Q:

With regards to the below question, I know that Dr. Lilic stated CMC patients often have a normal response and that many "normal" patients have recurrent yeast infections and there are many reasons for the abnormal mitogen response. But for those patients with recurrent vaginal infections resistant to diflucan and other standards of therapy, what prophylaxis would you use to prevent infections?


My question is about the significance of abnormal mitogen stimulation test to Candida. I have 2 such cases.
#1: Pt is a 32 yo woman with infertility (unclear etiology; is being followed by a fertility specialist) who presented with the concern of a history of oral thrush x1 (was apparently treated with diflucan) and fairly frequent vaginal yeast infections; no h/o skin rash or nail fungal infections. She has a h/o recurrent sinusitis which improved dramatically (only 2 sinus infections since tonsillectomy in 2010). Also has mild allergic rhinitis sxs. Her CBC with differential, B/T/NK cell subset analysis, and serum IgG/A/M/E were normal. IgG titers to H influenza, diptheria, and tetanus were inadequate. She reported multiple negative HIV tests done previously, so this was not repeated. Strep pneumo IgG titers were inadequate (no h/o pneumococcal vaccination) and mitogen stimulation test showed absent lymphocyte response to candida and low/nl lymphocyte response to tetnaus; nl responses to PHA/Con A/Pokeweed. I administered Penumovax and repeat titers will be checked in 6 weeks post vaccination. Do I need to proceed any further with the abnl mitogen test? Pt also wishes me to address any immunologic issues that might explain her "idiopathic" infertility and multiple failed in-vitro fertilization attempts.

Case#2: 37 yo woman with allergic rhinoconjunctivitis, recurrent sinus infections, asthma, chronic fatigue syndrome and recurrent oral ulcers, vaginal yeast infections and a fairly persistent skin rash (underarms and sometimes under breasts). She has had multiple dermatologic evaluations (I don't have the records of any skin bx reports or KOH studies) and the rash has failed to respond to topical steroid and antifungal therapy. No h/o opportunistic or viral infections. I'm not sure about nail fungus (will ask at the next visit). Her CBC with diff was normal; serum IgG/A/M normal. Serum IgE undetectable. Strep pneumoniae titers showed inadequate response, with good response post Pneumovax vaccination. HIV neg. Lympocyte subset analysis normal. Mitogen stimulation testing showed: Low lymphocyte response to candida, but normal response to tetanus, pHA, Concavalin A, and pokeweed mitogen.

I referred the patient to Infectious Disease-- impression: if painful oral ulcers reoccur, pt is to start acylovir-- if helpful, then a prolonged suppressive acyclovir course to be considered. If acyclovir not helpful, then a trial of fluconazole to be done. Requested HSV 1 and 2 serology; not done yet. Underarm rash improved some with Lotrimin. Consider autoimmune cause of oral ulcers-- w/u neg so far (ANA/RF/ESR).

Would in-vivo (intradermal skin test to tetanus) be of utility in these cases. Is the abnormal mitogen stimulation test of any significace (I see it being more important in case#2). Please advise on further diagnostic/therapeutic options.

Thank you so much for your time.
A:

Thank you for your inquiry.

I have no expertise in this area, and am therefore forwarding your inquiry to Dr. Desa Lilic, who is an internationally known expert in chronic mucocutaneous candidiasis and a consultant clinical immunologist at the University Hospital of North Durham, and senior clinical lecturer at the University of Newcastle upon Tyne, Institute of Cellular Medicine. As soon as we receive her response, we will forward it to you.

In the meantime, while we are awaiting Dr. Lilic's response, there is an excellent article about the clinical interpretation of lymphocyte transformation tests in general which was written by Dr. Francisco Bonilla. It is in the Annals of Allergy, Asthma, and Immunology 2008; Volume 101(1):51-56.

Thank you again for your inquiry.

Sincerely,
Phil Lieberman, M.D.

