Unique skin nodules following COVID-19 vaccination: a case report of cutaneous plasmacytosis and review of the literature

Abstract

Background

Cutaneous plasmacytosis (CP) is a rare disorder that may affect two or more organ systems, such as skin, lymph nodes or lungs. The pathogenesis of CP remains unknown, and in most cases, the condition follows a chronic and benign clinical course without spontaneous remission.

Case presentation

A 50-year-old male who developed necrotizing skin nodules without other systemic abnormalities four days after the first doses of the Coronavirus disease 2019 (COVID-19) vaccination. Oral prednisone improved the lesions by approximately 70%. However, signs of CP recurrence manifested 15 days after the second dose of COVID-19 vaccination. Ultimately, the patient experienced spontaneous remission after contracting SARS-CoV-2 infection.

Conclusion

This case uniquely associates COVID-19 inactivated vaccine with CP, where the same lesions appeared after two vaccinations and subsequently resolved following SARS-CoV-2 infection. This provides valuable clinical data for future studies on viral infections and cutaneous B-cell immunity.

Background

Cutaneous plasmacytosis (CP), first reported in 1976, is characterized by red-brown macules, papules and plaques with histopathology revealing a dermal infiltration of mature plasma cells [1]. Polyclonal hypergammaglobulinemia is a common symptom observed in 88–93% cases [2]. The condition was originally labeled “cutaneous plasmacytosis” but later renamed “cutaneous and systemic plasmacytosis” to reflect lymphoplasmacytic infiltration beyond the skin [3]. COVID-19 is a multisystem disease affecting several vital organs and has been a global pandemic from 2020 to 2023 [4]. The phenomenon of reactive plasmacytosis was observed in lung and bone marrow tissues of both fatal and non-critical COVID-19 pneumonia patients [5, 6]. Moreover, a 55-year-old woman developed cutaneous Rosai-Dorfman-Destombes disease with polyclonal plasmacytosis three months after being infected with COVID-19 [7]. Here, we describe a case of a patient who developed diffuse skin lesions resembling folliculitis following two doses of COVID-19 vaccines. Histopathological examination showed numerous mature plasma cell infiltrating with significant neutrophil presence. This case highlights a unique trigger, clinical manifestation and outcome of CP.

Case presentation

A 50-year-old male developed multiple oval-shaped, red papules and nodules (0.5–3 cm in diameter) on his trunk four days after receiving the first dose of the COVID-19 vaccine (CoronaVac, a inactivated vaccine, inoculation date: February 22, 2021). Despite the lesions, he reported no pain or itching. There were no preceding symptoms such as fever, cough, pharyngalgia, or muscle aches documented within one week prior to the onset of the condition. Initially, he was diagnosed as “folliculitis” and “insect bite dermatitis” in local hospital. Systemic treatment with amoxicillin and doxycycline were ineffective. Upon seeking treatment at our clinic, some of the lesions exhibited signs of necrosis and ulceration (Fig. 1). Polarized-light dermoscopy revealed violet lesions with yellow unstructured area in the center, as well as dotted and linear blood vessels, accompanied by white stripes. Most of these vessels and stripes were distributed radially around the center (Fig. 2).

Fig. 1

Multiple red papules and nodules appeared on the trunk of the patient after injection of the COVID-19 vaccine, and some nodules were necrotic

Fig. 2

(a) Polarizing dermoscopy showed a yellow unstructured area in the center of the violet lesion, with radial lines (red arrows), and punctiform (red box) vessels around the center (×50). (b) White stripes were radial arranged (white arrows)(×50)

The patient appeared in good spirits, with normal body temperature, respiratory rate, and heart rate. Physical examinations of the chest and abdomen revealed no abnormalities, and there was no enlargement of the superficial lymph nodes throughout the body. A skin biopsy revealed a significant infiltration of mature plasma cells throughout the dermis, along with a central necrosis area characterized by lymphocyte and neutrophil infiltration (Fig. 3). In addition, the results of immunohistochemical analysis of plasmacytoid cells in the superficial dermis showed that CD20 and CD5 were negative, CD79a, CD138, and CD38 were positive, and the MIBI-1 proliferation index was low. Lymphocyte clonality analysis did not find monoclonal gene rearrangement of IgH, IgK, and TCRG. On laboratory evaluation, complete blood cell count, as well as liver and kidney functions, were within normal parameters. Serologic tests for HIV and syphilis yielded negative results. Additionally, serum protein electrophoresis, serum immunofixation electrophoresis, and free light chain levels in urine were all within the normal range.

