Received: 18 February 2020 Revised: 7 March 2020 Accepted: 10 March 2020

DOI: 10.1111/dth.13308

ORIGINAL ARTICLE

Intralesional zinc sulfate 2% vs intralesional vitamin D

in plantar warts: A clinicodermoscopic study

Mahira H. El Sayed1 | Fatma S. Sayed2,3 | Ahmed A. Afify1

1
Department of Dermatology, Venereology,
and Andrology, Faculty of Medicine, Ain Abstract
Shams University, Cairo, Egypt Verrucae are benign proliferations seen in skin due to infection with papillomavi-
2
Ain Shams University, Cairo, Egypt
ruses. There are different treatment strategies for warts but all of these treatments
3
Dermatology resident, Ministry of Health,
Cairo, Egypt are painful, time consuming, expensive, and recurrence is common. To evaluate and
compare the efficacy of intralesional 2% zinc sulfate solution vs vitamin D3 in the
Correspondence
Ahmed A. Afify, Department of Dermatology, treatment of plantar warts, as well as reporting the side effects. This three-armed
Venereology, and Andrology, Faculty of randomized clinical trial included 105 patients presented with plantar warts divided
Medicine, Ain Shams University, Cairo, Egypt.
Email: [email protected] into three groups, 35 patients per group. The first group received intralesional 2%
zinc sulfate, the second group received intralesional 2% vitamin D3, and the third
group received normal saline. Four sessions were done, one every 2 weeks. At the
end of the study, patients showing complete response were more in zinc group
(71.4%), vitamin D3 group (62.9%) compared to saline group (40%). Most of the
patients in zinc group showed severe pain during injection (48.6%), most of the
patients in vitamin D3 group showed mild pain (80%), while most of the patients in
saline group showed no pain (57.1%). Both intralesional 2% zinc sulfate and vitamin
D3 are effective in treatment of plantar warts, with zinc sulfate being more effective.

KEYWORDS

intralesional, plantar, vitamin D, warts, zinc

1 | I N T RO DU CT I O N treatments to the lower epidermis.5 Therefore, immunotherapy seems

to be a promising modality in such cases.6
Warts are benign proliferations seen in skin and mucosa due to infec- Zinc sulfate has an immunomodulatory function and plays a role
tion with human papillomaviruses (HPV).1 Warts are small, rough, and in enhancing cellular and humoral immunity.7 It has been used suc-
hard growths that are similar in color to the rest of the skin.2 They are cessfully in the treatment of plane warts topically and common warts
usually asymptomatic except when present on the bottom of the feet and genital warts orally.8 A few studies have utilized intralesional
3
where they may be painful. injection of 2% zinc sulfate solution for the treatment of common
Different treatment strategies are available for warts, for exam- warts.9
ple, cryotherapy, electrocoagulation, topical salicylic acid, topical Topical vitamin D has been used successfully in some cases for
4
5-fluorouracil, laser surgery, and so forth. Response to any of these treatment of warts. The effect of vitamin D derivatives on warts is
treatment options is highly variable, patient dependent and recurrence believed to be due to its potential to regulate epidermal cell prolifera-
is common. Cure rates of plantar warts are even lower, probably due tion and differentiation and to modulate cytokine production through
to thicker cornified layer and subsequent worse penetration of its action upon vitamin D receptors.10
Aktaş et al11 clearly demonstrates that recalcitrant plantar
warts can be treated successfully with intralesional vitamin D3
Name of the institution(s) at which the research was conducted: Dermatology outpatient
clinic of Ain-Shams University Hospitals. injection.

Dermatologic Therapy. 2020;33:e13308. wileyonlinelibrary.com/journal/dth © 2020 Wiley Periodicals, Inc. 1 of 7

https://doi.org/10.1111/dth.13308
2 of 7 EL SAYED ET AL.

