Literature review: manifestation of skin lesion on COVID-19

INTRODUCTION

A new and unexplained pneumonia case started in Wuhan city, China in December 2019. Experts and the government are taking immediate steps to determine the etiology to prevent the epidemic. The world health organization (WHO) gave the new virus terminology as novel coronavirus 2019 (2019-nCoV) on January 12, 2020 and gave the disease caused by 2019-nCov as corona virus disease 2019 (COVID-19) and coronavirus study group (CSG) from the international committee on virus taxonomy called 2019-nCoV a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and became a global epidemic as a marker of a very serious problem on January 20, 2020.^1–3 The confirmed case of infection from SARS-COV2 on August 20, 2020 has infected 22,213,869 cases worldwide with a total death of 781,677 people. The country with the highest SARS-CoV infection is the United States with 11,887,224 cases, Europe 3,841,452 cases, Southeast Asia 3,308,987 cases, Eastern Mediterranean with 1,776,889 cases, and Africa with 966,352 cases.⁴ Indonesia as part of a Southeast Asian country reported 147,211 confirmed cases, 40,119 in treatment, 100,674 recovered and 6,418 deaths (case fatality rate: 4.4%) on 20 August 2020.^5,6

The clinical manifestations of COVID-19 infection are very unclear and resemble many other diseases. Reports from around the world have revealed that the spectrum of this disease is not only centered on the lungs but can extend to various organs to multiple organs with clinical symptoms from mild to severe and lead to death. Reports from various studies state that Covid-19 can attack the nervous system, gastrointestinal-hepatobiliary system, urological system, cardiovascular and metabolic systems, hematology system, reproductive system especially in pregnancy, integumentary or mucocutaneous system with a form of efflorescence that is actually typical for other diseases, such as varicella.^7-28

The most common symptoms form COVID-19 are fever, myalgia, cough, fatigue, pneumonia, and respiratory problems. Rare disorders include headache, hemoptysis, diarrhea and coughing up blood.^29-31

EPIDEMIOLOGY AND ONSET

In mid-August 2020 cases of COVID-19 were found that hit all countries, even though several countries had started declaring countries free of new COVID-19 cases but in fact, COVID-19 infection had to be watched out for because the transmission method was easy and had very clinical symptoms. diverse. One of the clinical symptoms that appear is skin manifestation. Symptoms or skin lesions do not always appear in all patients with confirmed COVID-19. Recalcati described that only 20.45% of COVID-19 patients treated at the Lecco hospital (Lombardy region, Italy) manifested in the form of an erythematous rash (n=14), extensive urticaria (n=3) or varicella-like vesicles (n=1).³² Firmansyah, Elizabeth and colleagues' study that reviewed clinical manifestations in key populations found that only 42.86% of patients presented with skin lesions.³⁰

Regarding the onset of skin manifestations presented in the literature in a very varied range. Research by Zhao et al reviewed skin lesions appearing 9.92 (1-30) days after the appearance of systemic symptoms such as fever, cough, diarrhea, weakness, fatigue, lethargy, and difficulty breathing.²⁹ Research by Firmansyah, Elizabeth, and colleagues revealed that maculopapular skin manifestations appeared 10.7 (7-13) days after the appearance of clinical symptoms of COVID-19.³⁰ Other studies have also revealed that skin manifestations can appear more than 30 days after the first onset of symptoms of COVID-19.³⁵

PATHOGENESIS

The new study concluded ACE-2 as a functional host receptor for infection from SARS-CoV-2. The expression of the ACE-2 receptor with its binding affinity for the SARS-Cov 2 virus was 10 to 20 times higher. It is on the basis of this receptor expression that clinical manifestations, replication, severity, and transmission of the SARS-Cov 2 virus are explained at the level of molecular biology. Research using animal or mouse studies found that the expression of ACE-2 plays an important role in the incidence of vascular disorders, lung pathology, severity of infection, and the occurrence of respiratory acidosis mechanisms that trigger respiratory failure.³⁶ Physiologically, the ACE-2 receptor is spread in various body tissues, one of which is excreted in keratinocyte tissue and epidermal basal cells.^37,38 Recent research has shown that the expression of ACE-2 extends to the basal cell layer of hair follicles, sebaceous gland cells and smooth muscle cells surrounding the sebaceous glands, and eccrine cells.³⁹ These results were further confirmed by IHC, which showed ACE2 positive keratinocytes in the basal stratum, spinosum stratum, and epidermal granulosum stratum.⁴⁰ In addition, Li et al. found that CD8 and T cells had a significant positive correlation with ACE2 expression in the skin.⁴¹ On the basis of the pathophysiology and pathogenesis of SARS-Cov 2 virus infection and its relationship with the ACE-2 receptor which is not only spread in the lungs but throughout the skin layer, it is not surprising if the manifestation of skin lesions also appears as a result of the similarity of the ACE-2 receptor on both types of organs

