Dermatologic Manifestation Of COVID-19: Review Of Case Series
Annisa Alviariza1*, Luh Made Budiani2
1 Internship Doctor, Dermato-Venereology Departement, Sanjiwani Gianyar Regional Hospital, Bali.
2 Dermato-Venereology Departement, Sanjiwani Gianyar Regional Hospital, Bali.
*Corresponding Author
Annisa Alviariza,
Departement of Dermato-Venereology, Sanjiwani General Hospital Gianyar, Bali, Indonesia.
Tel: +6285212130127
E-mail: annisaalviariza@gmail.com
Received: April 14, 2021; Accepted: May 07, 2021; Published: May 19, 2021
Citation: Annisa Alviariza, Luh Made Budiani. Dermatologic Manifestation Of COVID-19: Review Of Case Series. Int J Clin Dermatol Res. 2021;09(02):269-274. doi: dx.doi.org/10.19070/2332-2977-2100060
Copyright: Annisa Alviariza©2021. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: SARS-CoV-2 infections, causing disease known as COVID-19, has been associated with a myriad of symptoms,
including dermatological ones. Despite there has been a consensus on pulmonary and systemic signs and symptoms of
COVID-19, the same cannot be said of dermatological ones. We write in attempt to find a common theme of dermatological
manifestations of COVID-19.
Methods: We conducted literature searches from Medline databases as well as Google Scholar using keywords “cutaneous
manifestations of COVID-19” and “dermatologic manifestations of COVID-19”. We included case series in our pooled descriptive
analysis to describe types of cutaneous eruptions, localizations, and associated symptoms among COVID-19 patients
with confirmed RT-PCR results.
Results: We included 12 case series in our pooled analyses with 2 more analyzed separately due to non-comparable data presentations.
The results identified common types of cutaneous eruptions associated with COVID-19 to be maculopapular rash,
urticaria, vesicular rash, vascular rash. Eruptions tend to be localized on the trunks, with lesser frequency found on extremities,
and eruptions are often accompanied by pruritus of varying intensity. These various eruptions are associated with two distinct
pathological pathways, namely inflammation of skin tissues, causing inflammatory rashes, and hypercoagulable state which is
associated with vascular rashes.
Conclusion: Our literature review identified several common types of cutaneous eruptions associated with COVID-19 with
different proposed pathophysiological mechanisms for inflammatory and vascular rashes. This review is limited by its data
sources which includes only case series as well as the fact that at this stage in the pandemic, little biomolecular research has
been conducted to definitively associate SARS-CoV-2 infection with cutaneous manifestations.
2.Introduction
3.Methods
4.Results
5.Discussion
6.Acknowledgements
7.References
Keywords
COVID-19; SARS-CoV-2; Dermatologic Manifestations; Cutaneous Eruptions.
Introduction
Since early 2020 the world is faced with a novel viral pandemic.
SARS-CoV-2, a novel coronavirus strain related to previous novel
coronaviruses such as SARS and MERS, is currently infecting
most of the world. As of the writing of this article, there has
been 14.3 million confirmed cases of coronavirus disease of 2019
(COVID-19), disease caused by SARS-CoV-2 infection, with 600
thousand deaths [1].
Dermatologic manifestation of primarily non-dermatologic viral
infection has been previously described. As an example, hepatitis
C, a virus that primarily infect the liver, has been known to manifest
as pruritus, palmar erythema, and lichen planus [2]. However,
previous coronavirus diseases, namely SARS and MERS, has no
had widely reported cutaneous manifestation [3].
Nevertheless, there has been reported cutaneous manifestations
of COVID-19. A case series by Recalcati [4] in a letter to editor
was among the first that describe a cutaneous manifestation of
COVID-19. In that particular study, the manifestations include
erythematous rash, urticaria, and vesicles with varying frequency. Since that first case series, further studies have reported similar
manifestation, and other form of cutaneous manifestations, in
COVD-19 patients around the world.
Cutaneous manifestation of COVID-19 remains an understudied
and under-reported phenomenon. Nevertheless, dermatologists
worldwide has reported more findings of cutaneous manifestation
of COVID-19. This review attempted to summarize and interpret
what is currently known of the phenomenon.
Methods
We conducted literature review to describe types of cutaneous
lesions and efflorescence associated with SARS-CoV-2 infection.
For that objective, we conducted systematic search of literature
in open public scientific databases including Medline and Google
Scholar. Keywords used include “cutaneous manifestation of
COVID-19” and “dermatologic manifestations of COVID-19”.
We include only case series studies and exclude all other study
type. We conducted reference mining from all identified articles
to find further articles that fulfill inclusion criteria. In the end, we
selected for case series with comparable reported data which include
patients with confirmed SARS-CoV-2 infection by RT-PCR,
description of efflorescence, localization, symptoms, and onset.
From included studies we mined data on number of patients with
SARS-CoV-2 infection, as confirmed from RT-PCR. Data mined
including number of patients, type of cutaneous lesions found,
and other characteristics. Based on these mined data, we conducted
pooled analyses of these studies. We review the data and
interpret it based on other relevant evidences.
