Reactive infectious mucocutaneous eruption due to COVID‐19 with erythema‐multiforme‐like lesions and myeloid cells

Abstract

Reactive infectious mucocutaneous eruption (RIME) is a recently described entity in which there is prominent mucositis, most commonly involving the oral and urogenital mucosa, secondary to a variety of pathogens. There is typically minimal cutaneous involvement in RIME. This contrasts with erythema multiforme (EM) in which characteristic targetoid lesions predominate, usually in isolation (EM minor), but in a subset of cases, with severe mucositis (EM major). While the histopathologic features of RIME have not been as well defined, those of EM are characterized by epidermal apoptosis and interface dermatitis with lymphocytes making up the predominant cell type. We report a unique case of RIME in a 16‐year‐old male with COVID‐19 characterized by significant mucositis involving the oral and genital mucosa, as well as numerous targetoid lesions on the trunk and extremities. Histopathologically, there was an inflammatory infiltrate obscuring and disrupting the epidermal interface, associated with epidermal necrosis, and blister formation. The infiltrate was composed of cells with irregular, non‐segmented and elongate nuclei, with myeloid and histiocytoid cytomorphology. The cells were positive for myeloperoxidase, CD68, and CD163 (subset) suggesting myeloid lineage. RIME is a rarely reported COVID‐19‐related eruption, and targetoid lesions and myeloid interface reactions have not been described with RIME.

1. INTRODUCTION

A wide array of cutaneous manifestations associated with COVID‐19 have been reported ranging from morbilliform eruptions to pernio‐like lesions and even retiform purpura. ¹ There are few reports of erythema multiforme (EM) and EM‐like lesions associated with COVID‐19. ² , ³ , ⁴ More recently, reactive infectious mucocutaneous eruption (RIME), characterized by prominent mucositis, has been reported. ⁵ , ⁶ We report an unusual case of RIME secondary to COVID‐19 with EM‐like cutaneous lesions in which an inflammatory infiltrate composed of cells with myeloid lineage was observed in the biopsy specimen.

2. CASE REPORT

A 16‐year‐old male presented to the emergency department for evaluation of fever, cough, pharyngitis, painful oral lesions, and relatively asymptomatic rash on trunk and extremities. Five days prior, the patient tested positive for SARS‐CoV‐2 by polymerase chain reaction (PCR). Physical exam revealed numerous targetoid papules and plaques, some with central hemorrhagic crust and/or vesiculobullous and pustular morphology, distributed over the face, cutaneous lips extending on the vermilion border, chest, abdomen, back (Figures 1 and 2), and the bilateral upper and lower extremities including the dorsal hands and feet. The palms and soles were spared. Shallow erosions of the oral mucosa, periurethral glans penis, and scrotum were also present. Evaluation by ophthalmology showed mild conjunctivitis. Further extensive infectious work up was negative including herpes simplex virus 1 (HSV‐1) and HSV‐2 DNA by PCR of skin lesions, HSV‐1 and HSV‐2 immunoglobulin G (IgG), Mycoplasma pneumoniae IgG and IgM, human immunodeficiency virus (HIV) antigen and antibody, blood cultures and a respiratory pathogen panel by PCR. Erythrocyte sedimentation rate and C‐reactive protein were elevated at 27 mm/h and 179 mg/L, respectively. There were no significant abnormalities detected on complete blood count (CBC) with white blood cell differentiation or comprehensive metabolic panel. A peripheral blood smear showed normal white cell count with mildly elevated monocytes, 18%, on differential and occasional reactive lymphocytes without any blasts detected.

FIGURE 1.

Clinical images of reactive infectious mucocutaneous eruption due to COVID‐19. (A) Targetoid lesions involving perioral and nasal face, cutaneous lip, chest, and abdomen. (B) Targetoid lesions on the back. The biopsy was obtained from the site with the asterisk.

FIGURE 2.

Clinical images of reactive infectious mucocutaneous eruption due to COVID‐19. (A) closer view of the facial lesions involving the perioral face, cutaneous lips, nose, and inner nares. The lesions are polymorphous and include targetoid lesions, vesicles, broad pustules (lip), and necrotic and crusted lesions. (B) Targetoid lesions on the chest.

