SARS-CoV-2, skin lesions and the need of a multidisciplinary approach.

Editor

COVID‐19 is a disease caused by severe acute respiratory syndrome coronavirus 2 of the genus Betacoronavirus (SARS‐CoV‐2). It was first described in Wuhan (China) on December 2019 and has spread to become a pandemic. Its clinical presentation is mainly characterized by cough, fever and dyspnoea, although many other symptoms have been described within its presentation pattern. In some cases, it causes an acute respiratory distress that has lead to the death of thousands of people around the world. Furthermore, different types of skin lesions have been described during the infection period of illness. In this exceptional situation of global health emergency, physicians are undertaking research work in order to achieve notions on the aetiopathogenesis of these skin lesions. The first report of cutaneous manifestations described different forms of skin lesions such as erythematous rash, urticaria and chickenpox‐like vesicles. Further studies have classified 5 different type of skin lesions and associated them with patient demographics, timing in relation to symptoms of the disease, severity and prognosis. Acro‐ischaemic lesions have also been notified and attributed to disseminated intravascular coagulation and to the expression of secondary microthrombosis due to endothelial damage. , , However, to date, there is no clear understanding on whether the skin lesions are secondary to the viral infection nor why there are different presentations of skin lesions for the same viral infection.

We present 4 patients with COVID‐19, confirmed by positive polymerase chain reaction, who were referred to our service due to the appearance of skin lesions (Fig. 1). Two of them developed skin lesions during hospitalization whilst presenting respiratory symptoms, and the other two developed skin lesions many days after hospital discharge. Demographic data, description and histology of skin lesions, blood parameters, clinical symptoms and drugs administered are shown in Table 1. The algorithm of the spanish pharmacovigilance system (ASPS), which evaluates the possible implication of a drug reaction as a cause of the skin lesions, was also applied. The ASPS analyzes i) the interval between drug administration and the apparition of skin lesions, ii) the degree of knowledge of the relationship between the drug and the effect described in literature, iii) the evaluation of drug withdrawal, iv) the rechallenge effect and v) alternative causes. Each item receives an individual subscore, and a total sum ≥6 indicates a probable causality.

Figure 1

a) Clinical presentation: Patient 1: Dispersed hives over the face, trunk and lower limbs. Patient 2: Scattered, non‐confluent papules and vesicles disseminated on trunk. Patient 3: Confluent, erythemato‐oedematous plaques located on the trunk, neck and lower limbs. Patient 4: Confluent, erythematous macules and plaques with a violaceous targetoid appearance, predominantly on the trunk and proximal limbs, with scarce facial involvement. b) Histology. Patient 1: Urticarial pattern with mild oedema, perivascular inflammation and dilated vessels in the upper dermis. Inset: Vessels filled with neutrophils and mixed perivascular inflammation. Patient 2: Intraepidermal vesicle with fibrin debris, some necrotic cells and discrete ballooning keratinocytes in the margins. Immunohistochemistry against human herpes virus 1 was negative. Patient 3: Urticarial pattern that shows dilated vessels filled with neutrophils, mild perivascular lymphocytic inflammation and minimal blood extravasation. Patient 4: Mixed interface pattern with dilated vessels filled with neutrophils, frequent blood extravasation and scattered necrotic keratinocytes.

