
9. Andre M, et al. Public knowledge of antibiotic use in Sweden. J Antimicrob Chemother. 2010;65(6):1292‑1296.
10. Edgar T, Boyd SD, Palame MJ. Sustainability for behaviour change against antibiotic resistance. J Antimicrob Chemother. 2009;63(2):230‑237.
11. Fleming DW, et al. Day‑care attendance and pediatric URIs. Pediatrics. 1987;79(1):55‑60.
12. Arshad SH. Indoor allergen exposure and allergy development. Curr Allergy Asthma Rep. 2010;10(1):49‑55.
13. Lubitz S, et al. Diesel exhaust proallergic effects. Environ Toxicol. 2010;25(2):188‑197.
14. Tanaka K, et al. Smoking and tooth loss in Japanese women. Ann Epidemiol. 2005;15(5):358‑364.
15. McNeill RA. Bacteria in ear and nasopharynx in acute OM. J Laryngol Otol. 1962;76:617‑622.
16. Emerick KS, Cunningham MJ. Tubal tonsil hypertrophy after adenoidectomy. Arch Otolaryngol Head Neck Surg. 2006;132(2):153‑156.
17. Mattila PS. Amoxicillin and recurrent OM in young children. J Pediatr. 2010;156(1):163.
18. Kerschner JE, et al. Otitis media risk factor knowledge. Int J Pediatr Otorhinolaryngol. 2005;69(1):49‑56.
19. Luotonen M, et al. Recurrent OM and linguistic skills. Pediatr Infect Dis J. 1996;15(10):854‑858.
20. Bonsignori F, et al. Upper respiratory tract infections in children. Int J Immunopathol Pharmacol. 2010;23(suppl 1):16‑19.
21. Burton MJ, Glasziou PP. Tonsillectomy vs non‑surgical for chronic/recurrent tonsillitis. Cochrane Database Syst Rev. 2009;(1):CD001802.
22. Page C, et al. Immediate tonsillectomy for peritonsillar abscess. J Laryngol Otol. 2010:1‑6.

†The 3‑pillar regulation approach comprises detoxification and drainage; immunomodulation; and cell and organ support.

Allergic reactions and symptoms are extremely com- plex in their origins and not yet fully understood.

Allergies can be divided into three major types:

1. delayed reaction allergies caused by sensitized lymphocytes
2. antigen-antibody allergies caused by a reaction between immunoglobulin G (IgG) antibodies and antigens and
3. atopic or inherited allergies which are characterized by the presence of large amounts of sensitizing antibodies called IgE antibodies.

Examples of delayed reaction allergies, also called cell-mediated hypersensitivity allergies, include contact dermatitis or skin eruptions resulting from exposure to causative agents such as drugs, chemicals and the toxins of poison oak or poison ivy.

Antigen-antibody allergies occur when an individual has built up a high titer of antibodies following exposure to a specific antigen.Examples of antigen-antibody reactions include transfusion reactions and autoimmune disease.

Atopic allergies affect roughly 10% of the population. The hypersensitivity involves the production of excessive amounts of IgE antibodies. Allergens which react specifically in this way include pollen,dust, foods as well as bee,wasp and hornet venoms.Reactions of this type include hay fever, asthma, urticaria (hives) and potentially fatal anaphylaxis. Contact with an allergen by a person with an atopic allergy triggers a local inflammatory reaction with accompanying tis- sue damage.

At the metabolic crossroads of all these allergic reactions is histamine. An excess of histamine is apparently re- leased when the body comes into contact with substances to which is it sensitive.Histamine acting as a mediator of hypersensitivity triggers the inflammatory process.

A remedy which lends itself exceptionally well to the antihomotoxic treatment of various allergies is BHI Allergy, which has been specifically formulated for the treatment of allergic reactions and symptoms.

Focusing Ingredient:

Histamine hydrochloride 8x:

specific antiallergy effectiveness

Accompanying Ingredients:

Arnica 6x:

inflammations, tissue traumas, neurodermatitis

Ignatia amara 6x:

constrictive sensation in larynx and trachea,cough,dif- ficult breathing,fluent coryza, catarrh

Lycopodium clavatum 6x:

throbbing headache, cough, inflammation of the eyes, violent catarrh, difficult breathing, sore throat

Thuja occidentalis 6x:

skin inflammations, warts,nasal catarrh, asthma, eczema

Arctium lappa 8x:

chronic skin inflammations

Arsenicum album 8x:

eczema, itching, skin inflammations

Acidum formicum 8x:

stimulating factor for toxin elimination

Ledum palustre 8x:

constrictive oppression of the chest,suffocative breathing arrest, cough, painful respiration

Antimonium crudum 10x:

affections of the mucous membranes, nasal and bronchial catarrh, eczema, skin eruptions with itching

Embryo bouis 10x:

detoxicating factor for all tissues

Graphites 10x:

skin disorders with eczematous eruptions, scrofulous affections

Pix liquida 10x:

eczemas of the hands, itching, eruptions

Tellurium metallicum 10x:

eczema scrofulous conditions, eruptions and pain

Selenium 12x:

nasal catarrh, cough with mucus and expectoration, straining in the chest, skin inflammations, blisters, itching

Sulphur 12x:

skin conditions, eruptions,mucous membranes of the bronchi,allergic reactions

Psorinum nosode 15x:

nosode for skin infections, eczemas and inflammations

This combination of ingredients works together to mutually strengthen their effects on the histamine metabolismand allergic symptoms.

The respiratory symptoms associated with allergies such as sneezing,cough, itching, burning watery eyes, catarrh and difficult breathing respond well to treatment with BHI Allergy. Skin inflammations due to chemical or food allergies as well as poison oak or ivy and insect bites and stings may also be treated in this way.

