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Published by jpds.editor, 2021-05-18 01:12:01

JPDS MAY 2021_18MAY2021

JPDS MAY 2021_18MAY2021

JPDS
Journal of the Philippine Dermatological Society
Volume 30 Issue 1 • May 2021 • ISSN 2094-201X

Rosai-Dorfman disease

Cutaneous manifestations COVID-19 COVID-19
in SARS-CoV-2 (COVID-19) vaccination and vaccination
infection: A review of patients with a history and dermatologic
clinical, histopathologic of facial soft tissue patients on
features, and fillers and botulinum immunotherapy &
management toxin injection biologic therapies



Editorial Board 2021-2022

Journal of the Philippine Dermatological Society • Volume 30 Issue 1 • May 2021

EDITOR-IN-CHIEF

Bryan Edgar K. Guevara, MD, FPDS

DEPUTY EDITOR MANAGING EDITOR

Hester Gail Lim Bueser, MD, FPDS Mara P. Evangelista-Huber, MD, FPDS

ASSOCIATE EDITORS

Czarina Chavez, MD, FPDS Elisa Rae Coo, MD, FPDS

Lian Jamisola, MD, FPDS Maria Jasmin J. Jamora, MD, FPDS

Hanna Lucero Orillaza, MD, FPDS Melanie Joy Doria-Ruiz, MD, FPDS

Ana Aurelia M. Santos, MD, FPDS Jennifer Aileen A. Tangtatco, MD, FPDS

Patricia Tinio, MD, FPDS Angeli Eloise E. Torres, MD, DPDS

Emmerson Gale S. Vista, MD, FPDS

SECTION EDITORS

Gisella Adasa, MD, FPDS Joyce C. Castillo, MD, FPDS

Tanya Perez-Chua, MD, FPDS Lily Lyralin Laconico Tumalad, MD, FPDS

Stephen Lacson, MD, FPDS Sharon Lim, MD, FPDS

Eugenio R. Pipo III, MD, FPDS Cybill Dianne C. Uy, MD, FPDS

Mia Angela C. Verzosa, MD, FPDS

SOCIAL MEDIA EDITORS

Francesca Sumilang Sy-Alvarado, MD, FPDS Erin Jane L. Tababa-Santos, MD, DPDS

EDITORIAL ADVISER

Camille B. Angeles, MD, FPDS

COPYEDITOR LAYOUT ARTIST

Rodel C. Roño Clarence Xlasi D. Ladrero

EDITORIAL OFFICE

#73 Malakas Street, Diliman, Quezon City 1100 Philippines

(632) 8727 7309 • https://journal.pds.org.ph/

JPDS is indexed in the Western Pacific Rim Index Medicus (WPRIM) and HERDIN.

ISSN: 2094-201X PHILIPPINE COPYRIGHT @ 2014 Philippine Dermatological Society. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or
by any means without prior permission in writing from the copyright holder.

DISCLAIMER

The Philippine Dermatological Society and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the
views and opinions expressed do not necessarily reflect those of the Philippine Dermatological Society and Editors, neither does the publication of advertisments constitute any
endorsement by the Philippine Dermatological Society and Editors.

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X i

Philippine Dermatological Society

OFFICERS AND BOARD DIRECTORS 2021-2022

Journal of the Philippine Dermatological Society • Volume 30 Issue 1 • May 2021

PRESIDENT

Francisco D. Rivera IV, MD, FPDS

VICE PRESIDENT

Noemie Salta Ramos, MD, FPDS

SECRETARY

Roberto Antonio D. Pascual, MD, FPDS

TREASURER

Mary Charmaine G. Castillo, MD, FPDS

IMMEDIATE PAST PRESIDENT

Ma. Purita Paz-Lao, MD, FPDS

DIRECTORS

Christene Pearl F. Arandia, MD, FPDS
Blossom Tian Chan, MD, FPDS

Krisinda Clare Dim-Jamora, MD, FPDS
Lonabel A. Encarnacion, MD, FPDS
Nancy Garcia-Tan, MD, FPDS
Cecilia Roxas Rosete, MD, FPDS
Arnold C. Yu, MD, FPDS

ii J Phil Dermatol Soc · May 2021 · ISSN 2094-201X



Table of Contents

Journal of the Philippine Dermatological Society • Volume 30 Issue 1 • May 2021

EDITORIAL 41

1 Drug-induced chronic bullous disease of
childhood in a two-year-old Filipino male
Dermatology: Going Digital triggered by cefaclor or cefuroxime: A case
report
Bryan Edgar K. Guevara
Sher Claranza O. Liquido, Maria Jasmin J. Jamora
LET’S HEAR FROM A COLLEAGUE
45
3
Lupus panniculitis in an ANA-negative
Cutaneous manifestations in SARS-CoV-2 systemic lupus erythematosus patient: A case
(COVID-19) infection: A review of clinical, report
histopathologic features, and management
Ma. Corazon A. Iniego-Rodas, Maria Franchesca Quinio,
Terese Monette O. Aquino, Fendi EJ R. Bautista, Charlene Ang-Tiu
Patricia Angelica Pastrana-Mabanta
49
ORIGINAL ARTICLES
Angiosarcoma of the scalp in a 79-year-old
12 male: A case report

A randomized controlled study on the efficacy Erika Kim R. Chan, Charlene Marie U. Ang-Tiu,
and safety of zinc oxide 20% ointment versus Mary Elizabeth S. Danga, Michael Jeff B. Fontano
salicylic acid 15% + lactic acid 15% ointment in
the treatment of patients with verruca vulgaris 53
in a tertiary hospital
Cutaneous Rosai-Dorfman disease in a 40-year-
Hazel C. Hao, Daisy King-Ismael old female: A case report

19 Joland A. San Juan, Juan Antonio D. Cervantes,
Johannes F. Dayrit, Ricky H. Hipolito,
A double-blind, randomized controlled trial on Ma. Teresita G. Gabriel
the efficacy and safety of intralesional 2% zinc
sulfate in the treatment of verruca vulgaris in a POSITION PAPERS
tertiary hospital
57
Abigail T. Siggaoat, Arnelfa C. Paliza
COVID-19 vaccination and dermatologic
29 patients on immunotherapy and biologic
therapies
A triple-blind, randomized controlled trial on
the efficacy and safety of 1.5% Carica papaya Clarisse G. Mendoza, Bryan Edgar K. Guevara,
latex cream vs. 2% ketoconazole cream in Cybill Dianne C. Uy
the treatment of pityriasis versicolor among
Filipinos 63

Anna Cecilia Francesca I. Alvarez, Jose Giovanni E. Dimayuga COVID-19 vaccination and patients with
a history of facial soft tissue fillers and
CASE REPORTS botulinum toxin injection

37 Krisinda Clare C. Dim-Jamora, Zharlah Gulmatico-Flores,
Stephen Lacson, Ma.Cricelda Rescober-Valencia,
Syringocystadenoma papilliferum arising from Francesca Sy-Alvarado, Irene Gaile Robredo-Vitas,
a nevus sebaceus mimicking squamous cell Maria Cecilia Ingente-Tablante, Teresita Ferrariz,
carcinoma in a Filipino female: A case report Agnes Thaebtharm

Maria Kristina R. Fajardo, Daisy King-Ismael,
Bernardita O. Policarpio

iv J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

JPDS EDITORIAL
Journal of the Philippine
Dermatological Society Dermatology: Going Digital

1Department of Dermatology, Bryan Edgar K. Guevara, MD, FPDS1
Southern Philippines Medical
Center Digital dermatology has started and expanded exponentially due to the coronavirus disease 2019
Corresponding author (COVID-19) pandemic in 2020. The use of telecommunication among health care providers over dis-
Bryan Edgar K. Guevara, MD, tance was first documented in the 1950s.1 The ideal setting of any form of medical practice is a face-
FPDS to-face consult, but the pandemic led to virtual consults as an alternative. Teledermatology has shown
Conflict of interest excellent patient satisfaction with diagnostic concordance with face-to-face consultation.2,3 This shows
None the potential and acceptance of teledermatology among patients and dermatologists.
Source of funding
None A study by Angeles et al,4 showed how dermatologists shifted to the practice of teledermatology.
The data showed an increase of dermatologists doing teleconsultations from 14.1% before the pandem-
ic to 70% thereafter. The type of teledermatology platform used was mainly chosen due to the ease of
use for the patients and the dermatologists. Facebook Messenger was the most used platform according
to the study. The lack of patient information security in using Facebook messenger will likely be a bar-
rier for telemedicine. With the increasing popularity of teledermatology, obtaining consent for virtual
consult, keeping patient information private, and finding secure communication platforms are still
necessary to prevent data privacy violations.5

The continuing medical education landscape has been transformed as well, where most of the
face-to-face meetings and conferences have been cancelled due to the current situation. With the stay-
at-home orders and social distancing guidelines all over the world, there has been a pivot to virtu-
al conferences as the new normal. This also applies to department conferences, continuing medical
education activities, workshops, and examinations. Now, there is a virtual trend in endless knowl-
edge-sharing capabilities among different training institutions. The virtual meetings have allowed
sharing of information and education in a convenient and efficient manner wherever one may be in the
archipelago. We used to travel long distances to attend a one-hour or one-day meeting, thus this “new
normal” will be a valid alternative. On the other hand, we might feel overburdened by the series of on-
line meetings/webinars and miss the social interaction during face-to-face meetings.

Although COVID-19 related researches have rapidly proliferated to help physicians understand
and treat this new threat, researches not related to COVID-19 were then disrupted. This delay can be at-
tributed to the closure of laboratory/clinical facilities, subsequently leading to the delays in non-COVID
related clinical trials during this pandemic.6 This also poses a challenge to residents and researchers
to adapt and pursue research amidst the pandemic. Qualitative or mixed method research can be im-
plemented with modifications to data collection by using online platforms (social media/phone data
collection/other online platforms). This pandemic has already changed the landscape of research es-
pecially in training institutions.

Going digital is the way this pandemic directs the practice of dermatology inside and outside the
clinic. This kind of virtual world opens up new opportunities, and we have to choose wisely how to
adapt to the change it offers.

REFERENCES

1. Wittson CL, Affleck DC, Johnson V. Two-way television in group therapy. Mental Hospitals. 1961; 12(10): 22-23. DOI: 10.1176/ps.12.11.22.
2. Warshaw EM, Hillman YJ, Greener NL, Hagel EM, MacDonald R, Rutks IR, et al. Teledermatology for diagnosis and management of skin conditions:

a systematic review. J Am Acad Dermatol. 2011; 74(4):759-72.
3. N guyen A, Tran D, Uemura M, Bardin RL, Shitabata PK. Practical and Sustainable Teledermatology and Teledermatopathology: Specialty Care

in Cameroon Africa. The Journal of Clinical and Aesthetic Dermatology. 2017;10(1):47-56.

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 1

EDITORIAL JPDS
Journal of the Philippine
Dermatological Society

4. Angeles CB, Chavez CP, Lim HG, Guevara BK, Jamisola LC. Impact of the COVID-19 pandemic on dermatology practice in the Philippines: A
descriptive cross-sectional study (unpublished).

5. F arr, M.A., Duvic, M. & Joshi, T.P. Teledermatology During COVID-19: An Updated Review. Am J Clin Dermatol(2021). DOI: 10.1007/s40257-021-00601-y.
6. Chong S-A, Capps BJ, Subramaniam M, Voo TC, Campbell AV. Clinical Research in Times of Pandemics. Public Health Ethics. 2010 Apr 1;3(1):35–8.

DOI: 10.1093/phe/phq005.

2 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

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Journal of the Philippine
Dermatological Society

Cutaneous manifestations in SARS-CoV-2 (COVID-19)
infection: A review of clinical, histopathologic
features, and management

Terese Monette O. Aquino, MD, DPDS, DDSP-PDS,1,2 Fendi EJ R. Bautista, MD,1,2
Patricia Angelica Pastrana-Mabanta, MD, MBA, DPDS1

ABSTRACT

BACKGROUND Numerous studies have demonstrated various information about COVID-19 infection. With this, the authors intend
to abridge, present, and synthesize current available information, focusing on the cutaneous manifestations of COVID-19
infection, to help guide dermatologists in understanding the dermatologic aspect of this disease.

OBJECTIVE This study aims to review the different cutaneous manifestations of COVID-19 by morphology and to evaluate the
lesions seen in the different age groups. Furthermore, this study aims to discuss cutaneous findings together with histologic
evidence and hypothesized pathophysiology, and to review the management used in treating COVID-19-related cutaneous
manifestations.

METHODS OVID® and PubMed databases were used to search in detail for COVID-19-induced skin lesions across all ages and their
management.

DISCUSSION COVID-19 affects the skin, hair and nails of patients. These may be attributed to the different virologic phases as
well as the immune response of the body. Histopathologic findings of these lesions vary depending on the clinical presentation.
Use of corticosteroid therapy and antihistamines as treatment for some cutaneous manifestations of COVID-19 showed good
response.

CONCLUSION COVID-19 infection-associated cutaneous manifestations present with different morphologies. It is important for
dermatologists to gain better understanding of this disease in order to promptly identify and suspect the possibility of this illness,
as well as provide appropriate actions.

KEYWORDS COVID-19, coronavirus, skin, cutaneous manifestations, COVID-19 management

1Skin and Cancer Foundation, INTRODUCTION 2020, with person-to-person transmission occur-
Inc. ring in the community and healthcare settings.1,2
2Department of Dermatology, An outbreak of respiratory diseases was first Common clinical features of this virus infection
Quirino Memorial Medical reported in Wuhan, China, in December 2019. include fever, cough, headache, diarrhea, fa-
Center, Quezon City, Philippines The causative agent was then discovered to be a tigue, headache, and myalgia. Meanwhile, cuta-
novel betacoronavirus of the same subgenus as neous manifestations are reported sporadically,
Corresponding author SARS-CoV; hence, it was called severe acute re- ranging from erythematous rash, urticaria to li-
Terese Monette O. Aquino, MD, spiratory syndrome coronavirus 2 (SARS-CoV-2), vedo reticularis and acrocyanosis in patients of
DPDS, DDSP-PDS commonly identified as coronavirus disease all age groups. The roles of these skin lesions in
2019 (COVID-19). The disease was subsequently early recognition and disease progression have
Conflict of interest announced as a public health emergency of in- yet to be extensively studied.2,3
None ternational concern in January 2020, which rap-
idly disseminated worldwide by February 2020. With more than a year since the discovery of
Source of funding With clinical manifestations ranging from mild COVID-19 and declaration of a pandemic, there
None respiratory symptoms to severe pneumonia, fa- had been overwhelming publications regarding
tality rate of COVID-19 is estimated at around COVID-19 made available. Using the numerous
2%. COVID-19 was then declared a pandemic data collected, the authors intend to present in-
by World Health Organization (WHO) in March formation in a more abridged and orderly man-

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 3

LET’S HEAR FROM JPDS
A COLLEAGUE Journal of the Philippine
Dermatological Society

ner, focusing on COVID-19 cutaneous manifestations. This study rosea-like (PR-like), (6)erythema elevatum diutinum-like (EED-
aims to review the different cutaneous manifestations of COVID-19 like), and (7)perifollicular eruption.13 The authors concluded an
by morphology and to review COVID-19 manifestations in the dif- increased risk of being admitted at the intensive care unit (ICU)
ferent age groups, including the pediatric and the pregnant popula- among patients with morbilliform and EM-like lesions and an
tions. Furthermore, it aims to discuss cutaneous findings together increased administration of systemic medications was noted
with histologic evidence, pathophysiology of cutaneous manifesta- among patients with purpuric erythematous, morbilliform,
tions and to review the management used in treating COVID-relat- other maculopapular, and EM-like eruptions (Figure1).13 Exan-
ed cutaneous manifestations to help dermatologists better under- thematous petechial eruptions were also documented that mim-
stand the disease. icked dengue hemorrhagic fever (DHF) in Thailand14 and a case
of an 84-year-old female with flexural accentuation.15
METHODS
The histopathology from these types of cutaneous erup-
A systematic search was done using two databases (1) OVID® tions showed mild spongiosis, vacuolar interface change, der-
with resources from EMBASE Classic and OVID Medline®, mal edema with superficial perivascular lymphocytic infiltrate,
and (2) PubMed. The following keywords were used: SARS- and few extravasated red blood cells (RBCs).16,17 In addition, the
CoV-2, COVID-19, pandemic, coronavirus, skin, cutaneous, presence of dilated superficial dermal vessels17,18 and rare eosin-
dermatologic manifestations, urticaria, pregnancy, neonatal, ophils17 were seen in other biopsies. Electron microscopic (EM)
pediatric, and COVID-19 management. The search was refined studies showed viral inclusions within the endothelial cells in
using Boolean operators and limits such as the English language biopsies of erythematous exanthemic and purpuric eruptions
and publication date from January 2020 up to March 25, 2021. All from patients with positive and negative reverse transcrip-
relevant articles were considered regardless of the type. tase-polymerase chain reaction (RT-PCR) for COVID-19, respec-
tively.19 EM-like eruption from both confirmed and suspected
RESULTS AND DISCUSSION COVID-19 patients failed to show classic EM features.17,20 These
lesions showed superficial and deep perivascular and periec-
Different cutaneous manifestations have been documented in crine lymphocytic infiltrate with dilated vessels and lympho-
suspected and confirmed COVID-19 patients. Presentations may cytic vasculitis, which was more suggestive of perniosis. Subse-
vary due to the different virologic phases as well as the distinct quent immunohistochemical (IHC) study for SARS-CoV-2 spike
immune response of the body.4 The frequency of cutaneous protein showed cytoplasmic granular positivity within the en-
manifestations of COVID-19 vary from 0.2%, (N=2/1099),5 dothelial cells and eccrine glands.20
5.95%,6 7.8% (N=53/678),7 and 20.4% (N=18/88).8 The median age
of patients having cutaneous lesions was 57-years with a median CHILBLAIN-LIKE LESIONS (CLL)
duration of 12 days.9 Also known as pseudo-chilblain or pernio-like lesions, CLL
is the second most common cutaneous manifestation in
CUTANEOUS MANIFESTATIONS, CLINICAL, AND patients with suspected and confirmed COVID-19 infection,
HISTOPATHOLOGIC FEATURES with frequencies of 18%10 to 24.6%9 (Table1). Most patients
were asymptomatic and had no history of cold exposure.
MACULOPAPULAR ERUPTION This cutaneous manifestation was described as edematous,
The maculopapular or exanthemic eruption was the most erythematous to violaceous macules, papules, with or without
frequently reported cutaneous manifestation in patients with vesicles or bullae.21,22 A subclassification into (1) erythemato-
COVID-19 infection with median age of 52-years (36-66 years) edematous type and (2) blistering type was also proposed.23
at presentation (Table1).10 Lesions were erythematous macules, CLL were seen in the younger age group with the median age
papules, maculopapular, some coalescing to form plaques.9-11 of 35-years (22-59 years) (Table 1).10 The areas involved were the
It starts on the trunk with progression to the extremities12 hands and feet, usually asymmetrical, with varying localization
with associated pruritus being the most common cutaneous from toes, heels,24 fingers, or both toes and fingers.12,21,23 The
symptom.6,9,10,12 The onset of the rash varied from the same most common associated cutaneous symptoms were pain and
time12 or after the onset6,10 of systemic symptoms with median burning (Table1).6,10,12 These lesions usually occurred after the
duration of 10 days (7-14.5 days)9 (Table 1). Association with onset of systemic symptoms6,9 and have the most prolonged
COVID-19 severity was unclear but in one study, it failed to show duration lasting for two to four weeks.4,22 CLL was also
increased risk for moderate or severe COVID-19 infection.9 consistently associated with absent to mild COVID-19 systemic
symptoms.6,9,10,12
In the Spanish study, maculopapular eruption accounted
for 47% (N=176/375) of cutaneous lesions among suspected and The most common histopathologic findings were dense
confirmed cases.12 A follow-up study was done to subclassify superficial and deep perivascular and perieccrine lymphocytic
this eruption (Figure1). The patients were further classified infiltrate.22,25 Other reports showed vacuolar interface change
into (1)morbilliform, (2)other maculopapular, (3)purpuric ery-
thematous, (4)erythema multiforme-like (EM-like), (5)pityriasis

