Q:

5/6/2014
I recently evaluated a patient who is a 29 yo male with prior h/o very mild allergic rhinitis, oral allergy syndrome and a childhood h/o asthma who developed a red/itchy groin rash in December 2013. Through Urgent Care, he received a prescription for clotrimazole/bethamethasone cream which resolves the rash only if used daily. He was also given 1 dose of fluconazole and it is unclear if it helped, as the aforementioned cream was started at the same time. A trail of Nystatin cream did not help with the rash. About 3 months after the onset of the groin rash, he began to notice significant itching of the skin, inside of throat, mild dermatitis as well as significant dermatographism (very + dermatographism test on physical exam). He is also having more of a flare up of rhinoconjunctivitis symptoms than other years.

Labwork showed normal CBC with differential, comprehensive metabolic panel, thyroid function, thyroid autoantibodies,CRP, ESR, and ANA.  RAST to aeroallergens was positive to cat, dog, grasses, molds, trees and weeds. He does have a dog in the house (Due to dermatographism, I am not able to perform skin testing). Serum tryptase was ordered and not done by lab, so it has been reordered.

He was started on Cetirizine in pm (later Fexofenadine in am was added) and Montelukast. These medications have helped some with dermatographism but all other symptoms, including the itchy groin rash persist.

I have asked for a Dermatology consultation with regards to the groin rash under the impression that hopefully, a treatment with systemic antifungals might help resolve the rash. I was a bit hesitant to prescribed oral antifungals without a confirmation that rash is indeed fungal in nature (given that it did not respond to Nystatin cream).

Do you think that the new emergence of dermatographism, mild dermatitis and overall increased allergic/hypersensitivity symptoms were triggered by the possible fungal groin infection? The patient is understandably very frustrated with the new onset of symptoms and is wondering about the etiology of these. Is there any other labwork that you would recommend?

A:

Thank you for your inquiry.

Unfortunately I am not going to be able to give you definitive answers for your questions. However, the hypothesis, namely that a fungal dermatitis could be a catalyst to awaken atopic manifestations, is one that has been considered in the past, and there is a fairly extensive bibliography relating to this topic (1-16). As you can see from the references, most of these articles are in the older literature. However, there are a few more recent contributions as well (see abstracts copied below; Khosravi et al and Escalante et al).

It is difficult to come to a conclusion as to the importance of these observations, but they clearly leave the door open that immediate hypersensitivity responses can possibly be related to cutaneous fungal infections, especially trichophyton.

You asked whether or not there might be other tests to order, and I think it would be worthwhile for you to assess serum specific IgE to trichophyton. There are ImmunoCAPs to three species of trichophyton that can be ordered.

If indeed the trichophyton has played a role in the production of these symptoms, a serum specific IgE should be positive, and the treatment, at least based on this rationale, would be to clear the fungal dermatitis. I believe a consultation with the dermatologist is the correct strategy to accomplish this goal.

Finally, if you notice, a great portion of the literature regarding this topic is a result of work done by Dr. Thomas Platts-Mills and colleagues. Because of that, I am going to ask Dr. Platts-Mills to "weigh in" on this inquiry and my response. We are going to go ahead and send my response to you and post it on our website, but if Dr. Platts-Mills has anything further to add, we will forward it to you and add it to the website as well.

Thank you again for your inquiry and we hope this response is helpful to you.

Abstracts

Asian Pac J Allergy Immunol. 2012 Mar;30(1):40-7.
Immediate hypersensitivity and serum IgE antibody responses in patients with dermatophytosis.
Khosravi AR, Shokri H, Mansouri P.
Author information
1Mycology Research Center, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
Abstract
Background: The association of dermatophytes with atopic patients and improvement in allergic signs with antifungal treatment suggest a possible link between chronic infection and atopy.
Objective: The purpose of this study was to determine skin reactivity and serum IgE antibody responses in patients with chronic and acute dermatophytosis.
Methods: One hundred and sixty-three patients with chronic dermatophytosis, 35 patients with acute dermatophytosis, 41 atopic patients and 49 healthy subjects were enrolled in this study. Sensitization to Trichophyton mentagrophytes (T. mentagrophytes), Candida albicans and Aspergillus fumigatus antigens has been evaluated in patients by skin prick test (SPT) and by the presence of specific IgE antibody in enzyme-linked immuno-sorbent assay (ELISA).
Results: Positive immediate hypersensitivity (IH) reactions were obtained in 95.1% of the atopic patients with chronic infection for T. mentagrophytes, representing a significant difference from other patient groups (P < 0.05). Specificanti-T. mentagrophytes IgE antibodies were detected in atopic patients with chronic (65.9%) and acute (50%) dermatophytosis, while none of the atopic subjects had positive IgE reactions to T. mentagrophytes.
Conclusion: The results showed significant higher positive IH and specific anti-T. mentagrophytes IgE responses in atopic patients with chronic dermatophytosis than the other groups.

