Livedo reticularis and acrocyanosis as late manifestations of COVID‐19 in two cases with familial aggregation. Potential pathogenic role of complement (C4c)

Dear Editor,

Livedo or necrotic‐type manifest different levels of occlusive vascular disease and are more frequent in patients of advanced age and severe COVID‐19. ¹ However, transient manifestations, such as livedo reticularis, have been described in other cases. ² We present two cases with familial aggregation of transient livedo reticularis as a late manifestation of COVID‐19.

A 12‐year‐old boy presented with acrocyanosis and livedo reticularis on his extremities, which had evolved over the course of 3 weeks (Figure 1a,b). Six weeks before, he had presented with symptoms of catarrh and a dry cough accompanied by fever. Analytical tests were requested, including biochemistry, hemogram, hepatic and renal tests, coagulation test, autoimmunity, and urinalysis, which did not show any alterations. Nasopharyngeal swabs were taken for RT‐PCR for SARS‐CoV‐2 and other respiratory viruses, which came back negative. Serologies were also requested for cytomegalovirus, Epstein–Barr virus, parvovirus B19, Mycoplasma pneumoniae, herpes simplex virus, varicella zoster virus, hepatitis B and C, and HIV, as well as SARS‐CoV‐2‐specific IgA + IgM and IgG antibodies, all of which were negative. The anatomopathological analysis of a skin biopsy performed from a central blanched area of a livedoid lesion of the upper limb showed a chronic perivascular inflammatory infiltrate with prominent endothelium (Figure 1c). The immunofluorescence study highlighted the deposition of complement (C4c) in the epidermal basement membrane (EBM) and was negative for C1q, C3, fibrinogen, IgA, IgG, and IgM (Figure 1d).

Figure 1.

a. A marked livedo reticularis can be seen on the right hand. b. A gray‐blue coloration compatible with acrocyanosis can be observed on both feet. c. Pathological findings. Mild perivascular lymphoid infiltrate is present in superficial dermis (hematoxylin and eosin, 10x). d. The basement membrane zone shows a linear pattern of staining for complement (C4c) (direct immunofluorescence). e. His brother also showed marked acrocyanosis

Simultaneously, his 14‐year‐old brother also presented with acrocyanosis on his extremities which had evolved over the course of 2 weeks (Figure 1e). Also of note in his medical history were headaches, a fever of up to 38.5ºC, general malaise, a dry cough, and diarrhea at the same time as his brother had catarrhal symptoms. The same analytical and serological tests were requested as for his brother, with the test for SARS‐CoV‐2 IgG coming back positive. Nonetheless, the nasopharyngeal swab for SARS‐CoV‐2 was negative. These findings confirmed the suspicion of a previous infection.

A 10‐year‐old girl presented with livedo reticularis on her extremities, which had evolved over the course of 1 week (Figure 2a). Two weeks previously, she had fever, a dry cough, asthenia, and headaches. Her sister presented with the same cutaneous symptoms without having had any prior or associated systemic symptoms (Figure 2b).

Figure 2.

a. Livedo reticularis on the trunk and upper extremities. b. Reticulated lesions are perceived as a purplish discoloration of the skin on the left upper limb. c. Her sister also presented livedo reticularis and acrocyanosis. d. Pathological findings. Mild perivascular lymphoid infiltrate is present in superficial dermis (hematoxylin and eosin, 10x). e. The basement membrane zone, as well as the endothelium, shows a linear pattern of staining for complement (C4c) (direct immunofluorescence)

The tests carried out highlighted an erythrocyte sedimentation rate (ESR) of 28 mm, a fibrinogen of 416 mg/dl, and a D‐dimer of 545 μg/l. A nasopharyngeal swab was taken for RT‐PCR for SARS‐CoV‐2, which was negative. However, the serological tests were positive for SARS‐CoV‐2 IgA + IgM. Her sister also had a negative RT‐PCR result for SARS‐CoV‐2.

The histological examination of the biopsy performed from the central whitish area of a livedoid lesion of the upper extremity showed a chronic inflammatory component (Figure 2c). The immunofluorescence study showed a C4c complement deposition in the EBM and the endothelium of vessels and was negative for C1q, C3, fibrinogen, IgA, IgG, and IgM (Figure 2d).

In the familial cases presented, livedo reticularis was seen as a late manifestation of SARS‐CoV‐2 infection. In one of the cases, we were unable to find evidence of SARS‐CoV‐2‐specific antibodies. This is despite the patient being in an at‐risk environment with family members with a positive serological test for IgG antibodies that confirmed the SARS‐CoV‐2 past infection and having presented with similar systemic and cutaneous symptoms. This finding is frequent in cutaneous manifestations by COVID‐19 in which antibodies are not usually detected. ³

Immunofluorescence studies are frequently found in biopsies from cutaneous lesions caused by COVID‐19, showing deposition of IgM, IgA, and C3. ³ The existence of deposition of complements C5b‐9, C3d, and C4d has also been found in dermal capillaries of patients with severe COVID‐19. ⁴ However, C4c deposits in the EBM and the endothelium of vessels, as were observed in the immunofluorescence studies that we carried out, have not been reported.

In conclusion, we present two cases of livedo reticularis that emerged after presenting with symptoms compatible with COVID‐19. In the reported cases, deposition of C4c complement was found in the immunofluorescence studies. These findings identify a basis from which to carry out future research to clarify the pathogeny of these transient lesions that appear later on after infection by SARS‐CoV‐2.