Molluscum contagiosum (MC) is a viral infection of the skin produced by a member of the Poxvirus family, the genus Molluscipoxvirus. The virus spreads by direct contact with skin or mucous membranes; thus, casual and sexual contact can lead to contraction of disease. The MC virus can also spread through fomites or towels or in swimming pools 1.
A variety of treatments have been suggested to speed disease clearance in children with troublesome symptoms. These include curettage, cryotherapy, laser, and different topical agents such as tretinoin, imiquimoid, and KOH. Several immunomodulators such as interferon α, diphencyprone, and cidofovir are also suggested especially in immunodeficient patients. However, most of these methods are not tolerated by children and show an unsatisfactory response in patients with numerous lesions 2–4.
As cell-mediated immunity plays a role in the pathogenesis of MC, intralesional immunotherapy using measles, mumps, and rubella vaccine or Candida antigen has been suggested recently 5. Immunotherapy with Candida antigen involves an intralesional injection of a killed yeast protein into a molluscum lesion. The immune system mounts an immune response not only to the yeast protein but also against the MC virus, which offers widespread control of viral proliferation and subsequently destroys all lesions on the body 6,7.
The aim of this study was to evaluate the efficacy and safety of an intralesional injection of Candida antigen in the treatment of MC.
Patients and methods
This study, which was a randomized-controlled clinical trial, included 32 patients with multiple lesions of molluscum contagiosum selected from the Outpatient Clinic of the Dermatology and Venereology Department at Zagazig University Hospitals and approved by the Zagazig Institutional Review Board (ZU-IRB#1719/2014). Before injection therapy, all patients were tested for existing immunity to antigen preparation by an intradermal injection of 0.1 ml of Candida antigen into the skin of the forearm. They were 16 males and 16 females, and their ages ranged between 2 and 18 years. A written informed consent was obtained from all the patients before the start of the study. Patients were divided by matched randomization into two groups according to the modality of treatment used.
- Previous allergic response to Candida antigen.
- Pregnant and lactating women.
- Acute febrile illness.
- History of asthma or allergic skin disease.
- Iatrogenic or primary immunosuppressed patients.
- Concomitant and recent use of other treatment modalities.
- Any generalized dermatitis.
- Genital MC.
Each patient was subjected to the following:
- Complete and careful assessment of history including the following:
- Personal history, present history, family history, duration of MC, previous therapy, history of bronchial asthma, food or drug allergy, systemic disease, or immunosuppressive drug intake.
- Full clinical and dermatological examination including the following:
- General physical examination.
- Local examination of skin lesions including the number, size, site, type, and other associated skin lesions. Patients were instructed not to use any other MC treatment during the study period.
- Intralesional immunotherapy with Candida antigen (group I):
- A total of 16 MC patients were subjected to intralesional immunotherapy with Candida antigen (C. albicans 1 : 20 w/v 10 ml vial; Allergy Laboratories Inc., Oklahoma City, Oklahoma, USA).
- Before injection therapy, all patients were tested for existing immunity to antigen preparation by an intradermal injection of 0.1 ml of Candida antigen into the skin of the forearm. Determination of a positive reaction requires erythema and induration of at least 5 mm diameter within 48–72 h. Patients not reactive to the skin test were excluded.
- Responders to intradermal skin testing (16 patients) were subjected to immunotherapy by an injection of 0.3 ml of Candida antigen using a 1 ml syringe and a 30 G needle directly into an individual molluscum papule, avoiding an intradermal injection. For patients with exclusively small lesions, up to three largest lesions were injected to deliver the full volume and fill the treated molluscum papule(s). Injections were delivered at 2 week intervals for a maximum of five injections or clinical cure 5. Photographs of lesions in all patients before and at follow-up visits were taken to evaluate the clinical response.
Control group (group II)
This group included 16 MC patients, who were administered an intralesional injection of 0.3 ml of normal neutral saline at 2 week intervals for a maximum of five injections or clinical cure.
