The Differing Pathophysiologies That Underlie COVID-19-Associated Perniosis and Thrombotic Retiform Purpura

A Case Series

C.M. Magro; J.J. Mulvey; J. Laurence; S. Sanders; A.N. Crowson; M. Grossman; J. Harp; G. Nuovo

Disclosures

The British Journal of Dermatology. 2021;184(1):141-150. 

In This Article

Results

COVID-19-associated Perniosis

Case 1. A 16-year-old boy developed bilateral painful perniotic-like plaques on his toes (Figure 1a). He had been confined to his home and denied any significant cold exposure. His brother had a cough and fever several weeks earlier, which resolved without viral diagnostic testing. A nasopharyngeal swab was negative for SARS-CoV-2. Serologies to assess for past SARS-CoV-2 infection were not performed.

Figure 1.

Clinical morphology of COVID-19-associated perniosis, idiopathic perniosis and COVID-19-associated thrombotic retiform purpura. (a) In early April of 2020, the patient, a 16-year-old New York city resident, developed bilateral perniotic-like skin lesions without cold exposure. They are more extensive than conventional perniosis and include areas of ulceration and focal targetoid areas. (b) This 36-year-old woman presents with discrete somewhat painful erythematous papules on the distal toes temporally associated with cold exposure, compatible with idiopathic perniosis. (c) This critically ill patient with severe COVID-19 demonstrates a mottled livedoid rash of the arms bilaterally. [Colour figure can be viewed at wileyonlinelibrary.com]

Case 2. A 48-year-old female resident of New City, New York, developed fever, mild leucocytosis, a purpuric macular skin rash of the legs and perniotic lesions on the toes. A skin biopsy was performed on one of the toe lesions. Her nasopharyngeal swab test for COVID-19 was negative. Her COVID-19-associated IgG and IgM serologies were also negative.

Case 3. The patient was a 65-year-old woman who lived in very close proximity to the South Dakota Smithfield Pork processing plant, which had experienced a COVID-19 outbreak affecting 700 of its 3000 employees. At the time of the outbreak she developed distinct papular lesions of the fingers accompanied by a cough. Over the ensuing weeks the lesions underwent full resolution. She declined COVID-19 testing.

Light Microscopic Findings and Phenotypic Studies. The cases showed a similar morphology characterized by a mononuclear-cell-dominant interface dermatitis with an associated dense superficial and deep angiocentric lymphocytic and histiocytic infiltrate that surrounded and infiltrated the blood vessels and was adjacent to the eccrine coil, ducts and glands (Figures 2a and 3a). The histiocytes demonstrated reniform and serpiginous nuclei and intracytoplasmic cellular debris (Figure 3a). Papillary dermal oedema was seen in cases 1 and 3 (Figure 2a). There was endothelial cell swelling and red cell extravasation. Fibrin deposition within reticular dermal-based blood vessels was present but minimal.

Figure 2.

Comparative light microscopic findings and myxovirus resistance protein A (MXA) pattern of immunoreactivity in COVID-19-associated perniosis, idiopathic perniosis and COVID-19-associated thrombotic retiform purpura. (a) In acral perniosis of mild COVID-19, a striking inflammatory response is observed characterized by a mononuclear-cell-dominant interface dermatitis with an associated intense superficial and deep angiocentric lymphocytic and histiocytic infiltrate that surrounds and infiltrates the vessel walls of capillaries, venules and arterioles and is found in close apposition to the eccrine ducts and glands of the eccrine coil [haematoxylin and eosin (HE), original magnification × 40]. (b) In contrast, with the livedoid rash of severe COVID-19 there is a pauci-inflammatory thrombogenic vasculopathy that in this case involves the arterial system (HE, × 40). (c) In COVID-19-associated perniosis there is immunoreactivity for MXA within the epidermis and endothelial cells and amid inflammatory cells [diaminobenzidine (DAB), × 40]. (d) A virtually identical pattern of immunoreactivity is observed for MXA in idiopathic perniosis (DAB, × 40). (e) In the paucicellular thrombotic retiform purpura of severe COVID-19 there is no immunoreactivity for MXA (DAB, × 40). NK, natural killer; TH, T helper cell. Scale bars are set at 650 microns. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3.

