Introduction

SARS-CoV-2, the virus that causes COVID-19 infection, provokes a robust host inflammatory response involving cytokines such as IL-1, interferon gamma, and TNF-alpha [1]. A similar inflammatory cascade is implicated in the development of a number of pustular dermatoses, including acute generalized exanthematous pustulosis (AGEP) and generalized pustular psoriasis (GPP) [2,3,4,5,6]. Acute flares of generalized pustular psoriasis may arise in the background of viral infection, as nucleic acids from viruses can activate the innate immune system and increase the inflammatory cytokines involved in psoriasis [4]. Similarly, viruses may induce acute generalized exanthematous pustulosis, a primarily T-cell mediated response, by causing upregulation of cytotoxic T-cells thought to help regulate infection [5]. During the initial stages of AGEP, higher levels of interferon gamma and granulocyte/macrophage colony-stimulating factor stimulate T-cells and keratinocytes to release CXCL8, which recruits neutrophils to form sterile pustules [5]. The proinflammatory response elicited in patients with COVID-19 may precipitate an acute flare or onset of pustular disease in at-risk patients. In this review article, we summarize existing literature on patients diagnosed with acute pustular dermatoses in conjunction with a diagnosis of or treatment for COVID-19 infection, and we discuss four additional cases of acute generalized exanthematous pustulosis (AGEP) and two cases of generalized pustular psoriasis (GPP) in patients concomitantly diagnosed with COVID-19.

Methods

We performed a review of existing literature to identify case reports of patients with pustular dermatoses that have been reported thus far in conjunction with a recent diagnosis of or treatment for COVID-19 infection. Pubmed search terms included “pustular,” “acute generalized exanthematous pustulosis (AGEP),”and “pustular psoriasis,” along with the term “COVID” or “SARS-CoV-2 between April 30, 2020 to May 1, 2021. We additionally report six additional cases of new or acutely exacerbated pustular dermatoses that presented to the Northwestern University Department of Dermatology. These cases were identified via review of the inpatient dermatology consult record, including results from skin biopsy.

Results

Study characteristics

The initial literature search yielded a total of 35 unique reports. However, 20 articles were eliminated as they lacked discrete patient information (age, symptoms, clinical course) or were not written in English. In the 15 articles published between May 2020 and April 2021, there were a total of 34 patients with COVID-19 infection diagnosed with either new-onset or acutely exacerbated GPP or AGEP. We present 2 additional cases of GPP and 4 additional cases of AGEP for a total of 40 cases (Table 1).

Table 1 Summary of reported cases of new-onset or acutely exacerbated GPP or AGEP after COVID-19 infection
Full size table

Generalized pustular psoriasis

A total of seven patients with COVID-19 infection were diagnosed with new-onset or exacerbated generalized pustular psoriasis. The median age at presentation was 50 years (range 28–64 years). 57 percent of patients were female (4 of 7). Average time to eruption onset from either diagnosis of COVID-19 infection, symptom onset, treatment initiation, or symptom resolution was 19 days (range 7–28 days). Cutaneous morphologies primarily included non-folliculocentric pustules on erythematous or psoriasiform plaques. Four patients had no associated systemic symptoms. Of the remaining three patients, one developed arthritis and two developed infectious symptoms such as fevers, myalgias, and cough. Three patients had a prior history of psoriasis, with one patient specifically having a history of pustular psoriasis. Five patients (71%) had concomitant administration of potential culprit drugs; most notably, three patients received hydroxychloroquine and two patients received methotrexate. Treatment strategies included topical corticosteroids in four patients, oral corticosteroids in three patients, loratadine in two patients, and oral acitretin and cyclosporine in one patient each, respectively.