The aim of this work was to evaluate and compare the clinical 3 | RE SU LT S
efficacy of intralesional 2% zinc sulfate solution vs intralesional vita-
min D3 in the treatment of plantar warts as well as reporting the side This study included 105 patients, 35 for each group, zinc sulfate group
effects. included 17 females (48.6%) and 18 males (51.4%) with age ranged
from 21 to 54 years (mean = 33.03 ± 8.84 years) and disease duration
ranged from 3 to 19 months (mean = 6.43 ± 4.40 months), vitamin D3
2 | METHODS group included 10 females (28.6%) and 25 males (71.4%) with age
ranged from 18 to 58 years (mean = 32.03 ± 13.37 years) and disease
• This three-armed randomized clinical trial included 105 patients duration ranged from 3 to 18 months (mean = 7.46 ± 4.51 months),
recently diagnosed to have plantar warts. Patients were rec- and saline group (control) included 12 females (34.3%) and 23 males
ruited from the Dermatology outpatient clinic at Ain-Shams (65.7%) with age ranged from 18 to 59 years (mean = 34.63
University Hospital during the period from July 2018 to May ± 12.91 years) and disease duration ranged from 3 to 15 months
2019. Patients under 18 years, pregnant and lactating females, (mean = 6.6 ± 3.46 months). There was no statistically significant dif-
patients received vaccination, immunomodulation, or any other ference between the three studied groups as regards age (P = .654),
treatment of warts in the past 3 months, patients with any evi- sex (P = .204), and duration of the disease (P = .542).
dence of immunosuppression, patients with hypercalcemia or There was no statistically significant difference between the three
renal disease, patients with a prior history of hypersensitivity to studied groups as regards the response to treatment after first, sec-
vitamin D or zinc sulfate and patients with past history of men- ond, and fourth session. While after the third session, there was a sta-
ingitis, convulsions, hepatitis B or C were excluded. After taking tistically significant increase in the numbers of partial responders
the approval of the research ethics committee of faculty of (Figure 1A-D) in the three studied groups (P = .023). Also there was a
medicine, Ain Shams University (FWA 000017585), a written steady increase in the response to treatment in the three studied
informed consent was obtained from each patient. groups with zinc group showing an earlier response to treatment and
• All patients were subjected to: Full history taking, clinical exami- most of patients with complete response to treatment (Figure 2A-D)
nation, photography (Samsung ST66, 16 megapixels, China), after the fourth session (25 patients, 71.4%) (Figure 2A-D; Table 1).
and dermoscopic examination (Dermlite© DL3 Gen) for size On comparing zinc group and saline group as regards the
and dermoscopic features of warts at the first and follow-up response to treatment, there was no statistically significant difference
visits. after the first session (P = .314), while there was a statistically signifi-
• Patients included in the present study were divided into three cant difference after the second session (P = .019), after the third ses-
groups by simple randomization, 35 patients per group. Seventy sion (P = .047) and after the fourth session (P = .025; Table 2).
percent ethanol was used as an antiseptic agent before injection. On comparing vitamin D3 group and saline group as regards the
At first, 0.2 mL of lignocaine (20 mg/mL) was used a local analgesic, response to treatment, there was no statistically significant difference
after few minutes, the first group received intralesional 2% zinc after the first session (P = 1), after the second session (P = .131), and
sulfate (0.2 mL). The solution was prepared in laboratory at Ain after the fourth session (P = .111), while after the third session, there
Shams University Hospital. In the preparation of 2% zinc sulfate, was a statistically significant difference (P = .016; Table 3).
2 g zinc sulfate powder was dissolved in 98 mL of sterile distilled There was no statistically significant difference between zinc
water and autoclaved at 95 C, the second group received group and vitamin D3 group as regards the response to treatment in
intralesional 2% vitamin D3 (600 000 IU; 15 mg/mL; 0.2 mL) and all the treatment sessions. However, zinc group showed an earlier
the third group received normal saline (0.2 mL) injected gently into response to treatment and more patients showing complete response
the base of one wart, one injection session every 2 weeks (four to treatment compared to vitamin D3 group (Table 4).
sessions), follow-up was done every 2 weeks until 6 weeks after After the fourth session, there was no statistically significant cor-
the last session (3 months). relation between age, sex, and response to treatment in zinc group
• Response rate was evaluated clinically and dermoscopically and (P = .196; P = .999) and in vitamin D3 group (P = .328; P = .361).
was classified as complete response or 100% if they showed a After the fourth session in saline group, there was a statistically
complete disappearance, partial response if regressed in size significant correlation between sex and response to treatment
more than 50%, or no response if the improvement was less (P = .046), more females showed complete response (eight patients,
than 50%. 57.1%), whereas more males showed partial response (13 patients,
• Data management and analysis: Data were analyzed by Statistical 86.7%) and no response (four patients, 66.7%), whereas there was no
Package for Social Science (IBM SPSS) version 23. The quantitative statistically significant correlation between age and response to treat-
data were presented as mean, SDs, and ranges when their distribu- ment (P = .719).
tion found parametric. Also, qualitative variables were presented as There was a high statistically significant difference (P < .001)
number and percentages. P > .05: Non significant (NS), P ≤ .05: sig- between the three studied groups as regards pain during injection
nificant (S), P ≤ .01: highly significant (HS). were most of the patients in zinc group showed severe pain during
EL SAYED ET AL. 3 of 7