CLASSIFICATION

The various efflorescence of the skin manifestations caused by COVID-19 make it difficult to classify COVID-19 because of its manifestations that resemble other diseases. Joob et al reported a petechial rash in a COVID-19 patient from Thailand.⁴² The Italian study reported on varicella-like lesions, Fernandez (Spain) reported the appearance of urticaria rash (urticarifrom rash) after 6 days of symptom onset.³⁷ Zhang (China) reported urticaria lesions.³⁸ Estebanez (Spain) reported a pruritic lesion of the heel, Henry (France) reported urticarial lesions and disseminated erythematous plaques eruption.^39-43 Sachdeva (Italy) reported maculo-papular lesions, morbilliform spots and hemorrhagic macular patches.²⁰ Mazzota (Italy) reported round red-purple lesions measuring 5-15 mm with indistinct margins on the soles of the feet.⁴⁰ Alramthan (Qatar) reported bilateral ischemic lesions on the acral with purplish red color on the dorsal part of the fingers.⁴¹

There is a study that categorizes these skin manifestations very well, namely the study of Casas and colleagues who classified these skin manifestations into 5 main classifications based on three hundred seventy-five cases of patients infected with COVID-19 in Spain. The classification includes:⁵²

Erythema-edema with vesicles or pustules (pseudo-chilblain) in the leg area is found in 19% of cases in Spain. Some additional manifestations of this classification are the possible presence of cold acral, and there is purpura which focuses on the area of the extremities (hands and feet) which are generally asymmetric.

Vesicular eruptions that generally appear in the trunk area are monomorphic to poliform and contain hemorrhagic content in these vesicles which, if not managed properly, will become larger and spread rapidly to other areas of the body.

Urticaria lesions mostly spread over trunk to extremities. It was found in 19% of cases of skin manifestations.

Maculopapular rash of various sizes and numbers (Figure 5 A). Several case reports reveal a similar distribution picture of pityriasis rosea. A review of other cases also revealed infiltrated papules in the extremities (dorsum of the hands), pseudo vesicles (Figure 5 B) and erythema multiform is (Figure 5 C).

Livedo or necrosis that arises as a manifestation of vascular occlusive and is spread over the trunk and acral areas. This type of lesion was reported to occur in 6% of cases of patients with confirmed COVID-19 manifestations (Figure 6).

PREDISPOSITION FACTORS WITH SKIN MANIFESTATIONS ON COVID-19 INFECTION

There are still few studies that describe predisposing factors for the appearance of skin manifestations in COVID-19. Several studies have attempted to reveal the factors predisposing to the appearance of skin lesions in COVID-19, although they have not yet reached an advanced stage of research but can be considered as a factor predicting the appearance of skin lesions in COVID-19.

Age and gender

The distribution of data on age and sex in people with COVID-19 with skin manifestations is very broad. The distribution of age data in Zhao and colleagues' study revealed a very large age range starting from 5 years old to 91 years old with a mean age of 49.03 years. Research in China is also in line with Zhao's research, with the average age of people with COVID -19 and skin manifestations of 45.55 years. The distribution of sex also cannot be used as a benchmark for the appearance of skin manifestations, but from some epidemiological data it is found that men are more likely to develop skin manifestations when compared to women (53 to 65%).³⁴

An interesting thing about the relationship between age and skin manifestations was shown by the research of Nieto and colleagues which revealed a tendency for younger ages (children) with a mean age of 12 years (1-29 years) to have a tendency for skin lesions in the form of erythema multiforme while at age the older adults with a mean age of 23.4 (2-56) years were dominated by erythema-edema efflorescence with vesicles and pustules (pseudo-chilblain). The age difference between these two groups was statistically significant (p<0.05). ⁵²

