A rare case of reactive granulomatous dermatitis during COVID-19: a possible role of cephalosporine and potential mechanisms.

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This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.

Conflicts of interest

The authors have no conflicts of interest to declare.

Editor

Patients with COVID‐19 present with a wide variety of cutaneous manifestations. However, granulomatous lesions arising during or after COVID‐19 infection are rare and particularly reactive granulomatous dermatitis (RGD) has not been reported. Here, we report a case of COVID‐19 with a diffuse dermal infiltrate of epithelioid histiocytes possibly triggered by drug that resolved shortly.

A 61‐year‐old man with type 2 diabetes, hypertension and chronic renal failure requiring haemodialysis presented with headache, dry cough, and fever (38.5°C) for 2 days and SARS‐CoV‐2 polymerase chain reaction (PCR) test was positive. Computed tomography scan of the chest showed ground‐glass opacities and bilateral lung involvement. Significant laboratory findings were as follows: white blood cell count, 7900/mm3; lymphocyte count, 800/mm3, platelet count, 128 000/mm3; and C‐reactive protein, 8.75 mg/dL. He was started on dexamethasone 6.6 mg, heparin 10 000 U and favipiravir 1200 mg. Ceftriaxone 1000 mg was introduced empirically. The course of medications, clinical events, and therapies is shown in Fig. 1. On day 19, he developed neutropenic fever (39°C), elevated transaminase levels and an absolute neutrophil count decreased to 0 cells/mm3. He was treated with granulocyte colony‐stimulating factor (G‐CSF) (300 µg/day for 3 days) and cefepime for 2 days, which was replaced by meropenem, as a maculopapular‐erythematous to violaceous rash developed on the trunk and extremities (Fig. 2a and b). Histopathology showed a diffuse dermal infiltrate composed of lymphocytes and epithelioid histiocytes expressing CD163 (Fig. 2c, d and f). The majority of the infiltrates were CD3+T cells admixed with abundant CD163+ epithelioid histiocytes. Multinucleate giant cells were not present in most specimens. Bone marrow biopsy showed multiple non‐necrotizing granulomas composed of CD163+ epithelioid cells (Fig. 2e). After cessation of ceftriaxone, cefepime, and G‐CSF, the skin lesions rapidly and completely resolved over the following 2 weeks. Lymphocyte transformation test showed positive reactions to both ceftriaxone (Stimulation Index, 7.32) and cefepime (2.82). There was no recurrence during the 3‐month follow‐up period.

Figure 1

Clinical course of a patient who developed granulomatous drug reactions 4 weeks after onset of COVID‐19. CTRX, ceftriaxon; CFPM, cefepime; MEPM, meropenem.

Figure 2

Clinical manifestations and histopathology of a skin biopsy from violaceous erythema. (a) Diffuse erythema without erosion involving the trunk. (b) Violaceus plaques were diffusely distributed on feet. (c) Histopathology of a skin biopsy. Hematoxylin and eosin staining. ×100. (d) Immunohistochemical staining for CD163. ×200. (e) Histopathology of bone marrow biopsy. Hematoxylin and eosin staining. ×400. (f) Immunohistochemical staining for CD3. ×200.

Our patient’s clinical course was noteworthy. First, his granulomatous lesions resolved rapidly over 2 weeks after drug cessation. Second, our patient’s history of SARS‐CoV‐2 infection was likely a predisposing factor for the development of granulomatous lesions. No previous studies have detailed the unique constellation of clinical features observed in our patient. Given the atypical clinical presentations, it is appropriate to use the unifying umbrella term, RGD. An association between RGD and COVID‐19 has not been previously reported, but it is not surprising, considering the involvement of CD14+16+ proinflammatory monocytes producing IL‐6 in COVID‐19. The detrimental role of CD14+16+ proinflammatory monocytes in the pathogenesis of COVID‐19 is only beginning to be understood: the temporal population shift from CD14+16‐ classical monocytes to CD14+16+ intermediate or proinflammatory monocytes expressing CD163 in COVID‐19 patients are associated with progression to severe disease. , , This shift may share numerous features with monocyte responses in severe drug eruptions characterized by sequential reactivations of herpesviruses, that is drug‐induced hypersensitivity syndrome (DiHS) /drug reactions with eosinophilia and systemic symptoms (DRESS). Granulomatous inflammation has also been reported to occur as a manifestation of DiHS. However, some distinction between RGD and DiHS could be made: RGD differs from DiHS due to its rare association of viral reactivation and its complete resolution after cessation of offending drugs, which support our diagnosis of RGD and elevated transamidase levels and multiple drug hypersensitivity are also consistent with DiHS, but not with RGD. Thus, it can be speculated that RGD develops as an indirect consequence of SARS‐CoV‐2 infection via exaggerated monocyte activation. Although in our case granulomatous infiltrates resolved rapidly and did not progress to organ damage, long‐term monitoring of patients with both diseases is needed.