Results
We identified 14 articles which fulfill our inclusion criteria detailed
in Table 1, 12 of which showed comparable results and included
in pooled analysis while 2 more were less comparable and analyzed
separately. Most included articles described cases in Italy, with two
studies in United States, and one study each describing cases in
Russia, India, France, and Spain. Many of these articles does not
describe exclusively confirmed SARS-CoV-2 infected patients,
some also described suspected cases or cases with negative result
for RT-PCR test for SARS-CoV-2. Some studies also described
clinical manifestation in general, with dermatological manifestation
being one subset of clinical manifestations described.
Few articles described the frequency of dermatological manifestation among general SARS-CoV-2 infected population. Recalcati et al [4] was one that describe that among 88 patients with confirmed SARS-CoV-2 infection, 18 (20.4%) showed cutaneous manifestation. Similarly, De Giorgi et al [15] described that among 678 patients with confirmed SARS-CoV-2 infection, 53(7.8%) with inflammatory cutaneous manifestations and 13(1.9%) with vascular cutaneous manifestations.
Types of Cutaneous Efflorescence
We included 151 confirmed SARS-CoV-2 infection cases in our pooled analysis as can be seen in Table 2. The most frequent form of cutaneous efflorescence found in COVID-19 patients was erythematous maculopapular rash or morbilliform rash which was found 76(50.3%) patients. Other forms of cutaneous efflorescence found among confirmed SARS-CoV-2 infected patients included vesicle, pustule, or bullae which was found in 33(21.9%) patients, urticaria, papulosquamous eruptions found in 25(16.6%), and urticaria found in 23(15.2%) patients.
Our pooled analysis found a number of vascular eruptions, including petechiae, purpura, vasculitis, and chilblain/pernio, which was found in 29(19.2%) patients. Apart from the pooled analyses, Freeman et al [17] found 46 cases of confirmed SARS-CoV-2 patients, out of 171 described in the study, with vascular various. Another 23 cases of confirmed SARS-CoV-2 infection with pernio/chilblain was found by Freeman et al [16].
As can be noted from Table 2, the numbers do not add up to one hundred percent. This is due to the possibility that each case suffered more than one type of eruptions. This phenomenon is noted by Freeman et al which described that among 171 confirmed SARS-CoV-2 infections that exhibited cutaneous eruptions, 6 suffered multiple eruptions [17].
Localization
The most frequent localization for cutaneous efflorescence of SARS-CoV-2 infection was the trunk of the body. Ten out of twelve comparable studies provided data on lesion localizations with a total of 66 cases, as can be seen in Table 3. From these cases, 45(68.2%) was found with lesions localized to the trunk of the body. Extremities, including arms and legs, was found in 21(31.8%) of cases while lesion on hands, feet, and fingers/toes, was found in 4(6.1%) of cases. Meanwhile 6(9.1%) of cases experienced generalized lesions.
Freeman et al described a more detailed localizations of cutaneous lesions from 171 confirmed SARS-CoV-2 cases [17]. Broken down based on types of efflorescence, most lesions were predominantly found on the trunk. Lesions were found on chest, abdomen, and back of, respectively, 50%, 63%, and 61% of cases with maculopapular morbilliform lesions. Similar distribution, albeit lower, was found for urticaria and vesicular lesions. Meanwhile, chilblain lesions were found predominantly on the feet, with 84% of cases, rather than hands, with only 32% of cases.
In a marked difference from our pooled analyses, Freeman et al described significant amount of eruption localized on the head and face region [17]. Face is the more predominant localization among the two with 21% of maculopapular rashes, 30% of urticaria, and 33% of vesicular rashes found on faces of the patients. Our pooled analyses found no description of cutaneous eruptions on the head and face region.
Associated Symptoms
Six of the included studies described associated cutaneous symptoms associated with the eruption, including pruritus and pain. From these studies, we included 124 cases in pooled analysis, as visible in Table 4, and identified that 72(58.1%) of cases complained of pruritus while another 52(41.9%) cases complained of pain or burning sensation of the lesion. Note that our pooled analysis does not describe the intensity of the symptoms which may vary. Marzano et al, for example, described his 22 cases with which suffered varicella-like vesicles to suffer mild pruritus [13].
Freeman et al, mean while, varying associated symptoms based on type of eruptions suffered by the patients [17]. Pruritus was the predominant symptoms among patients which suffered morbilliform maculopapular rash and urticaria with 61% and 74% of cases respectively, while cases with chilblain mainly complained of pain or burning sensation with 71% of the cases. Patients with vesicular eruption, mean while, suffered both pruritus and pain with 72% suffered pruritus and 50% suffered pain or burning sensation.
Discussion
There has been little to no systematic population-based research
to study cutaneous eruption on SARS-CoV-2 infected patients.