The recommended dosage is one tablet taken six (6) to ten (10) times daily, or about every two hours at the onset of symptoms.This dosage should then be decreased to three (3) times daily upon improvement. In cases where symptoms are severe due to reexposure to causative agents, BHI Allergy may be administered, one tablet every 8-10 minutes to relieve the immediate discomfort. Once relief is observed, the normal dosage schedule is resumed.

This remedy combines well with other BHI remedies when,additional symptoms are present. For example:

Hay fever, catarrh:

BHI Sinus

Asthma:

BHI Asthma

Skin inflammations:

BHI Skin

Healing of skin lesions:

BHI Hair & Skin

These accompanying remedies should be administered six (6) to eight (8) times daily, every 2-2/2 hours, alternating with BHI Allergy.

For example:

For asthma with difficult breathing administer BHI Asthma upon rising, BHI Allergy one hour later, BHI Asthma one hour following Allergy and so on throughout the waking day until symptoms improve. For acute asthmatic attacks administer one tablet of BHI Asthma every eight (8) minutes until symptoms improve and then return to the previous schedule.

Reprint and translated from: Rosales-Estrada M. El syndrome de inflamación
de las mucosas en la enfermedad alérgica. Revista Colombiana de Pediatría.
2003;38(3):201-5.

INTRODUCTION
It is common to find allergic patients with simultaneous clinical signs or symptoms of the respiratory and/or gastrointestinal and/or genitourinary mucosal membranes. In the present study the common denominator was allergic rhinitis. Simultaneous clinical involvement, circumscribed to the aforementioned mucosal tissues (mucosae) clearly suggests common physiopathological factors in allergic disease; accordingly, alterations of one type of membrane affect the others, or alterations of two or more mucosae may be explained on the basis of a common mechanism.

Hypothesis. Allergic disease can give rise to simultaneous clinical manifestations of the respiratory, gastrointestinal and genitourinary mucosal membranes.

Objective. To determine whether allergic disease can give rise to simultaneous clinical manifestations of these mucosae.

Summary. Patients who have allergies can have simultaneous respiratory, digestive and genitourinary mucosal disease. I performed a retrospective study in 30 patients; 24 children and 6 women. The children were between 5 and 9 years old, and the women were between 26 to 40 years old. All of them suffer from allergic diseases.

Results. 100% had clinical respiratory diseases like rhinitis, asthma, arithenoids or vocal cord inflammation, tonsillectomy, and/or frequent respiratory viral infections. 100% of the patients had clinical digestive diseases such as gastro-esophageal reflux, gastroduodenitis, constipation and diarrhea. 87% of the female patients had clinical genitourinary diseases such as vulvovaginitis and urinary infections.

The results of this study are very important because they provide information regarding the clinical behaviour of allergic diseases, which can be systemic. According to this concept, its treatment should be holistic and individual because each patient can have one or more mucosae involved. The most recent articles of medical literature refer to rhinitis and asthma only as a like process.

MATERIALS AND METHODS
A retrospective analysis was made of 30 deliberately selected allergic patients with clinical manifestations of allergic rhinitis that coincided with clinical manifestations of the respiratory and/or gastrointestinal and/or genitourinary mucosal membranes. These clinical manifestations were: asthma, sinusitis, otitis media, acute and recurrent viral respiratory infections, adenotonsillar hypertrophy, inflammation of the vocal cords and arytenoiditis, esophagitis, gastroesophageal reflux (GERD), gastritis, duodenitis, diarrhea, constipation, vaginitis and urinary infections.

The study series comprised 24 children and 6 adult women. Of the pediatric patients, 10 were girls and 14 were boys. The patient age varied from 5-9 years among the children and from 26-40 years in the case of the adults. Three of the women were nulliparous. The study period was from April 30, 2002 to April 30, 2003.

Allergic patient classification was based on an evident clinical history of rhinitis, with or without simultaneous asthma and/or total immunoglobulin E (IgE) levels above normal or specific IgE positivity for a given antigen. Clinical antecedents of adenoid removal or tonsillectomy in a large proportion of cases contributed to establish the diagnosis. Thus, the sum of these clinical events undoubtedly would classify these patients as allergic subjects.

The definition of rhinitis was based on a clinical history of abnormally increased and chronic nasal itching, marked sneezing particularly in the morning, nasal congestion and rhinorrhea of variable intensity according to the severity of the clinical process. Almost all these patients had previously used local steroids applied to the nasal mucosa, prescribed by a physician unrelated to the
present study.

Asthmatic patients in turn were defined as those with two or more asthmatic episodes a year on average, in the previous three years, with frequent beta-2-adrenergic and/or inhalatory steroid use.

Esophago- and/or gastro- and/or duodenitis were diagnosed in the presence of endoscopic and histological findings corresponding to such disorders.

Recurrent acute viral respiratory infection (ARI) was diagnosed when the patient suffered one or more infections a month.

Clinical gastritis in turn was defined by clinical signs of acute gastritis – the latter being established by acute epigastric pain accompanied or not by vomiting and relief following antacid administration.

Chronic cough was defined as cough persisting for more than 20 days in different episodes, with a cause not different from allergy of the upper airways.

Gastroesophageal reflux (GERD) in turn was diagnosed by gammagraphy or a history of chronic vomiting in a child, or – in the case of adults – chronic heartburn.

Arytenoiditis and inflammation of the vocal cords was accepted when laryngoscopy confirmed inflammation of these structures.

Chronic diarrhea was defined as two or more daily depositions, with diarrheic consistency on one or more occasions – all with colic type abdominal pain.