A tangential biopsy was performed from a targetoid lesion on the upper back. H&E staining revealed a band‐like inflammatory infiltrate along the base of the epidermis and around the superficial vessels. The epidermal interface was obscured and disrupted by a moderately dense inflammatory infiltrate, associated with subepidermal‐dermal separation and areas of epidermal necrosis. The interface dermatitis involved hair follicles (Figure 3). Significant dyskeratosis was not observed. The cells constituting the inflammatory infiltrate involved in the interface dermatitis had irregular, non‐segmented and elongate nuclei with myeloid and/or histiocytic morphology (Figure 4). Immunohistochemical staining showed this same population of cells to stain positive for myeloperoxidase (MPO) and CD68 (Figure 5). A subset of these cells also stained positive for CD163. Anti‐CD3 was negative in these cells but stained sparse T‐cells (Figure 6).

FIGURE 3.

Reactive infectious mucocutaneous eruption due to COVID‐19. Histopathologic features from a targetoid lesion on the back. (A) There is a lichenoid and superficial perivascular infiltrate involving the base of the epidermis with area of blister formation (H&E ×4). (B) Interface dermatitis involving hair follicles and epidermis, with adjacent full‐thickness epidermal necrosis and subepidermal blister formation (H&E ×100).

FIGURE 4.

Reactive infectious mucocutaneous eruption histopathologic features of a targetoid lesion from the back. High power view of the interface dermatitis showing numerous inflammatory cells with myeloid and histiocytoid features within the lower portions of epidermis and rete, obscuring the basal layer, and at the along the blister roof (H&E ×400).

FIGURE 5.

Reactive infectious mucocutaneous eruption histopathologic and immunophenotypic features of a targetoid lesion from the back. H&E sections showing an interface dermatitis with blister formation. The inflammatory cells involving in the interface dermatitis are diffusely positive for myeloperoxidase (MPO) and CD68 in a similar distribution. Anti‐CD3 stains a mild infiltrate of perivascular lymphocytes and scattered intraepidermal lymphocytes, not corresponding to the interface reaction (H&E ×100; immunohistochemical stains MPO, CD3, and CD68 ×100).

FIGURE 6.

Reactive infectious mucocutaneous eruption histopathologic and immunophenotypic features of a targetoid lesion from the back. H&E showing myeloid and histiocytoid cells obscuring and disrupting the basal keratinocytes and involving the lower epidermis and rete. These are diffusely positive for myeloperoxidase (MPO) with a slightly smaller subset positive for CD163 (H&E ×200; immunohistochemical stains MPO and CD163 ×200).

The patient was started on systemic steroids with oral prednisone 60 mg (0.6 mg/kg) with rapid clinical improvement. The patient was discharged home after 5 days with completion of a 2‐week oral prednisone taper. Complete resolution of rash was seen at 2‐week follow‐up. A repeat CBC with white blood cell differentiation was performed 4 weeks after completion of the prednisone taper without any detected abnormalities, thereby excluding an underlying myelodysplastic syndrome or hematologic malignancy that may have contributed to the inflammatory infiltrate observed microscopically.

3. DISCUSSION

RIME is characterized by prominent mucositis most commonly involving the oral and urogenital mucosa with typically minimal cutaneous involvement of varying morphologies. The most frequently implicated pathogen is M. pneumoniae, hence the former diagnostic term M. pneumoniae‐induced rash and mucositis initially described in 2015, but numerous other pathogens have since been identified as triggers of this condition such as Chlamydophila pneumoniae, influenza B, enterovirus/rhinovirus, human metapneumovirus, and human parainfluenza virus 2, resulting in a more encompassing nomenclature. Despite the similarity to EM of which M. pneumoniae is also well known to be a causative agent, RIME is regarded as a distinct entity given the more significant mucositis that is the hallmark of this condition. ⁷ , ⁸ , ⁹ More recently, SARS‐CoV‐2 has been implicated as a causative agent in RIME. ⁵ , ⁶ This case represents the first report of histopathologic features seen in RIME due to COVID‐19, as well as the first report with EM‐like targetoid cutaneous lesions. The cutaneous lesions of EM are characterized by distinct, edematous and round typical target lesions with concentric color variation, identical to those observed in our patient. Lesions are symmetrically distributed and favor the extremities with palmoplantar lesions not uncommon. Mucosal involvement of the oral, genital, or ocular mucosa is sometimes seen. The infectious pathogen most often implicated is HSV‐1 followed by HSV‐2 and M. pneumoniae. ¹⁰ The histopathologic features of EM are well‐described and may show a vacuolar or sometimes lichenoid interface pattern with a mild‐moderate lymphocytic infiltrate that obscures the dermoepidermal junction, associated epidermal apoptosis, and subepidermal blister formation. ¹⁰ , ¹¹ , ¹² The histopathologic features of M. pneumoniae‐induced EM have previously been described and are reportedly distinct from HSV‐induced EM, with a lymphocytic infiltrate primarily composed of CD3⁺ T‐cells, as well as CD8⁺ effector cells, cytotoxic granzyme B⁺ cells, and few CD56⁺ natural killer cells. The histopathologic pattern of M. pneumoniae‐induced EM more closely resembles Stevens–Johnson syndrome–toxic epidermal necrolysis with prominent full‐thickness epidermal necrosis. ¹³

