FIELD OF THE INVENTION
[001] The present invention relates to the field of medical science, and more particularly, the present invention relates to a systematic review of cutaneous manifestations of coronavirus disease 2019 in 458 confirmed cases.

BACKGROUND FOR THE INVENTION:
[002] The following discussion of the background to the invention is intended to facilitate an understanding of the present invention. However, it should be appreciated that the discussion is not an acknowledgment or admission that any of the material referred to was published, known, or part of the common general knowledge in any jurisdiction as of the priority date of the application. The details provided herein the background if belongs to any publication is taken only as a reference for describing the problems, in general terminologies or principles or both of science and technology in the associated prior art.
[003] The World Health Organization on March 13, 2020 declared coronavirus disease 2019 (COVID-19) to be the cause of a pandemic. Although it predominantly affects the respiratory system, there are increasing reports of new manifestations, including diarrhea, anosmia, and dysgeusia. The recent literature shows a surge in reports of the cutaneous manifestations seen in COVID-19. These range from varicella-like eruptions, acute urticaria, chilblain-like lesions, and maculopapular exanthem to livedo reticularis. The incidence of cutaneous manifestations in COVID-19 has varied widely in the limited studies reported to date, ranging from as low as 0.2% to as high as 20.4%.In sick patients, cutaneous manifestations probably remain undocumented or overlooked due to other demanding issues. This review aims to discuss the reported manifestations of COVID-19. These might attain diagnostic or prognostic significance with the passage of time as we get better documentation and insight into their incidence as well as pathogenesis.
[004] The coronavirus disease 2019 (COVID-19) pandemic has affected the whole world for a short span of time. As it is a novel virus, its manifestations have been slowly revealed. Cutaneous manifestations of COVID-19 have gradually been reported from different regions of the world. However, their significance in diagnosis, as well as predicting prognosis, remains to be established. Objective: This review describes the cutaneous manifestations of COVID-19 patients from diverse regions with the aim of highlighting any important associations.
[005] In light of the foregoing, there is a need for the Systematic review of cutaneous manifestations of coronavirus disease that overcomes problems prevalent in the prior art.

OBJECTS OF THE INVENTION:
[006] Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.
[007] The principal object of the present invention is to overcome the disadvantages of the prior art by providing the Systematic review of cutaneous manifestations of coronavirus disease.
[008] An object of the present invention is to provide the Systematic review of cutaneous manifestations of coronavirus disease that describes the cutaneous manifestations of COVID-19 patients from diverse regions with the aim of highlighting any important associations.
[009] Another object of the present invention is to provide the Systematic review of cutaneous manifestations of coronavirus disease, wherein the review helps in the diagnosis of patients presenting with cutaneous lesions as the first manifestation.
[010] Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.

SUMMARY OF THE INVENTION:
[011] The present invention provides Systematic review of cutaneous manifestations of coronavirus disease.
[012] In one aspect of the present invention, the study comprises 458 confirmed COVID-19 cases.
[013] In another aspect of the present invention, the ratio of male to female patients was 0.94, and the patients’ age ranged from 2 months to 84 years.
[014] In another aspect of the present invention, in 10% of cases, skin lesions appeared before systemic manifestations.
[015] In another aspect of the present invention, the most common cutaneous manifestation was macular/maculo-papular rash (42.5%), followed by acute urticaria (17.9%), vesicular rash (15.3%), pseudo-chilblain or acral purpuric lesions (15.1), and livedo-reticularis (4.4%).
[016] In another aspect of the present invention, the majority of reported cases were located in Spain, Italy, and France.
[017] In another aspect of the present invention, the manifestations do not seem to be sex-, age-, or country-specific.
[018] In another aspect of the present invention, it is necessary to conduct worldwide registries and prospective studies to assess the true incidence of cutaneous manifestations of COVID-19 and to streamline their categorization based on their pathogenesis.
[019] In another aspect of the present invention, there appears to be no specific manifestation at present, but a high index of suspicion can help in the diagnosis of patients presenting with cutaneous lesions as the first manifestation.