Constipation was defined as an absence of bowel movement for over 48 hours, with hard stools and a large fecal bolus.

Vulvovaginitis was described as an episode of vaginal secretion, itching or inflammation of the skin of the vulva and vaginal mucosa.

Urinary infection in turn was considered for those patients presenting at least one episode of clinical signs and symptoms of urinary infection and positive urine culture for a microorganism known to cause such disorders (bacterial count: 100,000 CFUs or more).

Likewise, 100% had clinical manifestations of the gastrointestinal mucosa. These manifestations may or may not correspond to allergic physiopathological processes of the membranes. Many of these patients presented clinical signs and symptoms of gastritis in the presence of acute respiratory infection (ARI); 5 of them presented gastric ulcer as established at endoscopy, coinciding with an acute episode of viral respiratory infection.

On the other hand, 61.9% of the female patients, regardless of age, showed clinical alterations of these mucosae, manifesting as vulvovaginitis and/or urinary infection.

CONCLUSION
The selected allergic patients with clinical manifestations of the respiratory tract were seen to possibly present simultaneous alterations of the gastrointestinal and/or genitourinary mucosal membranes.

DISCUSSION
The following syndromic manifestations simultaneously affect the mucosal membranes of the respiratory and/or gastrointestinal and/or genitourinary tracts, and partially or completely confirm the different clinical manifestations of MUCOSAL INFLAMMATION SYNDROME, as described for the first time in the present article. These observations were made in allergic outpatients or allergic individuals admitted to hospital, and their detection merits attention and sensitivity on the part of the supervising physician.

1. Girls with sinusitis and/or allergic rhinitis and/or pharyngitis, with concomitant vaginitis. Eventual ascending urinary tract infection.
2. Nursing infant (age under 3 months) with gastroesophageal reflux (GERD) (or underlying gastroenteritis) and nasal congestion (noisy nasal breathing) – this latter symptom often being observed before manifestations of GERD become apparent.
3. Rhinitis, sinusitis and asthma.
4. Upper respiratory tract allergy and esophago-gastroduodenitis.
5. Acute viral respiratory tract infection and gastritis and/or exacerbation of gastritis.
6. Immediate recurrence of GERD (or underlying gastroenteritis), associated with acute viral respiratory infections.
7. Sinusitis and soft stools with mucus and sometimes of a foul-smelling nature, in children under three years of age.
8. Acute viral respiratory tract infections with soft stools, and sometimes diarrhea.
9. Concurrence of tonsillitis with right iliac fossa pain simulating appendicitis or diffuse abdominal pain.
10. Viral respiratory infections and so-called mesenteric adenitis (diffuse abdominal pain concomitant to viral respiratory infection).
11. GERD (or underlying gastroenteritis) and chronic cough and/or asthma.
12. GERD and recurrent airway infections.
13. Geographic tongue and manifestations of upper respiratory allergy and/or gastroduodenitis.
14. Reappearance of geographic tongue with acute viral respiratory infections.
15. Posterior laryngitis (edema, leveling and erythema of the inter-arytenoid mucosa) and edema of Reinke (vocal cord edema),
    associated with GERD.
16. Urinary infection and/or vulvovaginitis associated with constipation.
17. Urinary infection and/or vulvovaginitis associated with allergic enteropathy.
18. Endometriosis in allergic women and allergic enteropathy and/or constipation.
19. While GERD of the nursing infant (generally under 6 months of age) reflects gastrointestinal mucosal disorders, it has been seen to exacerbate if the mother consumes dairy products, suffers inflammatory enteric disease (constipation, diarrhea), asthma crises, or acute viral respiratory infections.
    
    • The medical literature reports the partial concurrence of these manifestations:
      • 77% of the adult asthmatic population experience symptoms of GERD.
      • 43% of asthmatic patients subjected to digestive tract endoscopy present esophagitis or Barrett’s esophagus.
      • 20% of children with rhinitis develop asthma.
      • 50% of children with asthma develop rhinitis.
      • Marked association of sinusitis, asthma, laryngitis, pneumonia and bronchiectasia in patients with GERD (patients aged 2-18 years).
      • Clinical association of tonsillitis and right iliac fossa pain simulating acute appendicitis (involving patients needlessly subjected
      to appendectomy). The importance of focusing attention on the global involvement of the mucosal membranes in a given
      patient is that the diagnostic and management approach should be holistic and individualized.
      A lack of response to treatment on the part of pathology related to a given mucosal membrane in the context of allergic disease is seen
      on a daily basis in medical practice when necessary attention is not focused on other simultaneously affected mucosal membranes. The
      following may serve as examples:

A lack of surgical intervention to correct important adenoid hypertrophy implies frequent respiratory infections (viral, otitis,
sinusitis).

1. Torpid course of asthma in patients with uncontrolled GERD (or underlying gastroenteritis).
2. Acute respiratory infections and the presence of GERD (or underlying gastroenteritis).
3. A lack of response in allergic patients with uncontrolled rhinitis.
4. Persistent asthma due to undiagnosed bacterial sinusitis.
5. Persistence of vaginal secretion and/or urinary infections in patients with constipation or allergic enteropathy.

In order to begin to modify old paradigms, allergic disease seen from this perspective would not be exclusive to the different subspecialties, determined by the affected body organ. In effect, such conditions could be treated by all physicians, regardless of their specialty, provided thorough knowledge is gained in all spheres where allergy as a systemic disorder produces its devastating effects. Neglect in this context would be a sign of incompetence.