4 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

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Journal of the Philippine A COLLEAGUE
Dermatological Society

Table 1. Summary of COVID-19 Cutaneous Manifestations

Maculopapular / Chilblain-like lesions Urticarial Eruption Vesicular Eruption Livedoid /Necrotic
Exanthematous lesions / Vascular
24.6§ 17† 6†
Frequency % 78† 19‡ 10.2§ 15.5§ 2.1§
25.7§ 18^ 19‡ 6%‡
47‡ 18.4# 16^ 9‡ 6.4^
22^ 15# 11^ 9.2#
37.3# 46/171§ 15#
71/375‡ 3/18† 1/18† 4/171§
Number of patients 14/18† 31/171^ 19/171§ 29/171§ 21/375‡
(Number of patients rash/N) 110/1847# 73/375‡ 34/375‡ 11/171^
176/375‡ 27/171^ 18/171^ 55/1847#
38/171^ 32‡ 89/18847# 89/1847#
223/1847# 48^ 90‡
44# 36‡ 44‡ 82^
Gender % 68‡ 22^ 44^ 61#
52^ 33# 51# 10‡
Male 44‡ 56# 56‡ 18^
50^ 64‡ 56^ 39#
49%# 35 (22-59)^ 78^ 49#
32.5‡ 67# 66 (51-73)^
Female 56‡ 40.7# 55 (36-58)^ 63.1‡
50^ 42 (29-54)^ 45.6‡ 72.3#
51# 7‡ 56.1#
16^ 48.7‡ 5‡
Age 11# 46.3# 15‡ 1^
34‡ 5.6^ 2#
Median age in years (IQR) 52 (36-66)^ 22^ 4‡ 6# 86‡
23# 7.4^ 56‡ 6^
Mean age in years 55.3‡ 59‡ 6# 22^ 39#
56.4# 22^ 20# 10‡
49# 61‡ 10‡ 91%F
Onset of lesions 67^ 72^ 58.5#
19^ 47# 74#
Before the onset of COVID-19 5‡ 14(5-27) §
systemic symptoms % 7.9^ 35‡ 10 (7-14) § 7(3-10)^
6# 22^
43.5# 10.4‡ 9.4‡
At the onset of COVID-19 61‡
systemic symptoms % 13^ 3.7^ 68‡ 14‡
41# 72^
89# 22#
After the onset of COVID-19 34‡ 3‡ 29‡
systemic symptoms % 76^ 63.5# 17#
51# 2‡ 10‡
14.5# 11#
No other COVID-19 2.6%^ 50^ 9.1^
symptoms % 11^ 73^

Duration of lesions 10 (7-14.5) § 22 (15-32) § 8 (5-13) § 18.2# 5#
Median duration in days (IQR) 7(3-10) ^ 14 (8-24) ^ 6.8‡ 32‡ 86‡
29# 27#
Mean duration in days 8.6‡ 12.7‡

Associated cutaneous
symptoms %

Pruritus 56‡ 73‡ 92‡
Pain 61^ 36^ 74^
75# 38# 27.5#
11‡ 1‡
2‡ 63.5# 7.5#
7.5# 30‡ 1‡
54# 9#
Burning 5‡ 71^ 22^
14# 9.7^ 3.7^

Pain/Burning 16^ 2.2# 3.4#
13‡ 44‡
Asymptomatic 21^ 14# 35#

Disease Severity % 3.6#
3.1#

Moderate 63‡
43#

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 5

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Dermatological Society

Severe 61‡ 3‡ 11‡ 6‡ 33‡
18# 4# 14# 21# 68#

Death 3.1# 3.6# 2.2# 3.4# 18.2#

COVID-19 status %

Suspected 31‡ 59‡ 33‡ 50‡ 19‡

Confirmed 69‡ 41‡ 67‡ 50‡ 81‡

IQR – Interquartile range
† Recalcati8 – N=18/88 confirmed COVID-19 cases developed cutaneous manifestation.
§ Marzano et al.9 – An Italian multicenter study of 187 of confirmed and probable COVID-19 infection presenting with one cutaneous phenotype.
‡ Gálvan Casas et al.12 – A Spanish prospective nationwide study in Spain consisting of 375 suspected and confirmed COVID-19 infection who developed cutaneous lesions.
^ Freeman et al.10 – An international registry for COVID-19 manifestation from 31 countries. 700 patients were registered but only 171 patients had confirmed COVID-19 infection.
# Jamshidi et al.6 – A systematic review which consisted of 1,847 confirmed COVID-19 infection.

Figure 1. Subanalysis of maculopapular eruptions in COVID-19 infected patient. The as scattered small monomorphic vesicles on the trunk with a
most common subclassification was morbilliform. The subclassifications associated tendency to coalesce, rupture, and form hemorrhagic crusts.12
with systemic treatment were morbilliform, other maculopapular, purpuric, and EM-like Other reports showed localized grouped vesicles on the trunk
eruptions. While most patients who were admitted at the ICU or needed non-invasive with surrounding erythema.30 Testing for varicella-zoster (VZV)
mechanical ventilation were patients who had morbilliform and EM-like eruptions. and herpes simplex viruses (HSV) were not constantly mentioned
in the reports. A study done in China and Italy performed PCR
and fibrin deposition beneath the ulcer base.19,26 Some studies for both VZV and HSV in patients with vesicular eruption, which
showed evidence of thrombus formation associated with were negative.7 The eruption mostly occurred after the onset
lymphocytic vasculitis with endothelial swelling and intense of systemic symptoms6,10 lasting for 10.4 (mean) days.12 The
inflammation in the deeper dermis.17,19,27 An EM study on CLL most common cutaneous symptom was pruritus (Table 1).6,10,12
in a 17-year-old male with (-)RT-PCR for COVID-19 showed viral Similar to maculopapular and urticarial eruptions, there was
inclusion within the endothelial cells.19 no clear association between having a vesicular eruption and
developing moderate to severe COVID-19 infection.9
URTICARIAL ERUPTION
Urticaria was a common cutaneous manifestation with frequen- Skin biopsies from these patients showed two different
cies of 10.2%9 to 19%12 (Table 1). The lesions were scattered wheals patterns, (1) focal acantholytic dyskeratosis with a collection
on the trunk,12 some coalescing to form larger plaques.28,29 The of Langerhans cells in the epidermis, superficial dilated
median age of affected patients was 42-years (29-54 years) (Ta- capillaries, and patchy bandlike lymphocytic infiltrate in the
ble 1).10 The onset of the eruption occurred same time as sys- dermis17 and (2) vacuolar interface change with disorganized
temic symptoms6,12 with a shorter duration of 6.8 (mean) days12 and multinucleated keratinocytes in the epidermis and minimal
(Table 1). The most frequent cutaneous symptom was pruri- inflammatory cells in the dermis.31
tus.6,10,12 Like the maculopapular eruption, the association with
COVID-19 infection severity was not clearly established.9 LIVEDOID, RETIFORM PURPURA, AND NECROTIC LESIONS
These are the least common dermatologic manifestations with
VESICULAR ERUPTION frequencies of 2.1%9 to 9.2%6 (Table 1). These were purpuric
Also referred to as chicken pox-like lesions,8 its frequency varied retiform lesions10 with a predilection to truncal, acral sites,12
from as low as 1.1%8 to 9%.12 The eruption occurred with median legs, and buttocks.10 Elderly patients with the median age of
age of 55.1-years (36-58 years)10 (Table 1), which was described 66-years (51-73 years) were mostly affected.10 These occurred
after the onset of COVID-19 systemic symptoms.6,10 However,
other studies reported at the onset of the infection.12 Most lesions
were asymptomatic,10 and some reported pruritus6,12 with the
mean duration of 9.4 days12 (Table 1). This manifestation was
consistently associated with severe COVID-19 infection9,10,12 and
with a 10% mortality rate.12

Histopathologic findings showed consistent features of
pauci-inflammatory thrombotic vasculopathy.10,17,32 Comple-
ment studies were done using IHC, which showed deposition of
C4d and C5b-9 within the vessel walls. C5b-9 was also present in
the normal skin of these patients. Interestingly, similar findings

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Dermatological Society

were also seen in the lungs and skin.32 ported include headache, myalgia, pharyngeal erythema, and
gastrointestinal clinical manifestations.37,38 Interestingly, a pap-
CUTANEOUS MANIFESTATIONS OF COVID-19 IN PREGNANT ulovesicular eruption consistent with Gianotti-crosti syndrome
PATIENTS was documented in a 10-month-old patient with (+)RT-PCR for
The clinical characteristics of pregnant patients with COVID-19 COVID-19 four weeks before the appearance of the rash.41
infection were similar to those of non-pregnant adults.33 At present,
there is still no evidence for intrauterine infection caused by vertical A recent case report showed a COVID-19 infected boy who
transmission in COVID-19 infected pregnant women.33–35 presented with conjunctivitis and eyelid dermatitis without any
other symptoms.42
A recent study, however, reported two cases of fetal
transient skin edema during the second trimester of pregnancy HAIR-ASSOCIATED CONDITION AND HAIR CHANGES
in women with COVID-19, which authors attribute to possible Increasing interest in androgenetic alopecia (AGA) as a potential
fetal infection or the consequence of the maternal infection in marker of severe COVID-19 infection has been studied.43–45 This
the fetal physiology.36 was referred as the “Gabrin Sign” to recognize the first American
physician with AGA who died from severe COVID-19 infection.46
CUTANEOUS MANIFESTATIONS OF COVID-19 IN NEONATAL In one study, it was observed that patients with Hamilton-
AND PEDIATRIC PATIENTS Norwood Scale (HNS) of >3 had worse hospitalization outcome.46
At the beginning of the pandemic, no cutaneous manifestations of Authors hypothesized the role of androgen receptors in regulating
COVID-19 in the pediatric population were reported; however, as transmembrane protease, serine 2 (TMPRSS2).22,45,25 Studies have
the pandemic spread, more neonatal and pediatric cases emerged. shown that androgen regulates TMPSS2, which primes the binding
of SARS-CoV-2 to the Angiotensin Converting Enzyme-2 receptor
A recent study presented two cases of neonates born to (ACE-2).27,44,47 In addition, men have more ACE-2 receptors than
two COVID-19 positive mothers, who were tested positive for women, thereby allowing more viruses to bind to these receptors.48
COVID-19 soon after birth.34 These two infants presented with This could explain the higher incidence of mortality among men46
cutaneous manifestations differently—one had a generalized with a difference in the mortality rate of 58% for men and 42% for
maculopapular rash with a solitary 0.3 × 0.5 cm2 ulcer on the women.45 However, this was challenged in a study done in Brazil
forehead, while the other presented with diffuse small miliary wherein they found no evidence linking AGA and worse COVID-19
red papules on the second day of life.34 The rashes of neonates outcome.43 Despite these growing data on AGA as a potential marker
resolved without any treatment, with the appearance of skin for severe COVID-19 infection, clinicians should not solely rely on
desquamation on day two and day ten, respectively.34 this parameter to associate severity of COVID-19 infection because
multiple factors can contribute to the disease, such as age, obesity,
In the pediatric population, cutaneous manifestations of and comorbidities. These studies had a small sample size; thus,
COVID-19 infection are similar to what is witnessed in adults further studies are needed to prove the association between AGA
and other viral exanthems, including macular, papular, vesic- and the severity of COVID-19.46,49
ular, and urticarial eruptions, some with acral involvement.37,38
One of the most commonly reported cutaneous manifestations Post-infectious telogen effluvium (TE) cases were not
of COVID-19 in pediatric population is an erythematous mac- surprisingly reported as well.43 The occurrence of TE was similar to
ulopapular rash—one reported similar to roseola and anoth- any other systemic insults that prematurely convert anagen hairs to
er accompanied by mild pruritus—spreading from the face telogen hairs. However, the presence of TE may be also due to drugs
to the extremities then the trunk.38 A recent case report re- and stress aside from probable infectious etiology.50
vealed a 12-year-old boy who, 4 weeks after a full recovery from
COVID-19, presented with a generalized maculopapular exan- NAIL CHANGES
them resembling pityriasis rosea, on the trunk, arms and legs There were a few case reports, which documented nail changes
that lasted for 2 weeks. This unusual prolonged dermatological post-COVID-19 infection. A case of Beau’s lines described
manifestation from a post-COVID-19 infection has rarely been as transverse grooves on both fingernails and toenails that
reported.39 EM-like eruption on the arms, legs, and ears, along- appeared 3.5 months after COVID-19 infection.51 Nail changes
side multiple erythemato-edematous macules and plaques on may be seen post-viral infection, especially with the Coxsackie
dorsal aspects of the fingers and toes, resembling CLL, have virus, which causes onychomadesis in children who had hand-
also been described.25,37 Suggested by some studies, CLL should foot-and-mouth disease.52 Similar to Beau’s lines documented
be considered a newly recognized manifestation of COVID‐19 in post-COVID-19 infection, these nail changes are due to the
in the pediatric population.40 These cutaneous manifestations temporary arrest of growth in the nail matrix.
were reported to fade after 7‐10 days and had an excellent prog-
nosis, without complications or severe disease manifestations.40 The “red half-moon sign” was another nail finding that
CLL is most commonly associated with asymptomatic to mild presented as a transient convex erythronichial band distal to
COVID-19 infection.6,10,12,37 Other accompanying symptoms re- the lunula, which appeared two weeks after being discharged

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from the hospital.53 An 89-year-old female who presented with however, show more extensive thrombus with very minimal
transverse orange discoloration at the distal nail bed, which inflammation.56 Patients who presented with CLL have decreased
appeared 16 weeks post-COVID-19 infection, was also reported.54 risk for developing moderate to severe COVID-19 infection while
The changes were probably due to microvascular injury and a livedoid, retiform purpura, or necrotic lesions have the increased
reflection of anemia and sarcopenia, respectively.53,54 risk of developing severe infection.9

PATHOPHYSIOLOGY OF CUTANEOUS We should always rule out the possibility of drug reactions
MANIFESTATIONS when we encounter these skin manifestations, especially those
presenting with maculopapular, urticarial, and vesicular
SARS-Cov-2 invades human cells by binding the virus’s S-protein eruptions. These are common manifestations of both viral
to the ACE-2 of the human cells. The ACE-2 receptors are not and drug reactions. Furthermore, in a tropical country with
only present in the lung epithelium, but also in endothelium, prevalent mosquito-borne diseases, COVID-19 may manifest as
oral cavity, renal tubule, adipocytes, keratinocytes, and cells an erythematous maculopapular rash like DHF.15
of the epidermis. The presence of ACE-2 in different cell types
may explain the various signs and symptoms associated with Evidence pointing out the presence of viral particles
COVID-19 infection. Severe diseases might also be attributed within the vascular system has been established.19 However, the
to the increased expression of ACE-2 in the elderly and obese potential infectivity of these particles is not yet clear, Standard
patients.48 In addition, the binding of SARS-CoV-2 to ACE-2 precautions must be in place during surgical management. As
causes overstimulation of the Renin-Angiotensin-Aldosterone- health care providers, we should be equipped whenever we
System (RAAS), leading to catastrophic endothelial dysfunction, attend to suspected COVID-19 patients.
inflammation, hypercoagulation, and respiratory collapse.27,48,55
These cascade might explain the occurrence of thrombotic MANAGEMENTOFCUTANEOUSMANIFESTATIONS
vasculopathy manifested as livedoid, retiform purpura, or IN COVID-19 PATIENTS
necrotic lesions in patients with severe COVID-19 infection. A
complement-associated microvascular injury and thrombosis CORTICOSTEROID THERAPY
presented with retiform purpuric lesions were demonstrated in Low-dose systemic corticosteroids have been suggested as a
a series by Magro et al.56 This mechanism involves the activation therapeutic option for COVID-19 associated with urticarial
of both alternative and lectin complement pathways leading to a rash, severe and widespread cases of confluent erythematous,
complement cascade with the generation of terminal membrane maculopapular, morbilliform rash, and severe cases of
attack complex (C5b-9), which causes direct cytolysis.56 purpuric “vasculitic” pattern (with necrotic-ulcerative lesions
and widespread presentation). On the other hand, topical
In contrast, in young and immunocompetent individuals, the corticosteroids have been successfully used for treating mild
clearance of the virus is achieved by immune response involving confluent erythematous rashes.10,24,58–62
the type I interferon (IFN-1), leading to short-lived to absent
systemic symptoms.26 IFN-1 is elevated during viral infection, ANTIHISTAMINES
autoimmune diseases such as systemic lupus erythematosus (SLE), Oral antihistamines contributed to clinical and symptomat-
and monogenic autoinflammatory interferonopathies (MAI).26 ic improvement in patients with urticarial rash.10,24,29,58,60,63 It is
Interestingly, patients with SLE and MAI present with perniosis well known that urticaria and angioedema can be triggered by
similar to CLL in COVID-19 infection. Hence, SARS-Cov-2 might viral and bacterial agents, such as cytomegalovirus, herpesvi-
trigger an exaggerated IFN-1 response causing CLL.57 The other rus, Epstein-Barr virus and mycoplasma.3 As with the case of
proposed mechanism of CLL is the effect on the RAAS in the acral COVID-19 infection, urticarial eruptions associated with this
vasculature, which promotes vasoconstriction.27 Despite this disease have been reported by Reaccati8 in his cohort of hospi-
evidence, direct causality remains unclear due to inconsistent talized patients. Urticaria is caused by immunoglobulin E- and
COVID-19 test positivity.5,21,22 However, the sudden increase of these non–immunoglobulin E-mediated histamine release and oth-
lesions during the pandemic might support an infectious etiology.23 er inflammatory mediators from mast cells and basophils;63
Physicians should be vigilant in recognizing these lesions as they hence, treatment with an antihistamine to control histamine
may be the potential spreaders of the virus since most of them release can be of benefit.
have mild infection. It is also important to emphasize that CLL
should not be referred to as acro-ischemic lesions. Both cutaneous There is currently no specific treatment or core guidelines
manifestations can present on the acral sites but with very different recommended in the management of cutaneous manifestations
features, the former being more erythematous and edematous of COVID-19. Policies and guidelines for the treatment of COVID-19
while the latter tends to be violaceous, purpuric to necrotic with were different among countries, and some researchers refused to
a retiform pattern. Histopathologic features of both may have give any treatments for asymptomatic patients or those with
microthrombi in the deep dermis. Retiform purpuric lesions, mild symptoms because the symptoms may remit spontaneous-
ly after several days. With the limited availability of significant
therapeutic options and given the tendency to spontaneously

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Dermatological Society

heal for these lesions associated with COVID-19, a “wait-and- the possibility of COVID-19 infection, especially for those who
see” strategy has frequently been suggested. Several studies are mildly symptomatic. CLL and livedoid lesions are the cuta-
have also demonstrated the usage of corticosteroid therapy and neous manifestations associated with mild and severe COVID-19
antihistamine in managing some of the skin manifestations of infection, respectively. Other cutaneous manifestations fall in
COVID-19, which yielded a good response.2,58 this spectrum and have yet to be studied to provide the causal
relationship with disease severity. Hair and nail manifestations
In a study by Shanshal,62 the author hypothesized that are potential research areas to explore and to further contrib-
low-dose systemic corticosteroids, combined with nonsedating ute to the pathogenesis of COVID-19. Histopathologic findings of
antihistamines, can help manage the hyperactivity of the these lesions vary depending on the clinical presentation. These
immune system in COVID-19 with their anti-inflammatory changes can be attributed to the body’s immune response direct-
properties. Usage of systemic corticosteroids, however, can ed against the virus or a consequence of a systemic disturbance
potentially increase the risk of infection as well. This may, due to COVID-19 infection. At present, there are limited thera-
therefore, restrict the use of these medicines for cutaneous peutic options for COVID-19-induced cutaneous manifestations,
lesions of COVID-19 patients.29 using mainly corticosteroid therapy and antihistamines, as nu-
merous studies have revealed spontaneous resolution of the le-
CONCLUSION sions and excellent prognosis.