Fig. 3

(a) Biopsy showed extensive plasma cell infiltration (a) across the dermis, with capillary lumen occlusion (white box). (b) The magnified view of the white box area in (a). (c) Epidermal and dermal necrosis with neutrophil infiltration can be observed in the center of the lesion

The patient was diagnosed with CP. After a two-week treatment of oral prednisone 30 mg/d, the lesions improved by approximately 70%. Subsequently, the patient continued to receive the second dose of COVID-19 vaccine (inoculation date: March 24, 2021). Fifteen days later, signs of CP recurrence manifested on the patient’s skin. Despite this recurrence, the patient did not seek for medical help, resulting in no improvement in his skin condition for two years. In November 2023, the patient developed symptoms of fever, muscle soreness, hoarse voice and coughs with a throat swab test confirmed a positive result for SARS-CoV2. After taking three doses of ibuprofen sustained-release capsules (300 mg) and one dose of acetaminophen tablets (500 mg), those symptoms relieved. By December 2023, the patient’s skin lesions began to subside spontaneously, demonstrating no recurrence to date. The patient has been followed up for nearly four years since the onset skin lesions, no abnormalities in other organ systems have been observed (Fig. 4).

Fig. 4

The clinical pictures from the latest follow-up showed that the patient currently does not have any CP lesions on his body, and part of the old lesions have transformed into scar tissue

Discussion and conclusions

Common local reactions to vaccines include pain, swelling, and redness at the injection site. Systemic reactions include fever, irritability, drowsiness, and rashes [8]. A review was conducted on PubMed using the following search terms: COVID-19 inactivated vaccine, dermatology, rash, skin, cutaneous, CoronaVac, Sinopharm, and Covaxin. The search covered the period from March 1, 2020, to November 30, 2024. A total of 1,091 cases of vaccine-related skin adverse reactions (excluding injection site reactions) were identified. These included type I hypersensitivity reactions, such as urticaria (341, 31.26%) and angioedema (128, 11.73%). Type II hypersensitivity reactions included purpuric rashes and vasculitis (24, 2.20%). Type IV hypersensitivity reactions encompassed morbilliform eruption (387, 35.47%), erythema multiforme (3, 0.27%), and toxic epidermal necrolysis drug eruption (TEN) (2, 0.18%). Additionally, autoimmune-mediated reactions were reported, including lichen planus (9, 0.82%), bullous pemphigus (4, 0.37%), pemphigus (3, 0.27%), vitiligo (1, 0.09%), and alopecia areata (2, 0.18%). Cases of pityriasis rosea, scleromyxedema, pyoderma gangrenosum, chilblain-like lesions, and herpes zoster have also been documented (Table 1) [9,10,11,12,13,14,15,16,17,18,19,20]. Plasmacytosis has been sporadically reported following injections of other vaccines. Steve et al. [21]. observed atypical lymphocyte infiltration at the injection site in two patients who received the influenza vaccine. One patient exhibited perivascular and periadnexal infiltration of lymphoplasmacytic cells with cytological atypia. In the other patient, the skin tissue showed a predominance of multiple types of plasma cells and histiocytic infiltration. Both patients achieved remission following radiotherapy.

Table 1 Cutaneous adverse reactions related to inactivated COVID-19 vaccines

The clinical manifestations of folliculitis-like skin papules and nodules in this case posed a challenge in diagnosing CP. Distinguishing features, such as radially arranged blood vessels and white stripes identified through dermoscopy, suggested a differentiation from common folliculitis [22]. Pathological examination in our case revealed epidermal and dermal necrosis with neutrophil infiltration, corresponding to the yellow unstructured area observed during dermoscopy. Fibroplasia and scarring indicated post-necrotic skin repair, aligning with the white stripe structure noted during the examination [23]. Vessels arranged in a radial pattern are commonly found in a variety of tumors, such as keratoacanthoma and squamous cell carcinoma, as well as non-neoplastic diseases like lichen planus, lupus erythematosus, and inverted follicular keratosis [24,25,26].