STUDY

As an example, an ear, nose and throat (ENT) specialist could not treat rhinitis if the intestinal alterations are not first dealt with. Gynecologists or urologists likewise would not be able to treat a large percentage of cases of vulvovaginitis and urinary tract infections without first treating the respiratory allergies and intestinal disorders. In turn, pneumologists would not diagnose gastritis if not intentionally explored. The same considerations apply to the other medical specialties that deal with allergic processes.

This clinical approach involving physiopathological dependency of the mucosae in allergic disease would fully reorientate the current treatment established by conventional medicine; each mucosal membrane deals with somewhat different immunological information, though with crossed immune data among different membranes. As an example, a food allergen can produce digestive tract and respiratory symptoms at the same time.

Food allergies can coincide with allergy produced by aeroallergens in up to 70% of cases, which increases the possibility of crossreactions between foods with aeroallergens. This data implicates the intestine as an important antigen generating source – a fact that must be taken into account when treating an allergic patient, regardless of where the allergic process manifests. It is our experience that once a patient starts a correct diet, with good intestinal hygiene and environmental control, allergic processes largely disappear.

Another mistake in medical practice is to consider these symptoms as a disease. Such manifestations are actually symptoms or signs of allergic disease, and the correct diagnosis of an allergic patient should be based on the following premises: allergic disease with manifestations of esophagitis, gastritis, rhinitis, asthma, vulvovaginitis, etc. The practice of considering an organ isolatedly from the rest of the organism fails to take into account that the mucosal membranes share immunological information, and that alterations of one membrane can affect others.

Lastly, another aspect that deserves mention on the basis of the findings of the present study is that ascending urinary tract infection and vulvovaginitis may be related to alterations of nearby mucosal membranes – such as constipation or allergic enteropathy – or more distant mucosae, such as in the case of allergic rhinosinusitis. A number of studies already mention allergic disease as a cause of vulvovaginitis, and even establish a relation to dust mite allergy.10 In my opinion, this problem is very common, though the medical literature does not yet report the situation as such.

It is hoped that the present study may serve as motivation for investigators to clarify the prevalence of this syndrome in allergic disease, to establish a new definition for the latter, and to explore the association between allergic pathology and other mucosal disorders such as GERD in the adult, vesicoureteral reflux, interstitial cystitis in the adult, constipation and endometriosis.

As a general conclusion, I am of the opinion that a clinical syndrome exists in allergic disease, which from the physiopathological perspective may partially or fully implicate the respiratory, gastrointestinal and genitourinary tracts, and that the medical literature has not yet recognized its relevance.

The scientific bases explaining the physiopathology of mucosal inflammation syndrome in allergic disease are based on the new concept of modern psycho-neuro-endocrino-immunology, which we hope to develop in the following issue pending publication.

The latest publications referring to allergies only view rhinitis and asthma as manifestations of one same process. The corroboration by other investigators of the simultaneous involvement of the mucosal membranes in the allergic patient would help confirm a new definition of allergic disease, and thus also promote a new approach to management.

Randomisierte Äquivalenzstudie zum Vergleich der Wirksamkeit und Verträglichkeit eines homöopathischen Nasensprays mit einem Cromoglicinsäure-Nasenspray bei der Behandlung der saisonalen allergischen Rhinitis

Michael Weiser’, Lutz H. Gegenheimer, Peter Klein3

1 Department of Antihomotoxic Medicine, Baden-Baden

2 Reporting and Consulting Services in Clinical Pharmacology, Mannheim

3 Datenservice Eva Hoenig GmbH, Rohrbach

Address of corresponding author:.

Dr. Michael Weiser

Department of Antihomotoxic Medicine

Dr. -Reckeweg-Str. 2-4, D 76532 Baden-Baden, Germany

KEY WORDS
Homeopathy, cromolyn sodium, clinical study, seasonal allergic rhinitis

SUMMARY
Background: The. objective of the clinical. study was to investigate the-efficacy and
tolerance of a homeopathic nasal spray in cases of hay fever (seasonal allergic rhinitis) in comparison with the conventional intranasal. cromolyn sodium therapy. Patients, and methods: In total 146 out-patients with symptoms of hay fever were enrolled into the clinical study(randomized, , double-blind, equivalence-trial)(time of treatment: 42 days). The homeopathic remedy (Luffa comp. -Heel'" Nasal Spray, dosage: 0. 14 ml per application, 4 times a day/naris) consisted of a fixed combination made up of Luffa operculata, Galphimia glauca, histamine, and sulfur. The main outcome measure of the efficacy was the quality of life as. measured by means of the Rhinoconjunctivitis Quality of Life-Questionnaire (RQLQ). The tolerance of the trial medication was registered by means of global assessment, rhinoscopy, recording of adverse events and with the aid of vital and laboratory parameters.

Results: The results of the study demonstrate a quick and lasting effect of the treatment that was independent from the medication applied and produced a' nearly complete remission of the hay fever symptoms. The RQLQ global score changed significantly in the course of the treatment indicating therapeutic equivalence between the two forms of treatment. Adverse systemic effects did not occur. Local adverse events appeared in three patients.

Conclusions: The . study proved that for the treatment of hay fever the homeopathic nasal spray is as efficient and well tolerable as the conventional therapy with cromolyn sodium.

INTRODUCTION
Seasonal allergic rhinitis (hay fever) is widespread among general·population. The prevalence of the disease in Central Europe is estimated to range around 20% [1, 2]. Seasonal allergic rhinitis is provoked by pollen from various plants. Via an immunological mechanism·they cause inflammation of the nasal, mucosa which is associated with characteristic symptoms including nasal hypersecretion and obstruction, mucosal erythema and enema, sneezing, and itchy. nose. Accompanying symptoms of allergic conjunctivitis, fatigue, and headache may in addition. impair subjective well-being. The intensity of these symptoms. depends. on the. extent of antigen exposure and is thus season-specific. Concentrations of tree pollens are generally highest in spring, while grass pollens are more abundant in summer and weed pollens in late summer and early autumn [3].