COVID-19 infection-associated cutaneous manifestations pres-
ent with different phenotypes. Dermatologists should familiar-
ize themselves as they may be the first to identify and suspect

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Clinical aspects and our management experience. Dermatologic Therapy [Internet]. 2021 Jan [cited 2021 Apr 9];34(1). Available from: https://
onlinelibrary.wiley.com/doi/10.1111/dth.14547. DOI: 10.1111/dth.14547.
51. Alobaida S, Lam JM. Beau lines associated with COVID-19. CMAJ. 2020 Sep 8;192(36):E1040–E1040. DOI: 10.1503/cmaj.201619.
52. Shin JY, Cho BK, Park HJ. A Clinical Study of Nail Changes Occurring Secondary to Hand-Foot-Mouth Disease: Onychomadesis and Beau’s Lines.
Ann Dermatol. 2014;26(2):280. DOI: 10.5021/ad.2014.26.2.280.
53. Neri I, Guglielmo A, Virdi A, Gaspari V, Starace M, Piraccini BM. The red half-moon nail sign: a novel manifestation of coronavirus infection. J
Eur Acad Dermatol Venereol [Internet]. 2020 Nov [cited 2021 Mar 28];34(11). Available from: https://onlinelibrary.wiley.com/doi/10.1111/jdv.16747.
DOI: 10.1111/jdv.16747.
54. Tammaro A, Adebanjo GAR, Erasmus H, Chello C, Pezzuto A, Ramirez-Estrada S, et al. Transverse orange nail lesions following SARS-CoV-2
infection. Dermatologic Therapy [Internet]. 2021 Jan [cited 2021 Mar 28];34(1). Available from: https://onlinelibrary.wiley.com/doi/10.1111/
dth.14688. DOI: 10.1111/dth.14688.
55. Wiese OJ, Allwood BW, Zemlin AE. COVID-19 and the renin-angiotensin system (RAS): A spark that sets the forest alight? Medical Hypotheses.
2020 Nov;144:110231. DOI: 10.1016/j.mehy.2020.110231.
56. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. Complement associated microvascular injury and thrombosis in the
pathogenesis of severe COVID-19 infection: A report of five cases. Translational Research. 2020 Jun;220:1–13. DOI: 10.1016/j.trsl.2020.04.007.
57. Magro CM, Mulvey JJ, Laurence J, Sanders S, Crowson AN, Grossman M, et al. The differing pathophysiologies that underlie COVID-19-
associated perniosis and thrombotic retiform purpura: a case series. Br J Dermatol. 2021 Jan;184(1):141–50. DOI: 10.1111/bjd.19415.
58. Genovese G, Moltrasio C, Berti E, Marzano AV. Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives.
Dermatology. 2021;237(1):1–12. DOI: 10.1159/000512932.
59. Karaca Z, Yayli S, Çalışkan O. A unilateral purpuric rash in a patient with COVID-19 infection. Dermatologic Therapy [Internet]. 2020 Jul [cited
2021 Apr 9];33(4). Available from: https://onlinelibrary.wiley.com/doi/10.1111/dth.13798. DOI: 10.1111/dth.13798.
60. Fernandez-Nieto D, Ortega-Quijano D, Segurado-Miravalles G, Pindado-Ortega C, Prieto-Barrios M, Jimenez-Cauhe J. Comment on: Cutaneous
manifestations in COVID-19: a first perspective. Safety concerns of clinical images and skin biopsies. J Eur Acad Dermatol Venereol [Internet].
2020 Jun [cited 2021 Apr 9];34(6). Available from: https://onlinelibrary.wiley.com/doi/10.1111/jdv.16470. DOI: 10.1111/jdv.16470.
61. Najarian DJ. Morbilliform exanthem associated with COVID-19. JAAD Case Reports. 2020 Jun;6(6):493–4. DOI: 10.1016/j.jdcr.2020.04.015.
62. Shanshal M. Low- dose systemic steroids, an emerging therapeutic option for COVID-19 related urticaria. Journal of Dermatological
Treatment. 2020 Jul 16;1–2. DOI: 10.1080/09546634.2020.1795062.
63. Schaefer P. Acute and Chronic Urticaria: Evaluation and Treatment. 2017;95(11):8.

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JPDS ORIGINAL ARTICLE
Journal of the Philippine
Dermatological Society

A randomized controlled study on the efficacy and
safety of zinc oxide 20% ointment versus salicylic acid

15% + lactic acid 15% ointment in the treatment of
patients with verruca vulgaris in a tertiary hospital

Hazel C. Hao, MD, DPDS,1 Daisy King-Ismael, FPDS1

ABSTRACT

BACKGROUND Verruca vulgaris are scaly, rough papules or nodules caused by the human papilloma virus.

OBJECTIVE To determine the efficacy and safety of topical zinc oxide ointment versus topical salicylic acid + lactic acid ointment
as treatment among patients with verruca vulgaris.

METHODS This randomized, double-blind, 6-week study involved 29 patients with verruca vulgaris in a tertiary center who received zinc
oxide 20% ointment or salicylic acid 15% + lactic acid 15% ointment applied daily and occluded with Leukoplast™ tape. Evaluation was done
every two weeks.

RESULTS There was significant decrease in number of warts in the zinc oxide group (p=0.004), while it was not significant in the
salicylic acid+lactic acid group (p=0.392). Comparison between the two groups was not significant (p>0.05). Both zinc oxide
(P=0.000) and salicylic acid+lactic acid groups (P=0.025) had significant decrease in size of warts from baseline to 6th week of
observation. No significant differences were observed between the two groups in terms of adverse events such as erythema
(P>0.05), edema (P>0.05), tenderness (P>0.05), and scaling (P>0.05); however, itching was significantly higher at 4th week in the
salicylic acid+lactic acid group B (16.7%). Among the zinc oxide group, 100% would recommend the treatment, while only 71.4%
would recommend salicylic acid+lactic acid. The satisfaction levels of zinc oxide group were also statistically higher than
salicylic acid+lactic acid group (p=0.000).

CONCLUSION Zinc oxide 20% ointment is a safe and effective option for the treatment of verruca vulgaris especially among patients
that would prefer non-traumatic measures in the removal of their warts.

KEYWORDS Verruca vulgaris, zinc oxide, salicylic acid, lactic acid

1Department of Dermatology, INTRODUCTION on several factors, including host immunity, age,
University of Santo Tomas HPV type, and site of infection. According to
Hospital, Manila, Philippines Verruca vulgaris or common warts are scaly, rough Lipke, spontaneous clearance rates are said to be
papules or nodules caused by the human papilloma 23% at 2 months, 30% at 3 months, and 65-78% at
Corresponding author virus (HPV) that occurs through inoculation of 2 years.5
Hazel C. Hao, MD, DPDS the virus into viable epidermis through breaks
in the skin barrier.1 The rough surface of the Currently, there is still no gold standard of
Conflict of interest warts together with trauma causes inoculation therapy for verruca vulgaris. Various treatments
None of the wart into adjacent sites. These may occur are available, however none has clearly been
singly, or grouped on the hands, fingers, feet, or proven superior. Physical destruction of infected
Source of funding elsewhere. Treatment usually causes physical cells include electrocautery, cryotherapy, curette,
None and emotional discomfort, and depends on the or laser treatment. Local caustic agents such as
extent and duration of lesions, and the patient’s salicylic acid, lactic acid, and trichloroacetic acid
immunologic status and desire for therapy.2,3 Even have also been used. However, treatment associated
though warts have a natural course and are known with physical destruction not limited to the
to spontaneously clear, recurrences are common epidermis is associated with irritation, pain, post-
with almost all treatment modalities.4 The rate treatment hyperpigmentation, hypopigmentation,
of resolution is highly variable and is dependent and scarring.5 Immunotherapy has also gained

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ARTICLE Journal of the Philippine
Dermatological Society

ground for treatment of common warts after reports of patients Review Board prior to commencement.
receiving intralesional therapy for treatment of recalcitrant
warts showed promising results. It is hypothesized to make use PATIENT SELECTION AND RECRUITMENT
of the immune system’s capacity to mount a type 1 helper T cell- Patients selected for this study were males and females, aged 13
mediated delayed hypersensitivity response to various antigens, to 60 years old, diagnosed with verruca vulgaris by the primary
including HPV.6 Over the years, these various destructive investigator.
procedures which carry a risk of scarring and are painful have
remained the only effective remedy. For this reason, effective Patients with known hypersensitivity to zinc, immunocom-
treatments that are less traumatic to patients are a necessity. promised patients, those with more than five warts, and those al-
ready on treatment for warts were excluded from the study. Once
Zinc, a divalent cation and an essential micronutrient, is assessed as suitable to participate, the nature of the study was ex-
known to modulate immune response through macrophage and plained to the patients using the information sheet and they were
neutrophil functions, natural killer cell/phagocytic activity, requested to sign the informed consent. Parents of those aged 13 to
and various inflammatory cytokines, and has been used in 17 years old were asked to sign the consent form as well.
the treatment of many dermatological disorders due to its
immunomodulatory properties. Zinc affects multiple aspects RANDOMIZATION AND BLINDING
of the immune system, from the barrier of the skin to gene For allocation of participants, we used www.randomizer.org to
regulation within lymphocytes, and could counteract viral generate the allocation sequence.
infections by having an effect on the synthesis of cytokines.7,8
In vitro, it induces IFN-α as well as IFN-γ, and can potentiate The randomization sequence generated was the following:
the antiviral action of IFN-α. In addition, clearance of viral • Random digits set 1 (zinc oxide group) – 1 3 6 7 9 10 12
infections requires cytotoxic T lymphocytes, which are highly
dependent on zinc. Both its oral and topical form has been 13 17 20 21 25 31 32 33
studied in the therapy of verruca vulgaris.9 • Random digits set 2 (salicylic+lactic acid group) – 2 4 5

Oral and topical zinc sulfate, as well as topical zinc oxide 8 11 16 19 22 23 24 26 27 28 29 30
have been investigated as a safe and painless treatment for The allocation followed by giving the first patient admitted
warts.10-12 in the study zinc oxide while the second patient was given
lactic+salicylic acid. The process continued as the treatment
This study aimed to determine the efficacy and safety of reached patient 33.
topical zinc oxide 20% ointment versus topical salicylic acid 15% The zinc oxide 20% ointment, and the salicylic acid 15%
+ lactic acid 15% ointment as treatment among patients with + lactic acid 15% ointment given were in identical containers
verruca vulgaris. labeled as A and B to blind the patients and the primary
investigator from seeing the treatment.
Specifically, it aimed to determine and compare the A research assistant randomly allocated the treatment
improvement of verruca vulgaris lesions in both treatment to the patients. A convenience sampling was done by giving
groups through evaluation of the following: treatment to the first 33 patients enrolled in the study. These
patients satisfied the inclusion criteria before admission
1. The proportion of patients with complete clearance into the study. Following the random numbers, sequence of
between both treatment groups patients who came in from the specified time-period were given
treatment assigned to them.
2. The proportion of patients with decrease in number
and size (measurement in cm) of warts between both INTERVENTION AND DATA COLLECTION
treatment groups On the first visit, demographic profiles and the following
baseline data were recorded: duration of disease, number of
3. The grading of cutaneous adverse events (erythema, anatomic sites, anatomic sites, number of warts, measurement
edema, itching, tenderness, scaling, and others) reported of warts (cm).
by the patient and/or observed by the investigator
Photographs limited to the site of the lesions were
4. Patient acceptability of the treatment through a survey taken using Olympus Model No. E-MS camera (macro mode
of visual analog scale of patient satisfaction and setting). The lesions were also inspected using Dermlite II Pro
likelihood of recommending the same treatment for dermatoscope for thrombosed capillaries within the lobules
family members and friends between both treatment and loss of normal dermatoglyphics. Dermoscopic hallmark
groups of verruca vulgaris consists of large dotted vessels. These
dermoscopic features help the diagnosis of doubtful cases,
METHODOLOGY e.g. irritated warts, or difficult localizations, e.g. subungual or
periungual warts.13
STUDY DESIGN
This is a randomized, double-blind, controlled study conducted
from July 2018 to September 2018 at the dermatology clinic of a
tertiary hospital. This study was approved by the Institutional

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Patients were instructed to apply either the zinc oxide group and lactic+salicylic acid on number of anatomic sites.
(Rash free™) 20% ointment (Group A) or the compounded lactic Mann-Whitney U test was used to compare for the age and
acid 15% + salicylic acid 15% (Group B) ointment acquired from satisfaction, and Fishers exact test was used to compare the sex
BCP Dermatological Corporation on all their warts, occluded distribution and location of anatomic sites.
with Leukoplast™ tape twice a day. Patients were asked to rub
the affected area with 4 to 5 strokes using a pumice stone prior For the comparison of baseline to 6th week observations
to the evening application. on number of warts, chi-square test for trend proportions was
used. Z-test for proportions was used for comparison between
The following data were recorded at every follow-up visit, Group A and B at each treatment week. For the comparison of
scheduled at 2nd, 4th, and 6th week from the beginning of baseline to 6th week observations on size of warts, analysis
treatment by the primary investigator: of variance was used, and Tukey test was used for post-hoc
analysis. Chi-square test was used for comparison of treatment
1. Number of warts weeks on adverse events while z-test of proportion was used to
2. Size of warts compare zinc oxide group and lactic+salicylic acid group at each
3. Adverse effects (erythema, edema, itching, treatment weeks.

tenderness, scaling) Chi-square was also used to compare the two groups on
Every follow-up, photographs were also taken. Cure was recommendation, and reason for recommendation.
assessed as resolution of the wart with return to normal skin
markings, assessed by dermoscopy. At the end of the treatment Line graph was used to illustrate the comparison of baseline
period (6 weeks or upon cure), survey of visual analog scale to 6th week observations on number of warts and size of warts
of patient satisfaction and likelihood of recommending the while column graph was used to illustrate the comparison of
same treatment for family members and friends between both zinc oxide group and lactic+salicylic acid group on satisfaction,
treatment groups were obtained. Patients were instructed to recommendation, and reason for recommendation. Microsoft
contact the primary investigator immediately if any adverse Excel and SPSS version 25.0 was used for data analysis. Null
events were experienced during the course of treatment. hypotheses were rejected at 0.05 level of significance

ASSESSMENT RESULTS
Primary efficacy end points were evaluated through the
decrease in number and measurement of lesions at each follow- PATIENT DISPOSITION
up visit until the end of treatment. Secondary efficacy end point A total of 33 patients were assessed for eligibility. Twenty-
included the survey of visual analog scale of patient satisfaction nine out of 33 patients completed the study. Four could no
and likelihood of recommending the same treatment for family longer be contacted after baseline assessment. These patients
members and friends after treatment. were excluded in the data analysis and were treated as per
protocol leaving unequal number of samples for zinc oxide and
Safety end points were the comparison between the two salicylic+lactic acid groups (Figure 1).
treatment groups of the following parameters: Erythema, edema,
itching, tenderness, scaling, and other adverse effects noted. The computed power of analysis for 29 patients and its
distribution (15 patients in Group A and 14 in Group B) has
STATISTICAL CONSIDERATION AND DATA ANALYSIS 83.72% power of analysis. This means that the sample size and
For sample size computation, the research used G*Power Software. the omitted samples do not have any significant effect with the
The proportions used for sample size computation was based on the overall power of the study.
results of the reference study: “Topical zinc oxide vs. salicylic acid–
lactic acid combination in the treatment of warts” by Khattar et al.12 DEMOGRAPHIC AND BASELINE CHARACTERISTICS
According to this, cure rate in patients treated with zinc oxide was The median age of the patients included in the study was
statistically higher than those treated with salicylic acid-lactic acid.
The error used was 0.05 at 95% confidence interval. A minimum 23 years old (ranging from 13 to 60 years old), 79.3% have the
sample size of 26 corresponds or 13 respondents per group, 81.48% disease for more than 6 months while only 20.7% have the
actual power (power of analysis). disease for less than 6 months. The average number of anatomic
sites was 1.24 ± 0.51 mostly located in the arm and palmoplantar
Frequency and percentages was used to report the area (31%) followed by legs and dorsal areas (27.6%).
sex distribution of patients as well as the location of warts
investigated and the duration of disease. Mean and standard The zinc oxide group had 15 patients (7 male, 8 female) with a
deviation was used to report the mean number of anatomic sites mean age of 15 years old. The salicylic acid + lactic acid group had
while median and range was used to report the average age of 14 patients (5 male, 9 female) with a mean age of 35 years old. There
the patients. was no significant difference between zinc oxide and salicylic acid +
lactic acid groups in terms of age (p=0.275), sex (p=0.710), duration of
Independent t-test was used to compare the zinc oxide disease (p=0.651), number of anatomic sites (p=0.665) and location
of anatomic sites (p>0.05). Therefore, profile distribution of both

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 14

ORIGINAL Assessment for eligibility (n=35) JPDS
ARTICLE Randomized (n=33) Journal of the Philippine
Dermatological Society
Enrollment
Excluded (n=2)
• Not meeting inclusion criteria

(n=2)
• Declined to participate (n=0)
• Other reasons (n=0)

Allocated to zinc oxide group (n=17) Allocation Allocated to salicylic+lactic acid
• Received allocated group (n=16)
• Received allocated
intervention (n=17)
• Did not receive allocated intervention (n=16)
• Did not receive allocated
intervention (n=0)
intervention (n=0)

Lost to follow-up (n=2) Follow-up Lost to follow-up (n=2)
• Could not be contacted after • Could not be contacted after

baseline assessment (n=2) baseline assessment (n=2)

Analysed (n=15) Analysis Analysed (n=14)
• Excluded for analysis (n=0) • Excluded for analysis (n=0)

Figure 1. Participant flow

groups was statistically similar (Table 1). acid group from baseline to 6th week (Figure 2 and 3).
In terms of size, both zinc oxide (p=0.000) and salicylic+lactic
EFFICACY AND SAFETY OUTCOMES
Among the 15 patients (7 males, 8 females) in the zinc oxide acid groups (p=0.025) presented a significant improvement from
group, 2 patients had complete cure (100% decrease in baseline to 6th week of observation. The mean values showed
number of warts) and 2 patients were partially cured with 50% that there was a significant decrease in the mean size of warts of
improvement rate. In the salicylic + lactic acid group, 1 out of 14 the patients (Figure 4).

patients (5 males, 9 females) achieved complete cure. No significant differences were observed between both groups
There was significant decrease in the number of warts of in adverse events such as erythema (p>0.05), edema (p>0.05),
itching (p>0.05), tenderness (p>0.05), and scaling (p>0.05). Itching
zinc oxide group with p-value of 0.049 while in the salicylic+lactic was significantly higher at 4th week on salicylic+lactic acid group
acid group, the decrease was not significant with p-value of (16.7%) but remained absent in the zinc oxide group (0%) until
0.310. Comparison between the two groups, however was not completion.
significant with p-value above 0.05.
PATIENT ACCEPTABILITY OF TREATMENT
Significant results in the zinc oxide group were due to Among the zinc oxide group, 100% of patients would recommend the
the decrease in number of warts on 4th and 6th weeks. The treatment, while only 71.4% will recommend salicylic+lactic acid.
percentage of warts decreased to 84% at 4th week from the The model was significant in favor of zinc oxide group (p=0.042).
baseline then it went down to 80% at 6th week. On the other
hand, no significant change was observed in the salicylic+lactic Among the zinc oxide group, 53.3% of patients cited that

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Dermatological Society
Figure 2. Number of warts between zinc oxide and salicylic acid+lactic acid at baseline
Table 1. Baseline characteristics of participants and treatment weeks 2, 4, and 6.