DETAILED DESCRIPTION OF DRAWINGS:
[020] While the present invention is described herein by way of example using embodiments and illustrative drawings, those skilled in the art will recognize that the invention is not limited to the embodiments of drawing or drawings described and are not intended to represent the scale of the various components. Further, some components that may form a part of the invention may not be illustrated in certain figures, for ease of illustration, and such omissions do not limit the embodiments outlined in any way. It should be understood that the drawings and the detailed description thereto are not intended to limit the invention to the particular form disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the scope of the present invention as defined by the appended claim.
[021] As used throughout this description, the word "may" is used in a permissive sense (i.e. meaning having the potential to), rather than the mandatory sense, (i.e. meaning must). Further, the words "a" or "an" mean "at least one” and the word “plurality” means “one or more” unless otherwise mentioned. Furthermore, the terminology and phraseology used herein are solely used for descriptive purposes and should not be construed as limiting in scope. Language such as "including," "comprising," "having," "containing," or "involving," and variations thereof, is intended to be broad and encompass the subject matter listed thereafter, equivalents, and additional subject matter not recited, and is not intended to exclude other additives, components, integers, or steps. Likewise, the term "comprising" is considered synonymous with the terms "including" or "containing" for applicable legal purposes. Any discussion of documents, acts, materials, devices, articles, and the like are included in the specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention.
[022] In this disclosure, whenever a composition or an element or a group of elements is preceded with the transitional phrase “comprising”, it is understood that we also contemplate the same composition, element, or group of elements with transitional phrases “consisting of”, “consisting”, “selected from the group of consisting of, “including”, or “is” preceding the recitation of the composition, element or group of elements and vice versa.
[023] The present invention is described hereinafter by various embodiments with reference to the accompanying drawing, wherein reference numerals used in the accompanying drawing correspond to the like elements throughout the description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiment set forth herein. Rather, the embodiment is provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art. In the following detailed description, numeric values and ranges are provided for various aspects of the implementations described. These values and ranges are to be treated as examples only and are not intended to limit the scope of the claims. In addition, several materials are identified as suitable for various facets of the implementations. These materials are to be treated as exemplary and are not intended to limit the scope of the invention.
[024] The present invention provides Systematic review of cutaneous manifestations of coronavirus disease.
[025] A literature search was conducted using “PubMed” for original articles, case series, and case reports using the search terms “cutaneous manifestations” and “skin manifestations” in combination with “COVID-19” published up to 31 May. The inclusion criteria were studies reporting cutaneous manifestations in confirmed cases published in the English language. Exclusion criteria were studies reporting suspected cases, review articles, and cutaneous manifestations attributed to drug hypersensitivity or use of personal protective equipment and hand hygiene practices. Two reviewers independently reviewed the abstracts and full text. A manual search of the reference lists of relevant papers and reports was performed to identify additional studies. Data regarding authors, region, number of participants, cutaneous manifestations, and time of onset with respect to systemic features were extracted.
[026] Nine original research papers [Table 1] and 35 case series/case reports that met the inclusion criteria were analyzed for this review [Table 2]. All studies were published between February 2020 and May 2020.

[027] The highest number of publications were from Spain (13), Italy (11), and France (5). The rest were from China, Kuwait, Russia, Indonesia, Belgium, Mexico, Poland, and the United States of America. There were 458 patients with confirmed COVID 19 with cutaneous manifestations. For studies reporting both confirmed and suspected cases, only confirmed cases were included in the analysis. The age of patients ranged from 2 months to 84 years. Because of the heterogeneity among studies, the mean age could not be calculated as some studies reported mean age while others reported median age.
[028] However, the maximum number of patients was in the 50–70 years age group. Data regarding sex were available for 412 patients. Of these, 200 (48.6%) were male and 212 (51.4%) were female. Information about the onset of cutaneous signs and symptoms with respect to systemic manifestations, including fever, cough, malaise, and respiratory distress, was available for 433 patients. Cutaneous lesions developed after, simultaneously with, and before the onset of systemic features in 212 (48.9%), 172 (39.7%), and 42 (9.7%) patients, respectively. Seven patients (1.6%) had only cutaneous manifestations and were otherwise asymptomatic.