Since pollen allergens are ubiquitous and difficult to avoid, and. since desensitization may take years, is not always successful, and carries risks (e. g. anaphylaxis), symptomatic

treatment of hay fever 'is often. necessary. Conventional medicine offers several well-established therapeutic strategies, such as intranasal cromolyn sodium, intranasal or oral antihistamines as well as intranasal and if necessary oral corticosteroids.

A homeopathic remedy for seasonal allergic rhinitis was developed as a therapeutic option comprised of Luffa operculata, Galphimia, glauca, histamine, and sulfur. The constituents of this remedy (manufactured and marketed as. Luffa comp. -Heel" Nasal.

Spray, by Heel GmbH, Baden-Baden, Germany)have accordingly been co-ordinated in such a manner that they effectively complement each other in their therapeutic action: Gallophilia glauca and histamine are two agents whose therapeutic effectiveness is well known, especially for affections of the skin and mucous membranes. Their therapeutic action is enhanced by sulfur as stimulation (reversal) remedy for chronic and inflammatory diseases and Luffa. operculata, indicated for common colds and allergic affections of the respiratory organs such as hay fever and asthma. The homeopathic nasal spray used in this study contains a fixed combination of Luffa operculata and Galphimia glauca in dilutions 4X, 12X, and 30X and histamine and sulfur in dilutions 12X, , 30X, and 200X (the degree of dilution is indicated by an X, which indicates the rati) of 1. part of active ingredient to. 10 parts of diluent. A"1X" indicates a ratio of 1:10, a "2X" indicates a dilution of 1:100, etc.（4, 5]). In a meta-analysis of seven randomized double-blind trials Galphimia glauca proved superior to placebo' in reducing ocular hay fever symptoms; the response rates of Galphimia glauca were estimated to he similar to those specified for conventional antihistamines [6]. The present study was designed to compare uffa comp. -Heel" Nasal Spray with a nasal spray containing 20 mg/ml cromolyn sodium (usual concentration marketed in Germany) with respect to both efficacy and tolerance in the therapy of seasonal allergic rhinitis.

PATIENTS AND METHODS

The study protocol was approved by an independent Ethics Committee (Ethikkommittee der Landesärztekammer Rheinland-Pfalz) and implemented in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. All patients participating in the study gave written informed consent. The study was performed according to a parallel group design.Within each study.center the patients were evenly randomized to cromolyn sodium or homeopathic treatment (because the number of patients recruited-by each center could not be estimated apriori, randomization was performed in blocks of 2). In a double-blind manner, one spray, about 0.14 ml, was administered 4 times daily into each nostril. During acute exacerbation of symptoms, up to 8 sprays per nostril were allowed. To ensure blinded conditions both compounds (representing aqueous solutions and containing benzalkonium chloride as a preservative) were dispensed in identical,neutral bottles (eventually by direct and immediate comparison the preparations were distinguishable by.taste).Sealed envelopes containing the code for each patient were supplied by the sponsor to the investigators. It was only allowed to break the individual random code in cases of emergency (the code was broken after data entry and the decision about protocol deviations/evaluations groups through the responsible biostatician). Patients were recruited from different study centers located in the same geographic region(Upper Rhine Valley of Germany) during the hay fever seasons of 1996 and 1997. They were to be seen for assessment of baseline status (visit 1), and after 7±1,14±2,28±3 and 42±3 consecutive days of treatment (visits 2 to 5). The treatment duration of 6 weeks was chosen based on clinical experience; it was short enough to ensure that in the majority of patients antigenic exposure persisted throughout their participation in the trial and long enough to compensate for variation of weather conditions affecting pollen concentrations.

Study Population

Male and female out-patients,.aged 18 to 60 years, suffering from seasonal allergic rhinitis as diagnosed by RAST (lgE-antibody measurement),'scratch or skin-prick test were eligible for the study. Patients were excluded if they had a diagnosis of perennial allergic rhinitis or infectious diseases of the upper respiratory tract; known hypersensitivity to the study medication; treatment with drugs containing cromolyn sodium or corticosteroids within two' weeks of the: study start; treatment with antihistamines or alpha-sympathomimetics within 24 hours of. the study start; or regular use of anti-inflammatory agents and analgesics. No pregnant or nursing women were accepted. In addition, to reduce the risk of dropouts due to the need for prohibited co-medication, patients were disqualified from study. participation if they had a history of emergency treatment of allergic symptoms or of regular treatment of hay fever with oral corticosteroids and/or antihistamines during the past two years (by this restriction an overrepresentation of patients suffering from mild to moderate symptoms was favoured). Prohibited co-medication encompassed any compounds used for treatment of hay fever (even if they were, not prescribed for this indication) other than the respective study. drug (in particular. alpha-sympathomimetics, corticosteroids and antihistamines); this also applied to the therapy of ocular hay fever symptoms.

