Trichophyton rubrum

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Code: m205
Latin name: Trichophyton spp.
Source material: Spores and mycelium
Family: Arthrodermataceae
Common names: Trichophyton
The following 3 allergens are included in this overview:
  • Trichophyton rubrum m205
  • Trichophyton ment. var goetzii m210
  • Trichophyton ment. var interdigitale m211
Mold
A mold, which may result in allergy symptoms in sensitised individuals.

Allergen Exposure

Geographical distribution
Trichophyton fungi inhabit the soil, humans and animals, different species preferring different environments. Most common are Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton schoenleinii, Trichophyton tonsurans, Trichophyton verrucosum, and Trichophyton violaceum. Some species are cosmopolitan. Others have a restricted geographic distribution. Trichophyton concentricum, for example, is endemic on Pacific Islands, Southeast Asia, and Central America. Trichophyton is one of the leading causes of hair, skin, and nail infections in humans.
 
Trichophyton (along with Epidermophyton and Microsporum) is a dermatophyte fungus; it has the ability to utilise keratin as a nutrient source. For this it uses a unique enzyme, keratinase; acid proteinases, elastase, and other proteinases are also major virulence factors of the fungi of this genus (1). These organisms can result in dermatophytosis (tinea or ringworm) of the scalp, and glabrous skin and nails. Dermatophytosis is unique in that no living tissue is invaded; keratinised stratum corneum is simply colonised, and the presence of the fungus and its metabolic products usually induces an allergic and inflammatory eczematous response in the host.
 
The genus Trichophyton is characterised by the development of smooth-walled macro- and microconidia (2). In cultures, the growth rate of Trichophyton colonies is slow to moderately rapid. The texture is waxy, glabrous or cottony. From the front, the colour is white to bright yellowish beige or red-violet. From the reverse it is pale-yellowish, brown, or reddish-brown
 
Environment
Trichophyton species play a major role in dermatophyte infections of both the feet and skin (3). Trichophyton rubrum is the commonest causative agent of dermatophytoses worldwide (4). In North America, T. rubrum and T. mentagrophytes are the most frequent pathogens associated with onychomycosis (5). Similar results have been reported from other parts of the world (6). There has been a large increase in infections of the skin caused by T. tonsurans, with this species surpassing M. canis as the primary aetiologic agent in urban settings. Scalp ringworm, also caused by Trichophyton, is reaching epidemic proportions in urban areas of Europe and both North and South America, with a predominance in children of African, Caribbean or African-American descent (6). Trichophyton species may cause invasive infections in immunocompromised hosts (7).
 
Allergens
Trichophyton proteins are members of diverse enzyme families; this fact supports our understanding of a dual role for these proteins in fungal pathogenesis and allergic disease (6).
 
A number of allergens has been characterised.

Trichophyton tonsurans:

  • Tri t 1, a 30 kDa protein, a major allergen, an exo 1,3-beta-glucanase (8-9).
  • Tri t 4 (previously known as Protein IV) (10-11).
Trichophyton rubrum:
  • Tri r 2, a 29 kDa protein, a serine protease, a subtilase homologue (12-15).
  • Tri r 4, an 83 kDa protein (12-13).
Tri t 1 allergen was measurable in 22 of 30 (73%) of sera from subjects with asthma, rhinitis, or urticaria who were sensitised to Trichophyon, as shown by the presence of serum- or skin-specific IgE to this fungus; it follows that this protein represents a major allergen (8). This allergen was associated with a delayed hypersensitivity reaction in only a single patient.
 
Tri t 4, previously known as Protein IV, is associated with delayed hypersensitivity (DH) reactions and has no homology to Tri t 1 or to any other known protein. This protein has the ability to elicit delayed hypersensitivity skin reactions in subjects with a history of athlete's foot, but also to cause immediate hypersensitivity skin reactions. In a study, immediate hypersensitivity skin reactions were associated with specific IgE antibodies to Tri t 4 in 13 of 23 patients. Delayed hypersensitivity skin tests were not associated with the presence of serum-specific IgE. Specific IgG antibodies to Tri t 4 were highest in immediate hypersensitivity subjects, and lowest in those with delayed hypersensitivity or negative skin tests. Tri t 4 was the first defined protein associated with both delayed and immediate hypersensitivity skin reactions (10).
 