Below is the response we received from Dr. Desa Lilic. Thank you again for your inquiry.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Lilic:
In general, in spite of a few earlier reports, Candida lymphocyte stimulation assays do not show good correlation with susceptibility to mucocutaneous candidiasis. In my own experience, all of my >20 patients with the primary immune deficiency coined Chronic Mucocutaneous Candidiasis (CMC) actually have NORMAL proliferation to both mitogens (PHA) and Candida antigens. As opposed to this, I have seen several perfectly “normal” controls not respond to Candida stimulation. The reasons for this are unclear but probably involve 1) technical issues with the stimulating Candida antigen which is not readily available so is often “home-made” and is usually a protein extract of candida which means that most of the stimulating carbohydrates located on the membrane have been removed; 2) immune protection of mucosal surfaces is highly dependent on Th17 lymphocytes which are very infrequent in blood (>1% ex vivo) so that their proliferation may escape detection in this assay; 3) marked inter & intra personal variability of this test. It is essential that any results of proliferation assays (as with any laboratory tests) must be interpreted in the light of clinical findings to be of any use (Bonvilla's article that Dr Liberman referred you to explains this nicely). In vivo delayed type hypersensitivity (DTH) skin tests were previously often done with PPD and Candida extracts to assess T cell immunity but have largely been abandoned due to ethical issues.

Case #1. This lady does not have much clinically that would be suggestive of increased susceptibility to Candida infections (no oral thrush, nails, ears, skin). Please note that vaginal thrush (which she has) is very frequently seen in otherwise healthy women and (amazingly!) relatively infrequently in patients with CMC. It is believed that vaginal immunity is dependent on local and environmental factors (such as micobicidal peptides, pH etc) far more than on T&B cell immunity and is therefore not seen as a sign of systemic immune deficiency. From what you write, she no longer seems to have problems with infections at all and the low responses to Pneumococcal ag are likely due to lack of exposure. Her infertility may or may not have an immune/autoimmune component but is unlikely to be linked to immune deficiency (which she is unlikely to have). Apart from the infertility, what exactly is her clinical problem now?

Case #2. This lady has complex problems but not much apart from vaginal thrush that is due to candida infection. Oral ulcers are often non-infectious (has anything ever been isolated?) and I'd be reluctant to treat her oral ulcers with fluconazole without microbiological proof. The rash can also have multiple ethiologies and again should not be assumed fungal unless there is microbiological evidence (in which case oral antifunglas should be considered). There is not much to justify further immunological assessments but she needs to have her current clinical problems (CFS, recurrent sinusitis, oral ulcers, skin rash, rhinoconjunctivitis asthma) controlled.

Lastly, in patients that present clinically with possible CMC (persistent severe oral thrush, severe nail infections, skin abscesses / boils, recurrent severe respiratory infections & pneumonia requiring antibiotic treatment of hospital admission) genetic tests are available such as STAT1 and other mutations.

Please let me know if you have any further queries or thoughts.

Desa Lilic

A:

There are many immunologic dysfunctions that predispose to candida infections and there are multiple barrier dysfunctions or exogenous factors, such as diabetes mellitus, that increase occurrence. Specific prevention measures would need to be tailored to the factors that are predisposing your patient to the symptomatic colonization.

Before discussing the potential strategies it is worth emphasizing that the diagnosis should be secure. The definition of recurrent vulvovaginal candidiasis is 4 or more symptomatic episodes per year (Epidemiology and pathogenesis of recurrent vulvovaginal candidiasis (Sobel JD Am J Obstet Gynecol. 1985;152(7 Pt 2):924). I have evaluated women who have recurrent symptoms but the diagnosis of candidiasis is not secure. Occasionally anxiety about symptoms or nonspecific vaginal pruritus or irritant/allergic contact vaginitis is misinterpreted as candidiasis, so it is reasonable to request confirmation of the diagnosis on several occasions. If the vaginal secretions/discharge has a pH greater than 4.5 with increased leukocytes, coexisting bacterial vaginosis is a consideration. Twenty-30% of women with bacterial vaginosis are coinfected with candida (Mixed vaginitis-more than coinfection and with therapeutic implications. Sobel JD, Subramanian C, Foxman B, Fairfax M, Gygax SE Curr Infect Dis Rep. 2013;15(2):104), so failure of treatment for one cause may be due to a second cause. Finally, evidence of candida is not a reason for therapy as 10-20% of women are asymptomatic with vaginal candidiasis and these women do not require therapy.