Follow-up and evaluation
Follow-up and evaluation was performed at each visit and for 3 months after the completion of therapy for detection of any recurrence. At follow-up visits, response to treatment was evaluated. Patients showing complete disappearance of lesions were defined as responders. Patients showing more than 50% clearance of lesions were defined as partial responders, whereas patients showing less than 50% clearance were defined as nonresponders. Following injection, evaluation of immediate and late adverse effects such as flu-like symptoms, regional pain, swelling, vesiculation, and discoloration at the site of injection were assessed.
All data were collected, tabulated, and statistically analyzed using SPSS 19.0 for windows (SPSS Inc., Chicago, Illinois, USA) and MedCalc 13 for windows (MedCalc Software bvba, Ostend, Belgium). Quantitative data were expressed as the mean±SD and median (range) and qualitative data were expressed as absolute frequencies ‘number’ and relative frequencies (%). Continuous data were checked for normality using the Shapiro–Walk test. Independent Student’s t-test was used to compare two groups of normally distributed data. Mann–Whitney U-test was used to compare two groups of non-normally distributed data.
The one-way analysis of variance test was used to compare more than two groups of normally distributed data. The Kruskal–Wallis H-test was used to compare more than two groups of non-normally distributed data. Percent of categorical variables was compared using χ2-test or Fisher’s exact test when appropriate. Spearman’s coefficient was calculated to assess the relationship between response and selected study parameters; a (+) sign indicates a direct relation and a (−) sign indicates an inverse relation. Also, values close to 1 indicate a strong correlation and values close to 0 indicate a weak relation. All tests were two sided. P value less than 0.05 was considered statistically significant.
This group included 16 selected MC patients subjected to intralesional immunotherapy using C. albicans antigen. Ten (62.5%) patients were boys and six (37.5%) patients were girls. Their ages ranged from 2 to 18 years, with a mean of 6.93±4.61 years. The duration of the disease ranged from 10 to 90 days, with a mean of 30.12±22.00 days. Thirteen (81.3%) patients had lesions on the face, three (18.8%) had lesions on the neck, one (6.3%) had lesions on the back, another one (6.3%) had lesions on the chest, two (12.5%) patients had lesions on the abdomen, and one (6.3%) patient had lesions on the arm. Ten patients had few MC lesions (<five lesions), whereas six patients had multiple lesions (>five lesions).
This group included 16 MC patients administered an intralesional injection of normal neutral saline as a control group. Ten (62.5%) patients were girls and six (37.5%) patients were boys. Their ages ranged from 2 to 7 years, with a mean of 4.87±1.50 years. The duration of the disease ranged from 7 to 60 days, with a mean of 29.75±19.52. Twelve (75%) patients had lesions on the face, two (12.5%) had lesions on the back, four (25%) had lesions on the neck, and two (12.5%) had lesions on the chest. Six patients showed few MC lesions whereas 10 patients had multiple lesions. No statistically significant difference was detected between the two groups in terms of age, sex, duration of lesions, site of lesions, and number of patients with multiple or few lesions.
In group I, eight (50%) patients showed complete clearance of lesions after 4–5 sessions of intralesional Candida antigen, with no recurrence in the 3-month follow-up period (Fig. 1), whereas four (25%) patients showed a partial response and four (25%) patients showed no response.
In group II, 14 (87.5%) patients showed no response to intralesional saline after five sessions, whereas two (12.5%) patients showed a partial response. Comparison of clinical responses in the two groups showed a highly significant difference (P<0.001) (Table 1 and Fig. 2).
No significant relation was detected between the clinical response and age, sex, duration of the disease, and number of lesions (few or multiple) in the Candida group (Table 2). No significant relation was also detected between the clinical response and the site of lesions or number of sessions (Table 3).
