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A 78-year-old man presents to an emergency department in Pennsylvania after being transferred from a nursing facility; he has septic shock secondary to a Pseudomonas aeruginosa urinary tract infection. His medical history includes benign prostatic hyperplasia, coronary artery disease, and atrial fibrillation.

The patient is admitted to the intensive care unit, where intake assessment reveals hemodynamic instability, leukocytosis, deteriorating renal function, and high potassium levels.

Clinicians start the patient on treatment with cefepime for the urinary tract infection, and a brief period of vasopressor support.

On day 7 in the hospital, the patient develops a fever of 38.3°C, along with a pustular rash on an erythematous base that covers his trunk and upper extremities.

There is no evidence of mucosal involvement. Clinicians obtain samples of the affected skin and surrounding area for testing.

Clinicians order a chest x-ray, which shows no acute cardiopulmonary abnormalities. Repeat cultures of blood, urine, and pustule cultures for bacteria are negative.

Laboratory tests identify leukocytosis with neutrophilia (8,170 neutrophils/μl; normal range 1,800-7,500), and elevated C-reactive protein (4.15 mg/dL; normal range 0-1).

On day 8 in the hospital, the patient's low blood pressure persists, with no evidence of any other symptoms. He undergoes a second chest x-ray, which reveals new-onset bilateral interstitial opacities and consolidation.

Based on the x-ray findings and given the patient's arrival from a nursing facility, clinicians test him for COVID-19 via the SARS-CoV-2 RNA nasopharyngeal swab, followed by real-time reverse transcription polymerase chain reaction; both results come back positive. In the absence of any signs of respiratory distress or need for supplemental oxygen, the patient is treated supportively.

Skin biopsy of the rash shows papillary dermal edema and subcorneal/intracorneal pustules. The surrounding skin shows mixed inflammatory infiltrate composed of lymphocytes, neutrophils, and rare eosinophils.

Based on the patient's score of 12, calculated via the EuroSCAR study group , the medical team arrives at a definite diagnosis of acute generalized exanthematous pustulosis (AGEP) and discontinue cefepime. Topical emollients are used to manage the patient's skin symptoms, which results in expedient resolution of the exanthem within a few days, followed by postpustular desquamation.

Discussion

Clinicians reporting this of AGEP following treatment with cefepime for a urinary tract infection in an older man note that it is the second reported case of the rare widespread rash in a patient with COVID-19.

However, unlike the patient in the , published in May 2020 and involving a 39-year-old woman who developed AGEP 18 days after starting hydroxychloroquine treatment, the current patient had not received that drug. The authors of the current case speculate that the man's vigorous immune response to COVID-19, coupled with concurrent cefepime use, may have triggered the appearance of AGEP.

AGEP is a rare exanthem characterized by the acute development of a multitude (often up to several hundred) of small, non-follicular, sterile pustules arising on an erythematous base, and is usually related to medication use. In addition to antimalarials such as hydroxychloroquine, common culprits include aminopenicillins and diltiazem.

The rash generally erupts within 48 hours of exposure to the medication, with even less for antibiotics (median of 24 hours). The condition is self-limiting, and usually resolves within 2 weeks of withdrawal of the offending drug. Resolution is marked by desquamation with characteristic collarettes of scale.

AGEP has also occurred in connection with certain viral infections, including cytomegalovirus, parvovirus B19, and Epstein-Barr virus. In addition, the authors note, in the time since the pandemic began, there have been numerous reports of associated skin manifestations, including petechial rashes, vesicles, chilblains, and urticaria. Less commonly, AGEP has been associated with exposure to spider bites and mercury.

Diagnosis is based on clinical presentation and histologic findings. The AGEP from by the EuroSCAR study group includes the following diagnostic criteria:

• Fever (>38°C)

• Acute pustular eruption

• Blood neutrophilia (>7,000 neutrophils/μL)

• Spongiform subcorneal or intraepidermal pustules on skin biopsy

• Spontaneous resolution of the pustules in less than 15 days

Histologically, features of AGEP are characterized by subcorneal pustules, mild spongiosis in the surrounding epidermis, and superficial mixed infiltrate composed of lymphocytes, neutrophils, and occasional eosinophils.