Zinc oxide group Salicylic+Lactic p-value AB
(n=15) acid group 0.275
(n=14)
Age (years) 15.0 (13 – 62) 0.710
Sex 32.5 (13 – 56)
7 (46.7%) 0.651
Male 8 (53.3%) 5 (35.7%)
Female 9 (64.3%) 0.665
Duration of disease 4 (26.7%)
<6 months 11 (73.3%) 2 (14.3%) 1.000
>6 months 1.20 ± 0.41 12 (85.7%) 0.483
1.29 ± 0.61 0.245
Number of anatomic sites 0 (0%) 0.427
Location 0 (0%) 0 (0%) 0.682
3 (20%) 1 (7.1%) 0.427
Neck 3 (20%) 6 (42.9%) 0.999
Trunk 5 (33.3%) 5 (35.7%)
Arms 6 (40%) 3 (21.4%)
Legs 1 (6.7%) 3 (21.4%)
Dorsal 0 (0%)
Palmoplantar
Periungual

the reason they would recommend the treatment was because
it was effective, while 28.6% of patients in the salicylic+lactic
acid group said that they would not recommend it because the
treatment did not give them as much effect than they expected.

The satisfaction levels of patients in the zinc oxide group
were statistically higher than patients in the salicylic+lactic
acid group with p-value of 0.000.

DISCUSSION Figure 3. Wart on the finger. A. At baseline. B. Six weeks after zinc oxide application.

The primary treatment methods of warts are physical destruction hands, it may be easily removed by daily activities of the patient.
such as electrocautery, cryotherapy, laser therapy.14 However, Occlusion by application of a durable and waterproof tape would
these treatments are not suitable for patients with multiple lesions therefore aid in penetration and keeping the topical medication
or those with fear of pain and scarring. Therefore, immune- in place. In the present study, topical zinc oxide was occluded by
modifying agents such as zinc may be a useful therapeutic Leukoplast™ tape to aid in penetration and keeping the topical
alternative as they are painless and easy to apply. Zinc is said medication in place. Occlusion is covering the applied dose,
to counteract viral infections by its effect on the synthesis of either intentionally (e.g., bandaging) or unintentionally (e.g.,
cytokines such as IFN-α as well as IFN-γ. In addition, clearance putting on clothing) after applying a topical agent. Occlusion
of viral infections requires cytotoxic T lymphocytes, which are results in a combination of many physical factors that affect
highly dependent on zinc. Both its oral and topical form has been the skin and the applied compound by enhancing hydration
studied in the therapy of verruca vulgaris.15-17 In the study of and sometimes increasing skin temperature. It also prevents
Khattar, patients were instructed to apply the medication twice the accidental wiping or evaporation of the applied compound,
per day, wait for the medication to dry, and to rub the wart with ensuring a higher applied dose. This is a practical clinical
an emery stone before the evening application. Rubbing the method of enhancing cutaneous absorption.18
lesion daily with pumice stone was said to disrupt the keratinized
surface, thus helping penetration of zinc oxide.12 However,
another concern would be that since the medication is topically
applied to warts which are typically on exposed areas such as the

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Dermatological Society

Figure 4. Average size of warts between salicylic acid+lactic acid at baseline and was an expected finding, as salicylic acid and lactic acid are both
treatment weeks 2, 4, and 6. caustic agents, which are known to cause irritation and itching.

This study showed a statistically significant decrease in At the end of the treatment period, 100% of patients in the
the number of warts in the zinc oxide group compared to the zinc oxide group would recommend the treatment, while only
salicylic+lactic acid group. The number of warts was noted to 71.4% would recommend salicylic+lactic acid. The satisfaction
decrease at 4th and 6th week of observation. Clearance of warts levels of patients in the zinc oxide group were also statistically
was assessed clinically and using a dermatoscope, when there higher than patients in the salicylic+lactic acid group.
were no thrombosed capillaries visualized and also return of
normal dermatoglyphics. Among the zinc oxide group, patients cited that the
reason they would recommend the treatment to family and
Decrease in size of warts was also higher in the zinc oxide friends was because treatment with zinc oxide ointment was
group compared to salicylic+lactic acid group. The decrease in effective, painless, easy to apply, and they noted decrease in
size of warts was noted at 2nd to 6th week of observation for size of their lesions. Most also didn’t want to undergo traumatic
respondents. The difference, however, was not statistically measures to remove their warts. Among the respondents in the
significant between the two groups. A longer follow-up period salicylic+lactic acid group that would recommend treatment,
may be needed to show a statistically significant difference in decrease in size of lesions and absence of pain were the main
decrease of size between the two groups. reasons. Among those in the salicylic+lactic acid group that said
they would not recommend treatment, their reason was because
In other studies using topical zinc oxide, there were the treatment did not give them as much effect than expected.
minimal side effects noted such as erythema, swelling, scaling,
and hyperpigmentation.12 In studies using topical zinc sulphate, Our results further support that zinc oxide ointment,
side effects included itching, pain, and post-inflammatory therefore, is a well-tolerated, painless and safe treatment option
hypopigmentation.11 In our study, no adverse effects were noted by for verruca vulgaris.
the zinc oxide group until completion. Itching, however, was noted
in some respondents in the salicylic+lactic acid group (16.7%). This Limitations of the study include the short observation
period, as a longer period may document further reduction in
number and measurement of warts, as well as recurrence of
warts. The study also had a limited number of subjects, and the
pediatric age group was not included.

CONCLUSION

Review of literature has shown that zinc can be utilized in the
treatment of patients with verruca vulgaris as it targets many
pathogenic factors involved in the disease. The results of this
randomized controlled study show the efficacy of topical zinc
oxide 20% ointment in the treatment of verruca vulgaris as well
as its safety and tolerability. These data are valuable in future
studies so that a safe and painless treatment option would be
available for patients with verruca vulgaris. These endpoints
can subsequently improve the overall quality of life of patients
with verruca vulgaris.

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9. Moniem E, Genedy R, Moussa R. Oral zinc sulfate in treatment of recalcitrant warts. Egypt J Dermatol Venereol 2016; 36:34-38. DOI: 10.4103/1110-

6530.202637.
10. Mun J, Kim S, Jung D. Oral zinc sulfate treatment for viral warts: an open-label study. J Dermatol 2011; 38: 541–545. DOI: 10.1111/j.1346-

8138.2010.01056.x.
11. Sharquie K, Khorsheed A, Al-Nuaimy A. Topical zinc sulphate solution for treatment of viral warts. Saudi Med J 2007; 28(9): 1418–1421.
12. Khattar J, Musharra U, Tamim H, and Hamadeh G. Topical zinc oxide vs salicylic acid-lactic acid combination in the treatment of warts. Int J

Dermatol 2007; 46(4): 427–430. DOI: 10.1111/j.1365-4632.2006.03138.x.
13. Papakonstantinou E, Raap U. Alternative uses of dermoscopy in general dermatology. J Surg Dermatol 2017; 2(2): 67-74.
14. Banihashemi M, Pezeshkpor F, Yazdanpanah M, Family S. Eficacy of 80% phenol solution in comparison with cryotherapy in the treatment of

common warts of hands. Singapore Med J 2008; 49 (12): 1035-1037.
15. Sinha S, Relhan V, and Garg V. Immunomodulators in warts: unexplored or ineffective. Indian J Dermatol. 2015 Mar­Apr; 60(2): 118–129. DOI:

10.4103/0019-5154.152502.
16. S harma S, Barman K, Sarkar R, Manjhi M, and Garg V. Efficacy of oral zinc therapy in epidermodysplasia verruciformis with squamous cell

carcinoma. Indian Dermatol 2014; 5:55–58. DOI: 10.4103/2229-5178.126034.
17. Sharquie K, Al-Nuaimy A, Treatment of viral warts by intralesional injection of zinc sulphate. Ann Saudi Med; 22(1-2): 26–28, 2002. DOI:

10.5144/0256-4947.2002.26.
18. Wester R, Maibach H. Topical drug delivery: percutaneous absorption. In: Shah P, Maibach H, editors. Topical drug bioavailability,

bioequivalence, and penetration. New York: Plenum Press; 1993. p. 3-15.

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JPDS ORIGINAL ARTICLE
Journal of the Philippine
Dermatological Society

A double-blind, randomized controlled trial on the
efficacy and safety of intralesional 2% zinc sulfate in the

treatment of verruca vulgaris in a tertiary hospital

Abigail T. Siggaoat, MD, DPDS,1 Arnelfa C. Paliza, MD, FPDS1

ABSTRACT

BACKGROUND Verruca vulgaris ranked 10th in the top 10 diseases in 2019 seen among the Philippine Dermatological Society
training institutions. The efficacy of immunotherapy, such as intralesional zinc sulfate (ZS), for warts were reported. Considering
the limited studies with promising results on verruca, a study on the efficacy and safety of intralesional zinc in the treatment
of verruca was considered.

OBJECTIVE This study aims to determine the efficacy and safety of intralesional 2% ZS in comparison to intralesional purified
protein derivative (PPD) among adult patients with verruca vulgaris.

METHODS This is a double-blind, randomized, controlled trial involving 44 patients allocated to group ZS (n=22) and PPD (n=22).
Intralesional injections of ZS or PPD to the largest wart were done at weeks 0, 2, 4, 6, 8, 10. Clearance and size reduction of the target and
distant wart at 12th week and recurrence at 14th week were assessed. Adverse effects were checked.

RESULTS At the 12th week of treatment, higher proportion in group ZS patients achieved total resolution of the target lesion
compared to PPD, but results were not statistically significant (29% vs. 19%). Both groups showed decline in the target lesion size.
The median size reduction between the two groups showed no significant differences. Three patients from group ZS showed
clearance of distant warts while none in group PPD. There was no recurrence of all previously resolved warts. Adverse reactions
were pain, edema, and erythema.

CONCLUSION Intralesional 2% zinc sulfate (29%) was efficacious and safe compared to Intralesional PPD (19%) but the difference
was not statistically significant. There was clearance of distant warts in 5% of group ZS patients. The mild adverse events did not
warrant discontinuation of treatment.

KEYWORDS intralesional zinc sulfate, intralesional purified protein derivative, verruca vulgaris

1Department of Dermatology, INTRODUCTION The most common treatment for warts is
University of Santo Tomas physical destruction of the lesion. Treatment
Hospital, Manila, Philippines Verruca vulgaris, caused by human papilloma on numerous lesions using physical destruc-
virus (HPV), is a common skin condition world- tion, such as electrocautery, curettage, and
Corresponding author wide which may be transmitted through breaks cryotherapy is avoided by some patients due
Abigail T. Siggaoat, MD, DPDS in the skin or autoinoculation into adjacent skin. to pain, discomfort, recurrence and prolonged
It ranked 10th in the top 10 diseases in 2019 seen healing time. Moreover, the goal of physically
Conflict of interest among the training institutions of the Philippine destructive therapies is to eliminate the lesion
None Dermatological Society with a prevalence rate of but this does not completely eradicate the vi-
2.2%.1 It presents as small hyperkeratotic prolif- rus. Success rates of 65-85% were found with
Source of funding erations which can spread and remain subclin- the use of electrocautery and curettage but the
None ical.2 In the treatment of warts, the modality is high recurrence rate of 30% should be consid-
chosen after considering the location, extent of ered when choosing these as treatments.3 There
the lesions and patient’s cooperation. The treat- were also findings of peripheral spread of virus
ment modalities which are currently available in warts treated with electrocautery which was
are topical caustics and acids, electrodessication, attributed to incomplete eradication of the virus
cryotherapy, surgical excision and immunother- or koebnerization.3
apy.2 These modalities are not consistently effec-
tive and may be cumbersome for a lot of patients. Chemical treatment for verruca consists of

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salicylic acid, trichloroacetic and monochloroacetic acid, glu- Monochloroacetic acid showed a cure rate of 61%; however, it is
taraldehyde, and cantharidin. The cure rates for salicylic acid highly corrosive and toxic.4 Glutaraldehyde 10% paint showed a
vary between 15-49% which is low when compared to physi- cure rate of 71% but there were reports of deep necrosis due to
cal destruction or immunotherapy.4 There is inadequate trial repeated application. Cantharidin showed good response rates
evidence of trichloroacetic acid in the treatment of verruca. in the treatment of verruca; however, it involved prolonged and

EXCLUSION Selection of patients diagnosed with
Allergy to PPD and Zinc Sulfate, Verruca

ongoing other treatment for INCLUSION
warts, use of immunomodulators, 18 to 50 years old, male or female,
diagnosed with verrucae vulgaris,
chronic systemic illness, history of Bacilli Calmette Guerin
immunocompromised state, pregnant vaccination, lesion count of 2-20,
largest diameter of lesions between
and lactating women
0.1-5cm

Review of patient information sheet
and signing of informed consent

Randomization

Intralesional 2% Zinc Sulfate (ZS Intralesional Tuberculin Purified
group) Protein Derivative (PPD group)
• 0.1 mL • 0.1 mL
• Given at 0, 2, 4, 6, 8, 10th week for • Given at 0, 2, 4, 6, 8, 10th week for

a maximum of 6 injections a maximum of 6 injections

Assessment at baseline using size, photography, dermoscopy

Assessment every 2 weeks using clearance, size reduction,
photography, dermoscopy

Final assessment at the week of complete resolution using
clearance, size reduction, photography and dermoscopy

Electrocautery on unresolved lesions

Adverse events in both groups

Assessment of recurrence at 1 month from the last injection

Figure 1. Schematic diagram of patient disposition for Zinc sulfate (ZS) and PPD groups.

