Key Words:
COVID-19; AGEP; drug reaction; Remdesivir
Introduction:
Coronavirus disease 2019 (COVID-19), caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well-known for
its multi-systemic involvement; besides respiratory manifestations,
mucocutaneous symptoms have been among the most common presentations of
SARS-CoV-2 infection(1). Cutaneous manifestations of SARS-CoV-2
infection can range from erythematous or maculopapular eruptions and
urticaria to blisters, petechiae, and livedo reticularis(2). Skin
involvement can occur as the sole manifestation of COVID-19 infection,
intervene during the course of the infection, or appear after the
infection has subsided(3, 4). On the other hand, cutaneous reactions can
be a manifestation of a new-onset dermatosis, or exacerbation of a
preexisting condition(5). The underlying cause for this phenomenon can
be the virus direct invasion to the skin and mucosal surfaces, the
immunologic inflammatory response elicited by the virus, or the side
effect of therapeutics used in the settings of SARS-CoV-2 infection(6,
7).
Acute generalized exanthematous pustulosis (AGEP) is an exanthematous
condition with abrupt onset, which predominantly occurs as a result of
drug reaction. In fact, other factors such as infections, vaccination,
chemicals contact and insect bite can also be triggering factors for
AGEP(5). Since the beginning of the COVID-19 pandemic, increased rate of
AGEP has been reported, which could be attributed to the high prevalence
of the SARS-CoV-2 virus as the causative pathogen, or the result of
medications used in this settings. Here, we report a case of COVID-19
associated AGEP with significant diagnostic challenges and
complications, and present a brief literature review.
Case presentation
A 62-year-old woman presented to the dermatology clinic with generalized
pruritic skin rash. She mentioned a history of SAR-CoV-2 infection one
month earlier, for which she had undergone remdesivir treatment. Two
days after the completion of treatment, she developed cutaneous
reactions beginning in the trunk and extending to the extremities. She
also mentioned a history of Addison’s disease, for which she was taking
prednisolone and fludrocortisone. On physical examination, widespread
pustular eruptions with erythematous base were covering all over her
body surface except for head and neck area (Figure 1). Hair and nails
were intact. No mucosal involvement was detected. She was started on
high dose oral prednisolone and cyclosporine in conjunction with
acitretin and topical emollient. A few days later, she returned to the
clinic with fever and toxicity. Laboratory evaluation revealed a
thrombocytopenia and transaminitis. Therefore, we admitted her for
further workup. We initially stopped all the drugs she was taking,
including cyclosporine and acitretin, and took a skin biopsy.
The histopathology report was indicative of linear neutrophilic
parakeratosis with mild acanthosis and focal spongiosis, along with
scattered necrotic keratinocyte, ectatic capillaries, and perivascular
interstitial lymphocytic and eosinophilic infiltration in the dermis,
all compatible with the diagnosis of AGEP (Figure 2). Then, we started
her on methylprednisolone pulse and IVIG due to the possibility of
idiopathic thrombocytopenia (ITP) in this patient. She was tested
negative for COVID-19 and HIV Ab. Chest CT scan, as was expected, showed
diffuse ground-glass opacities in both lungs compatible with
convalescent pulmonary phase of SARS-CoV-2 infection (Figure 3). Three
days after the initiation of intensive therapy, platelets count
increased and liver enzymes decreased. The eruptions rapidly resolved
within a few days, therefore, we switched the therapy to intravenous
hydrocortisone and then to prednisolone with gradual tapering. At the
time of discharge, post-pustular desquamation was demonstrated. At
follow-up visits, the patient did not describe any relapses.
Discussion
Acute generalized exanthematous pustulosis (AGEP) is an acute pustular
dermatosis with abrupt onset of a great number of pustules with
edematous and erythematous base(8).
Several conditions, including infections, vaccination and medications
have been mentioned as precipitating factors of AGEP(9). The COVID-19
pandemic has unveiled a wide range of dermatologic disorders, new-onset
or flare, in SARS-CoV-2 infected patients. Therefore, this virus should
also be listed in the infectious causes of AGEP(10).
Medications most commonly associated with AGEP include pristinamycin,
aminopenicillins, fluoroquinolones, antimalarials, sulphonamides,
terbinafine, azoles, protease inhibitors, dapsone, pantoprazole,
diltiazem, corticosteroids, azithromycin, NSAIDs, and antiepileptic
agents(8). Among the common therapeutics used during a SARS-CoV-2
infection with the probability of inducing AGEP, we can name
hydroxychloroquine, which is the most notorious medication for inducing
AGEP, favipiravir, azithromycin, NSAIDs, protease inhibitors such as
lopinavir-ritonavir, anticoagulants, and glucocorticoids(11-19). Our
patient had received azithromycin, dexamethasone, naproxen, and
remdesivir for SARS-CoV-2 infection. Therefore, the onset of AGEP could
be attributed to any of the mentioned agents, although there has been no
definite report of remdesivir-associated AGEP.
In AGEP, the duration of drug exposure before onset of the symptoms is
varying from a few hours to a few weeks depending on the causative drug
(17). Our case has presented with AGEP 4 weeks after receiving COVID
treatment which was a longer latency period compared to AGEP reported in
COVID-19 infected patients in the recent literature which make it
difficult to attribute the AGEP to these medications. However, one can
infer that combination of each of these medications including remdesivir
and genetic disposition with COVID-19 induced cytokine storm led to
delayed development of AGEP in this case. Hence, AGEP might be
considered as an unreported side effect of remdesivir which has been
widely used during COVID era. Further reports will shed more light on
this issue.
Eliminating the causative trigger, such as ceasing the drug or treating
the infection, is the cornerstone of AGEP management. Other potentially
useful options include moist dressings and topical antiseptics, systemic
antibiotics if superinfection intervenes, and topical or systemic
corticosteroids(20-21). However, in severe or recalcitrant cases,
cyclosporine and intravenous immunoglobulin may be beneficial(22).
Conclusion:
we reported a case of AGEP which might has been triggered with COVID-19
infection itself or be considered as an unreported possible side effect
of remedesivir to emphasize the necessity of paying more attention to
history taking and clinical suspicion as key factors to reaching the
correct diagnosis [23-28]. Furthermore, one can infer from our
report that when dealing with skin findings, remdesivir should be kept
in mind as a causative agent.