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\begin{document}

\title{Enoxaparin-Induced DRESS Syndrome in a Pediatric Patient}



\author[1]{Aarti Kamat}%
\author[1]{Mary McGrath}%
\author[1]{Angela Weyand}%
\affil[1]{University of Michigan Michigan Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\begin{abstract}
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome
is a drug hypersensitivity reaction characterized by rash, multiple
systemic symptoms, and eosinophilia. DRESS syndrome develops following
exposure to inciting medications, typically antibiotics and
antiepileptics. Anticoagulants are not classically associated with this
syndrome, though cases exist in association with vitamin K antagonists
and oral anticoagulants. There are two known cases of enoxaparin-induced
DRESS syndrome in adults, but no reports in the literature in the
pediatric setting. In this report, we present the case of a pediatric
patient who developed classic symptoms and lab findings of DRESS
syndrome secondary to enoxaparin therapy.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome
is a rare drug hypersensitivity reaction characterized by diffuse skin
eruption and systemic symptoms including fever, lymphadenopathy,
elevated transaminases, and eosinophilia.\textsuperscript{1} DRESS
syndrome typically develops 2-6 weeks after a viral infection or
exposure to inciting medications, most commonly antibiotics,
antiepileptics, and allopurinol.\textsuperscript{1} The clinical
presentation of DRESS syndrome is variable and non-specific, and is
associated with high morbidity and mortality, therefore a high index of
suspicion is necessary. While anticoagulants aren't typically associated
with DRESS syndrome, there are documented cases in the literature
involving vitamin K antagonists and oral anticoagulants, as well as two
enoxaparin related cases in adult patients.\textsuperscript{2,3,4} There
are no reports of DRESS syndrome in children secondary to
anticoagulants. We present a case of a pediatric patient with DRESS
syndrome secondary to therapy. As anti-coagulants are increasingly
prescribed to pediatric patients, especially in the wake of
hyper-inflammatory syndromes caused be COVID19, it is crucial for
pediatricians and pediatric hematologists to consider enoxaparin as a
potential cause in patients with DRESS syndrome.

\textbf{Case Presentation}

A previously healthy 11-year-old female was admitted with sepsis
secondary to osteomyelitis and a periosteal abscess of the left lower
extremity, as well as methicillin-resistant staph aureus bacteremia. The
patient was initiated on clindamycin and vancomycin for treatment of
these infections. Ten days into her hospitalization, she was noted to
have swelling of her left lower extremity and imaging revealed an acute
deep venous thrombosis of the left popliteal vein. The patient was
started on unfractionated heparin and subsequently transitioned to
enoxaparin one week later.

Two weeks following enoxaparin initiation, the patient developed facial
swelling, a generalized morbilliform rash over her face, trunk, and
upper and lower extremities, and diffuse lymphadenopathy (palpable on
physical examination and confirmed on radiologic imaging). She continued
to have persistent, high-grade fevers despite multiple washouts of the
extremity and appropriate antimicrobial coverage with negative blood
cultures. Liver enzymes increased concurrently (AST 362 IU/L (normal
5-60 IU/L), ALT 371IU/L (normal \textless{}35 IU/L) at peak) with
development of these symptoms. She had leukocytosis with atypical
lymphocytes noted on peripheral smear. Eosinophilia was not present on
her complete blood count (CBC) at the onset of these symptoms, though
she did subsequently developed mild eosinophilia (1.1 K/ul at peak).
Human herpesvirus 6 (HHV6), cytomegalovirus (CMV), and Epstein Barr
Virus (EBV) serologies were all negative. Skin biopsy was performed and
was consistent with a drug eruption. With a score of 6, based on the
RegiSCAR criteria, the patient's constellation of symptoms and biopsy
findings were consistent with a definite case of DRESS syndrome. Given
the diagnosis, treatment with high-dose steroids was initiated.
Clindamycin and vancomycin were both discontinued due to their known
association with DRESS syndrome, and she was transitioned to
doxycycline. However, over the course of the next five days, no
improvement in rash, fevers, or liver enzymes was seen. Enoxaparin, her
only remaining medication, was therefore transitioned to apixaban.
Within a few days, the patient improved with resolution of rash, fevers,
and improvement of her laboratory abnormalities.