Light microscopic, inflammatory cell phenotypic profile and SARS-CoV-2 viral protein distribution in COVID-19-associated perniosis. (a) There is a brisk angiocentric lymphocytic and histiocytic infiltrate. While the infiltrate permeates the vessels and endothelial cell swelling is observed there is no frank fibrin deposition (haematoxylin and eosin, original magnification × 400). (b) The infiltrate is predominated by CD3+ T cells [diaminobenzidine (DAB), × 200]. (c) The CD4 antibody highlights T cells and histiocytes (DAB, × 200). (d) A minor lymphoid populace is represented by CD8 (DAB, × 200). (e) The CD20 antibody shows only rare B cells (DAB, × 200). (f–h) The histiocytes demonstrate positivity for CD14 (f, DAB, × 200) CD11c (g, DAB, × 200) and CD123 (h, DAB, × 200). (i) There is positive immunoreactivity for myxovirus resistance protein A within the epidermis, endothelia and inflammatory cells in all cases (DAB, × 200). (j) In all three cases of COVID-19-associated perniosis, only rare SARS-CoV-2 RNA-positive cells are present (one to three cells) (DAB, × 1000). (k) Antibody to SARS-CoV-2 envelope protein (DAB) is colocalized with SARS-CoV-2 membrane (red chromogen). Using Nuance software (PerkinElmer, Waltham, MA, USA) the envelope protein fluoresces green while the membrane protein fluoresces red, producing a yellow signal when colocalized in a few extravascular mononuclear cells, likely of histiocytic derivation (DAB, × 400). (l) In the two studied cases of perniosis only a few to rare positive cells for interleukin-6 are observed and are primarily mononuclear cells likely of histiocytic origin (DAB, × 400). Scale bars are set at 125 microns. [Colour figure can be viewed at wileyonlinelibrary.com]

Phenotypic studies revealed an infiltrate predominated by CD3+ T cells (Figure 3b) and CD163+ CD68+ histiocytes. Rare CD20-positive B cells were seen (Figure 3e). The CD4 to CD8 ratio was within normal limits (Figure 3c, d). The histiocytes were highlighted by CD163, lysozyme, CD68, CD14 (Figure 3f), CD11c (Figure 3g) and CD123 (Figure 3h); a subset was positive for myeloperoxidase. Significant MXA positivity in the epidermis, endothelia and inflammatory cells was seen in the three cases (Figures 2c and 3i). Complement studies, namely C3d, C4d and C5b-9, were conducted and found to be either absent or minimally positive.

Idiopathic Perniosis

Six cases of idiopathic perniosis were retrieved from the archival files of the Division of Dermatopathology, Weill Cornell College of Medicine. The biopsies were procured from three male and three female patients ranging in age from 16 to 65 years. A diagnosis was made of idiopathic perniosis in all patients. The typical clinical presentation is illustrated in Figure 1(b) and is characterized by discrete erythematous papules on the toes and/or fingers.

In each case there was a superficial and deep angiocentric lymphocytic infiltrate (Figure 4a). There was lymphocytic eccrine hidradenitis in four of the six cases (Figure 4b). The infiltrate surrounded and permeated capillaries and venules of the superficial and deep dermis (Figure 4c). Vascular fibrin deposition in reticular dermal-based blood vessels was not seen, although there was endothelial cell swelling and red cell extravasation. Papillary dermal oedema was seen in four of the six cases, with a variable interface dermatitis localized to the tips of the rete ridges (Figure 4a). In all cases there was intense expression of MXA in the epidermis, eccrine ducts and glands, inflammatory cells and endothelium (Figures 2d and 4d).

Figure 4.

Light microscopic findings and myxovirus resistance protein A (MXA) expression in idiopathic perniosis. (a) In each case there is a superficial and deep angiocentric lymphocytic infiltrate [haematoxylin and eosin (HE), original magnification × 100]. (b) There is a lymphocytic eccrine hidradenitis (HE, × 200). (c) The infiltrates surround and permeate capillaries and venules in the superficial and deep dermis. There are proplastic endothelial cell alterations and focal red cell extravasation without fibrin deposition (HE, × 200). (d) In all cases there is a striking expression of MXA in the epidermis, eccrine ducts and glands, inflammatory cells and endothelium (diaminobenzidine, × 200). Each scale bar is set at 125 microns. [Colour figure can be viewed at wileyonlinelibrary.com]