Mild side effects were encountered in six (37.5%) patients in group I (Fig. 3). Pain at the site of injection was the main side effect experienced in three (18.75%) patients. Two (12.5%) patients developed edema, whereas one (6.25%) patient had local erythema. None of the patients suffered from flu-like symptoms or blistering.
Since Harada 8 reported the efficacy of Candida vaccine in the treatment of warts in 1979, various antigens have been used as intralesional therapy for warts 9. To our knowledge, there are only two reports on the treatment of MC with intralesional Candida antigen 7. The aim of this matched randomized-controlled clinical study was to evaluate the efficacy and safety of immunotherapy of MC with intralesional Candida antigen.
In this work, a complete clinical response was achieved in 50% of MC patients and a partial response in 25% of patients after 4–5 sessions of intralesional Candida antigen, with an overall response of 75%. No recurrence was detected after 3 months in all patients showing a complete response. In the control group, no response was detected in 87.5% of MC patients to an intralesional saline injection, whereas 12.5% of patients showed a partial response. Comparison of the clinical response between the two groups showed a highly statistically significant difference. These results are in agreement with those reported by Maronn et al.6 of 56% complete response, 28% partial response, and 16% no response after an intralesional Candida antigen injection in 25 MC patients.
Similarly, Enns and Evans 7 indicated that immunotherapy with an intralesional Candida antigen injection may serve as a promising treatment modality for pediatric MC infections. They reported complete clearance in 55.2% of 29 pediatric patients and partial clearance in 37.9% of patients, with a total response of 93%. It is noteworthy that the patients were administered no more than 0.3 ml of Candida antigen at 4 week intervals until clearance. In contrast, in the present study, injections were administered at 2 week intervals, which may explain in part the difference in the total response rate.
Na et al.5 reported the first two cases of a successful mumps–measles–rubella intralesional injection in MC. They detected complete resolution of lesions after 2–4 injections at 2 week intervals, with no recurrence after 3 months of follow-up. They concluded that the mumps–measles–rubella vaccine could be a promising treatment modality for MC, particularly for generalized lesions and uncooperative patients.
The mechanism of action of intralesional immunotherapy is still not clear. It is suggested that an intralesional antigen injection may induce a nonspecific inflammatory response against virus-infected cells 8. Also, an antigen injection may induce a proliferation of blood mononuclear cells that promote TH-1 cytokines, INF-γ and IL-2, which activate cytotoxic T cells to kill infected cells 7.
In this work, intralesional candida immunotherapy was well tolerated. Mild local side effects were detected in 37.5% of patients, mainly pain at the time of injection, edema, and local erythema. Similarly, the only reported side effects by Maronn et al.6 and Enns and Evans 7 were pain and discomfort at the time of injection. In contrast, other modalities of treatment of MC such as curettage, cryotherapy, or topical therapy with cantharidin are associated with adverse effects such as scarring, excessive blistering, and pain, with a high recurrence rate 10,11.
Common complications such as pruritus and pain usually start immediately and up to 24 h following intradermal injections of Candida antigen. Other possible complications such as burning, blistering, peeling, local erythema, and edema may also occur 12.
The results of this study indicate that intralesional immunotherapy with Candida antigen can represent a valuable, safe, and effective option for MC, especially for children with numerous lesions. It has the advantages of lack of scarring and blistering and is well tolerated by children.
Prospective studies are recommended for the evaluation of response rates, adverse effects, and cost–benefit analysis of intralesional Candida antigen compared with other treatment modalities. Further studies are also needed to clarify the exact immune mechanism of action of Candida antigen immunotherapy in MC.
The limitations of our study were the small patient sample size and the lack of continued follow-up, which had shown complete resolution in 50% of patients. It is likely that a longer study period would provide more accurate data on the recurrence rate.
Participation in the study and taking of photographs were performed after obtaining written consent.
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest work.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2017 Egyptian Women's Dermatologic Society
Candida antigen; immunotherapy; molluscum contagiosum