Assessments

Drug efficacy was assessed primarily with a validated self-rating (patient) instrument, the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)[7,8].The German adaptation of the questionnaire [9].was completed at visits 1 through 5. The questionnaire consists of 28 items that pertain to particular symptoms and their practical consequences for daily life. The items are subdivided into seven ·domains: 1) nasal symptoms (4 items); 2) ocular symptoms (4 items); 3) general non-hay fever symptoms (7 items); 4) sleep disturbances (3 items); 5) practical problems associated with rhinoconjunctivitis, such as carrying tissues and nose blowing (3 items); 6) implications on 3 personal activities named by the patient at the outset (3 items); and 7) emotional symptoms, such as frustration (4 items). The particular items are represented by questions of the general form 'how troubled have you been by (e.g. stuffy nose)' that refer to the preceding week. Patients rated the degree (physical symptoms and their practical implications) or the temporal extension (emotional symptoms) of their, subjective impairment on a 7-point scale ranging from 0 (not troubled at all; none of the time) to 6 (extremely troublesome; all the time). Domain-specific scores were obtained by averaging the numerical values of the pertinent items. Division of the sum of the domain-specific scores by the number of domains yielded an overall score reflecting the quality of life of patients suffering from seasonal allergic rhinitis. This overall score, ranging from 0 to 6 (highest to lowest quality) was the main efficacy parameter.

In addition, efficacy was measured by using the domain-specific subscores and the global assessment of the present quality of Life on a visual analog scale that ranged from 0mm.("could not be worse") to 100 mm ("could not be better") at visits 1 through 5.The global al assessment of therapeutic efficacy at the end of treatment was measured by both patient and investigator on a 4-point scale ranging from "excellent" to "poor."

Local tolerance was assessed at visits 2 through 5 by rhinoscopic examination（using a nasal speculum) of the nasal mucosa for erythema, edema, and dryness of nose. These symptoms were classified on 'a 5-point scale ranging from "missing" to "strong." Patients also rated nasal pruritus, urge of sneezing, and feelings of burning and dryness of nose on 5-category scales according to frequency (from-"never" to "after each administration") and intensity (from "slight" to "very strong").

At the end of treatment, tolerance was globally assessed by both the patient and the investigator on a 4-point scale ranging from 1 (very good)to 4 (poor).Physicians performed drug safety evaluations based on the incidence of adverse events reported at visits 2 through 5 and monitoring of vital signs and laboratory status, such as hematology, clinical chemistry, and urinalysis at visits 1 and 5.

Statistical Evaluation

To show the non-inferiority of the homeopathic group according to the "Statistical Principles of Clinical Trials" a one-sided (1-a). confidence interval was. used. Equivalence was inferred if the lower limit of the interval was larger than the equivalence limit. For the main efficacy parameter (overall.RQLQ scores at visits 2 through 5) ·a generalized Wilcoxon-Mann-Whitney procedure was used (directional test for stochastic. ordered alternatives according to Wei and Lachin).[10-12].A one-sided equivalence test can be formulated using the Mann-Whitney statistic P(X<Y)+0.5P(X=Y)[abbreviated as P(X<Y)].It is a measure of stochastic superiority. Values lower then 0.5 denote inferiority and values higher then 0.5 denote superiority. The test for one-sided equivalence ("equivalent “or＂better") can be performed by means of .a one-sided (1-a) confidence interval (Cl) in the following way If the lower bound of the Cl is larger then 0.36 (corresponding to a medium- sized inferiority according to Cohen [13]) the null hypothesis of inferiority. can be rejected（null hypothesis Ho:P(X<Y)≤0.36; alternative hypothesis HA:P(X<Y)>0:36).

Analysis of all randomized patients may be biased toward demonstrating equivalence. For this reason the first-line analysis for efficacy was a per-protocol analysis considering dropout rates and major study protocol deviations. Missing values because of dropouts were replaced using the principle of "last value carried forward". None of the patients excluded from per-protocol analysis had an observation after medication. Therefore an additional intention-to-treat analysis was not performed. Demographic' data and baseline characteristics were analysed by means of Mann-Whitney's U-test and Fisher's exact test. Domain-specific RQLQ  scores visual analog scores, results· of global assessment of therapeutic efficacy, and tolerance ratings performed by patients and investigators were analysed by means of explorative methods based on Mann-Whitney statistics and pertinent. 95% CI. An analysis of homogeneity of efficacy data across study centres was performed by providing an overview of treatment effects by mean scores. Because there was no evidence of interaction between centres and treatment no supportive analysis was done.

Sample Size Calculation
At the time the study was designed (1995) there was no sample algorithm available for the test to be used. Thus, an appropriate procedure was used:t-test one-sided with the analog difference, which was a standardized difference of 0.5. When the sample size in each group is 72,a two group 0.05 one-sided t-test will have 91% power to reject the null hypothesis that the test and standard are not équivalent (the difference in means is 0.5 or farther from zero in the same direction) in favor of the alternative hypothesis that the means of the two groups are equivalent, assuming that the expected difference in means is 0.0 and the common standard deviation is 1.0.