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repeated treatments of more than 6 weeks in duration with blis- zinc can increase its cytotoxicity and killing activity.11,12 This
tering and discomfort in the patients.4 increase in NK cell activity can help in eradicating HPV, and
consequently, clearance of warts. Immunotherapy using
The antiproliferative treatment for verruca consists of topical intralesional zinc sulfate was regarded as effective, but only
5-fluouracil, podophyllotoxin, bleomycin, cidofovir, and retinoids. few studies have been done.13-15 Furthermore, these studies
All treatments are available in our setting; however, the prolonged had lesser treatment sessions, did not expound on the effect of
duration and high cost of treatment are the deterrents in choosing intralesional zinc sulfate on size of the lesion and had a short
these treatments. Occlusotherapy or the use of occlusion of duct observation period. Considering the many health benefits from
tape on verruca had varying cure rates as well.4 zinc,16 its availability and the need of additional studies, a study
on the efficacy and safety of intralesional zinc in the treatment
Considering the limitation of these previously mentioned of verruca was considered.
treatment modalities, immunotherapy may be a better treat-
ment for verruca. Immunotherapy that induces a localized im- METHODS
mune response against the virus, is now considered by many
dermatologists because of ease of use, efficacy on distant le- A double-blind, randomized, controlled study was done in a
sions, less discomfort, and absence of delayed healing time. In- tertiary hospital from January-June 2019. The study protocol
tralesional immunotherapy utilizes the ability of the immune was approved by the hospital’s institutional review board and
system to mount a delayed hypersensitivity response to the wart was conducted in accordance to the Declaration of Helsinki.
tissue and has been associated with the production of Th1 cy-
tokines which activate the cytotoxic and natural killer cells to Inclusion criteria were 18 to 50 years old, male or female,
eradicate the HPV infection.5 Therefore, intralesional immuno- with 2-20 warts with the largest diameter measuring 0.1-5cm,
therapy may eradicate not only the target wart but also the dis- and a history of BCG vaccination. Exclusion criteria were those
tant warts by strengthening the immune system. with the largest wart located on the tips of fingers and toes, gen-
itals, eyelids, history of adverse reactions to zinc sulfate and tu-
In a study done by Khozeimeh et al (2017), the patients berculin PPD, undergoing other wart treatment, immunocom-
who were given immunotherapy using intralesional candida promised state, history of tuberculosis or negative tuberculin
antigen showed significant therapeutic response compared to test, active illness, pregnant or lactating women (Figure 1).
cryotherapy.6 Several studies reported on the efficacy of Tu-
berculin Purified Protein Derivative (PPD), Measles, Mumps, A primary investigator and two research assistants partici-
Rubella (MMR) vaccine, Trichophyton, Propionebacterium, pated in the study. Prior to the start of the study, the first research
Vitamin D, candida antigen, mycobacterium vaccine, Inter- assistant, who was not blinded to the study, assessed the eligibility
feron-alpha, Interferon-beta, and Interferon-gamma. Other of patients, assigned these patients with an alphanumeric identifi-
forms are via oral administration of zinc sulfate and cimeti- er and generated the treatment allocation. The list of patient num-
dine.7 According to the network meta-analysis by Salman et al bers were entered in www.randomization.com which randomly
(2018), there are few controlled trials done using the treatment assigned the patients. The 2nd research assistant, who was blinded
of intralesional candida antigen and propionebacterium.7 to the treatment allocation, assessed and recorded the treatment
Moreover, these treatment modalities are not readily available outcomes. The primary investigator, who was also blinded to the
in our setting. In the same study, PPD and MMR were regarded treatment allocation, administered the treatment to the patients
as the top ranked treatment modalities in achieving complete and assessed the overall results.
recovery of initial and distant lesions in comparison to the
other modalities.7 The high cost of MMR in our setting, may be Table 1. Outcome Assessment.8
a limiting factor for our patients. However, tuberculin Purified
Protein Derivative (PPD), used in tuberculin skin test, is widely Outcome Definition
available, cost effective and well-known in the Philippines. It is Cleared/resolved
derived from the Mycobacterium Tuberculosis human strain.8 Complete removal of the wart (injected largest target wart and
Various studies were reported about its ability to treat warts.7 non-injected distant wart)
The cost, availability and efficacy on viral warts of PPD served
as the reason for choosing this as the control in this study. Improved/evident clear- Decrease in size by =/>50% of the original wart
ance
Zinc sulfate is an compound that is available, affordable,
and approved by the Food and Drug Administration in the Partial clearance Decrease in size by < 50%
Philippines.9 It plays a vital role in regulating the inflammatory
response. It could lead to the eradication of the HPV virus No change from the previ- Increase in size of the wart from baseline
that causes viral warts.10,11 Low zinc levels cause a decrease ous lesion
in natural killer (NK) cell activity, but supplementation with
Worsening

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PREPARATION AND INTERVENTION testing. A shelf-life of 1 month was observed.
The solution was prepared in the pharmacy of a tertiary hospital The largest wart was injected intralesionally with an 0.1mL
using 2g of zinc sulfate powder dissolved in 100ml of sterile
distilled water, packaged in bottles and was subsequently zinc sulfate or 0.1mL PPD (Arkray Healthcare Private Limited)
autoclaved. The first batch of the solutions underwent sterility e ve ry 2 we e ks. Afte r comple te cle arance of the wart or comple tion
of 6 injections, the participants followed up after 2 weeks and 4

EXCLUSION Selection of patients diagnosed with
Allergy to PPD and Zinc Sulfate, Verruca

ongoing other treatment for INCLUSION
warts, use of immunomodulators, 18 to 50 years old, male or female,
diagnosed with verrucae vulgaris,
chronic systemic illness, history of Bacilli Calmette Guerin
immunocompromised state, pregnant vaccination, lesion count of 2-20,
largest diameter of lesions between
and lactating women
0.1-5cm

Randomization

Allocation

Zinc sulfate group PPD group
N = 22 N = 22

Follow-up

Zinc sulfate group PPD group
Lost to follow up Lost to follow up
N=1
N=1

Analysis

Zinc sulfate group PPD group

Complete clearance of target wart at Complete clearance of target wart at
12th week = 6 12th week = 4

Complete clearance of distant warts = 3 Complete clearance of distant warts = 0

Figure 2. Consort flow diagram for Zinc sulfate and PPD groups.

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weeks to assess for response and recurrence, respectively. In resolution and absence of recurrence of the warts. Using a list of
order to standardize the study, the same dose and schedule of possible adverse reactions,7 the 2nd research assistant examined
treatment was used for both groups. The dose and schedule of each participant and asked about the effect of treatment which
treatment were based on a previous study7 that used 0.1mL PPD were recorded at each follow up. The possible adverse reactions
every 2 weeks. Treatment was discontinued if withdrawal from were erythema, pain at injection site, pruritus, edema, hyper-
study was requested, the patient was noncompliant, or there pigmentation, hematoma, scarring and vascular necrosis.7 The
was intolerable adverse reaction that needed treatment. participants were also asked if there were any side effects which
were not found in the list. Pain medication and warm compress
CLINICAL ASSESSMENT where used when necessary. Electrocautery was done on unre-
The primary outcome was the complete clearance of the injected solved lesions during the last follow up.
largest wart. The secondary outcomes were reduction in size of the
injected wart, percentage of patients with complete clearance of SAMPLE SIZE DETERMINATION
distant warts, recurrence after 1 month and adverse events. PASS 2008 was used to calculate the minimum sample size of the
study. The proportion of 87% complete clearance among patients
At baseline and follow ups, photographs of all the warts were given PPD was used.12 A sample size of 38 patients achieved 82%
taken and measurement of the largest wart injected was done us- power to detect at least a 40% difference in proportions given an
ing a measuring tape (Table 18). Clearance of injected target and alpha equal to 0.05. It was increased to 44—22 for each group—
non-injected distant warts was clinically indicated by complete to account for 10% dropout. Convenience sampling design was
resolution of the lesion with absence of black dots. Recurrence employed.
of warts was considered clinically when there was elevation of
the lesion with presence of black dots. Using dermoscopy, dense DATA ANALYSIS
papillae, whitish halos surrounding central red dotted vessels Data were encoded via Microsoft Excel. Stata MP version 14 was
with hemorrhagic reddish to black dots or streaks were assessed used for data processing and analysis. Continuous variables
at baseline.18 Black dots signify thrombosed capillaries in warts were presented as mean ± SD or median/IQR depending on
which were examined during physical examination and der- data distribution while categorical variables were presented
moscopy. Disappearance of these findings confirmed complete as frequency/percentage. Comparison of continuous variables
were performed using independent t-test or Mann Whitney U
Table 2. Demographic and clinical profile of patients with verruca vulgaris seen at a tertiary test while comparison of categorical variables were done using
hospital (n=44). Chi Square test or Fisher’s exact test.

Characteristics Group ZS Group PPD P-value Chi square test or Fisher’s exact test was utilized to
(n= 22) (n= 22) compare the proportion of complete clearance and recurrence
n(%) n(%) in the target wart between the two treatment groups. Percent
clearance at each follow-up period was compared between the
Age (in years), median 27.50 27.50 0.7959a two groups using independent t-test. Reduction in target wart

[IQR: 20 – 46] [IQR: 21 – 43]

Sex, n(%)

Male 8 (36) 11 (50) 0.361b
Female 14 (64) 11 (50)

Duration of verruca vulgaris, n(%) Table 3. Distant lesion location and size by group (n=229).

1-3 months 3 (14) 1 (5) Group ZS Group PPD P-value
3-6 months 3 (14) 4 (18) (n=137) (n=92) 0.376a
0.0073*b
0.767c Lesion site

>6 months 16 (73) 17 (77) Face 1 (1) 0

Total number of lesions, mean ± SD 5.18 ± 2.95 7.14 ± 4.62 0.1021d Scalp 4 (3) 0

Number of distant lesions, median (IQR) 3 6 0.1272a Upper extremities 16 (11) 7 (8)
[IQR: 2 -6 ] [IQR: 2 – 8]

Size of largest lesion (in cm), mean ± SD 1.07 ± 0.44 1.03 ± 0.52 0.7792d Lower extremities 4 (3) 1 (1)

Location of target lesion, n(%) Palmoplantar 86 (63) 63 (68)

Palmoplantar 9 (41) 11 (50) Periungual 26 (19) 21 (23)

Periungual 8 (36) 6 (27) 0.832 Lesion size, median 0.30 0.40
Upper extremity 2 (9) 3 (14) [0.20 – 0.50] [0.30 – 0.60]
aFisher’s exact test
Lower extremity 3 (14) 2 (9) bMann Whitney U test

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Figure 3. Proportion showing complete clearance of largest wart of patients in both treat-
Table 4. Median reduction in size (cm) of largest wart of patients compared to baseline ment groups seen at a tertiary hospital (n= 44).a
seen in both treatment groups at a tertiary hospital (n= 44). aFisher’s exact test

Follow-up Group ZS Group PPD P-valuea
(n= 22) (n= 22)
Median Median
[IQR] [IQR]

2nd week 0.10 0.10 0.2913
[0 – 0.20] [0 – 0.02]

4th week 0.30 0.20 0.2573
[0.20 – 0.40] [0.10 – 0.30]

6th week 0.40 0.40 0.3872
[0.30 – 0.60] [0.20 – 0.50]

8th week 0.50 0.40 0.3863
[0.30 – 0.70] [0.30 – 0.70]

10th week 0.60 0.40 0.2895
[0.40 – 0.80] [0.40 – 0.90]

12th week 0.70 0.40 0.2310
[0.40 – 0.80] [0.40 – 0.90]

aMann Whitney U test

Table 5. Proportion of patients showing complete clearance of distant lesions of patients
in both treatment groups seen at a tertiary hospital (n= 44).

Follow-up Group ZS Group PPD P-value
(n= 22) (n= 22)
n(%) n(%)

2nd week 00 -

4th week 00 -

6th week 00 -
8th week 00 -

10th week 00 -

12th week 1 (5) 0 1.000

14th week 3 (14) 0 0.232 Figure 4. Treatment response at 12th week by group (n=42).

size was analyzed using Repeated Measures ANOVA for within- Figure 5. Mean size of target lesion over time by treatment group.
group differences and One Way ANOVA for between group
differences. Significant ANOVA results were further analyzed
using Tukey HSD.

Intention-to-treat analysis was implemented wherein all
patients with at least 1 follow-up were included in the analysis
(i.e. available case). In order to determine if missing data on 2
patients can affect the study results, sensitivity analyses using
simple imputation (last observation carried forward) and
per-protocol analyses were performed on primary outcome
(i.e. complete clearance of target wart). P values ≤0.05 were
considered statistically significant.

RESULTS

A total of 44 patients participated in the study, randomly allocat-

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ARTICLE Journal of the Philippine
Dermatological Society
A1 A2
B2

A3 A4
B3 B4

A5 A6 A7

Figure 6. Patient with warts on the right index finger (A1, A2), right big toe (A3, A4), left big toe (A5, A6) and left 4th toe (A7) treated with PPD at baseline (A1-A7) and 12th week of follow up
(B1-B4).

ed to either Group ZS (n=22) or Group PPD (n=22). Two patients significant. However, the median size of distant lesions was sig-
dropped out, one patient from Group ZS at the 4th week and one nificantly higher in Group PPD (Table 3).
patient from Group PPD at 10th week (Figure 2). The follow-up
rate was 95% for both groups. The proportion of patients who achieved complete
clearance of the target lesion at each follow-up period was
A total of 44 patients, with 1 dropout from each group, were compared (Figure 3). At 12th week, an increasing number of
randomly allocated to either Group ZS or PPD (Table 2). The patients achieved target lesion clearance. A higher proportion
patients’ age ranged from 18 to 53 years with a mean of 31.75 of patients in Group ZS showed complete clearance compared to
± 11.83. A slightly higher proportion of patients were females Group PPD except at 10th week. The differences in proportions
(57%). The difference between the two treatment groups in terms did not reach statistical significance across all follow-up period.
of median age, sex, total number of lesions, median number of
distant lesions, target lesion and location was not statistically At 12th week, a total of 10 patients – 6 (29%) in Group ZS and
significant. 4 (19%) in Group PPD – achieved complete resolution of target
lesions (Figure 4). Improved to complete resolution of target
Among the 44 patients included in the study, 279 distant lesion was higher in Zinc (71%) versus PPD (48%) group at 12th
lesions were recorded—137 in Group ZS and 92 in Group PPD. week, but the differences in proportion failed to show statistical
In both groups, most distant lesions were located in the pal- significance (p=0.431).
moplantar area followed by periungual area. The difference of
distant lesion site between the two groups was not statistically Both groups showed a decline in mean lesion size over time
(Figure 5) which was statistically significant (p<0.00001).

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A1 B2

A3 A4 B4
B3

Figure 7. Patient with warts on the left index finger (A1, A2) and right 2nd toe (A3, A4) treated with zinc sulfate at baseline (A1-A4) and 12th week follow up (B1-B4).

For Group ZS, the mean target lesion size at 6th, 8th, 10th was observed in both groups but it continued in Group PPD until
and 12th week was significantly lower compared to baseline and 10th week. Hyperpigmentation was observed in 1 ZS patient and
2nd week. For Group PPD, the mean target lesion size at 4th, 6th, 2 PPD patients. Only 1 patient in Group ZS developed hemato-
8th, 10th and 12th week was significantly lower compared to ma at 2nd week. Scarring and vascular necrosis did not occur
baseline (Figure 6). in both groups.

The median reduction in size of the target lesion is higher DISCUSSION
in Group ZS compared to Group PPD except at 6th week (Table
4). However, the difference in median size reduction was not Zinc stimulates dendritic cells and activates both the innate and
statistically significant. adaptive immunity to clear the virus.12,11,16 Intralesional PPD
administration increases IL-12 and activates T-cells to release
Only three patients from Group ZS had complete clearance gamma interferon which helps to eliminate the virus.17,19-21
of distant lesions (Figure 7). Repeated injections further boost the immune response.8,19,22

The difference in the proportion of patients who achieved The current study revealed a lower percentage (29%) of
total clearance at distant lesions between the two groups was complete wart clearance in Group ZS compared to other studies
not statistically significant (Table 5). (60-98.2%)13-15 where zinc sulfate was injected until blanching
or bleb formation. In this study, a fixed dose was administered
There were adverse reactions that developed in both groups without blanching or bleb formation to standardize the dose
(Table 6). A higher proportion of Group ZS developed erythema similar to PPD and to avoid necrosis.23 Studies have shown
compared to Group PPD. The resolution of this adverse reaction that complete clearance of injected warts was achieved by
was observed at 6th week. Pain at the injection site was higher 60-94% with 0.1mL intralesional PPD8,22,24-26 compared to 19%
in Group ZS compared to PPD. Pruritus was only experienced by
18% of Group ZS patients compared to 32% of Group PPD. Edema

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Table 6. Adverse events in patients in both treatment groups seen at a tertiary hospital in the current study. Milante et al. concluded that multiple
(n= 44). intralesional injection of PPD was superior to single injection
of multiple warts but more painful.27 The higher dose of zinc
Follow-up Group ZS Group PPD P-value sulfate13-15 and PPD27 used in the previous studies could have
(n= 22) (n= 22) elicited a better response but with more side effects such as
n(%) n(%) increased pain in the injection site.

Erythema, %yes 00 - Moubasher et al. reported that the proportion of patients
who achieved total clearance of the target site did not signifi-
Percentage of patient with erythema cantly differ between ZS and PPD.15 The current study showed
comparable efficacy between groups in clearing target lesions
2nd week 5 (23) 2 (9) 0.412 even when intention-to-treat analysis was performed.
4th week 3 (14) 1 (4) 0.345
Immunotherapy has an advantage of clearing both target and
6th week 0 2 (9) 0.488 distant warts.26,27 Pande et al. suggested that distant wart clearance
is a product of strengthening the immune system by stimulation of
8th week 00 - cytokines and gamma interferon.17 Three patients from Group ZS
achieved clearance of distant warts compared to none in Group PPD
10th week 0 1 (5) 1.000 although the difference was not statistically significant. Previous
studies showed that intralesional PPD led to higher clearance of dis-
12th week 00 - tant warts which can be attributed to 6-10 treatment sessions15,22,24,26
compared to only 6 in this study. Immunotherapy decreases the
Pain at injection site, %yes recurrence of warts.4,12,14,15,17 None of the six patients with resolved
target warts exhibited recurrence.
2nd week 16 (73) 9 (41) 0.033*
Injection site pain observed in both groups were similarly
4th week 7 (33) 4 (18) 0.255 observed in previous studies.13-15 Injection site pain associated
with pruritus was observed in group PPD. Edema and erythema
6th week 2 (10) 1 (5) 0.607 were common in previous studies22 but occurred less in PPD
group. Observed adverse effects such as injection site pain,
8th week 2 (10) 2 (9) 1.000 pruritus, edema and erythema may have been caused by the
inflammatory reaction triggered by the intralesional zinc
10th week 0 1 (5) 1.000 sulfate11,12,28 and PPD antigen.21

12th week 00 - A limitation of the study is non-inclusion of pediatric pa-
tients and participants’ assessment of the treatment. Future
Pruritus, %yes studies on the effect of combining oral and intralesional zinc
sulfate are suggested.29
2nd week 4 (18) 7 (32) 0.296
CONCLUSION
4th week 0 4 (18) 0.108
Intralesional 2% zinc sulfate is efficacious and safe in the treatment
6th week 0 1 (5) 1.000 of verruca vulgaris with effects comparable to intralesional PPD.
The percentage of patients with improved to complete resolution of
8th week 00 - target and distant warts was higher in the zinc sulfate group com-
pared to PPD, however, the difference did not reach statistical sig-
10th week 0 1 (5) 1.000 nificance. The adverse effects of erythema and pain at injection site
were higher in the zinc sulfate group. However, pruritus was higher
12th week 00 - in the PPD group. Edema was observed in both groups but the dura-
tion was longer in the PPD group.
Edema, %yes

2nd week 6 (27) 2 (9) 0.240

4th week 1 (5) 2 (9) 1.000

6th week 1 (5) 2 (9) 1.000

8th week 0 2 (9) 0.488

10th week 0 1 (5) 1.000

12th week 00 -

Hyperpigmentation, %yes

2nd week 00 -

4th week 1 (5) 2 (9) 1.000

6th week 0 1 (5) 1.000

8th week 00 -

10th week 0 1 (5) 1.000

12th week 0 2 (10) 0.488

27 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society

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1. Skin Contact. The Official Newsletter of the Philippine Dermatological Society. March 2020; Volume 16 Number 66.
2. Goldsmith LA, Fitzpatrick TB (Thomas B. Fitzpatrick’s Dermatology in General Medicine.; 2012.
3. Lipke MM. An Armamentarium of Wart Treatments. Clin Med Res. 2006;4:273-293.
4. Sterling JC, Gibbs S, Haque Hussain SS, Mohd Mustapa MF, Handfield-Jones SE. British Association of Dermatologists’ guidelines for the

management of cutaneous warts 2014. Br J Dermatol. 2014;171(4):696-712.
5. Chandrashekar L. Intralesional immunotherapy for the management of warts. Indian J Dermatol Venereol Leprol 2011;77:261-3. DOI: 10.4103/0378-

6323.79694.
6. Khozeimeh F, Jabbari Azad F, Mahboubi Oskouei Y, et al. Intralesional immunotherapy compared to cryotherapy in the treatment of warts. Int

J Dermatol. 2017;56(4):474-478. DOI: 10.1111/ijd.13535.
7. Salman S, Ahmed MS, Ibrahim AM, et al. Intralesional immunotherapy for the treatment of warts: A network meta-analysis. J Am Acad Dermatol.