F I G U R E 1 A, Clinical and B,
dermoscopic images of a 32-years-old
male patient before treatment with
intralesional vitamin D. C, Clinical and D,
dermoscopic images after treatment
showing partial clearance (reduction in
size of wart but still few black dots are
present)

F I G U R E 2 A, Clinical and B,
dermoscopic images of a 29-years-old
female patient before treatment with
intralesional zinc sulfate. C, Clinical and D,
dermoscopic images after treatment
showing complete clearance
(disappearance of all red and black dots
with restoration of normal furrows and
ridges of the plantar skin)
4 of 7 EL SAYED ET AL.

TABLE 1 Comparison between the three studied groups as regard response to treatment per session

Zinc group Vitamin D3 group Saline group

No. % No. % No. % Test valuea P value Sig.

First session No response 21 60.0% 25 71.4% 25 71.4% 1.392 .499 NS
Partial response 14 40.0% 10 28.6% 10 28.6%
Complete response 0 0.0% 0 0.0% 0 0.0%
Second session No response 6 17.1% 9 25.7% 15 42.9% 5.880 .053 NS
Partial response 29 82.9% 26 74.3% 20 57.1%
Third session No response 4 11.4% 2 5.7% 11 31.4% 11.353 .023 S
Partial response 24 68.6% 28 80.0% 22 62.9%
Complete response 7 20.0% 5 14.3% 2 5.7%
Fourth session No response 4 11.4% 2 5.7% 6 17.1% 8.993 .061 NS
Partial response 6 17.1% 11 31.4% 15 42.9%
Complete response 25 71.4% 22 62.9% 14 40.0%
a
ANOVA test.

TABLE 2 Comparison between zinc group and saline group as regards response to treatment

Zinc group Saline group

No. % No. % Test valuea P value Significance

First session No response 21 60.0% 25 71.4% 1.014 .314 NS
Partial response 14 40.0% 10 28.6%
Complete response 0 0.0% 0 0.0%
Second session No response 6 17.1% 15 42.9% 5.510 .019 S
Partial response 29 82.9% 20 57.1%
Third session No response 4 11.4% 11 31.4% 6.131 .047 S
Partial response 24 68.6% 22 62.9%
Complete response 7 20.0% 2 5.7%
Fourth session No response 4 11.4% 6 17.1% 7.360 .025 S
Partial response 6 17.1% 15 42.9%
Complete response 25 71.4% 14 40.0%
a
Chi-square test.

injection (17 patients, 48.6%), most of the patients in vitamin D3 diagnosis is usually based on typical clinical features, clinicians may
group showed mild pain (28 patients, 80%), whereas most of the sometimes be faced with features that overlap with other skin lesions
patients in saline group showed no pain (20 patients, 57.1%). or that make it difficult to accurately diagnose based on clinical
Edema and erythema after injection was observed in 31 patients criteria only. Dermoscopy of palmoplantar warts typically reveals mul-
(88.5%) in zinc group, 29 patients (82.8%) in vitamin D3 group and in tiple prominent hemorrhages within a well defined, yellowish
21patients (60%) in saline group. There were no reported cases with papilliform surface in which skin lines are interrupted. Disappearance
ulcerations or hypersenstivity reactions or vasovagal attacks. of these dermoscopic features could be used in monitoring the
response to treatment.12
In the present work, we used dermoscopy in assessment of treat-
4 | DISCUSSION ment response and classifying the response into complete, partial and
no response and this allows accurate grading of treatment response
Considering the rarity of previous studies comparing the clinical effi- instead of the previous methods that are based on clinical examina-
cacy of intralesional vitamin D3 and 2% zinc sulfate in wart treatment, tion only and this may have some fallacies by considering the
we aimed in this work to compare both modalities. response of some warts to treatment as a complete response although
Dermoscopy has been demonstrated to be a valuable tool in HPV these warts might not be completely resolved when examined by
infections both for diagnosis and treatment monitoring. Although their dermoscopy.
EL SAYED ET AL. 5 of 7