Table 1

Clinical and analytical characteristics of the patients

	Patient 1	Patient 2	Patient 3	Patient 4
Demographic characteristics
Gender	Female	Male	Female	Female
Age (years)	32	64	59	58
Clinical manifestations	F, P	C, D, F, M, P	Ag, An, F, H, M, N	C, D, Di, F, M, P
Skin lesions
Onset† (days)	6	15	16	25
Duration (days)	5	7	17	19
Analytical parameters ‡
Creatinine (mg/ml)	0.88/0.73	1.01/0.81	0.65§	0.81/0.79
LDH (U/I)	169/202	264/242	247§	474/314
GOT‐GPT (U/I)	18–16/21–15	23–20/27–31	15–11§	41–62/17–53
CRP (mg/L)	32/13.9	57.4/75.8	154.4§	187.7/1
D‐dimer (ng/mL)	321/578	1034/721	1687§	1186/1098
Lymphocytes (103/µL)	1/1.47	2.36/3.32	1.57§	0.9/1.94
Eosinophils (103/µL)	0.02/0.01	0.01/0.017	0.73§	0.0/0.02
IL‐12 (pg/mL)	NP/NP	0.21/ NP	0.0§	2.88/NP
IL‐10 (pg/mL)	NP/NP	0.64/NP	0.0§	NP/NP
IL‐6 (pg/mL)	NP/NP	1.75/NP	1.58§	29/NP
Ferritin (ng/mL)	12.97/NP	788.6/NP	428§	43.94/NP
Total IgE (kU/L)	NP/NP	NP/NP	1476§	NP/50
Drugs ¶
	Time (days)**/ ASPS††	Time (days)**/ASPS††	Time (days)**/ASPS††	Time (days)**/ ASPS††
Hydroxycloroquine	14/5	3/5	14/1	16/1
Azithromycin	15/4	3/0	5/0	16/‐1
L + R	NP/NA	2/4	NP/NA	11/4
Other:
Ceftriaxone	NP/NA	0/5	NP/NA	NP/NA
Tocilizumab	NP/NA	NP/NA	NP/NA	10/‐3

Ag, ageusia; An, anosmia; C, cough; CRP, c‐reactive protein; D, dyspnoea; Dh, diarrhoea; F, fever; GOT, glutamic oxaloacetic transaminase; GPT, glutamate pyruvate transaminase; H, headache; IL, interleukin; LDH, lactate dehydrogenase; L + R, Lopinavir–Ritonavir; M, myalgia; N, nasal congestion; NA. not applicable; NP, not prescribed; P, pneumonia.

Time interval between the onset of clinical symptoms and the development of skin lesions.

The results are expressed at the time of hospital admission and the determination closest to the development of the skin lesions, separated by a forward slash.

The development of the skin lesions occurred the same day of hospital admission.

Drugs used in the treatment of the disease which might be suspicion of being related to the development of skin lesions.

Development of the lesions as compared to the beginning of treatment with the drug.

ASPS score: algorithm of the spanish pharmacovigilance system. Final score: <0, not related; 1–3 conditional; 6–7 probable; 8 definite.

As mentioned above, skin lesions appear to be a sign within patients suffering from COVID‐19. To date, no hypothesis has been proposed to explain if the lesions (including the different types) are attributable to the virus, to drug adverse reactions or to any other clinical condition. Histopathological study alone cannot conclude an aetiology, as it does not distinguish between a possible viral exanthema and a toxicoderma (Fig. 1). In our series, small enough to draw conclusions, we have found no differences between the multiple types of skin lesions and analytical or clinical features. Even in lesions with apparent vascular involvement, which have been associated with alterations in coagulation, , , the analytical parameters did not differ from those with other types of skin lesions. Regarding drug involvement, since all the patients were exposed to multiple drugs at the same time, the ASPS was not able to differentiate the possibility of drug implication nor the immune mechanisms involved. Thus, further assays with selective (in vitro or in vivo) tests for each drug seem necessary in order to completely rule out drug involvement. In addition, since many patients worldwide are being infected with SARS‐Cov‐2, and many of them present similar medical history and receive the same treatments, it seems necessary to investigate the existence of an individual predisposition that facilitates the development of skin lesions. For all these reasons, in order to correctly study the aetiology of the skin lesions, a multidisciplinary approach should be carried out.

Conflicts of interest

Dr. Cabrera‐Hernández, Dr Solano‐Solares, Dr Chica‐Guzmán, Dr Fernández‐Guarino, Dr Fernández‐Nieto, Dr Ortega‐Quijano, Dr de‐Andrés‐Martín, Dr Moreno, Dr Carretero‐Barrio, Dr García‐Abellás, Dr González‐de‐Olano and Dr de‐la‐Hoz‐Caballer have nothing to disclose.

Funding sources

The article has no funding source.