J Allergy Clin Immunol. 2000 Mar;105(3):547-51.
Trichophyton-specific IgE in patients with dermatophytosis is not associated with aeroallergen sensitivity.
Escalante MT, Sánchez-Borges M, Capriles-Hulett A, Belfort E, Di Biagio E, González-Aveledo L.
Author information
1Instituto de Oncología y Hematología, Ministry of Health, and Central University of Venezuela, Caracas, Venezuela.
Abstract
Background: It has been proposed that Trichophyton infection is associated with atopy and allergy.
Objectives: Our purpose was (1) to confirm whether atopy predisposes to chronic dermatophytosis and (2) to investigate whether Trichophyton infection induces atopic disease.
Methods: Patients attending dermatology clinics and suspected of having dermatomycosis underwent in a prospective manner fungal culture and Trichophyton and inhalant skin tests, and blood serum was collected for total IgE and Trichophyton radioallergosorbent testing. Personal and family history of atopic diseases was also investigated.
Results: According to mycologic culture, atopic history, and inhalant skin test results, patients were classified into 4 groups: (1) atopy plus mycosis (n = 28), (2) atopy (n = 26), (3) mycosis (n = 35), and (4) no atopy, no mycosis (n = 33). Patients with active mycosis (groups 1 and 3) demonstrated significantly increased positivity of Trichophyton skin tests compared with patients without fungal infection (groups 2 and 4), regardless of their atopic status, whereas atopic patients (those in groups 1 and 2) had significantly increased levels of total serum IgE compared with nonatopic subjects. Trichophytosis was not more prevalent in atopic than in nonatopic subjects, and atopic diseases were not more frequent in culture-positive than in culture-negative patients.
Conclusions: Our results indicate that Trichophyton -specific IgE is observed in patients with trichophytosis regardless of atopy.

References:
1. Platts-Mills TA, Woodfolk JA. Trichophyton asthma. Chest. 2009 Apr;135(4):887-8. doi: 10.1378/chest.09-0114.

2. Woodfolk JA, Platts-Mills TA. The immune response to intrinsic and extrinsic allergens: determinants of allergic disease. Int Arch Allergy Immunol. 2002 Dec;129(4):277-85.

3. 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 Nov 1;167(9):5412-9.

4. Ludwig RJ, Woodfolk JA, Grundmann-Kollmann M, Enzensberger R, Runne U, Platts-Mills TA, Kaufmann R, Zollner TM. Chronic dermatophytosis in lamellar ichthyosis: relevance of a T-helper 2-type immune response to Trichophyton rubrum. Br J Dermatol. 2001 Sep;145(3):518-21.

5. 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 Oct 15;165(8):4379-87.

6. Scalabrin DM, Bavbek S, Perzanowski MS, Wilson BB, Platts-Mills TA, Wheatley LM. Use of specific IgE in assessing the relevance of fungal and dust mite allergens to atopic dermatitis: a comparison with asthmatic and nonasthmatic control subjects. J Allergy Clin Immunol. 1999 Dec;104(6):1273-9.

7. Ward GW Jr, Woodfolk JA, Hayden ML, Jackson S, Platts-Mills TA. Treatment of late-onset asthma with fluconazole. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):541-6.

8. 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 Nov 6;273(45):29489-96.

9. Woodfolk JA, Platts-Mills TA. The immune response to dermatophytes. Res Immunol. 1998 May-Jun;149(4-5):436-45.

10. Slunt JB, Taketomi EA, Platts-Mills TA. Human T-cell responses to Trichophyton tonsurans: inhibition using the serum free medium Aim V. Clin Exp Allergy. 1997 Oct;27(10):1184-92.

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 Dec 1;157(11):5192-7.

12. 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 Feb 15;156(4):1695-701.

13. Deuell B, Arruda LK, Hayden ML, Chapman MD, Platts-Mills TA. Trichophyton tonsurans allergen. I. Characterization of a protein that causes immediate but not delayed hypersensitivity. J Immunol. 1991 Jul 1;147(1):96-101.

14. Ward GW Jr, Karlsson G, Rose G, Platts-Mills TA. Trichophyton asthma: sensitisation of bronchi and upper airways to dermatophyte antigen. Lancet. 1989 Apr 22;1(8643):859-62.

15. Platts-Mills TA, Fiocco GP, Hayden ML, Guerrant JL, Pollart SM, Wilkins SR. Serum IgE antibodies to Trichophyton in patients with urticaria, angioedema, asthma, and rhinitis: development of a radioallergosorbent test. J Allergy Clin Immunol. 1987 Jan;79(1):40-5.

16. Platts-Mills TA, Fiocco GP, Pollart S, Hayden ML, Jackson S, Wilkins SR. Trichophyton allergy in a 24-year-old man with "intrinsic" asthma. Ann Allergy. 1986 Jun;56(6):454-5, 470-1.

Sincerely,
Phil Lieberman, M.D.

We received a response from Dr. Platts-Mills. Thank you again for your inquiry.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Platts-Mills:
Thank you for your kind references to our work on Trichophyton. I agree with your response, however there are two aspects I would emphasize.

Firstly it is important to recognize that intertrigo can be caused by Yeast or Dermatophytes. In most cases in men it is caused by dermatophytes. The doctor reports that this case did not respond to Nystatin cream. Actually while Nystatin is effective for many or most species of yeast it is largely ineffective for Trichophyton species.

Secondly although it is preferable to establish the organism by culture, and to get sensitivity this not easy to achieve in practice. In our experience many laboratories are not very successful at growing dermatophytes. While in part this may reflect inadequate samples, it is not easy to grow these fungi. In a case which has severe disease I would always skin test and or get assays of IgE to Candida and Trichophyton. If there was a clear distinction in the results I would use that to guide treatment. If trichophyton is the likely cause of the intertrigo or the nail infection the choice is between fluconazole and Itraconazole. Given the remarkably benign side effect profile of Fluconazole we usually start with that for 3 months but if there is no response I would not hesitate to use Itraconazole with Liver function tests.

Best,
Tom Platts-Mills

AAAAI - American Academy of Allergy Asthma & Immunology