[029] The most common cutaneous manifestation observed was macular/maculo-papular exanthem in 195 (42.5%) patients. In most cases, it was generalized. Acute urticaria was reported in 82 (17.9%), vesicular/varicella-like rash in 70 (15.3%), chilblain/pernio-like lesions in 69 (15.1%), and livedo reticularis in 20 (4.4%) patients. Vesicular lesions were localized in a few patients and generalized in others. Livedo reticularis was transient and was present for less than a day in some patients, while in others it persisted for weeks. Less commonly reported manifestations include erythema multiforme (6), panniculitis (3), cutaneous hyperesthesia (2), small vessel vasculitis (1), and purpuric lesions (2). Reactivation of herpes simplex virus was reported in four patients and herpes zoster in two patients.
[030] Analysis of the available data revealed that the age of patients with pseudo-chilblain lesions ranged from 16 years to 74 years, with most patients in their 5th to 6th decade. No sex-related predilection was noted. However, Casas et al. reported that young patients presented more commonly with such lesions. Similarly, for vesicular lesions, there appeared to be no sex-related predilection and a substantial proportion of patients were in their 5th or 6th decade. Casas et al. and Giorgi et al. reported an association between cutaneous manifestations and the severity of COVID-19 infection. Both reported that diffuse petechiae, dependent purpura, and acral ischemia/necrosis are associated with severe disease with coagulation defects. Casas et al. reported livedo reticularis in older patients and vesicular rash in middle-aged patients.
[031] The true incidence of cutaneous manifestations is difficult to ascertain due to the lack of large-scale prospective studies. The current literature reveals a wide disparity in the incidence of cutaneous manifestations, ranging from 0.6% to 20.4%.Whether this reflects geographical variation or erroneous documentation remains to be seen. The likelihood of identifying skin changes is high if the primary care team involves a dermatologist. The analysis of 458 reported cases found an almost equal number of male and female patients (male: female = 0.94), ruling out sex as a risk factor. Cutaneous lesions appeared after systemic features in close to half of the cases. However, in 11.3% of patients, cutaneous lesions were the presenting manifestation, with 1.6% of patients being otherwise asymptomatic.
[032] Thus, a high index of suspicion can help in the diagnosis of this subset, which, if missed, could increase the spread of COVID-19. The literature on cutaneous manifestations in COVID-19 is growing, and a few recent large case series have tried to classify them systematically. Casas et al. in a multi-center study from Spain, including 375 patients, categorized cutaneous findings into five sub groups: pseudo chilblain like lesions, other vesicular eruptions, urticarial lesions, other maculo-papular exanthems, and livedo reticularis/necrosis.
[033] The limitation of their study was the inclusion of suspected as well as confirmed cases. Pseudo-chilblain-like eruptions are described as erythema and edema with few vesicles or pustules with or without purpura over the hands and feet. Casas et al. reported this in 19% of their patients. These were reported to occur in younger patients with less severe disease and manifested late during the course of the disease. On average, these lasted for 12.7 days. Alramthan et al. and Recalcati et al. reported similar findings in two and one patient, respectively.They described them as red-purple papules over the dorsal aspect of the fingers. Estebanez et al. reported a similar presentation in Spain, where a patient with COVID-19 developed erythematous, yellow papules and plaques over the heels during the convalescent period (12 days after testing positive) that resolved without treatment.
[034] Small vessel occlusion similar to that seen in the autopsies of lung specimens could be the underlying pathology behind this cutaneous presentation. This is potentiated by visualizing hyaline thrombi in microvessels of the skin in the histopathology of such lesions. Varicella-like vesicular eruptions were one of the first manifestations reported in COVID-19 patients. Recalcati et al. reported chickenpox-like vesicles in one of their 18 patients and Tammaro et al. in two patients. Marzano et al. reported a large series of 22 patients with varicella-like exanthem from Italy. These developed after a median latency period of three days after the onset of systemic features. These lesions were scattered in 72.7% of patients and diffuse in 27.3% of patients. The trunk was almost always involved, and the face and mucosae were spared. In seven patients in whom a biopsy was performed, it was reported to be consistent with viral infection. Casas et al. described such lesions in 9% of their patients. The important differentiating point is that these vesicles are monomorphic, unlike varicella, where polymorphic vesicles are seen. These lesions were seen more commonly in middle-aged patients with intermediate disease severity, and developed even before the onset of fever and cough and lasted for an average of 10.4 days. Similar eruptions were reported in an 8-year-old girl who had a history of varicella infection. Five days later, she and her family members tested positive for COVID-19. The varicella-like eruptions could be coincidental as they resemble lesions produced by other parvoviruses.