The histopathologic features of RIME have not been as well described, probably related to the minimal cutaneous involvement that is observed and the fact that the diagnosis can be made clinically. Our case is the first report of RIME attributed to COVID‐19 with EM‐like targetoid lesions for which the histopathologic features are described. In this unique case, the inflammatory infiltrate was composed primarily of cells with myeloid or myelomonocytic cell lineage, as evidenced by positivity for MPO and CD68 on IHC stains and negative staining for CD3. The histiocyte‐like cytomorphology of the cells in the case presented is reminiscent of that seen in histiocytoid Sweet syndrome, ¹⁴ which is distinct from the typical small lymphocytes seen in EM, prompting immunohistochemical evaluation. This inflammatory component is a unique finding, not hitherto reported in EM‐like targetoid lesions. These cytomorphologic features and myeloid immunophenotype might raise concern for a hematologic disorder, but the classic RIME/EM presentation and clinical course showing complete clearance without peripheral blood abnormalities excluded myeloid sarcoma or a myelodysplastic disorder in this patient. There is a dearth of literature on the immunohistochemical characteristics of EM. T‐lymphocytes that express CD4 more prominently than CD8 has been reported. ¹⁵ Upon reviewing multiple reports and images in PubMed of EM histopathology, we were able to identify one case that might represent a similar presentation as our patient. ¹⁶ The authors' histopathologic image appears to show similar myeloid/histiocytoid morphology; however, they report their findings as histiocytic EM. MPO was reported to be positive, but this is not detailed as a prominent feature. As discussed by Alegría‐Landa et al, ¹⁴ the MPO⁺ immunophenotype supports myeloid lineage, as MPO is not typically expressed in histiocytes. Their patient had a very similar EM major presentation, which was recurrent. IgM titers were initially negative upon admission but repeat lab work performed 4 months postdischarge showed positive titers for IgG and IgM at 1.25 and 2344 U/ml, respectively. Thus, their patient essentially presented with an EM‐major‐like RIME with an unusual immunohistochemical phenotype, possibly similar to our case.

The overlapping clinical features seen in this case support the idea that RIME and EM, while regarded as separate entities, may exist on a spectrum, at least in the context of COVID‐19. A cross‐sectional study found that 11.7% of patients diagnosed with COVID‐19 had lesions involving the oral mucosa and 3.9% had mucositis. ¹⁷ EM‐like eruptions with discrete targetoid papules on acral surfaces have also been reported in the setting of COVID‐19. However, prominent mucositis, as was seen in our case, was absent in these cases. ² , ³ , ⁴ In addition, histopathologic examination of biopsies from these cases revealed more typical lymphocytic inflammation. ³

This case expands the clinical and histopathologic features seen in RIME to include more extensive skin involvement by targetoid lesions similar to EM major and the presence of a unique myeloid component involved in the interface reaction. The histiocytoid cytomorphologic features, possibly in conjunction with less prominent cytotoxic dyskeratosis, may be histopathologic clues to a diagnosis of RIME or COVID‐19 induced EM‐like presentation. Histopathologic descriptions are lacking in the literature, and further immunohistochemical investigations of RIME and EM are encouraged to determine if this is a unique histopathologic presentation, possibly related to COVID‐19 or a characteristic feature of RIME.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Ortiz EG, Junkins‐Hopkins JM. Reactive infectious mucocutaneous eruption due to COVID‐19 with erythema‐multiforme‐like lesions and myeloid cells. J Cutan Pathol. 2022;1‐5. doi: 10.1111/cup.14339

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.