Most available literatures were case reports or case studies with
varying number of reported cases and description detail. Some
studies reporting dermatologic features of SARS-CoV-2 infections
also included suspected cases or cases with negative SARSCoV-
2 RT-PCR results, meanwhile others failed to conduct diagnostic
tests to exclude other infectious causes for the described
cutaneous eruptions. With this situation, there has been no established
studies to definitively linked these eruptions to be caused
by SARS-CoV-2 infection although some pathophysiologic mechanisms
have been proposed. Nevertheless, our literature review
has identified two major themes of discussions, namely the description
of the major cutaneous manifestations of COVID-19
as well as its pathophysiologic mechanisms.
Describing Types Of Eruption Associated With COVID-19
Our review of literature identified several types of cutaneous
eruption that has been thematically described to be associated
with SARS-CoV-2 infection or COVID-19 which is summarized
in Table 5. These includes maculopapular/morbilliform rash, varicella-
like vesicular rash, and vasculitis or vascular rash.
Maculopapular or morbilliform rash with distribution predominantly on the trunk and upper extremities was found to be the dominant form of cutaneous eruption found in COVID-19 patients, based on our pooled analyses. This is also compounded by similarly described papulosquamous eruptions, which may share similar process of formation with aforementioned maculopapular rash.
Prevalence of similarly described rash has been previously described in reviews by Suchonwanit et al [18] and Wollina et al [19]. Wollina et al further described the maculopapular rash in a spectrum from morbilliform rash to papulosquamous plaques or pityriasis rosea-like lesion, accompanied by pruritus [19]. This is similar to our findings.
Vesicular eruption, including bullae and pustule, was also frequently found among COVID-19 patients. Marzano et al described a cohort of 22 patients who all exhibited vesicopapular exanthema with age mostly in the adult to elderly range, with one exception of a 8-year old child [13]. Wollina et al has noted that chickenpox-like vesicular eruption was found in 1% to 9% of confirmed SARS-CoV-2 infections [19].
Mean while, vascular eruptions among COVID-19 patients varied from petechiae and purpura to chilblain. Chilblain is particularly described among COVID-19 patients with a recent Spanish study reporting 19% of confirmed SARS-CoV-2 infection [20]. Chilblain is a lesion of particular interests with several studies focusing on describing chilblain-like lesions among children suspected of COVID-19 [21-23]. However, these studies included both suspected cases and confirmed SARS-CoV-2 negative patients in their description, making it difficult to establish association of these lesions with exclusive SARS-CoV-2 infection as its etiology.
Pathophysiology Of Cutaneous Eruptions In COVID-19
There are two pathologic mechanism suspected to play a role in cutaneous manifestations of COVID-19, each with differing types of cutaneous eruptions. The proposed mechanisms and its pathways to cutaneous eruptions can be seen in Figure 1.
Figure 1. Summary of proposed pathophysiology of SARS-CoV-2 infection and its associated cutaneous eruptions.
The first suspected mechanism is an antibody mediated immune response against a pathogenic virus. It is suspected that cutaneous eruptions, especially inflammatory eruptions such as exanthems and vesicular rashes, to be caused by antibody-antigen reaction in or near dermatologic tissues [24]. It has been further demonstrated that SARS-CoV-2 entry factor, ACE2, was found to be expressed in skin tissue as well, mainly in keratinocytes and basal layer, probably contributing to local inflammation in those tissue in event of SARS-CoV-2 infection [25].
Mean while, this immune system and antibody mediated pathophysiology is found to be less likely mechanism for vascular eruptions of COVID-19, such as petechiae, purpura, and chilblain-like lesions. This premise was proposed by Mahieu et al who found no anti-SARS-CoV-2 antibodies on these lesions [26]. As such, the second proposed mechanism come into play, which involved thrombosis and endothelial damage related to SARS-CoV-2 infection.
SARS-CoV-2 infection has been previously associated with hypercoagulable state, as evident by increasing risk of thromboembolism [27]. This hypercoagulable state, as well as formation of thromboembolism, may be associated with expression of ACE2 in endothelial tissues, mediating viral invasion of these tissues, causing damage through inflammation and viral activities [28].
This hypercoagulable state and thromboembolism are proposed to be associated with the process that manifested as vascular lesion on the skin. Vascular damages on superficial blood vessels near skin surfaces may be visible as vasculitis, petechiae, or purpura. Meanwhile, vascular blockage due to thromboembolism may be associated with chilblain-like lesions associated with COVID-19.
Acknowledgements
We reviewed data and materials available the current time, it may
be limited compared to future literature which would have shed
more light on the association between SARS-CoV-2 infections and
cutaneous eruptions. Nevertheless, we identified several groups
of cutaneous eruptions associated with COVID-19, namely maculopapular
rash, urticaria, vesicular rash, and vascular rash. These
different eruptions were proposed to be caused SARS-CoV-2
infection with different pathophysiological mechanisms, namely
inflammation and hypercoagulable state. Inflammation near skin
surfaces was associated with maculopapular rashes, urticaria, and
vesicles while hypercoagulation of superficial blood vessels may
manifest as petechiae, purpura, vasculitis, or chilblain. More studies
needs to be conducted to definitively associate these various
cutaneous eruptions with SARS-CoV-2.
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