The main differentials to be considered for AGEP are pustular psoriasis and drug rash with eosinophilia and systemic symptoms (DRESS), the case authors note. Key differences of pustular psoriasis include slow onset and often personal or family history of psoriasis. DRESS is typically associated with a longer latent period of 2 to 6 weeks.

In this patient's case, the lack of personal history of psoriasis, acute onset of symptoms, and the timely resolution after cefepime was discontinued, as well as the histologic features of eosinophils in the mixed infiltrate, helped to distinguish AGEP from pustular psoriasis and DRESS.

As noted, antibiotics typically induce development of AGEP within 24 hours after administration; this patient, however, had a delayed reaction 7 days after starting cefepime. He was, however, diagnosed with COVID-19 on the same day that his fever began and his rash appeared.

The pathophysiology of AGEP is only partially understood, the authors note. They cite studies suggesting that AGEP is a T cell-mediated neutrophilic inflammatory response, involving drug-specific T cells (CD4+ and CD8+), Th17 cells, inflammatory cytokines, and chemokines. Pro-inflammatory cytokines IL-17 and IL-22 produced by Th17 cells contribute to host defense by recruiting neutrophils and macrophages to infected tissues.

Indeed, patients with AGEP have been noted to possess a markedly higher percentage of Th17 cells compared with healthy controls. In addition, potential genetic involvement may occur through mutations in the IL-36 receptor antagonist (IL36RN) gene, although patients with AGEP and IL36RN gene mutations are more likely to have lip/oral involvement, although that was not seen in this case.

Other research suggests that systemic organ involvement is an important finding in AGEP patients, with the potential to result in admission to intensive care and resulting in a poor outcome. A of 10 years of hospital experience with patients with AGEP in Tunisia note that systemic involvement can be considered positive in cases in which any of the following criteria are detected:

• Serum creatinine level rising above 1.5 times higher than baseline, or ratio of blood urea nitrogen to creatinine above 20 within 48 hours after the initiation of the treatment and hydration

• Elevated liver function tests more than two times higher than the reference limit, and lasting at least 2 days (with either hepatocellular, cholestatic, or mixed pattern)

• Presence of dyspnea, respiratory rate of more than 20 breaths per minute, or oxygen saturation level less than 90%

Antiviral immune response in COVID-19 is crucial to eliminating the invading virus, and researchers are finding that pro-inflammatory subsets of T cells (including Th17 and other CD4+ T cells, as well as CD8+ T cells) are likely responsible for the severe immune-related injury to various organ systems, the case authors state.

Theoretically, a robust and lasting immune response may result in overproduction of inflammatory cytokines, thus damaging host tissues, and studies have implicated cytokine storm as a major contributor to disease progression in the later stages of COVID-19 infection.

Additionally, elderly patients tend to exhibit chronic low-grade inflammation that develops from the continual production of inflammatory mediators and cytokines, thereby lowering the threshold to develop cytokine storm during COVID-19 infection.

Given that AGEP usually develops 24 hours after cephalosporin use, this patient's vigorous immune response to COVID-19 infection, combined with cefepime use, may be factors in the delayed emergence of AGEP, the case authors speculate.

They suggest that accumulating information regarding the manifestations of COVID-19 may help identify initially overlooked aspects of the infection, such as cutaneous manifestations, and that while this patient's AGEP was likely induced by exposure to cefepime, it is also possible that development of AGEP may have been multifactorial.

Thus, the authors theorize, the combination of cephalosporin exposure, genetic predisposition, and the production of pro-inflammatory cells and cytokines induced a vigorous immune response leading to delayed development of AGEP.

The hope, the team said, is that sharing this patient's case may assist other clinicians dealing with rashes during the pandemic.

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