RESULTS
Demographic and Baseline Characteristics
A total of 146 patients (82 male, 64 female) recruited from 17 centers (each
contributing 1-25 cases), including 10 general, 5 ear-nose-throat physicians and 2 internists in private practice, were enrolled in the study. From this population 72 patients were randomly assigned to the homeopathic group and 74 to the cromolyn sodium group. A total of 135 patients (68 in the homeopathic,67 in the cromolyn sodium group) completed the trial according to protocol Seven patients dropped out after visit 2 (2 patients in either group due to end of pollen season; one from the homeopathic and 2 from the cromolyn sodium group due to lack of efficacy/wish of patient/or other reasons).They were included in the analysis of efficacy, whereas 4 other patients could not be included because they dropped out before visit 2 (one of the cromolyn sodium group due to adverse events and 2 from the cromolyn sodium group and one from the homeopathic group due to lack of efficacy/wish of patient/other reasons)(fig.1): Demographic characteristics of the total study population are summarized in table 1. There were no statistically significant differences between the two treatment groups with respect to sex, age, height and weight. The same applies to the overall RQLQ score at visit 1 which averaged 2.37 in the cromolyn sodium and 2.41 in the homeopathic group (but individually reached up to 4.7 and 4.9 respectively, thus indicating that higher baseline scores were disfavoured in this study but not excluded). Comparability can also be assumed for the essential anamnestic parameters (table 2). In only 4 of the enrolled patients hay fever was newly diagnosed; the others had suffered from one or more previous episodes of the disease (mean duration of medical history: 9.3 years in the homeopathic and 7.2 years in the cromolyn sodium group), most of them for 1-6 months during spring and/or summer. In the 51 patients of either group for which they were documented the provoking allergen(s) were tree pollens (mostly hazel, birch; alder, ash), alone or in combination with grass or weed pollens (such as mugwort and rye) without notable group-specific differences. Since the patients lived in the same geographic region it can be concluded that the patients and thus the treatment groups were simultaneously exposed to roughly the same pollen types and concentrations (fig. 2). In both groups the beginning of treatment was similarly distributed to the months of the year (between February and August with an accumulation·in spring). Equivalence considerations can therefore be carried out disregarding environmental and predisposition conditions. An influence of concomitant medication (which was used by 16 patients in the homeopathic
group and 12 patients in the cromolyn sodium group) on the study results did not become evident. The average compliance with the administration of the two study drugs (93% in the homeopathic group and 98% in the cromolyn sodium group) was comparable.

Efficacy
Data from a total of 142 patients (71 homeopathic and 71 cromolyn sodium) were subjected to efficacy analysis. Figure 3 which illustrates the time course of the mean overall RQLQ score from visit 1 to visit 5 reveals a marked reduction of subjective impairment in both treatment groups starting from nearly equal baseline levels. The decrease of the primary parameter was slightly more pronounced in the cromolyn sodium group (from 2.37 to 1.33) than in the homeopathic group (from 2.41 to 1.57). Under both treatments, the effect was most striking during the first week. The alternative hypothesis (therapeutic non-inferiority of homeopathic versus cromolyn sodium treatment) with a=0.05 with the chosen equivalence bound P(X<Y)=0.36 is confirmed The Mann-Whitney statistic for the combined（directional) test of this study was P(X<Y)=0.44, showing the homeopathic group to be slightly inferior. However, the lower bound of the confidence interval was 0.37 which is above the equivalence bound of 0.36. Thus, equivalence (efficacy) of the homeopathic treatment could be proven.

All RQLQ subscore means showed tine courses Similar to that of the overall score. Mean baseline subscores ranged from 3.34 jo 1.53 and mean final scores from 1.93 to 0.99. The most marked reductions, amounting to 1.2 to 1.6 points, were related to nasal symptoms, practical problems and individual activities (table 3). The results of the visual analog scores were in accordance with the RQLQ scores, indicating that the perceived quality of life increased during the study. Between visit 1 and visit 5, the visual analog scores of the homeopathic group increased 24% (from 55 to 68mm) and those of the cromolyn sodium group increased 29% (from 57 to 74 mm) (Visit 1:U-test P=0.72,P(X<Y)=0.47,95% CI-LB=0.38; Visit 5:U-test P=0.92,P(X<Y)=0.43,95% CI LB=0.35).

Global assessments of therapeutic efficacy did not markedly differ with respect to treatments or the rating person. The therapeutic efficacy of the homeopathic treatment (vs. the cromolyn sodium treatment) was rated as "excelļent" by 13% (vs. 24%) of the patients and 16% (vs. 18%) of the investigatorş, as "good" by 63% (vs. 55%) and 63%(vs. 66%) respectively as "satisfactory" by 18% (vs. 14%) and 17% (vs. 9%), respectively and as“poor" by 6% (vs. 6%) and.4% (vs. 6%), respectively (patient assessment: U-test P=0.92, P(X<Y)=0.44,95% CI LB=0.37;investigator assessment: U-test P=0.82,P(X<Y)=0.46,95% CI LB=0.39).

Tolerance
Under both treatments rhinoscopic assessments of erythema, edema, and dryness of the nasal mucosa remained largely unchanged during visits 2 through 5. In the cromolyn sodium group there was a sustained minor relief of all symptoms whereas the ratings in the homeopathic group, also being consistently slightly better at the beginning than at the end of the observation period, were subjected to some intermediate fluctuation. Similar results occurred relative to patients' assessments of nasal pruritus, sneezing, and sensations of burning and dryness of the nose. All of these symptoms were rated as less intense and less frequent at visit 5 than at visit 2. The differences were small and comparable for both treatments. The tolerance of the homeopathic treatment (vs. the cromolyn sodium treatment) was assessed as "very good" by 25% (vs. 28%) of the patients and 29% (vs. 31%) of the investigators; as "good" by 69% (vs. 61%) and 63% (vs. 58%), respectively; and as“satisfactory/poor” by 4% (vs. 5%) and 7% (vs. 5%), respectively. In general, the vast majority of investigators and patients had no complaints about tolerance (patient
assessment: U-test P=0.70, P(X<Y)=0.48,95% CI LB=0.41;investigator assessment: U test P=0.63,P(X<Y)=0.48.95% CI LB=0.40).