2018;80(4):922-930.e4. DOI: 10.1016/j.jaad.2018.07.003.
8. Ramos J, Paliza A, Palmero M. A Double-Blind Randomized Controlled Trial in the Treatment of Verruca Vulgaris Using Intralesional Tuberculin

Purified Protein Derivative (PPD); 2013.
9. FDA Philippines approval for Zinc Sulphate Heptahydrate. Available from fda.gov.ph
10. Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients. 2017;9(12).
11. Yaghoobi R, Sadighha A, Baktash D. Evaluation of oral zinc sulfate effect on recalcitrant multiple viral warts: A randomized placebo-controlled

clinical trial. J Am Acad Dermatol. 2009;60(4):706-708. DOI: 10.1016/j.jaad.2008.09.010.
12. Deligeoroglou E, Giannouli A, Athanasopoulos N, et al. HPV infection: Immunological aspects and their utility in future therapy. Infect Dis

Obstet Gynecol. 2013.
13. Sharquie K, Al-Nuaimy A. Treatment of viral warts by intralesional injection of zinc sulphate. Ann Saudi Med. 2002;22(1-2):26-28. DOI: 10.5144/0256-

4947.2002.26.
14. Mohamed EEM, Tawfik KM, Mahmoud AM. The Clinical Effectiveness of Intralesional Injection of 2% Zinc Sulfate Solution in the Treatment of

Common Warts. Scientifica (Cairo). 2016;2016. DOI: 10.1155/2016/1082979.
15. Moubasher AEA, Hassan OM, Youssef EMK, Sabek MMA. Intralesional injection of purified protein derivatives versus zinc sulfate 2% in

recalcitrant palmar and/or plantar warts. J Egypt Women’s Dermatologic Soc.
16. Prasad AS. Zinc in Human Health: Effect of Zinc on Immune Cells. Mol Med. 2008;14(5-6):353-357. DOI: 10.2119/2008-00033.Prasad.
17. Thappa D, Chiramel M. Evolving role of immunotherapy in the treatment of refractory warts. Indian Dermatol Online J. 2016 Sep-Oct; 7(5):

364–370. DOI: 10.4103/2229-5178.190487.
18. Lacarrubba F, Verz AE, Dinotta F, et al. Dermatoscopy in inflammatory and infectious skin disorders. G Ital Dermatol Venereol. 2015;150(5):521-

531.
19. Pande S, Sontakke A, Tayade B. Purified protein derivative immunotherapy for viral warts and interpretation of tuberculin skin tests and

interferon gamma release assay for diagnosis of tuberculosis in India. Indian J Drugs Dermatology. 2016;2(2):73. DOI: 10.4103/2455-3972.196165.
20. Abd-Elazeim FMA, Mohammed GFA, Fathy A, Mohamed RW. Evaluation of IL-12 serum level in patients with recalcitrant multiple common warts,

treated by intralesional tuberculin antigen. J Dermatolog Treat. 2014;25(3):264-267. DOI: 10.3109/09546634.2013.768760.
21. Abou‐Taleb DAE, Abou‐Taleb HA, El‐Badawy O, Ahmed AO, Thabiet Hassan AE, Awad SM. Intralesional vitamin D3 versus intralesional purified

protein derivative (PPD) in treatment of multiple warts: A comparative clinical and immunological study. Dermatol Ther. 2019:e13034. DOI:
10.1111/dth.13034.
22. Wananukul S, Chatproedprai S, Kittiratsacha P. Intralesional immunotherapy using tuberculin PPD in the treatment of palmoplantar and
periungual warts. Asian Biomed. 2009;3(6):739-743. DOI:10.5372/ABM.V3I6.279.
23. Farajzadeh S, Hakimi Parizi M, Haghdoost AA, et al. Comparison between intralesional injection of zinc sulfate 2 % solution and intralesional
meglumine antimoniate in the treatment of acute old world dry type cutaneous leishmaniasis: a randomized double-blind clinical trial. J
Parasit Dis. 2016;40(3):935-939. DOI: 10.1007/s12639-014-0609-1.
24. Al-Mendalawi M. Tuberculin purified protein derivative immunotherapy in the treatment of viral warts. Indian J Drugs Dermatology. 2016;2(2):105.
DOI: 10.4103/2455-3972.196173.
25. Elela IMA, Elshahid AR, Mosbeh A. Intradermal vs intralesional purified protein derivatives in treatment of warts. Gulf J Dermatology Venereol.
2011;18(2):21-26.
26. Mohamed F, Al-Adl A, Hasanein Y. Comparative study between intralesional Candida antigen and tuberculin PPD in treatment of multiple
warts. Nat Sci. 2017;15(1). DOI:10.7537/marsnsj150117.12.
27. Milante R, Isamel D. Efficacy and safety of single versus multiple intralesional immunotherapy with purified protein derivative (PPD) in the
treatment of multiple verruca vulgaris. Int J Dermatol. 2019;58(12):1477-1482. DOI: 10.1111/ijd.14652.
28. El Taweel AA, Salem R, Allam A. Intralesional 2% zinc sulfate solution for plane warts: A case report. Dermatol Ther. 2019;32(1):27-28. DOI: 10.1111/
dth.12761.
29. Deshmukh N, Belgaumkar V, Mhaske C, Doshi B. Intralesional drug therapy in dermatology. Indian J Dermatology, Venereol Leprol. 2016;83(1):127.
DOI:10.4103/0378-6323.190870.

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 28

JPDS ORIGINAL ARTICLE
Journal of the Philippine
Dermatological Society

A triple-blind, randomized controlled trial on the
efficacy and safety of 1.5% Carica papaya latex
cream vs. 2% ketoconazole cream in the treatment of

pityriasis versicolor among Filipinos

Anna Cecilia Francesca I. Alvarez, MD, DPDS,1 Jose Giovanni E. Dimayuga, MD, FPDS1

ABSTRACT

BACKGROUND Carica papaya latex has been found to have antifungal properties rendering an alternative treatment for fungal
infections, i.e. pityriasis versicolor. It has remarkable mycelial inhibition, and static effect on fungal growth in cultures. Its
keratolytic effect can remove diseased skin cells, and enhance drug penetration. Moreover, it is organic, locally available, and
relatively inexpensive.

OBJECTIVE To compare the efficacy and safety of 1.5% Carica papaya latex cream vs. 2% ketoconazole cream in the treatment
of pityriasis versicolor among Filipinos.

METHODS A single-center, parallel group, triple-blind, randomized controlled trial in the Dermatology out-patient clinic of Makati
Medical Center was conducted. Sixty-four patients with pityriasis versicolor were randomly allocated to the two treatment groups,
and received either 1.5% Carica papaya latex cream or 2% ketoconazole cream that they used twice daily for four weeks or until cured.
The participants, researcher, and assessor were blinded to the treatment assignments. Therapeutic response was assessed at weeks
1, 2, 3 and 4 based on clinical and mycologic cure. Adverse events were identified. Patients’ assessment of their improvement was done
at the end of the treatment.

RESULTS All 64 subjects in both treatment groups (100% in the Carica papaya and 100% in the ketoconazole group) achieved clinical
and mycologic cure within the four-week study period. The adverse reactions noted (pruritus and erythema for Carica papaya
latex cream, and pruritus for ketoconazole cream) were mild, did not cause disruption of daily activities, and spontaneously
resolved.

CONCLUSION 1.5% Carica papaya latex cream is an effective and safe alternative treatment to the first line therapy, ketoconazole
cream, for pityriasis versicolor.

KEYWORDS Carica papaya, pityriasis/tinea versicolor

1Department of Dermatology, INTRODUCTION tinea corporis (22.63%), and tinea cruris (16.7%).2
Makati Medical Center, Makati Pityriasis versicolor is a chronic, superficial
City, Philippines Superficial fungal infections are among the most
common infections in the world with incidence fungal infection, characterized by changes in
Corresponding author rates increasing significantly over the last 15 to 20 skin pigmentation due to the colonization of
Anna Cecilia Francesca I. years. This infection, known as tinea, has many the stratum corneum by Malassezia furfur, a
Alvarez, MD, DPDS types, one being tinea versicolor or pityriasis dimorphic lipophilic fungus. The azelaic acid
versicolor. Pityriasis versicolor is a common der- produced by the organism inhibits pigment
Conflict of interest matosis in tropical regions like the Philippines, transfer to keratinocytes, making infected skin
None where high humidity and temperature increase more demarcated from the uninfected, more
its prevalence.1 A study done by Handog, et al in heavily pigmented skin.3 Patients present with
Source of funding 2005 showed that fungal infections has a preva- multiple oval to round patches with mild, fine,
None lence of 12.98%, and is the second leading cause scaly lesions that are often confluent centrally.
of consultation in dermatology training institu- Seborrheic regions are the favored sites of this
tions in the Philippines, with pityriasis versicol- organism.4 Versicolor refers to the variety in
or as the leading diagnosis (25.34%), followed by changing shades of colors present in this disease.

29 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

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Journal of the Philippine ARTICLE
Dermatological Society

Pityriasis versicolor occurs most commonly in adolescents the clinical resolution of scaling and erythema. Resolution was
and young adults.3 This may be because adolescents have achieved in 14 days compared to 21 and 28 days in ketoconazole
increased sebum production, leading to easier growth by the and placebo, respectively.10
lipophilic fungi.1 It is usually asymptomatic but the appearance
may lead to significant emotional distress, particularly in Another property of papaya that may provide cure
adolescents, and thus needs to be addressed.5 for pityriasis versicolor is its keratolytic effect. Some of
the established treatments for pityriasis versicolor include
Patients with pityriasis versicolor are usually treated keratolytic agents such as selenium sulfide, and salicylic acid. It
with topical antimycotics like ketoconazole (1% or 2%), or 2.5% removes diseased skin cells and replaces them with healthy new
selenium sulfide shampoo. In the study done by Muzaffar, et cells. Its keratolytic property also tends to improve the delivery
al (2008), they identified topical antifungals as the established of antimycotic drugs through the skin.1 Thus, it can both give
first line of therapy.6 Other treatment options include: azole/ treatment, and enhance its delivery to the affected areas.
allylamine creams and lotions, nystatin, salicylic acid, and
dandruff shampoos. Systemic therapy with ketoconazole, With regards to safety, topical papaya fruit has been used
fluconazole or itraconazole can also be used.4 as a major component of burn dressings in the Royal Victoria
Hospital Pediatric Unit in Quebec, Canada and was found to be
Despite treatment, the rate of recurrence of pityriasis safe for use in children.8 However, it can induce hypersensitivity
versicolor is very high, especially in hot humid climates, like reaction in individuals with allergy to papaya. It can be an
the Philippines.4 It is a relapsing disease that tends to recur irritant, and a vesicant at certain concentrations. The safe
in about 60% within one year after treatment and in 80% after concentration of papain extract that does not produce adverse
two years.1 This is addressed by giving ketoconazole shampoo reactions as determined through patch test was found to be at
once weekly as a body cleanser, or once-monthly dosing of oral 1.5%.10
ketoconazole (400 mg), fluconazole (300 mg), or itraconazole
(400 mg).4 However, these medications can have serious side With its antifungal, keratolytic, and drug delivery
effects,i.e. hepatotoxicity, and ventricular dysrhythmias.5 Thus, enhancement properties, papain latex extract shows potential
the use of herbal remedies has become popular since they are in the effective and safe treatment of pityriasis versicolor. This
generally economical, natural, and safe antifungal remedies study aims to compare the efficacy and safety of 1.5% Carica
without known side effects.3 papaya latex cream vs. 2% ketoconazole cream in the treatment
of Filipino patients with pityriasis versicolor. Specifically, this
An herbal remedy of growing interest is Carica papaya. It is a study aims to:
plant that grows in all tropical and many sub-tropical regions of
the world.7 Carica papaya is mainly grown (>90%) and consumed 1. To determine and compare the overall clinical cure
in developing countries, like the Philippines.7 rate (measured by Grading of Scaling and Pruritus
Rating Scale) and mycologic cure rate (through
Papain is an endolytic plant cysteine protease enzyme Potassium Hydroxide Smear Mycologic Examination)
isolated from Carica papaya latex by cutting the skin of the of pityriasis versicolor patients treated with 1.5%
unripe papaya and then collecting and drying the latex that Carica papaya latex cream vs. 2% ketoconazole cream,
flows from the cut. The protein ferment papain is the milky taken weekly for four consecutive weeks
substance from the leaves and unripe fruit of papaya.8 Papain
has proven to have many medicinal uses. It has been used as a 2. To compare the Patient’s Assessment of Improvement
debris-removing agent, with no harmful effect on sound tissues. from Baseline Scale score, taken at the end of the
It has analgesic, antibacterial, and anti-inflammatory activity. treatment, of those treated with 1.5% Carica papaya
Moreover, papain has been studied for its antifungal properties,7 latex cream vs. those treated with 2% ketoconazole
thereby rendering a promising alternative treatment for cream
fungal infections such as pityriasis versicolor. In a study by
Chukwuemeka & Anthonia in 2012, it has been shown to have 3. To identify any adverse reactions which may occur
remarkable mycelial inhibition with mean zones of inhibitions with the use of 1.5% Carica papaya latex cream
between 0.23 - 1.73 mm in different fungal isolates like Rhizopus compared with 2% ketoconazole cream in the course
spp., Aspergillus spp., and Mucor spp., supporting its antifungal of treatment of pityriasis versicolor, taken weekly for
properties.9 The review paper by Krishna et al, states that four consecutive weeks, and to compare the Adverse
latex has a static effect on fungal growth in cultures. The lytic Event Grading Scale of the two treatment groups at the
enzymes on the extracts target the sugar residue on the cell wall end of the treatment period.
of the fungi resulting in cell wall degradation.8
METHODS
In the study done by Buensalido, Carica papaya latex extract
was found to be superior to ketoconazole and placebo in the STUDY DESIGN
treatment of tinea corporis. It was also found to work faster in This study assessed the efficacy and safety of 1.5% Carica pa-
paya latex cream vs. 2% ketoconazole cream in the treatment
of pityriasis versicolor among Filipinos in a randomized, tri-

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 30

ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society

ple-blind controlled trial. The study was based in the Derma- B on the container cover) have no significant difference in the
tology Out-Patient Department of Makati Medical Center. The consistency, appearance, and smell and were stored in identical
research protocol was approved by the Makati Medical Center 15-gram containers.
Institutional Board Review (MMCIRB 2014-074).
OUTCOMES
PARTICIPANTS The primary outcome measure is the therapeutic response,
Participants for this study were Filipino patients of either sex, measured by clinical cure rate and mycologic cure rate.
clinically diagnosed with pityriasis versicolor and confirmed Clinical cure rate was assessed using the Grading of Scaling and
by positive mycologic examination (KOH). Clinical diagnosis Pruritus Rating Scale. Mycologic cure rate was assessed using
was made based on the appearance of hyperpigmented or the Potassium Hydroxide Smear Microscopic Examination.
hypopigmented patches with mild, fine scales. Interpretation was based on the amount of hyphae present in
the examination.13
Subjects under the age of 18 were accompanied by a
guardian who read and signed the assent forms. Excluded The secondary outcome measures were the patients’ sub-
from this study were patients with extensive involvement (>4 jective assessment of improvement and the severity of adverse
sites; defined as: face, neck, anterior trunk, posterior trunk, effects measured by the Patients’ Assessment of Improvement
upper extremity, lower extremity); size of >3% estimated body from Baseline Scale and Adverse Event Grading Scale, respec-
surface (size of the face); with concomitant active, localized, tively.
or systemic infection; in immunocompromised state; with
known or suspected hypersensitivity to any constituent of the Therapeutic response was considered a treatment success
medications; pregnant or breastfeeding women. Patients who if all the following conditions were satisfied within the treat-
have used topical and systemic steroids or immunomodulating ment period of four weeks: negative mycologic examination re-
drugs, keratolytic agents, or topical and systemic antifungals sult and absence of pruritus and scaling, defined as score of 0
within the last 30 days were likewise excluded. in the Grading of Scaling, Pruritus Rating Scale, and Potassium
Hydroxide Smear Microscopic Examination. In case of treat-
INTERVENTIONS ment failure, the investigator will give immediate and free med-
The Carica papaya latex cream used for this study was patterned ical treatment with a standard topical antifungal treatment and
after the study made by Buensalido in 2009 but this study used will be monitored until resolution of lesions. But in this study,
aquaphor and water as vehicle instead of Cetaphil cream. Like no treatment failure was encountered.
in the study of Buensalido, the Carica papaya latex cream used in
this study was also compounded by the Industrial Technology SAMPLE SIZE
Development Institute of the Department of Science and Using G Power 3.1.3 for the minimum sample size computation,
Technology (ITDI-DOST), Bicutan, Taguig City. 40 subjects in each arm were included based on 90% power,
5% level of significance and 0.75 effect size with 20% possible
The study medication was formulated as follows: latex attrition rate.
was collected through 1-2mm deep vertical incisions on the
skin of the unripe fruit early in the morning as the latex flow RANDOMIZATION
is low during the day. The latex is dried at room temperature The participants, the inve stigator, and the analyst we re not aware
until crumbly and non-sticky. The dried latex was triturated of the sequence of group allocations done by the Department of
using a mortar and pestle and sieved through a mesh size 170. Science and Technology personnel who prepared, pre-coded,
The concentration of the papain extract used was 1.5%. The and labelled each medication as either A or B. Fishbowl method
collected latex was stored at 4-8°C until incorporated with the was done to assign the coded cream to each participant of the
vehicle.10 study to ensure randomization.