Acute generalized exanthematous pustulosis

A total of 33 patients with COVID-19 infection were diagnosed with acute generalized exanthematous pustulosis. The median age at presentation was 67 years (range 29–88 years). 56 percent of patients were male (18 of 32 reported). Average time to eruption onset from either diagnosis of COVID-19 infection, symptom onset, treatment initiation, or symptom resolution was 24 days (range 0–90 days). Cutaneous morphologies primarily included pustules scattered on erythematous plaques. Four of 33 patients developed fevers; the remainder had no associated systemic symptoms. One patient had a prior history of psoriasis, but no patients had a prior history of pustular dermatoses. Seventeen patients (52%) had concomitant administration of potential culprit medications. Most common potential drug triggers included cephalosporin antibiotics (24%, 8 of 33), hydroxychloroquine (18%, 6 of 33), and azithromycin (15%, 5 of 33). Notably, 16 patients (48%) who developed AGEP had no known administration of any culprit medications. Treatment strategies primarily included no treatment (30%, 10 of 33), topical corticosteroids (12%, 4 of 33), and oral corticosteroids (18%, 6 of 33).

Discussion

Several cutaneous eruptions associated with SARS-CoV-2 infection have been reported in the literature thus far, including erythema multiforme, papular-pustular lesions, livedo reticularis, chilblains, exanthematous and morbilliform reactions, petechiae, vesicular, and telogen effluvium [7]. We present this review of cases of acute pustular dermatoses to help further characterize the spectrum of cutaneous disease seen with COVID-19 infection.

Generalized pustular psoriasis, or GPP, is a psoriasis variant that typically presents with pustules on background erythematous skin. The pathogenesis of generalized pustular psoriasis is not fully understood. Mutations in the genes IL36RN, CARD14, and AP1S3 have been associated with the proinflammatory pathophysiology of pustular psoriasis, as these mutations cause dysregulation of inflammatory cytokines [2,3,4]. Over fifty percent of cases of generalized pustular psoriasis in patients without a background of plaque psoriasis are thought to be a result of recessive mutations in the IL36RN gene, which encodes the interleukin-36-receptor antagonist responsible for antagonizing IL-1F6, IL-1F8, and IL-1F9, cytokines involved in pro-inflammatory signaling pathways. Mutation in the IL36RN gene results in unopposed disinhibition of these cytokines and activation of inflammatory pathways. In patients with a history of plaque psoriasis, mutations in the CARD14 gene are thought to be a predisposing factor. The CARD-14 gene is implicated in activation of the nuclear factor-kB signaling pathway, which is involved in the expression of pro-inflammatory molecules and cytokines such as TNF-alpha, IL-1, IL-6, and IL-8 [2]. Patients typically present with pustules overlying erythematous skin and often have associated systemic symptoms such as fever and malaise as well as elevated inflammatory markers (leukocytosis, elevated CRP levels, and eosinophilia). Many drug triggers have been described, including amoxicillin, hydroxychloroquine, and TNF-alpha inhibitors. A number of viral triggers have also been described, including varicella zoster virus, Epstein-Barr virus, and cytomegalovirus [2].

Acute generalized exanthematous pustulosis is most commonly classified as an adverse drug eruption associated with administration of a variety of medications, including aminopenicillin, sulfonamide, and quinolone antibiotics; hydroxychloroquine; diltiazem; and certain anti-fungal medications. Rarely, however, viral triggers including parvovirus B19 and cytomegalovirus have also been described. The eruption is thought to develop after exposure to a causative agent causes CD4 and CD8 T cell activation, ultimately leading to apoptosis of epidermal keratinocytes causing vesicle and pustule formation and destruction of tissue. These activated T cells predominantly display a Th1 type cytokine profile, producing mediators such as CXCL8, a neutrophilic cytokine, as well as interferon gamma and granulocyte/macrophage colony-stimulating factor. Some patients also display high levels of T cells with Th2 as well as Th17 cytokine patterns, leading to increased production of IL-4/IL-5 and IL-17/IL-22, respectively. Additionally, although IL36RN gene mutation is not directly linked to development of AGEP, mutation of this gene was found to be significantly higher in patients who developed AGEP compared to controls [3]. In addition, patients with HLA B51, DR11, and DQ3 may also have a genetic predisposition in developing AGEP [8].