Tri r 2 has a 41-58% overall sequence identity with the class D subtilase subfamily (13). Tri r 2 also exhibits the ability to elicit immediate or delayed-type hypersensitivity skin tests in different individuals (14).

Potential Cross-reactivity

An extensive cross-reactivity within the genus, and possibly the family, could be expected (6) but has not been fully elucidated to date.

Clinical Experience

IgE-mediated reactions
Fungal infections of the skin, nails or hair are extremely common and often caused by dermatophyte fungi of the genus Trichophyton. Trichophyton spp. classically induce delayed-type, or cell-mediated, hypersensitivity (11, 16-17), but a unique feature of Trichophyton allergens is the ability of the same antigen to elicit immediate-type hypersensitivity reactions as well (10, 14). The possible role of Trichophyton spp. in IgE-mediated urticaria, asthma, and rhinitis has been debated for decades, but only within the last couple of decades has a definitive link between sensitisation to Trichophyton and allergy been established.
 
As Trichopyton fungal infection is common, it may be that Trichophyton sensitisation is more common than has been thought. Skin-specific IgE tests performed in 4962 respiratory subjects, aged 3-80 years, with fungal extracts from Alternaria, Aspergillus, Candida, Cladosporium, Penicillium, Saccharomyces, and Trichophyton, demonstrated that 19% had skin-specific IgE to 1 or more of the fungi. Alternaria and Candida accounted for the largest number of positive tests, and along with Trichophyton they were the main sensitisers in the subset of patients with an isolated sensitisation. The majority of patients exhibited mono-sensitisation with these 3 fungi. Of subjects who had skin-specific IgE to at least 1 fungus, 10.2% exhibited immediate hypersensitivity to Trichophyton (18). However, a study reported that Trichophyton-specific IgE may be found in patients with trichophytosis, regardless of atopy (19).
 
It is therefore not surprising that, in an early study, a series of patients was identified who demonstrated immediate positive skin-specific IgE tests to intradermal Trichophyton extract. These skin responses did not correlate with other fungal skin tests and were present both in atopic and nonatopic patients, including patients with urticaria, angioedema, asthma and/or rhinitis, as well as 5 of 34 normal control subjects. Most test-positive individuals had a history of or clinical signs of a local fungal infection. Using Trichophyton tonsurans extract, serum-specific IgE tests confirmed that most skin test-positive individuals had IgE-mediated hypersensitivity to Trichophyton (20). Similarly, in a study of 12 adult patients with chronic skin infection and intrinsic asthma who were found to have immediate hypersensitivity to Trichophyton spp., 10 developed an immediate hypersensitivity response when tested by bronchial provocation or by double-blinded nasal challenge to an extract of T tonsurans. In addition to perennial asthma, most of the patients had persistent eosinophilia and chronic rhinosinusitis (21). T. tonsurans contains Tri t 4, an allergen that may result in immediate or delayed-type hypersensitivity reactions, as well as Tri T 1, an allergen which appears to be involved only in immediate hypersensitivity reactions (8).
 
Trichophyton was reported to result in asthma and rhinitis over 2 decades ago. In a report on 8 individuals with rhinitis and asthma, the authors suggested that cutaneous Trichophyton infection, of which the patients were often unaware, was responsible for the episodes. This was supported by skin-specific IgE testing, positive respiratory provocation tests, and improvement following dermatologic treatment. The authors suggested that such infections were on the increase, due to faulty hygiene and the use of mass swimming facilities (22).
 