The ketoconazole cream served as the control in this study Baseline demographic data were collected and clinical
since it has been proven in literature11 and in research studies examination of the patient was done by the primary investigator.
to be an effective treatment for pityriasis versicolor. A clinical The clinical presentation of the patient was documented
study by Bakr et al, in 2020 showed significant improvement in using the Grading of Scaling and Pruritus Rating Scale of the
patients with pityriasis versicolor after four weeks of treatment hyperpigmented or hypopigmented patches. A pre-treatment
with 2% ketoconazole cream.12 Like the study medication, the specimen of the lesion was obtained for mycologic examination
2% ketoconazole cream from the Pharmaceutical Section of the (KOH smear). Photograph of the skin lesion was taken.
Chemicals and Energy Division of IDTI-DOST was also mixed
with aquaphor and water as vehicle. All patients were given instructions on the daily cleansing
of the affected area with the standard cleanser provided by the
Treatment compounds were placed in a container and pre- investigator. Patients were instructed to apply the assigned
coded. The pre-coded treatment compounds (labelled with A or cream (labeled as A or B) over the affected areas two times a day,

31 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society

for four weeks using a sterile cotton tip applicator. Patients were at the end of the treatment. Patients’ subjective assessments
instructed to bring the cream container on each follow-up visit were documented using the Assessment of Improvement from
to ensure compliance. A set of four 15g cream per container was Baseline Scale, given at the end of the treatment.
allotted for each participant throughout the duration of study,
but the assigned medication was given one container at a time BLINDING
depending on the amount consumed noted on each follow-up. The participants, the investigator, and the analyst were blinded
Patients were asked to do weekly follow-up for four consecutive with the treatment assignment. The pre-coded medications were
weeks or until KOH was negative, and pruritus and scaling were handed by DOST to the investigator and were labelled only with
absent. either A or B on the container cover. The treatment compounds
have no significant difference in consistency, appearance, and
Patients were evaluated at baseline then weeks 1, 2, 3, smell and were stored in identical containers.
and 4. On each visit, the investigator evaluated the clinical
cure using the Grading of Scaling and Pruritus Rating Scale The investigator recruited the participants, assigned the
and the mycologic cure using the Potassium Hydroxide Smear participants to treatment A or B using fishbowl method, did the
Microscopic Examination. Scales were obtained using the blunt weekly assessment, and tabulated the data. The tabulated data
side of a blade from the lesion. Ten percent (10%) potassium were analyzed by an independent statistician. The treatment
hydroxide was used to determine the presence or absence of assignment of the participants were only revealed after data
hyphae. Photograph of the skin lesion was taken at baseline, analysis was done.
during each follow-up and at the end of the treatment.
STATISTICAL ANALYSIS
Adverse reactions like irritation, blistering, peeling, Intention-to-treat and per protocol analysis were performed.
urticaria, pruritus, erythema4 to the site of application were Demographic and clinical data of the two treatment groups were
likewise documented at each week of treatment and the described and compared. Results were presented as distribution
Adverse Event Grading Scale of the two groups were compared

Block 1 1st set of 40 subjects (n=40)

Randomization by fishbowl method

Treatment assignments

Pre-coded ketoconazole cream Pre-coded Carica papaya latex cream
(n=20) (n=20)

Block 2 1st set of 40 subjects (n=40)

Randomization by fishbowl method

Treatment assignments

Pre-coded ketoconazole cream Pre-coded Carica papaya latex cream
(n=20) (n=20)

Figure 1. Method of treatment assignment of participants.

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 32

ORIGINAL CONSORT 2010 Flow Diagram JPDS
ARTICLE Assessment for eligibility (n=64) Journal of the Philippine
Dermatological Society
Enrollment Randomized (n=64)
Excluded (n=0)
• Not meeting inclusion criteria

(n=0)
• Declined to participate (n=0)
• Other reasons (n=0)

Block 1 Allocation Block 2
Allocated to intervention (n=40) Allocated to intervention (n=24)
• Received allocated • Received allocated

intervention (n=40) intervention (n=24)
• Did not receive allocated • Did not receive allocated

intervention (n=0) intervention (n=0)

Lost to follow-up (n=0) Follow-up Lost to follow-up (n=0)
Discontinued intervention (n=0) Discontinued intervention (n=0)

Analysed (n=40) Analysis Analysed (n=24)
• Excluded for analysis (n=0) • Excluded for analysis (n=0)

Figure 2. Flow of participants from assessment of eligibility to analysis

frequencies for categorical data and means and standard to assess the effect of these drop-outs and withdrawals on the
deviations for continuous data. An independent statistician was conclusion of the study.
hired to conduct the data analysis. Only codes were provided to
ensure the blinding of the data analyst. RESULTS

The comparisons of interest are the efficacy and safety A total of 64 patients diagnosed with pityriasis versicolor were
of 1.5% Carica papaya latex cream with the standard therapy, included in this study. Sample size of 80 subjects was not met
2% ketoconazole cream. Efficacy was analyzed statistically. due to lack of eligible patients seen during the recruitment
Comparison on the categorical outcome measures between period from May to September 2016.
treatment groups was done by Chi-square.
The demographics of the 64 study patients are shown
Adverse events were categorized as a frequency in Tables 1 and 2. Of the 64 patients, 37 (57%) are male and 27
distribution. Counting of adverse events will be based on the (43%) are female, with age range of 6-46 years. Majority are
number of subjects, not on the number of adverse events. students comprising more than half (51%) of the participants.
Participants reporting more than one adverse event will be Mean duration of the development of skin lesion is 8.9 weeks,
counted only once in the organ system total. with chest (41.3%) and back (39.1%) as the most affected parts.
As stated on the p-value column in Table 2, the 2 groups were not
Missing data may be due to drop-outs or withdrawals. significantly different from each other in terms of the duration
Sensitivity analysis using a worst-case scenario was performed

33 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

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Journal of the Philippine ARTICLE
Dermatological Society

of their skin lesions. More than a quarter (26.6%) used topical was no significant difference between the two treatments used.
antifungal medication but more than 4 weeks prior to joining The cure rate based on scaling score, pruritus scale, and KOH
the study. None of the participants used any topical or oral mycologic examination smear score for both treatments are
corticosteroids, as well as oral antifungal medications. comparable.

Primary outcome measure results are shown on Tables Adverse effects that were reported by the patients
3, 4, and 5. As stated on the p-value column of the tables participating in the two study groups are tallied and presented
below, all comparisons made from Week 1 to Week 4 were not in Table 6. In this study, pruritus is the most common adverse
significantly different from each other, indicating that there event experienced by a patient receiving either treatment A

Table 1. Demographic profile of the patients Table 3. Summary of the number of patients per Grading of Scaling Score.

Profile Zinc oxide group Salicylic+Lactic P-value Scaling Treatment A Treatment B P-value
(n=15) acid group score (1.5% Carica papaya latex (2% ketoconazole cream)
(n=14) #% 0.934
#% #% 64 100 cream) 0* 1† 2‡ 0.942
30 46.9 34 53.1 0.738
5 7.8 0* 1† 2‡ 0.750
3 4.7 2 3.1 31 48.4 1.000
Total 13 20.3 18 28.1 9 14.1 Week 0 0 20 10 0 23 11
5 7.8 4 6.3 15 23.4
Age group 7 10.9 8 12.5 4 6.3 Week 1 2 22 6 1 27 6
• <11 years old 2 3.1 2 3.1
• 11-20 years old 37 57 Week 2 20 10 0 24 10 0
• 21-30 years old 19 29.7 18 28.1 27 43
• 31-40 years old 11 17.2 16 25.0 Week 3 28 2 0 31 3 0
• >40 years old 33 51.6
16 25.0 17 26.6 5 7.8 Week 4 30 0 0 34 0 0
Gender 4 6.3 1 1.6 9 14.1
• Male 3 4.7 6 9.4 *0=no scaling, †1=few scales, ‡2=many scales
• Female 6 9.4
3 4.7 3 4.7 6 9.4 Table 4. Summary of the number of patients per Pruritus Scale Score.
Type of Work 1 1.6 5 7.8 3 4.7
• Student 2 3.1 1 1.6 23 Pruritus Treatment A Treatment B P-value
• Housewife 1 1.6 1 1.6 scale (1.5% Carica papaya latex (2% ketoconazole cream)
• Employee (Office 29 45.3
work) 14 21.9 15 23.4 25 39.1 Week 0 cream)
• Construction 13 20.3 12 18.8 21 32.8
• Vendor 8 12.5 13 20.3 16 25.0 0* 1-3† 4-6‡ 7-8§ >9|| 0* 1-3† 4-6‡ 7-8§ >9||
• Guard 9 14.1 7 10.9 1 1.6
• None 0 0.0 1 1.6 3 15 12 0 0 5 14 15 0 0 0.994
17 26.6
Affected areas 9 14.1 8 12.5 00 Week 1 7 17 6 0 0 10 20 4 0 0 0.994
• Chest 0 0.0 00
• Back 0 0.0 Week 2 20 10 0 0 0 22 12 0 0 0 0.873
• Head 0 0.0 0 0.0 0 0.0
• Upper extremities 0 0.0 0 0.0 Week 3 29 1 0 0 0 33 1 0 0 0 0.911
• Neck
Week 4 30 0 0 0 0 34 0 0 0 0 1.000
Use of antifungals
• Topical *0=no pruritus, †1-3=mild pruritus, ‡4-6=moderate pruritus, §7-8=severe pruritus,
• Oral ||>9=very severe pruritus

Use of corticosteroids Table 5. Summary of the number of patients per KOH smear Mycologic Examination score.
• Topical
• Oral KOH Treatment A Treatment B
Smear (1.5% Carica papaya latex (2% ketoconazole cream)
Table 2. Duration of the lesions. Score P-value
cream) 0* 1† 2‡ 3§ 0.208
Week 0 0 16 12 6
0* 1† 2‡ 3§

0 9 14 7

Treatment Range Mean Standard P-value Week 1 0 22 8 0 1 24 9 0 0.836
8.43 deviation 0.425 0 12 20 2 0 0.444
Treatment A 9.32 Week 2 9 17 4
(1.5% Carica papaya latex 8.91 7.31
cream) 1 - 28 weeks Week 3 25 5 0 0 29 5 0 0 0.831
6.48
Treatment B 1 - 20 weeks 6.84 Week 4 30 0 0 0 34 0 0 0 1.000
(2% ketoconazole cream) 1 - 28 weeks
*0= negative (no hyphae), †1= few hyphae (<5 hyphae per high power field), ‡2= moderate
Total hyphae (≥5 but <10 hyphae per high power field), §3= abundant hyphae (≥10 hyphae per
high power field)

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 34

ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
AB
AB

CD

CD

Figure 3. A and C. Representative clinical photo and KOH result of a patient treated with
Treatment A (1.5% Carica papaya latex cream) at baseline. B and D. After 3 weeks of
treatment.

(1.5% Carica papaya latex cream) or B (2% ketoconazole cream), Figure 4. A and C. Representative clinical photo and KOH result of a patient treated with
followed by redness or erythema. Erythema was reported only Treatment B (2% ketoconazole cream) at baseline. B and D. After 4 weeks of treatment.
in patients receiving Treatment A. Adverse effects for both
treatments are comparable statistically. Table 6. Summary of adverse effects reported by patients.

No adverse effect (as defined in the Advent Event Grading Adverse Treatment A Treatment B P-value
scale) was reported or observed among the patients in both effect (1.5% Carica papaya latex (2% ketoconazole cream)
groups in the study. The adverse events (pruritus and erythema) 0.709
reported in the first two weeks are considered as minor only, cream) 0.750
spontaneously resolved, and caused no disruption in the 0.287
patient’s daily activities. P* R† P*&R† No P* R† P*&R† No 1.000
AE‡ AE‡
Table 7 shows the summary of the Patient’s Assessment of
Improvement. Chi-square test was employed to demonstrate Week 1 2 1 2 25 5 0 0 29
whether the patient’s assessment varies significantly. The
analysis resulted into a p-value of 0.000, which means that a Week 2 2 0 0 28 3 0 0 31
significant difference exists in the assessment of these patients.
Week 3 0 0 1 29 0 0 0 34

Week 4 0 0 0 30 0 0 0 34

*P=pruritus, †R=redness, ‡AE=adverse effect

DISCUSSION Score, as well as the mycologic cure rate measured by KOH
smear Mycologic Examination Score, are comparable in both
The results of the study support the use of 1.5% Carica papaya the treatment groups. The efficacy of Carica papaya against
latex cream as an alternative treatment to the first line pityriasis versicolor proven in this study is consistent with the
therapy, which is 2% ketoconazole cream, for the treatment of study done by Buensalido in 2009 where Carica papaya was used
pityriasis versicolor. The two groups did not differ significantly to successfully treat another fungal infection, tinea corporis.10
in their baseline data. All subjects enrolled in the study were
cured within the 4-week study period. The clinical cure Although there are more side effects noted in the Carica
rate, measured by Grading of Scaling Score, Pruritus Scale

35 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society

Table 7. Summary of the patient’s assessment of the improvement. answered “almost clear” in this field reported skin discoloration as
the sign that was not completely addressed by the treatment. This
Patient assessment was not measured in this study since skin tone may take several
months to return to normal, even after being treated.4 This was
0 - Clear 1 – Almost P-value reiterated to the patients who had unresolved skin pigmentary
clear 0.000 alteration after completing the study.
0.000
TREATMENT A 17 13 CONCLUSION
(1.5% Carica papaya latex cream)
1.5% Carica papaya latex cream may prove to be a worthwhile
TREATMENT B 29 5 approach to treatment of pityriasis versicolor. 1.5% Carica
(2% ketoconazole cream) papaya latex cream and 2% ketoconazole cream showed similar
clinical and mycologic cure rates in this study.
Table 8. Summary of the patient’s assessment of the improvement.
As pityriasis versicolor tends to be recurrent in many cases
Frequency especially in tropical areas like the Philippines, treatment may
need to be employed more than once in an affected individual
Chi-Square 18.750a as dictated by its recurrence. Carica papaya, which is mainly
grown (>90%) and consumed in developing countries like the
Df 3 Philippines1 might be a good alternative to explore as it showed
similar clinical and mycologic cure rates as the current first line
Asymp. Sig. .000 therapy, 2% ketoconazole cream, in this study.

a. 0 cells (0.0%) have expected frequencies less than5. The minimum expected cell However, alteration in skin color, which is an unaddressed
frequency is 16.0. complaint in this study, although not a parameter for cure, can
be better assessed with a longer follow-up period as it takes
papaya latex cream group, namely pruritus, and erythema, the several months to normalize.4 It is recommended that further
adverse effects are mild, spontaneously resolving, and do not studies be done with a larger sample size, long term follow-
cause disruption in daily activities. up, and assessment of skin tone normalization to have more
comprehensive conclusions.
However, significantly more patients reported better overall
improvement in the 2% ketoconazole group as compared to the
1.5% Carica papaya latex cream group as shown in their Patient’s
Assessment of Improvement. This is a subjective assessment of
the patient at the end of the treatment. Most of the subjects who

REFERENCES

1. Morais P, Cunha M, Frota M. Clinical aspects of patients with pityriasis versicolor seen at a referral center for tropical dermatology in Manaus,
Amazonas, Brazil. An Bras Dermatol. 2010; 85(6):797-803. DOI: 10.1590/s0365-05962010000600004.

2. Handog E, Dayrit J. Mycology in the Philippines, revisited. Jpn. J. Med. Mycol. 2005; 46(2):71-76. DOI: 10.3314/jjmm.46.71.
3. Sharma R, Sharma G, Sharma M. Comparative antifungal study of essential oil with allopathic drugs against Malassezia furfur. International

Journal of Pharmaceutical & Biological Archives 2012; 3(1):89-93.
4. Bolognia, J, Jorizzo, J, Schaffer J. Dermatology. 3rd ed. USA: Elsevier Saunders; 2012.
5. Rai M, Wankhade S. Tinea versicolor - an epidemiology. Journal of Microbial & Biochemical Technology. 2009; 1(1):51-56. DOI:10.4172/1948-5948.1000010.
6. Muzzafar F, Ejaz A, Mahmood K. Determination of cost effective topical therapy for pityriasis versicolor. Journal of Pakistan Association of

Dermatologists. 2008; 18(3):159-164.
7. Amri E, Mamboya F. Papain, a plant enzyme of biological importance: a review. American Journal of Biochemistry and Biotechnology, 2012; 8(2):99-

104. DOI: https://doi.org/10.3844/ajbbsp.2012.99.104.
8. Krishna K, Paridhavi M, Patel J. Review on nutritional, medicinal, and pharmacological properties of papaya. Natural Product Radiance. 2008;

7(4):364-373.
9. Chukwuemeka O, Anthonia A. Antifungal effects of pawpaw seed extracts and papain on post-harvest Carica papaya L. fruit rot. African Journal

of Agricultural Research. June 2010; 5(12):1531-1535. DOI: 10.5897/AJAR.9000056.
10. Buensalido J, Dimagiba T. The efficacy and safety of Carica papaya latex 1.5% cream compared to 2% ketoconazole cream and a paraffin-based

vehicle in the treatment of tinea corporis: a randomized, double blind controlled trial. J Phil Dermatol Soc. May 2011: 20(1):15-20.
11. Kang S, Amagai M, Bruckner A, Enk A, Margolis D, McMichael A, et al. Fitzpatrick’s Dermatology in General Medicine. 9th ed. NY: The McGraw-Hill

Companies, Inc.; 2012.
12. Bakr E, Abdo H, Abd-Elaziz H, Abd-Elrazek H, Amer M. Adapalene gel 0.1% vs ketoconazole cream 2% and their combination in treatment of pityriasis

versicolor: A randomized clinical study. Dermatol Ther. June 2020; 33(3):e13319. DOI: 10.1111/dth.13319.
13. Indoor Air Quality Association, Inc. Recommended Guidelines for Indoor Environments: IAQA 01-2000. Connecticut: Indoor Air Quality Association;

2000.

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 36



JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

Syringocystadenoma papilliferum arising from a
nevus sebaceus mimicking squamous cell carcinoma

in a Filipino female: A case report

Maria Kristina R. Fajardo, MD1, Daisy King-Ismael, MD, FPDS1,
Bernardita O. Policarpio, MD, FPDS1

ABSTRACT

INTRODUCTION Syringocystadenoma papilliferum (SCAP) is a relatively rare benign adnexal skin tumor which can manifest in a
variety of clinical forms. Nearly one-third of cases are known to develop within a pre-existing nevus sebaceus (NS). The peculiar
feature of this case was the appearance of a large exophytic tumor within a congenital verrucous plaque, which raised the
suspicion of a malignant transformation. This is a case of a young Filipino adult with an unusual presentation of syringocystad-
enoma papilliferum in a nevus sebaceus mimicking squamous cell carcinoma.

CASE REPORT A 27-year-old Filipino female presented a persistently enlarging exophytic pedunculated cribriform tumor within
a congenital verrucous plaque on the left temporal area. The tumor started to appear when she was 20 years old. One month
prior to consult, it rapidly increased in size and bled on gentle manipulation. She has neither comorbidities nor any family history
of a similar condition. Her physical examination was normal, with no palpable lymphadenopathies. The biopsy showed syringo-
cystadenoma papilliferum on a nevus sebaceus. She underwent carbon dioxide (CO2) laser excision under local anesthesia. The
procedure was uneventful and the patient is on regular follow-up and close monitoring for any possible malignant change or
recurrence.

CONCLUSION A case of syringocystadenoma papilliferum on a nevus sebaceus mimicking squamous cell carcinoma in a Filipino
female treated with carbon dioxide laser excision was presented. The unusual presentation of SCAP can mimic malignancy and
histopathologic evaluation is warranted to rule out malignant transformation for proper management.