In this case series, patients diagnosed with COVID-19 infection with concomitant GPP or AGEP were primarily noted to have non-folliculocentric pustules with 3 of 7 GPP patients (42%) and 7 of 33 AGEP patients (21%) presenting also with head and neck involvement. Among the subset of 33 patients diagnosed concomitantly with SARS-CoV-2 and AGEP, 16 patients (48%) were not documented to have concomitant administration of a potential culprit medication and thus are favored to have AGEP triggered primarily by COVID-19 infection, although we acknowledge co-administration of potential culprit medications among the remaining 17 patients as a major limitation of this review. Among this subset of patients without co-administration of a potential culprit medication, time to eruption onset is only available for four patients, with a mean time to onset of 22.5 days, range 0–33 days. None of these patients were specifically noted to have fever, although two were noted to have respiratory distress severe enough to require intubation and ultimately passed away. The EuroSCAR diagnostic scoring criteria for the diagnosis of AGEP includes fever of greater than or equal to 38 degrees Celsius, and in one review of 58 patients with AGEP, approximately 17% were noted to have internal organ involvement, including hepatic, pulmonary, and renal dysfunction. Patients with classic drug-triggered AGEP typically develop reaction onset within 72 h of drug exposure, with antibiotic-associated AGEP developing within 24 h [9]. Compared to drug-associated AGEP, patients with AGEP triggered by the SARS-CoV-2 virus were thus noted to have longer time to eruption onset and less likely to be febrile.

There is some evidence in the literature that viral nucleic acids act as strong agonists of the innate immune system and can trigger the release of inflammatory cytokines such as IL-36 that are implicated in psoriasis pathogenesis [4]. One such study that provides support is a small cohort study of 25 patients with psoriasis (21 with psoriasis vulgaris, 4 with generalized pustular psoriasis), who presented with 31 total psoriasis flares after respiratory tract infections. These patients received PCR testing of 16 viral pathogens and 4 bacterial pathogens by nasopharyngeal swab at time of psoriasis flare. 21 of these 25 patients (84%) were found to have at least one positive PCR test, with a rhinovirus and a coronavirus being the most frequently detected pathogens. 24 out of 31 flares (77%) were not noted to have any other associated trigger, and median delay between first symptoms and flare onset was 2 days [10]. Of note, median time to eruption onset among our patients with COVID-19 infection and GPP is longer than described in this small case series (19 days, range 7–28 days). Data on infectious triggers and their potential pathophysiology in acute generalized exanthematous pustulosis is more scant, although parvovirus B19 reactivation in the setting of amoxicillin administration, Chlamydia pneumoniae infection, and cytomegalovirus infection have all been reported in conjunction with AGEP [11].

SARS-CoV-2, the virus that causes COVID-19 infection, is thought to cause viral-mediated cell death in airway epithelial cells causing release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), leading to recognition by Toll-like receptors and nucleotide-binding domain leucine-rich repeat proteins. This ultimately triggers production of proinflammatory cytokine transcription factors such as NF-kappa-beta, activation of interferon regulatory factors, and activation of inflammasomes and conversion of proIL-1-beta to active IL-1-beta. Taken together, this leads to increased secretion of proinflammatory cytokines such as IL-6 and interferon-gamma as well as pulmonary recruitment of immune cells such as dendritic cells and macrophages. In a majority of patients, this immune response leads to SARS-CoV-2 clearance from the pulmonary system. In patients who ultimately develop severe COVID-19 infection, however, a dysregulated combined Th1 and Th2-type immune response occurs to initial viral infection, leading to increased levels of inflammatory mediators (IL-6, IL-2, IL-10, IL-7, G-CSF, and IFN-gamma) and greater disease severity and mortality [1]. It is possible a genetic predisposition may play increase the risk for these reactions. As described above, a similar inflammatory cascade is implicated in the development of generalized pustular psoriasis and acute generalized exanthematous pustulosis. We thus postulate that this inflammatory response triggered by SARS-CoV-2 infection may precipitate an acute flare or onset of disease in patients genetically at risk for or already living with a pustular dermatosis.