In a study evaluating Trichophyton sensitivity among 86 adult patients with allergic and nonallergic asthma in combination with tinea, the skin-specific IgE test positivity rate to Trichophyton extract of the group with nonallergic asthma plus tinea was 63.1%; for those with allergic asthma plus tinea, it was 46.7%; and for those with tinea but no asthma, it was 47.1%; this can be compared to the groups with asthma and without tinea (4.4%), and to the healthy controls (7.7%). The rates of sensitivity to T. rubrum (63.1%) and of severe asthma (31.6%) were higher in the group with nonallergic asthma plus tinea than in other groups. The authors concluded that the presence of fungal infection seems to be an important determinant in hypersensitivity to Trichophyton, whether or not the subject is asthmatic and/or allergic, and that, since a greater proportion of patients with nonallergic asthma – in whom the rate of severe asthma was also higher – showed positive skin tests to Trichophyton extracts, patients with severe, intrinsic asthma should be examined for signs of fungal infection and tested to determine immediate hypersensitivity to dermatophyte antigens (23).
 
Other authors have concurred that intrinsic or late-onset asthma may in some cases be associated with overt dermatophyte infection and immediate hypersensitivity to proteins derived from fungi of this genus. In a study of 11 patients with severe or moderately severe asthma treated with fluconazole (100 mg daily), at the end of the first 5 months of active treatment, there was a highly significant decrease in bronchial sensitivity to Trichophyton and in oral steroid requirement. Mean peak expiratory flow rates increased in 9 of 11 patients (24). Similarly, in a report on 2 atopic patients with tinea unguium caused by Trichophyton rubrum, both patients had symptoms of allergies: 1 had perennial rhinoconjunctivitis and bronchial asthma, while the other had chronic dermatitis of the face and neck. In both cases, their allergy symptoms improved dramatically during oral therapy with the antifungal agent terbinafine (250 mg/day) and relapsed after its discontinuation (25). A case report described a patient who developed bronchial asthma subsequent to an infection of tinea pedis and pedal onychomycosis; antifungal management resulted in full resolution of his tinea pedis, onychomycosis and asthma (26).
 
Likewise, in 8 patients with perennial rhinitis in combination with skin or toe-nail infection who were shown to have immediate-mediated hypersensitivity to Trichophyton confirmed by the presence of skin- and serum-specific IgE and by nasal provocation, significant improvement occurred in both their skin and nasal symptoms when they were treated with oral fungicides (27).
 
Trichophyton rubrum has been implicated as a potential trigger in flares of atopic dermatitis. Similarly to patients with uncontrolled asthma who improve following antifungal treatment, a patient with atopic dermatitis, a history of multiple flares and concurrent acute tinea pedis and onychomycosis, was relieved, through the use of systemic antifungals during each flare, of symptoms of atopic dermatitis and acute infection with T. rubrum (28). Nonetheless, this relationship may not be a simple one. In a study investigating IgE-sensitisation to fungi in patients with atopic dermatitis, using extracts of Candida albicans, Fusarium moniliforme, and Penicillium notatum, Pityrosporum ovale and Trichophyton rubrum, 14 (93%) patients were shown to be hypersensitive to 1 or several fungal extracts, as shown by histamine-release tests. The study concluded that patients with atopic dermatitis may develop specific IgE-antibodies to a number of fungi. In selected patients, fungi may trigger an IgE-mediated reaction that may contribute to the exacerbation of eczema. Approximately half of the patients, however, produced IgE-antibodies to fungal (glyco)proteins without a significant histamine release or the presence of skin-specific IgE, possibly because of nonspecific interaction with carbohydrate moieties on IgE and poor biologic activity of IgE antibodies directed to cross-reactive carbohydrate determinants of fungal glycoproteins. The authors concluded that this warrants caution when interpreting the clinical relevance of serologic measurements of fungal IgE-antibodies (29).
 