KEYWORDS Syringocystadenoma papilliferum, secondary tumors, nevus sebaceus

1Department of Dermatology, INTRODUCTION exophytic tumor over a nevus sebaceus. Suspicion
University of Santo Tomas of malignant transformation was raised due
Hospital, Manila, Philippines Syringocystadenoma papilliferum is a relative- to the abrupt increase in size (>4 cm over one
ly rare benign adnexal skin tumor, which can month) of lesion, malodorous exudates, and
Corresponding author manifest in a variety of clinical forms. Nearly associated spontaneous bleeding. The lesion was
Maria Kristina R. Fajardo, MD one-third of cases develop in a pre-existing ne- clinically diagnosed as squamous cell carcinoma
vus sebaceus.1-3 Using the Health Research and but subsequent histopathologic results showed
Conflict of interest Development Information Network (HERDIN), syringocystadenoma papilliferum.
None there are no reported cases of syringocystade-
noma papilliferum arising within a nevus in the CASE REPORT
Source of funding Philippines. Tumors associated with nevus seba-
None ceus are primarily benign. However, malignant A 27-year-old Filipino female was born with a
neoplasms such as basal cell carcinoma, squa- yellow to dark brown, linear, and hairless plaque
mous cell carcinoma, and sebaceous carcinoma on the left temporal area. The plaque enlarged
have also been reported to arise within a nevus gradually and became more verrucous during
sebaceus.1,2 To rule out malignant transforma- her adolescent years. A malodorous exophytic
tion, histopathologic examination is usually war- pedunculated mass emerged in the center of the
ranted. plaque when she was 20 years old. One month
prior to the consult, the tumor rapidly increased
This report describes a 27-year-old Filipino in size, and bled on gentle manipulation.
female who consulted due to a rapidly growing

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 37

CASE REPORT JPDS
Journal of the Philippine
Dermatological Society

AB luminal rows of cells displayed evidence of active decapitation
secretion. There were dilated and congested dermal blood ves-
Figure 1. Exophytic pedunculated cribriform tumor measuring 4.5 x 4 x 2.5 cm attached to sels, dense superficial and deep perivascular mixed cell infil-
a yellow-brown verrucous plaque. trates consisting of lymphocytes, histiocytes, eosinophils, and
plasma cells (Figure 2). There was absence of atypia, mitotic
Skin examination showed a solitary flesh-colored figures, or nuclear pleomorphism. The case was signed out as
exophytic, pedunculated cribriform tu­mor topped with yellow, syringocystadenoma papilliferum in nevus sebaceus.
hemorrhagic crusts with clefts filled with purulent, foul-
smelling exudates measuring 4.5 x 4 x 2.5 cm (Figure 1). Its base The nodular-type of tumor appeared on the temporal area
showed a hairless, yellow to brown, well-demarcated verrucous and scalp, which are areas where cosmesis is a concern. Since
linear plaque measuring 3.5 x 6 cm (Figure 1). The lesions were histopathology results revealed a benign lesion, carbon dioxide
movable, not indurated, not friable and non-tender on palpation. laser excision was done at an output of 8-12 watts in ablative
There were no palpable lymphadenopathies. continuous mode under local anesthesia with curettage and healing
by secondary intention (Figure 3). The postoperative wound healed
Skin punch biopsy on the verrucous plaque, and shave bi- with granulation tissue formation and good reepithelialization. The
opsy of the exophytic tumor was done. Histologic examination patient tolerated the procedure well and healing was uneventful.
of the verrucous plaque showed serum crusts, hyperkeratosis, The patient is on regular follow-up and close monitoring for any
papillomatosis, irregular acanthosis, and dense superficial possible malignant change or recurrence.
perivascular mixed cell infiltrates consisting of lymphocytes,
histiocytes, and few eosinophils. There were immature hair DISCUSSION
follicles with enlarged mature sebaceous glands in the dermis
(Figure 2). Microsections of the exophytic tumor showed hyperker- Nevus sebaceus is a congenital hamartoma with epidermal,
atosis, varying degrees of papillomatosis, and irregular acanthosis. sebaceous, and apocrine differentiation.4,5 It occurs in 0.3% of
There were cystic invaginations from the epidermis extending to newborns or early childhood.4 It is predominantly distributed
the dermis with numerous papillary projections in which the on the head and neck, presenting as hairless verrucous
plaque.1 Nevus sebaceus usually undergo three clinical and
developmental stages. The alopecic or infantile stage (stage
I) appears as a hairless yellowish plaque with primordial hair
follicles and hypoplastic sebaceous glands on histopathology.
The plaque becomes more prominent and firm during the
verrucous-papillomatous plaque stage (stage II). Benign and
malignant neoplasms usually develop at the tumoral stage (stage
III).4,6 The lesions usually become more verrucous at puberty,
and hormonal influence may play a role in its pathogenicity.1,4

The susceptibility of a nevus sebaceus for secondary tumors
has been associated with somatic mosaicism. Mutations in HRAS
and KRAS in nevus sebaceus lesional keratinocytes led to the

A BC

Figure 2. A. Skin punch biopsy of the verrucous plaque showed an exophytic structure showing hyperkeratosis, papillomatosis, and irregular acanthosis with immature hair follicles and
enlarged sebaceous glands in the dermis (H&E stain; 10x). B. Shave excision biopsy of the exophytic tumor showed hyperkeratosis, varying degrees of papillomatosis, irregular acanthosis with
cystic invaginations from the epidermis extending to the dermis (H&E stain; 10x). C. Numerous papillary projections in which the luminal rows of cells displayed evidence of active decapitation
secretion (H&E stain; 40x).

38 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

activation of the RAF-MEK-ERK and phosphoinositide 3-kinase AB
signaling pathways with subsequent cellular proliferation and
increased susceptibility to tumor formation. Secondary neoplasms Figure 3. A. Photograph of the left temporal area immediately after CO2 laser treatment.
may develop in approximately 25% of nevus sebaceus cases, B. There is a reduction in size and proper wound healing one month after (30 days after
with mostly benign tumors.5 Nevus sebaceus is associated most CO2 laser treatment).
commonly with benign neoplasms such as trichoblastoma and
syringocystadenoma papilliferum. However, malignant neoplasms options are Mohs micrographic surgery or carbon dioxide laser
such as basal cell carcinoma, squamous cell carcinoma, and excision in unfavorable excision and grafting areas.Cribrier et al.2,6
sebaceous carcinoma have also been reported to arise within a reviewed 596 cases of nevus sebaceus and reported that most of
nevus sebaceus.1,2,4,6 There are only two published reports in local the associated tumors were benign.2 The authors believe that,
literature with tumors arising in nevus sebaceus. Piansay-Soriano in children, close observation and clinical follow-up are better
et al. reported a case of a 9-year-old girl with a basal cell carcinoma than prophylactic excision. Patients must have a comprehensive
arising from a nevus sebaceus on the scalp and an infundibuloma understanding of the condition, and should be compliant with
arising from a separate nevus sebaceus on the face.7 Lagunzad the recommended follow-up to observe new growth or changes
et al. reported sebaceoma and squamous cell carcinoma cases suggesting malignancy.2,6
arising on top of a congenital nevus sebaceus and epidermal nevus,
respectively.8 Most studies suggest that full-thickness surgical excision
is the treatment of choice. In cases where the ensuing defect is
Syringocystadenoma papilliferum usually appears at birth too large for primary closure, rotation flap and tissue expansion
and before puberty in 50% and 15%-30% of cases, respectively.1,3 It procedures are more suitable. However, these extensive
occurs commonly on the scalp or the face and typically measures surgeries will require a more prolonged recovery period, a slower
from 1 cm to 3 cm. Clinical presentations include plaque-type, cicatrization, and risk of hypertrophic scars and keloids.6,10 The
linear-type, and nodular-type. The plaque-type is often associated carbon dioxide (CO2) laser has been recognized as an excellent
with nevus sebaceus, characterized as a hairless patch on the alternative to surgery. CO2 laser has benefits of reduced healing
scalp. The linear-type comprises of multiple reddish-pink papules time, less requirement for anesthesia, less bleeding and
or nodules on the face and neck region. The nodular-type are inflammation, and easy access to anatomically difficult areas.10
dome-shaped pedunculated nodules measuring between 5-10 mm Side effects are minimal such as pain, erythema, and edema.
with predilection on the trunk, shoulder, and axilla.3 Unusual The CO2 laser could be a treatment option in areas unfavorable
presentations of a large syringocystadenoma papilliferum (>4 cm), to excision and grafting, but it is critical to consider how much
with bleeding, and malodorous exudates have been reported in the lesion is being removed. There is a greater chance of recurrence
literature. Agrawal et al. reported a 35-year-old male presenting if fragments remain, so further follow-up is necessary.6
with multiple papules and nodules on the right lower abdomen
with an accelerated increase in size and foul-smelling discharge CONCLUSION
diagnosed as syringocystadenoma papilliferum.9 Hence, a biopsy is
warranted for proper diagnosis and management. A case of syringocystadenoma papilliferum in nevus sebaceus
mimicking squamous cell carcinoma in a Filipino female
Histopathologic examination of syringocystadenoma pa- treated with CO2 laser excision was presented. It is essential to
pilliferum often shows characteristic epidermal invaginations, be mindful of the various presentations of syringocystadenoma
and the presence of papillary processes lined with two epithe- papilliferum because atypical forms can mimic malignancy.
lial cell layers. Decapitation secretion is usually found at the Histopathologic evaluation is warranted to rule out malignant
luminal surface. Another common feature is the presence of transformation for proper management. CO2 laser ablation can
inflammatory infiltrates, mostly of plasma cells.9 be a treatment alternative to produce a cosmetically acceptable
result but close observation and further follow-ups are necessary
Malignant transformations arising from a nevus sebaceus for monitoring of relapse.
have been reported, and is related to aggressive behaviors, i.e.
sudden accelerated growth, the large size of a developed nodule,
bleeding, and the presence of metastatic lymph nodes.1,2 In our case,
the rapid growth of the tumor warranted further investigation.

The treatment of choice for syringocystadenoma papilliferum
is excision, followed by a detailed histological examination.3 The
definitive treatment for nevus sebaceus is full-thickness epidermal
and dermal excision. This is because the nevus extends deep as the
subcutaneous tissue, including adnexal structures. Other treatment

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CASE REPORT JPDS
Journal of the Philippine
Dermatological Society

REFERENCES

1. Baykal C, Buyukbabani N, Yazganoglu KD, Saglik E. Mit Naevus sebaceus assoziierte Tumoren [Tumors associated with nevus sebaceous]. J
Dtsch Dermatol Ges. 2006 Jan;4(1):28-31. German. doi: 10.1111/j.1610-0387.2006.05855.x.

2. Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: A study of 596 cases. J Am Acad Dermatol. 2000 Feb;42(2 Pt 1):263-8. doi:
10.1016/S0190-9622(00)90136-1.

3. Vyas S, Kothari D, Goyal V. Syringocystadenoma papilliferum of scalp: a rare case report. Int J Sci Stud. 2015;2(12):182-185. doi:10.17354/
ijss/2015/133.

4. Muñoz-Pérez MA, García-Hernandez MJ, Ríos JJ, Camacho F. Sebaceus naevi: A clinicopathologic study. J Eur Acad Dermatology Venereol.
2002;16(4):319-324. doi:10.1046/j.1468-3083.2002.00543.x.

5. Aslam A, Salam A, Griffiths CEM, Mcgrath JA. Naevus sebaceus: A mosaic RASopathy. Clin Exp Dermatol. 2014;39(1):1-6. doi:10.1111/ced.12209.
6. Moody MN, Landau JM, Goldberg LH. Nevus sebaceous revisited. Pediatr Dermatol. 2012;29(1):15-23. doi:10.1111/j.1525-1470.2011.01562.x.
7. Piansay-Soriano E, Pineda V, Jimenez R, Mungcal V. Basal Cell Carcinoma and Infundibuloma Arising in Separate Sebaceous Nevi During

Childhood. J Dermatol Surg Oncol. 1989;15(12):1283-1286. doi:10.1111/j.1524-4725.1989.tb03148.x.
8. Lagunzad J, King-Ismael D, Tan E. Two rare cases of epidermal hamartomas developing secondary tumors. J Phil Dermatol Soc. 2010;19(1):30-

33.
9. Agrawal R, Kumar P, Varshney R. Syringocystadenoma papilliferum: An unusual presentation. J Clin Diagnostic Res. 2014;8(5):3-4. doi:10.7860/

JCDR/2014/8172.4336.
10. Campolmi P, Bonan P, Cannarozzo G, et al. Highlights of thirty-year experience of CO2 laser use at the Florence (Italy) Department of

Dermatology. Sci World J. Published online 2012. doi:10.1100/2012/546528.

40 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X

JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

Drug-induced chronic bullous disease of childhood in
a two-year-old Filipino male triggered by cefaclor or

cefuroxime: A case report

Sher Claranza O. Liquido, MD1, Maria Jasmin J. Jamora, MD, FPDS1,2,3,4

ABSTRACT

INTRODUCTION Chronic bullous disease of childhood (CBDC) is a rare immune-mediated subepidermal vesiculobullous eruption,
characterized by linear IgA deposition along the basement membrane zone of the skin. Although mostly idiopathic, CBDC may
be triggered by factors such as infection, and drugs. Clinical and immunohistopathological features of drug-induced cases are
heterogeneous and indistinguishable from the idiopathic form.

CASE REPORT A two-year-old Filipino male presented with pruritic vesicles and bullae on the back several days after finishing a course
of cefuroxime, and cefaclor. Examination revealed multiple tense vesicles and bullae, some coalescing into a rosette pattern with
central crusts on the perioral, scalp, neck, back, perineal, and perianal areas.

Histopathology showed a subepidermal split with neutrophilic and eosinophilic infiltrates. Direct immunofluorescence revealed
strong linear deposition of IgA, and granular deposits of C3 and IgM at the basement membrane zone, thus confirming the di-
agnosis of CBDC.

Dapsone at 2mg/kg/day was started, with oral prednisolone (1.3mg/kg/day), and cloxacillin syrup (40mg/kg/day). Topical care
with betamethasone dipropionate and mupirocin ointment was included. After eight weeks, patient showed significant im-
provement with few vesicles and resolved lesions healing with post-inflammatory hyperpigmentation.

CONCLUSION We report a case of a two-year-old male presenting with vesiculobullous lesions after a course of cefuroxime,
and cefaclor. As both were given and withdrawn in a period of close proximity, it is difficult to determine the probable culprit
drug. Spontaneous resolution upon withdrawal of the suspected drug is variable. Systemic therapy such as dapsone may be
necessary for treatment.

KEYWORDS vesiculobullous, linear IgA bullous dermatosis, cefaclor, cefuroxime

1 Department of Dermatology, St. INTRODUCTION heterogeneous and completely indistinguishable
Luke’s Medical Center, Quezon from the idiopathic form, and are more common-
City, Philippines Chronic bullous disease of childhood (CBDC) and ly reported among adults as LABD.5
2Skin and Cancer Foundation, linear IgA bullous dermatosis (LABD), are rare
Inc., Pasig City, Philippines immune-mediated subepidermal vesiculobullous In this case report, we describe a case
3Department of Dermatology, eruption with different presentations of the same of CBDC in a two-year-old Filipino male who
Makati Medical Center, Makati disease process.1 presented with vesicles and bullae after finishing
City, Philippines a course of cefuroxime, and cefaclor.
4Section of Dermatology, International data of LABD shows incidence
Department of Medicine, of 0.5 to 2.3 cases per million individuals per CASE REPORT
University of the East Ramon year.2 Locally, data gathered from the Philip-
Magsaysay Memorial Medical pine Dermatological Society Health Information A two-year-old Filipino male presented with
Center, Quezon City, Philippines System (PDS HIS) show a total of 142 newly diag- pruritic vesicles, and bullae on the perioral,
nosed cases of CBDC from 2011 to 2018.3 scalp, neck, back, perineal, and perianal areas
Corresponding author of eight days’ duration. Three weeks prior to
Sher Claranza O. Liquido, MD Most cases of CBDC are idiopathic, however, consultation, the patient was admitted for sepsis
it may also be triggered by infection, drugs, vac- from unspecified organism. Cefuroxime was
Conflict of interest cinations, and malignancy. However, it may also given for five days and was shifted thereafter to
None be triggered by infection, drugs, vaccinations, cefaclor for seven days with complete recovery.
and malignancy.4 Drug-induced cases are highly
Source of funding
None

J Phil Dermatol Soc · May 2021 · ISSN 2094-201X 41

CASE REPORT JPDS
Journal of the Philippine
Dermatological Society

Figure 2. Tense vesicles and bullae with areas of moist erosion and brown crusts on the
upper back.

Figure 1. Vesicles and bullae coalescing into a rosette pattern with central crusts. kg/day), and topical care was continued daily. The patient was
also started on dapsone at 2mg/kg/day.
A few days after completing the antibiotics treatment, multiple
pruritic vesicles with an erythematous base appeared on the After five weeks of dapsone and prednisolone, the patient’s
upper back. He was started on a five-day course of acyclovir, mother noted a decrease in the number and size of new blisters.
which he completed. However, new vesicles continued to At eight weeks of treatment, there was significant improvement
present prompting consult, and admission. wherein fewer blisters were present, and previous lesions
healed with post-inflammatory hyperpigmentation.
Past medical history showed a positive skin test to
ceftriaxone, others were unremarkable. Examination showed During the course of treatment, laboratory evaluation was
multiple tense vesicles, and bullae on an erythematous base, done regularly. At eight weeks of dapsone, complete blood count
coalescing in a rosette pattern (Figure 1), with areas of moist showed decreased hemoglobin (11.2 g/dL RI: 13-17 g/dL), hemato-
erosion and brown crusts on the perioral, scalp, neck, back, crit (35.8% RI: 40-52%), and red blood cell count (4.58 mil/mm3 RI:
perineal, and perianal areas (Figure 2). 4.7-6.1 mil/mm3), with corresponding reticulocytosis (2.5% RI: 0.5-
2%) which is expected with dapsone intake. Improvement of counts
Laboratory evaluation revealed leukocytosis with a WBC was eventually observed at eleven weeks of treatment.
count of 18,380 mm3 (RI: 4,800-10,800 mm3). Gram stain revealed
gram positive cocci in pairs and small clusters. Histopathologic No untoward adverse events were noted. However, the
findings showed subepidermal vesiculobullous disease consistent patient was then lost to follow-up. The mother self-medicated,
with CBDC, with neutrophilic and eosinophilic infiltrates in the and tapered administration of dapsone (2mg/kg/day) to twice or
blister cavity (Figure 3). Direct immunofluorescence showed a thrice a week, and discontinued oral prednisolone, cloxacillin,
strong linear IgA deposit, and weak granular deposit of C3 and and topical care. Recurrence after four months was noted with
IgM along the basement membrane zone (Figure 4). Based on the increase in vesicles prompting follow-up, hence the patient was
clinicopathologic features, the diagnosis of CBDC was made. restarted on dapsone (2mg/kg/day), prednisolone (1.3mg/kg/
day), cloxacillin (30mg/kg/day), and daily topical care.
The patient was started on oxacillin (165mg/kg/day),
and hydrocortisone (4mg/kg/day), along with betamethasone As of time of this writing, the patient is still undergoing
dipropionate, and mupirocin ointment. Hydrocortisone was treatment with plans to taper accordingly and to continue
shifted to oral prednisolone (1.3mg/kg/day), which was continued regular monitoring for adverse events.
upon discharge. Antibiotic was shifted to oral cloxacillin (40mg/
DISCUSSION

Drug-induced LABD in adults can occur in 37.5% of cases, while

42 J Phil Dermatol Soc · May 2021 · ISSN 2094-201X


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