One option would be to utilize weekly oral fluconazole 150mg therapy for 6 months (Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, Filler SG, Fisher JF, Kullberg BJ, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD, Infectious Diseases Society of America .) Clin Infect Dis. 2009;48(5):503.) . Your question stated that the infection was resistant, but I was not sure if this meant no response to therapy or susceptibility for relapse. Weekly therapy would not be effective for the former. Sensitivity testing of the candida may be helpful as 200 mg fluconazole twice weekly for 6 weeks may be effective if the minimal inhibitory concentration is between 4-8 mcg. However up to 50% of women relapse following such prolonged treatment. Candidal susceptibility to other azoles and subsequent treatment is also a consideration.

If azoles are not an option, additional therapies are of unproven benefit or are poorly tolerated. Probiotics (eg lactobacillus), although very popular, have limited data to support either orally or with topical yogurt. Topical gentian violet may be helpful but can cause mucosal irritation. Topical pH modification with sitz baths containing vinegar is unproven. However for azole resistance boric acid suppositories, 600 mg daily for 2 weeks, may be helpful (Boric acid for recurrent vulvovaginal candidiasis: the clinical evidence. Iavazzo C, Gkegkes ID, Zarkada IM, Falagas ME J Womens Health (Larchmt). 2011 Aug;20(8):1245-55. Epub 2011 Jul 20. ). Of interest to immunologists, candida hypersensitivity has been suggested as a cause of susceptibility to symptomatic candida colonization and candida vaccines have been or are under investigation (Recurrent allergic vulvovaginitis: treatment with Candida albicans allergen immunotherapy. Rigg D, Miller MM, Metzger WJ  Am J Obstet Gynecol. 1990 Feb;162(2):332-6. New immunotherapeutic strategies to control vaginal candidiasis; Magliani W, Conti S, Cassone A, De Bernardis F, Polonelli L Trends Mol Med. 2002 Mar;8(3):121-6; Vulvovaginal Candida albicans infections: pathogenesis, immunity and vaccine prospects Cassone A Br J Obstet Gynaecol. 2015;122:785. ). Discussion of a vaccine has been in the literature for over 20 years but there has not been a great deal of progress to my knowledge. Treatment of sexual partners or oral garlic and tea tree oil are not supported by medial literature.

In summary, the most likely effective treatment strategy would be prolonged suppression with an azole if high level of resistance is not an issue. Topical therapy with gentian violet or boric acid are considerations but these may be a source of irritation.

I have copied below a prior question from the Ask the Expert archives which provide some additional information.

I hope this information is of help to you and your practice.

All my best.

Dennis K. Ledford, MD, FAAAAI

9/30/2009: Immunotherapy for vaginal candidiasis
A wife of a colleague has been troubled with recurrent vaginal candidiasis. Eight to ten infections a year for the past 3-4 years. No seasonality. Healthy otherwise. Pt. wondered about the possibility of a trial of immunotherapy with candida to see if this would be helpful. Patient has read that this has been performed at some centers with some success. Any thoughts on this?
 
Thanks!
Thank you for your recent inquiry.

The literature has been peppered with articles designed to assess any immunologic defect associated with recurrent vaginal candidiasis, and there have been a few articles looking at immunotherapeutic approaches. Not all of these have been concerned with typical "allergen immunotherapy." These articles have looked at a multiplicity of immunotherapeutic approaches.

To date, however, I know of no well constructed therapeutic trial that would offer us any evidence that immunotherapy is effective in this condition, and thus any treatment of vaginal candidiasis with classical allergen immunotherapy would be done only in a speculative manner.

Even considering the data contained in the abstracts listed below, as stated above, the use of allergen immunotherapy for this disorder remains at this time unproven, and the decision to institute it as a form of therapy will of course simply be based on your perspective after looking at the available data. There is no documentation with large placebo controlled trials of its efficacy in this disorder.
Thank you again for your inquiry and we hope this response is helpful to you.