\textbf{Discussion}

The diagnosis of DRESS syndrome can be challenging due to its
nonspecific presentation, particularly in pediatric patients where
symptoms can overlap with common viral syndromes and Kawasaki disease.
The first presenting symptoms typically involve fever and a
maculopapular rash. Patients then develop lymphadenopathy and
hematologic abnormalities, including leukocytosis with eosinophilia and
atypical lymphocytes, as well as
transaminitis.\textsuperscript{5}Symptoms develop 2-6 weeks following
exposure to an inciting drug and can also be triggered by viruses most
commonly HHV6, as well as EBV and CMV.\textsuperscript{1,5} The RegiSCAR
is used to identify DRESS syndrome given the diagnostic uncertainty. The
criteria includes a combination of symptoms (rash, fever,
lymphadenopathy), laboratory findings (atypical lymphocytes,
eosinophilia, elevated liver enzymes), biopsy results, duration of
symptoms, and exclusion of other diagnosis (Table
1).\textsuperscript{1,5} A score of 2-3 indicates possible, 4-5
indicates probable, and greater than 5 indicates a definite case of
DRESS syndrome.\textsuperscript{1,5}

If left untreated, given its multisystem involvement, DRESS syndrome can
result in multi-organ failure and significant morbidity and mortality,
with a 10\% mortality rate.\textsuperscript{1} A high index of suspicion
is therefore required in order to prevent both short- and long-term
complications, especially as immediate discontinuation of the offending
medication is vital to control the disease.

The most common inciting drugs include antiepileptics (carbamazepine,
phenytoin, phenobarbital), antibiotics (Bactrim, clindamycin,
vancomycin), and allopurinol.\textsuperscript{1,5} DRESS syndrome has
been described rarely in association with Vitamin K antagonists and
direct oral anticoagulants in adult patients.\textsuperscript{2,3,4} In
an in-depth examination of existing literature, there are only two
reported cases of DRESS syndrome associated with enoxaparin therapy,
both in adult patients, and no reports of pediatric DRESS syndrome
secondary to anticoagulants. Rates of venous thromboembolism requiring
treatment with anticoagulation have been increasing overall in the
general pediatric population. This is especially true in the wake of the
COVID-19 pandemic and increasing inflammatory syndromes in children
post-infection. Enoxaparin is a widely used anticoagulant in the
pediatric population. As such, general pediatricians, as well as
specialists, should be comfortable with identifying and managing the
complications associated with it. DRESS syndrome should be included on
the differential for any patient on enoxaparin who develops rash,
fevers, lymphadenopathy, and eosinophilia. Similarly, enoxaparin should
be considered as a possible causative agent in patients diagnosed with
DRESS syndrome.



\textbf{References:}

\begin{enumerate}
\tightlist
\item
  Brandon Pye, Jessica M. Aguilar, Ashley M. Maranich. A 15-year-old Boy
  Presents with Fever and Pruritic Rash for 6 Days. \emph{Pediatrics in
  Review} January 2021; 42.
\item
  Dabas G, De D, Handa S, et al. Delayed-type hypersensitivity reaction
  to enoxaparin in a pregnant woman. \emph{Postgrad Med J} 2019;95:506.
\item
  Ronceray S, Dinulescu M, Gall F, et al. Enoxaparin-Induced Dress
  Syndrome.\emph{Case Rep Dermatol}. 2012 Sep-Dec; 4(3): 233--237.
\item
  Mente\selectlanguage{polish}ş\selectlanguage{english}o\selectlanguage{polish}ğ\selectlanguage{english}lu D, Do\selectlanguage{polish}ğ\selectlanguage{english}an G\selectlanguage{ngerman}ünayd\selectlanguage{polish}ı\selectlanguage{english}n S, Ersoy-Evans S. Drug Reaction with
  Eosinophilia and Systemic Symptoms Syndrome Induced by
  Apixaban.\emph{Dermatologic Therapy} . 2020; 33: e13719.
\item
  Cardones AR. Drug reaction with eosinophilia and systemic symptoms
  (DRESS) syndrome. \emph{Clin Dermatol} . 2020;38(6):702-711.
\end{enumerate}

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