The patient did not develop any rashes at the vaccination site, suggesting that the occurrence of CP may not be related to the vaccine adjuvant. Instead, it was the antigens from the carrier that triggered the abnormal immune response. Current evidence indicates that environmental factors, genetic predisposition, or an infectious etiology may contribute to CP, with a particular emphasis on the dysregulated production of interleukin (IL)-6 in its pathogenesis [2]. IL-6 is the cytokine responsible for B-cell proliferation and terminal differentiation into plasma cells [27]. After vaccine injection, antigen-presenting cells (APCs) phagocytize foreign vaccine antigens, which are processed and presented on their surface by major histocompatibility complex (MHC) class I and II proteins. These APCs then migrate from the antigen-exposed tissue to nearby draining lymph nodes, where they present the MHC complexes to T and B lymphocytes. The activation of T and B cells triggers a response against the antigen, contributing to a potential long-term immune response. Under the influence of helper T cells (CD4 + T cells), B cells rapidly proliferate and form clones. Some of these B cells undergo maturation to become plasma cells, which secrete large amounts of antibodies to combat infection [28]. Normally, the plasma cells were distributed throughout the body through lymphatic vessels and blood vessels, and they migrate specifically to survival “niches” such as bone marrow and lymphatic tissues for long-term retention [29]. A recent study by Gribonika et al., revealed for the first time that the skin can function as an autonomous “tertiary lymphoid organ”, by capturing microbial antigens through Langerhans cells, activating functional T cells, promoting B-cell activation, and facilitating the production of specific antibodies by plasma cells [30]. This finding supports previous speculations about the pathogenesis of CP, suggesting that skin tissue may serve as a source of plasmablasts that can mature into fully functional plasma cells. Furthermore, the regulation of IL-6 and other environmental factors enhances the retention and homing abilities of plasma cells in the skin, similar to the presence of other “survival” niches [3], contributing to the cutaneous symptoms of CP.

CP should be differentiated from other conditions resulting in plasma cell proliferation including chronic infection, collagen vascular disease, and generalized cutaneous B-cell pseudolymphoma [31]. Currently, there is no standardized treatment, and patients may be resistant to multiple therapies. Treatments include systemic glucocorticoids, cyclophosphamide, and chemotherapy combined with anti-CD20 antibodies. Thalidomide reduce the progression of CP lesions by reducing IL-6 secretion. While biologics targeting IL-6 could theoretically be applied to CP, there have been no reported cases of successful treatment in patients to date [2, 31]. Most cases of CP follow a chronic and benign clinical course without spontaneous remission [31]. Notably, in this particular case, the skin lesions of the patient gradually diminished following the SARS-CoV2 infection. We speculate that repetitive exposure to the same antigen may have induced immunotolerance, mitigating the aberrant immune response. Regulatory T (Treg) cells and other inhibitory T cells modify the duration, intensity, and chemistry of antigen delivery to immune cells. Additionally, some microbial metabolites in vivo, including short-chain fatty acids like butyric acid, can act on antigen-presenting cells to promote the formation of Treg cells or directly influence the differentiation, migration, and function of pathogenic T cells [32].

In conclusion, this is the first reported case of CP associated with COVID-19 vaccination. Unlike other vaccine-associated skin cases and COVID-19-related skin diseases, this case uniquely associates COVID-19 with CP, where the same lesions appeared after two vaccinations and subsequently resolved following SARS-CoV-2 infection. This provides valuable clinical data for future studies on viral infections and cutaneous B-cell immunity. However, as this is a single case report, confounding variables cannot be excluded during the observation period, and the proposed hypothesis cannot be verified, making it challenging to draw general conclusions. Although uncommon, clinicians should be aware that vaccines have the potential to induce immune disorders in humans. While a benign course is characteristic of CP, patients should be monitored longitudinally for potential disease progression and the possibility of malignant transformation.