COVID-19-associated Thrombotic Retiform Purpura

Skin biopsies of an acral fixed livedoid and/or retiform purpuric rash from SARS-CoV-2-positive patients were retrieved from the archival files of the Division of Dermatopathology, Weill Cornell Medicine. The patient cohort was represented by three men who were 70, 71 and 73 years of age and three women who were 36, 40 and 66 years of age (Figure 1c). Two of the patients developed a stroke. Acute renal injury developed in four of the six, requiring dialysis in one. Pre-existing conditions included hypertension in three, overweight in two, obesity in one, diabetes mellitus in one and hyperlipidaemia in one. The patients had acral livedoid rashes involving the hands bilaterally in three, the plantar aspect of the feet in one and the forearms in two (Figure 1c). All were categorized as being critically ill with COVID-19 based on prolonged ventilator-dependent respiratory failure. They had evidence of a hypercoagulable state characterized by elevated D-dimers ranging from 1026ng mL−1 to 40 135ng mL−1 (mean 12 027ng mL−1) and fibrinogen ranging from 518 to 983 mg dL−1 (mean 649 mg dL−1), whereby there was a direct parallel between the extent of D-dimer elevation and fibrinogen elevation. Of the six patients, three died and three had hospitalizations of greater than 2 months.

Light Microscopic Findings and Phenotypic Studies. The biopsies showed a pauci-inflammatory thrombogenic vasculopathy affecting capillaries, venules and arteries (Figure 5a). This was within the mid and deeper dermis and associated with microvascular deposition of C3d, C4d, C5b-9 and MASP-2 (Figure 5d). In all cases MXA was negative (Figures 2e and 5b).

Figure 5.

Light microscopic findings, myxovirus resistance protein A (MXA) expression and SARS-CoV-2 protein distribution in thrombotic retiform purpura. (a) The biopsies show a pauci-inflammatory thrombogenic vasculopathy affecting capillaries, venules and arteries within the mid and deeper dermis (haematoxylin and eosin, original magnification × 200). (b) MXA is negative [diaminobenzidine (DAB), × 200]. (c) In all cases of thrombotic retiform purpura, SARS-CoV-2 viral spike proteins are readily detected in the endothelia exhibiting an extensive pattern of cytoplasmic immunoreactivity involving both diseased and relatively normal-appearing blood vessels (DAB, × 1000). (d) Prominent deposits of C5b-9 are observed within the cutaneous microvasculature of thrombosed and normal-appearing vessels (DAB, × 1000). (e, f) There is endothelial cell localization of caspase 3 (e, DAB, × 1000) and interleukin-6 (f, DAB, × 1000) in thrombosed and normal-appearing blood vessels. Each scale bar is set at 125 microns. [Colour figure can be viewed at wileyonlinelibrary.com]

Viral Immunohistochemical Protein and RNA Assessment in COVID-19-Associated Perniosis and Thrombotic Retiform Purpura of Critically Ill Patients With COVID-19 and Non-COVID-19 Perniosis. In the three cases of COVID-19-associated perniosis, only rare SARS-CoV-2 RNA-positive cells were present (Figure 3j), while a few mononuclear cells showed detectable SARS-CoV-2 membrane and envelope protein (Figure 3k). In all cases of thrombotic retiform purpura, extensive SARS-CoV-2 envelope and spike proteins were detected in the endothelial cytoplasms in thrombosed and normal-appearing blood vessels (Figure 5c), but viral RNA was not detected. The three cases of non-COVID-19-associated perniosis had no detectable protein or virus. For comparison with controls, SARS-CoV-2 viral proteins and RNA were examined in the lung of the COVID-19-associated fatal pneumonias and normal skin and lung. They were extensively positive in the COVID-19 lung specimen and negative in the pre-COVID healthy skin and lung blocks (Figure 6a, b).

Figure 6.

Distribution of SARS-CoV-2 viral RNA and SARS-CoV-2 protein in a lung sample of a patient with COVID-19. (a) SARS-CoV-2 viral RNA demonstrates striking capillary localization within the interalveolar septa of the lung of a patient who died from COVID-19 [diaminobenzidine (DAB), original magnification × 200]. (b) SARS-CoV-2 membrane protein demonstrated a similar pattern of microvascular localization (DAB, × 400) Scale bars are at 200 microns and 100 microns, respectively. [Colour figure can be viewed at wileyonlinelibrary.com]

Interleukin-6 and Caspase 3 Studies in COVID-19-associated Perniosis and Thrombotic Retiform Purpura of Critically Ill Patients With COVID-19. In the three studied cases of COVID-19-associated perniosis only a few cells of probable histiocytic origin expressed interleukin-6 (Figure 3l). There were scattered inflammatory cells and degenerated keratinocytes positive for caspase 3. Vascular expression was noticeably absent. All cases of thrombotic retiform purpura showed extensive endothelial cell expression of caspase 3 (Figure 5e) and interleukin-6 (Figure 5f) within the diseased and normal-appearing blood vessels, mirroring the pattern of SARS-CoV-2-associated protein detection.

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