Safety
A total of four adverse events (observed in three patients) reported during the study were rated as "possibly," "probably," or "very probably" related to treatment. All were mild to moderate. Minor intermittent nose bleeding occurred for two days after 30 days of homeopathic treatment. A sensation of burning in the nose, as well as discrete facial exanthema occurred for 8 days after 1 day of homeopathic treatment. A sensation of burning in the nose, which caused the patient to drop out of the study, occurred after 5 days of cromolyn sodium treatment. All adverse events disappeared spontaneously; a premature revelation of the random code was not necessary: All clinically relevant laboratory values
measured during the study resulted from concomitant.or intervening diseases. Medians of haematology clinical chemistry, urinalysis, and vital signs at visit 1 and visit 5 were consistent with normal values. There was no evidence of adverse systemic action for either the homeopathic or cromolyn sodium treatment.

DISCUSSION
Topical cromolyn sodium is a well-established standard therapy for seasonal allergic rhinitis and·conjunctivitis that proved superior to placebo in many clinical trials and has frequently been used as reference (e.g. [14-21]). By this means it was possible to avoid the ethical problems arising from implementation of a placebo treatment in patients suffering from symptoms of considerable intensity. For the present study these problems would have been particularly relevant due to the long duration of 6 weeks. Moreover, to prevent a high dropout rate. in a placebo group and yet to maintain double-blind conditions it would have been necessary to allow non-homeopathic rescue medication (e.g. a topical antihistamine) also to the patients of the homeopathic group; this however would have restricted the validity of the study. results since the interaction of homeopathic and non-homeopathic medication cannot be evaluated. For the same reason the only rescue measure allowed in this trial was a short-term dose increase of the regular compound to which the particular patient had been randomized.

However, even in the absence of a placebo control the study results strongly suggest that both treatments were in fact effective. About 70-80% of the total mean overall RQLQ score reduction. Occurred within the first two weeks of treatment in both groups. Because most patients were experienced hay fever sufferers who consulted physicians at an early stage of symptom development, it is likely that antigen exposure increased rather than decreased during the initial treatment period. From anamnestic data we know that the majority of patients were sensitive to different antigens being present during different periods so that their hay fever persisted for months. Moreover, only 4 patients dropped out due to end of pollen season (i.e. due to cessation of airborne pollen dissemination). It can therefore be assumed that antigenic exposure was maintained throughout the 6 weeks of treatment.

In their validation studies Zander et al [9] found a mean overall RQLQ score of 1.0 in a population of asymptomatic hay fever patients investigated during the winter; in a group of symptomatic patients completing the RQLQ during hay fever season they found a score of. 3 0 before and a score of 1.5 after 14 days of anti-allergic treatment. For the present study these results suggest two conclusions. First at the end of both homeopathic and cromolyn sodium treatment the remission·of hay fever symptoms and associated subjective impairment was larġely complete. The final mean RQLQ scores of 1.57 for the homeopathic group and 1.33 for the cromolyn sodium group (which correspond fairly well to the post-treatment result of the validation study) are close to the putative minimum level, which likely could not have been reduced much further considering the persistence of antigen exposure.

Second, the mean pretreatment overall RQLQ score in the symptomatic groups of the Zander et.al studies.[9] may have been more representative than the mean pre-treatment scores in the present study, in which participation depended on certain restrictions that disfavoured the enrolment of patients with severe allergic reactions. Therefore, the statements about the efficacy of homeopathic and cromolyn sodium therapy may be particularly valid in cases of mild or moderate symptoms of seasonal allergic rhinitis that prevail in the general population.

Interestingly, the intensity of ocular. symptoms in this study was reduced, according to the pertinent drop in RQLQ score, from 1.87 to 1.26 in the homeopathic group, and from 2.12 to 1.10 in the cromolyn sodium group, although only 6 patients in the homeopathic and 2 in the cromolyn sodium group used eye drops. This ocular relief has also been described in other studies [17,22] involving intranasal cromolyn sodium and antihistamines (and may therefore represent a general indicator of a successful therapy) and was not attributed to a systemic action but to an improved nasal drainage.

A recent meta-analysis showed that the clinical effects of homeopathy generally are due to more than a placebo effect [23], and in a study using an oral formulation of mixed grass pollens this was demonstrated for the therapy of hay-fever in particular [24]. However, the mode of action of homeopathic treatment is controvérsial. According to one hypothesis, homeopathic drugs act through regulation of gene expression [25]. A different view suggests they act by stimulating an immunological bystander reaction [26,27]. Up to now the effects of homeopathic remedies on the lgE- and mast cell-mediated pathopysiology of allergic rhinitis have not been investigated.

Homeopathic therapies represent an alternative to conventional methods for
physicians and patients who seek unconventional treatments. The demand for effective medical alternatives was highlighted by a study in 1990 which estimated that Americansmade 425 million visits to providers of unconventional therapy, compared with 388 million visits to all U.S. primary care physicians [28]. In conclusion; the homeopathic nasal spray proved as effective, safe; and well-tolerated therapy for seasonal allergic rhinitis as the conventional cromolyn sodium nasal spray in this study.

Tab. 1: Demographic and baseline characteristics of total population by treatment group（SD=standard deviation).

Tab. 2: Allergy-specific anamnestic data of patients included in efficacy evaluation by treatment group ('mean duration of individual history before enrolment±SD [years], 2 duration unknown, 3 patients could be assigned to more than one category, SD=standard deviation).

Tab. 3: Means±SD of RQLQ subscores at visit 1 and visit 5 (Mann-Whitney statistic P(X<Y), and pertinent lower 95% confidence bounds in parentheses, SD=standard deviation).

Fig. 2: Classification of pollen exposure (1=first half of_the month,2=second half of themonth, the data based on the information from the Deutsche Pollenflugwetterdienst and were pooled for the years 1996/97:1=mild,2=moderate,3=severe,4=very severe).

Fig. 3: Time course of the mean overall RQLQ·score under homeopathic and cromolyn sodium treatment.