TABLE 3 Comparison between vitamin D3 group and saline group as regards response to treatment

Vitamin D3 group Saline group

No. % No. % Test valuea P value Significance

First session No response 25 71.4% 25 71.4% 0.000 1.000 NS
Partial response 10 28.6% 10 28.6%
Complete response 0 0.0% 0 0.0%
Second session No response 9 25.7% 15 42.9% 2.283 .131 NS
Partial response 26 74.3% 20 57.1%
Third session No response 2 5.7% 11 31.4% 8.236 .016 S
Partial response 28 80.0% 22 62.9%
Complete response 5 14.3% 2 5.7%
Fourth session No response 2 5.7% 6 17.1% 4.393 .111 NS
Partial response 11 31.4% 15 42.9%
Complete response 22 62.9% 14 40.0%
a
Chi-square test.

TABLE 4 Comparison between zinc group and vitamin D3 group as regards response to treatment

Zinc group Vitamin D3 group

No. % No. % Test valuea P value Significance

First session No response 21 60.0% 25 71.4% 1.014 .314 NS
Partial response 14 40.0% 10 28.6%
Complete response 0 0.0% 0 0.0%
Second session No response 6 17.1% 9 25.7% 0.764 .382 NS
Partial response 29 82.9% 26 74.3%
Third session No response 4 11.4% 2 5.7% 1.308 .520 NS
Partial response 24 68.6% 28 80.0%
Complete response 7 20.0% 5 14.3%
Fourth session No response 4 11.4% 2 5.7% 2.329 .312 NS
Partial response 6 17.1% 11 31.4%
Complete response 25 71.4% 22 62.9%
a
:Chi-square test.

Zinc has an immunomodulatory effects; it can counteract viral complete response. The similarity between the results may be attrib-
infection by stimulating cytokine production and through its cytotoxic uted to the injection of a relatively close number of patients, using the
effects.13 same concentration of zinc sulfate, similar patients' age groups
Zinc sulfate has an immunomodulatory function and plays a role and race.
in enhancing cellular and humoral immunity owing to its modulating On the other hand, Sharquie and Al-Nuaimy18 and Mohamed
actions on macrophage and neutrophil functions, NK cell/phagocytic et al9 showed different response rates. Sharquie and Al-Nuaimy18
7
activity, and various inflammatory cytokines. Hence, it is used in the reported a total cure rate in 98.2% of cases, and most of them needed
treatment of different skin and systemic diseases.14 The mechanism just a single injection. This difference might be because of the differ-
of action of zinc sulfate in viral warts cannot be speculated but is ent study design, as in their study they injected verruca vulgaris not
probably similar to the action of zinc sulfate in cutaneous leishmania- plantar warts. Mohamed et al9 reported 88% complete response. This
sis and bleomycin in viral warts, as both induce necrosis and inflamma- higher improvement rates may be attributed to the inclusion of more
tion.15 When zinc sulfate is injected intradermally, it causes a marked patients (120) and the higher dose of the used zinc sulfate 2% per
infiltration of inflammatory cells (first a wave of eosinophils then lym- patient as they are used to inject more than wart in the same patient,
16
phocytes, and finally fibroblasts) toward the injection site. whereas in our work, we injected only one wart for every patient.
The current results with intralesional 2% zinc sulfate are very Moreover, in the former studies, none of them used dermoscopy to
close to those given by Moubasher et al17 who reported a 72% evaluate the clinical response, so these results might be not accurate.
6 of 7 EL SAYED ET AL.