Occupations at particular high risk for sensitisation to Trichophyton are those of podiatrists, manicurists and chiropodists. Trichophyton rubrum is the most common fungal cause of nail dystrophy. Use of drills and burrs to reduce the thickness of hyperkeratotic nails generates dust, and chiropodists, along with their patients, develop precipitins or antibodies to T. rubrum. They are also exposed to mycotic particles which may be present in the nail dust (30). Human nail dust may act as an irritant (31). Both patients and workers may therefore experience a worsening of their symptoms as a result of exposure to nail dust (30). In a survey of the prevalence of antibodies in state-registered chiropodists, 14% were estimated to have antibodies to T. rubrum. In response to a questionnaire, 49% stated that toe-nail dust troubled them; complaints of nasal and eye symptoms were made by 72 and 41% respectively. In 384 chiropodists, ventilatory function was tested with a vitalograph, and restrictive lung disease appeared to be more common in chiropodists than in other sedentary workers (32).
 
Other reactions
Fungal infections of the skin are caused by dermatophyte fungi. Infections can be acute and inflammatory or chronic and non-inflammatory. See under Geographical distribution and Environment.

Compiled by Dr Harris Steinman, harris@zingsolutions.com

References

  1. Weitzman I, Summerbell RC. The dermatophytes. Clin Microbiol Rev 1995;8(2):240-59
  2. Trichophyton sp. University of Adelaide. http://www.mycology.adelaide.edu.au/Fungal_Descriptions/
    Dermatophytes/Trichophyton/
  3. Woodfolk JA, Platts-Mills TA. The immune response to dermatophytes. Res Immunol 1998;149(4-5):436-45
  4. Arenas R, Dominguez-Cherit J, Fernandez LM. Open randomized comparison of itraconazole versus terbinafine in onychomycosis. Int J Dermatol 1995;34(2):138-43
  5. Summerbell RC. Epidemiology and ecology of onychomycosis. Dermatology 1997;194 Suppl 1:32-6.
  6. Woodfolk JA. Allergy and dermatophytes. Clin Microbiol Rev 2005;18(1):30-43
  7. Squeo RF, Beer R, Silvers D, Weitzman I, Grossman M. Invasive Trichophyton rubrum resembling blastomycosis infection in the immunocompromised host. J Am Acad Dermatol. 1998;39(2 Pt 2):379-80
  8. Deuell, B., L.K. Arruda, M.L. Hayden, M.D. Chapman and T.A.E. Platts-Mills. Trichophyton tonsurans Allergen I. J Immunol 1991;147:96-101
  9. Stewart GA. Sequence similarity between a major allergen from the dermatophyte Trichophyton tonsurans and exo 1,3-beta-glucanase. Clin Exp Allergy 1993 Feb;23(2):154-5
  10. Woodfolk JA, Slunt JB, Deuell B, Hayden ML, Platts-Mills TA. Definition of a Trichophyton protein associated with delayed hypersensitivity in humans. Evidence for immediate (IgE and IgG4) and delayed hypersensitivity to a single protein. J Immunol 1996;156(4):1695-701
  11. Slunt JB, Taketomi EA, Woodfolk JA, Hayden ML, Platts-Mills TA. The immune response to Trichophyton tonsurans: distinct T cell cytokine profiles to a single protein among subjects with immediate and delayed hypersensitivity. J Immunol 1996;157(11):5192-7
  12. Gao J, Takashima A. Cloning and characterization of Trichophyton rubrum genes encoding actin, Tri r2, and Tri r4. J Clin Microbiol 2004;42(7):3298-9
  13. Woodfolk JA, Wheatley LM, Piyasena RV, Benjamin DC, Platts-Mills TA. Trichophyton antigens associated with IgE antibodies and delayed type hypersensitivity. Sequence homology to two families of serine proteinases. J Biol Chem 1998;273(45):29489-96