Comorbidity and history of previous disease

A literature that discusses the relationship between comorbidity and previous disease history is presented by Galvan and colleagues who in their paper found no difference between smoking, hypertension and diabetes on the appearance of skin manifestations in COVID-19 sufferers. The search from various sources revealed 44 of the 375 patients smoked. 10 out of 18 patients had hypertension, and 6 of 18 patients had a history of diabetes mellitus.⁵³ This variable was chosen because the hypothesis in the form of skin manifestations emerged as a result of low body immunity.

Immunity reaction and laboratory parameters

Deductively, lower immunity will cause more severe clinical manifestations than population groups with a better immune system. Research from Zhao and colleagues revealed that the group with skin manifestations of COVID-19 infection found lymphocytopenia in 76.92% of cases, an increase in CRP in 33.33% of cases, an increase in LDH in 46.17% of cases.³⁴ On the other hand, Zhang et al also revealed thrombocytopenia as an important factor in the occurrence of petechias in confirmed cases of COVID-19 infection.^50-51

Research from Firmansyah and colleagues also revealed a possible correlation between laboratory profiles and the incidence of COVID-19 skin manifestations in key population groups, namely health workers of the same age, found the fact that levels of hemoglobin, hematocrit, platelets, erythrocytes, leukocytes, and neutrophils-lymphocyte Ratio (NLR) was lower in COVID-19 cases with skin manifestations.³⁰

Infection severity

The severity of infection as a predictor of the incidence of skin manifestations of COVID-19 was described by Zhang et al who reported 7 cases of COVID -19 infection with critical clinical symptoms and physical parameters that found limb ischemia with various symptoms followed by other manifestations of cyanosis, purpura, and dry gangrene. This may be caused by multiple organ damage due to immune system reactions and vascular disorders. ³⁴

Research from Recalcti et al explained that skin manifestations due to COVID-19 are a common manifestation like other viral infections and there is no related relationship between pneumonia due to COVID-19.³² Contradictory to the literacy of Galvan et al revealed that the increasing severity of pneumonia will increase the likelihood of skin manifestations ranging from vascular lesions, urticaria lesions, maculopapular lesions, pseudo-chilblain lesions, to necrotic lesions.⁵³

PROGNOSIS AND MANAGEMENT

Until mid-August 2020 (August 16^th 2020), confirmed cases had reached 21,462,593 incidents with a cure rate of 13,448,779 events and a case fatality rate of 3.59%.⁴ Indonesia has recorded a number of confirmed cases of 137,468 cases with a case fatality rate of 4.4%.^5,6 The overall prognosis of the incidence of COVID-19 is dubia and bonam. Some cases of death occur because of comorbid factors, with causes of death in the form of respiratory failure, hypoxemia, and respiratory acidosis. Management of the manifestations of skin lesions in COVID-19 is still supportive, such as treatment with antihistamine drugs, topical steroids and other symptomatic drugs. Special management of COVID-19 infection includes administration of hydroxychloroquine, vitamin C, azithromycin, levofloxacin, and others.⁵³

CONCLUSION

COVID-19 infection has various target organs, one of which is the skin. The skin manifestations of COVID-19 infection can resemble other diseases, are not specific and do not necessarily appear in all patients, but can help make the diagnosis. Some of the clinical features that have been reported are erythema-edema with vesicles or pustules (pseudo-chilblain), vesicular eruption, maculopapular rash, urticaria, and livedo lesion. Cutaneous manifestations usually appear at the end of the acute phase, following the respiratory symptoms. Age, sex, and lower immunity are thought to be predisposing factors for skin manifestations. Management of skin manifestations to date has been in the form of conservative medical therapy.

Recommendations

Clinicians should consider cutaneous manifestations as a characteristic feature of COVID-19 infection so that the diagnosis can be made earlier and exclude the differential diagnosis. The most important thing to do in clinical practice is to always keep the hygiene and protect yourself with personal protective equipment. A decrease in awareness of various diseases is a very fatal thing.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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