Abstract 1:
Rev Iberoam Micol. 2002 Sep;19(3):144-8.
New strategies for treatment of Candida vaginal infections.
Magliani W, Conti S, Salati A, Arseni S, Frazzi R, Ravanetti L, Polonelli L.
Dipartimento di Patologia e Medicina di Laboratorio, Sezione di Microbiologia, Universita degli Studi di Parma, Viale Gramsci 14, 43100 Parma, Italy.
New strategies for treatment of vaginal candidiasis have been recently exploited, due to widespread occurrence of this disease, in particular as recurrent infections, limitations of safe and efficacious antifungals as well as the lack of reliable preventative approaches. In this review new chemotherapeutic and immunotherapeutic strategies, based on the improved understanding of the immunopathogenesis of this prevalent human infection, will be discussed. The role of killer antibodies (or their molecular derivatives), i.e. antibodies that show antibiotic activity bearing the internal image of a yeast killer toxin (KT), characterized by a wide spectrum of microbicidal activity, and of the specific cell wall KT receptor as putative new therapeutic agents and preventative or therapeutic vaccines, respectively, will be particularly outlined.

Abstract 2:
Trends Mol Med. 2002 Mar;8(3):121-6.
New immunotherapeutic strategies to control vaginal candidiasis.
Magliani W, Conti S, Cassone A, De Bernardis F, Polonelli L.
Microbiology Section, Dept of Pathology and Laboratory Medicine, University of Parma, Viale Gramsci 14, 43100 Parma, Italy. magliwal@unipr.it
The widespread occurrence of mucosal infections caused by Candida, in particular recurrent vulvovaginal candidiasis among fertile-age women, together with the paucity of safe candidacidal antimycotics, have prompted a great number of investigations into the immunotherapy of candidal vaginitis. This article will discuss three different experimental approaches demonstrated to be potentially transferable to human disease: (1) the use of antibodies against well-defined cell-surface adhesins or enzymes; (2) the generation of yeast killer-toxin-like candidacidal anti-idiotypic antibodies and their engineered molecular derivatives (e.g. single chains, peptides); and (3) the generation of therapeutic vaccines and immunomodulators.

Abstract 3:
Int J Gynaecol Obstet. 2007 Feb;96(2):130. Epub 2007 Jan 18.
Candida autovaccination in the treatment of vulvovaginal Candida infections.
Rusch K, Schwiertz A.
Background: Recurrent vaginal candidiasis (RVC) is an important health problem with unknown pathogenesis. Although impairment of the T-cell response is associated with persistent or recurrent candidiasis, data on immunologic responses in patients with RVC are controversial. Objectives: To evaluate the T-cell response in patients with RVC and the ability of cytokines and cytokine antagonists to modulate IFN-γ production in cultures stimulated with Candida albicans antigens. Methods: Participants in the study included 13 patients with RVC and 7 control women with sporadic candidiasis. Cytokines were determined by ELISA in supernatants of mononuclear cells with C albicans , purified protein derivative, or tetanus toxoid antigen. Results: IFN-γ production was absent or low in 11 of 13 women (84.6%) with RVC. Absent or low IFN-γ production was specific to C albicans antigens (189 ± 389 pg/mL), because high IFN-γ levels were found in cultures stimulated with purified protein derivative (739 ± 774 pg/mL) or tetanus toxoid antigens (1085 ± 546 pg/mL). Monoclonal antibody anti-IL-10 enhanced IFN-γ levels (750 ± 753 pg/mL), and IL-10 suppressed this cytokine production in patients with sporadic candidiasis. Conclusions: Mononuclear cells from patients with RVC stimulated with C albicans antigen have low or absent IFN-γ production. IL-10 plays an important role in downregulation of the T-cell response in these patients. (J Allergy Clin Immunol 2002;109:102-5.)

Abstract 4:
Ann Allergy. 1979 Oct;43(4):250-3.
Hyposensitisation in the management of recurring vaginal candidiasis.
Rosedale N, Browne K.
Hyposensitisation with a commercially available antigen has been attempted in the treatment of women suffering from recurring monilial vaginitis. Ten women entered the trial, each being used as her own control. Eight of them showed undoubted improvement and the average interval between relapses increased from 5.1 to 15.7 months (p. less than .01). Reasons are given for believing that allergic reactions play a part in recurrent vaginal thrush.

Sincerely,
Phil Lieberman, M.D.

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