  14. Woodfolk JA, Sung SS, Benjamin DC, Lee JK, Platts-Mills TA. Distinct human T cell repertoires mediate immediate and delayed-type hypersensitivity to the Trichophyton antigen, Tri r 2. J Immunol 2000;165(8):4379-87
  15. Woodfolk JA, Platts-Mills TA. Diversity of the human allergen-specific T cell repertoire associated with distinct skin test reactions: delayed-type hypersensitivity-associated major epitopes induce Th1- and Th2-dominated responses. J Immunol 2001;167(9):5412-9
  16. Vijay HM, Kurup VP. Fungal allergens. In: Lockey RF, Bukantz SC, Bousquet J editors. Allergens and allergen immunotherapy. 3rd ed. New York: Marcel Dekker, Inc; 2004:223-49.
  17. Horner WE, Helbling A, Salvaggio JE, Lehrer SB. Fungal allergens. Clin Microbiol Rev 1995 ;8(2):161-79
  18. Mari A, Schneider P, Wally V, Breitenbach M, Simon-Nobbe B. Sensitization to fungi: epidemiology, comparative skin tests, and IgE reactivity of fungal extracts. Clin Exp Allergy 2003 Oct;33(10):1429-38
  19. Escalante MT, Sanchez-Borges M, Capriles-Hulett A, Belfort E, Di Biagio E, Gonzalez-Aveledo L. Trichophyton-specific IgE in patients with dermatophytosis is not associated with aeroallergen sensitivity. J Allergy Clin Immunol 2000;105(3):547-51
  20. Platts-Mills, T. A. E., G. P. Fiocco, M. L. Hayden, J. L. Guerrant, et al. Serum IgE antibodies to Trichophyton in patients with urticaria, angioedema, asthma, and rhinitis: development of a radioallergosorbent test. J Allergy Clin Immunol 1987;79:40-45
  21. Ward GW Jr, Karlsson G, Rose G, Platts-Mills TA. Trichophyton asthma: sensitisation of bronchi and upper airways to dermatophyte antigen. Lancet 1989;1(8643):859-62
  22. Huguenin-Dumittan SA. Respiratory allergy to trichophyton. [French] Schweiz Med Wochenschr 1977;107(6):200-2
  23. Mungan D, Bavbek S, Peksari V, Celik G, Gugey E, Misirligil Z. Trichophyton sensitivity in allergic and nonallergic asthma. Allergy 2001;56(6):558-62
  24. Ward GW Jr, Woodfolk JA, Hayden ML, Jackson S, Platts-Mills TA. Treatment of late-onset asthma with fluconazole. J Allergy Clin Immunol 1999;104(3 Pt 1):541-6
  25. Hurlimann A, Fah J. Asthma, rhinitis and dermatitis triggered by fungal infection: therapeutic effects of terbinafine. Dermatology 2001;202(4):330-2.
  26. Elewski BE, Schwartz HJ. Asthma induced by allergy to Trichophyton rubrum. J Eur Acad Dermatol Venereol 1999;12(3):250-3
  27. Kivity S, Schwarz Y, Fireman E. The association of perennial rhinitis with Trichophyton infection. Clin Exp Allergy 1992;22(4):498-500
  28. Klein PA, Clark RA, Nicol NH. Acute infection with Trichophyton rubrum associated with flares of atopic dermatitis. Cutis 1999;63(3):171-2
  29. Nissen D, Petersen LJ, Esch R, Svejgaard E, Skov PS, Poulsen LK, Nolte H. IgE-sensitization to cellular and culture filtrates of fungal extracts in patients with atopic dermatitis. Ann Allergy Asthma Immunol 1998;81(3):247-55
  30. Alonso A, Pionetti CH, Mouchian K, Albonico JF, Iraneta SG, Potenza M, Iovannitti C. Hypersensitiviy to Trichophyton rubrum antigens in atopic and non-atopic podiatrist. [Spanish] Allergol Immunopathol (Madr) 2003;31(2):70-6
  31. Davies RR. Human nail dust in chiropodial practice: irritant, allergen and source of antibodies to Trichophyton rubrum. J R Soc Health 1984;104(1):1-5
  32. Davies RR, Ganderton MA, Savage MA. Human nail dust and precipitating antibodies to Trichophyton rubrum in chiropodists. Clin Allergy 1983;13(4):309-15

 

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.