[035] Acute urticaria as a manifestation of COVID-19 has been reported quite widely. Recalcati et al. first described cutaneous findings in three of their patients. Casas et al. reported acute urticaria in 19% of patients. It is widespread and involves the palms. Urticaria develops simultaneously with systemic features, such as fever and cough, and resolves after an average of 6.8 days.
[036] Patients developing urticaria were found to have severe disease with higher mortality. However, it appears unclear if these urticarial lesions represent a manifestation of COVID-19 itself or are drug-induced as sick patients are on multiple drugs. Viral infections are a known trigger for urticaria, especially in children, and thus is likely to be seen in COVID-19. Maculo-papular exanthems have been described variably by researchers as erythematous, morbilliform, and purpuric rash. However, all fit the description of maculo papular rash similar to that seen in other viral exanthems. Casas et al. reported different morphologies of maculo-papular rash in 47% of patients.
[037] These include pityriasis rosea-like, purpuric, peri-follicular rash with scaling, erythema multiforme-like, and erythema elevatumdiutinum-like. Some patients develop erythematous infiltrated papules over the extremities resembling pseudo-vesicles. Like urticarial lesions, maculo-papular rash is also associated with severe disease and high mortality. These last for a mean of 8.6 days and subside without any post-inflammatory pigmentation. Underlying lymphocytic vasculitis with red blood cell extravasation and papillary dermal edema exacerbated by complement deposition, as seen in histopathology. Occlusive vascular disease can also explain the development of livedo reticularis.
[038] Casas et al. reported livedo reticularis in older patients with severe disease. However, age is a poor prognostic factor itself and may be responsible for the higher mortality. Livedo reticularis has been reported as a transient finding in some patients who do not require specific treatment. A few patients also developed cutaneous necrosis secondary to small vessel thrombosis. Other manifestations include enanthems, purpuric flexural lesions, and reactivation of herpes simplex and varicella zoster virus. It is difficult to specifically attribute the cutaneous manifestations to COVID-19 to the virus itself because of a lack of histopathological and virological confirmation in most studies. It is even difficult to obtain photographs because of the risk of disease transmission. The findings reported to date may be incomplete, and new manifestations will be added with time. There is a need to develop countrywide registries to maintain records of cutaneous manifestations. With a better understanding of the pathogenesis of the disease, as well as its cutaneous manifestations, their significance will be clear.
[039] The disclosure has been described withreference to the accompanying embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein.
[040] The foregoing description of the specific embodiments so fully revealed the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the scope of the embodiments as described herein.

We Claim:

1) A systematic review of cutaneous manifestations of coronavirus disease, the study comprises 458 confirmed COVID-19 cases;
wherein the ratio of male to female patients was 0.94, and the patients’ age ranged from 2 months to 84 years.
2) The systematic review as claimed in claim 1, wherein in 10% of cases, skin lesions appeared before systemic manifestations.
3) The systematic review as claimed in claim 1, wherein the most common cutaneous manifestation was macular/maculo-papular rash (42.5%), followed by acute urticaria (17.9%), vesicular rash (15.3%), pseudo-chilblain or acral purpuric lesions (15.1), and livedo-reticularis (4.4%).
4) The systematic review as claimed in claim 1, wherein the majority of reported cases were located in Spain, Italy, and France.
5) The systematic review as claimed in claim 1, wherein the manifestations do not seem to be sex-, age-, or country-specific.
6) The systematic review as claimed in claim 1, wherein it is necessary to conduct worldwide registries and prospective studies to assess the true incidence of cutaneous manifestations of COVID-19 and to streamline their categorization based on their pathogenesis.
7) The systematic review as claimed in claim 1, wherein there appears to be no specific manifestation at present, but a high index of suspicion can help in the diagnosis of patients presenting with cutaneous lesions as the first manifestation.