Intralesional vitamin D is used as an immune stimulant in case of Al-Nuaimy18 who reported the need to use local anesthesia before
recalcitrant warts.19 The proposed mechanism for vitamin D deriva- injection of zinc sulfate.
tives on warts is proposed to be due to its potential to regulate epi- In conclusion, both intralesional 2% zinc sulfate and vitamin D3
dermal cell proliferation and differentiation and to modulate cytokine are effective in treatment of plantar warts with zinc sulfate being
production. Upregulation of vitamin D receptors in the skin leads to more effective. Severe pain during zinc injections limits its acceptance
the induction of AMPs.11 It also acts on Toll-like receptor activation by most of the patients.
that causes human macrophages upregulation and expression of VDR
and vitamin D1-hydroxylase genes, leading to expression and secre- CONFLIC T OF INT ER E ST
tion of AMPs.19 None.
Our results of intralesional vitamin D3 were less than
Raghukumar et al19 study which reported 90% complete clearance OR CID
and this can be explained by the higher number of patients included Ahmed A. Afify https://orcid.org/0000-0002-7163-5383
(64), higher dose of intralesional vitamin D3 injected (up to 0.5 mL per
lesion), more warts injected per session (maximum five warts). RE FE RE NCE S
Intralesional saline is generally used as the placebo control for the 1. Sterling JC, Handfield-Jones S, Hudson PM. Guidelines for the man-
treatment of warts. Few studies evaluated the effect of intralesional agement of cutaneous warts. Br J Dermatol. 2014;144:4-11.
2. Ting Y, Manos MM. Detection and typing of genital human papilloma-
saline in wart treatment. Our results with intralesional saline (40%
viruses. In: Innis M, Gelfand D, Sninsky J, White T, eds. PCR Protocols:
complete response) are different from those reported by Zamanian a Guide to Methods and Applications. San Diego: Academic Press;
et al20 (27% complete response) in which the injections were repeated 1990:356-367.
every 2 weeks for maximum three injections. 3. Rollins MD, Vanderhooft SL. Benign skin lesions. Fundamentals of
Pediatric Surgery. Cham: Springer; 2017:853-862.
The mechanism of action of intralesional saline is unknown, it may
4. El-Mohamady A-S, Mearag I, El-Khalawany M, Elshahed A, Shokeir H,
be due to the trauma produced during the injection which may expose Mahmoud A. Pulsed dye laser versus Nd: YAG laser in the treatment
the viral particles to the immune system that later attacks them. of plantar warts: a comparative study. Lasers Med Sci. 2014;29:1111-
The current study shows a comparable clinical efficacy of 2% zinc 1116.
5. Atherton MJ, Stephenson KB, Pol J, et al. Customized viral immuno-
sulfate and vitamin D3 in the treatment of plantar warts. This, to the
therapy for HPV-associated cancer. Cancer Immunol Res. 2017;5:
best of our knowledge, is the second report on their comparative clini-
847-859.
cal evaluation after Abd El-Magid et al.21 Although our results were 6. Meena JK, Malhotra AK, Mathur DC, Mathur DK. Intralesional immu-
better with intralesional zinc sulfate compared to vitamin D and this notherapy with mycobacteriumw vaccine in patients with multiple
disagrees with the results of Abd El-Magid et al21 (80% of vitamin cutaneous warts: uncontrolled open study. JAMA Dermatol. 2013;
149:237-239.
D3-treated patients and 70% of zinc sulfate patients showed com-
7. Gupta, R., Mahajan, V. K., Mehta, K. S., & Chauhan, P. S. (2014). Zinc
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A better clinical response might have been obtained if the volume 8. Sharquie KE, Khorsheed AA, Al-Nuaimy AA. Topical zinc sulphate
solution for treatment of viral warts. Saudi Med J. 2007;28:1418.
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9. Mohamed ME, Tawfik KM, Mahmoud AM. The clinical effectiveness
warts were treated at a time and more treatment sessions were used. of intralesional injection of 2% zinc sulphate solution in the treatment
As an emerging therapy, different protocols should be tried in an of common wart. Scientifica. 2016;1082979:1-4. https://doi.org/10.
attempt to improve the response rates. 1155/2016/1082979.
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Our study showed absence of a significant correlation between
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age, sex, and the response to treatment in both group I and II, and this 2013;79:750.
is consistent with Mohamed et al9 and Raghukumar et al.19 In con- 11. Aktaş H, Demir B, Ekiz Ö, Ergin C. Intralesional vitamin D injection
trast, El-Taweel et al22 and Sabry et al23 reported better response of may be an effective treatment option for warts. J Cutan Med Surg.
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capable of mounting effective immune responses. under the dermoscope. SM Dermatolog J. 2019;5:1030.
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(P = .046). But this observation was not reported in other studies con-
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