To the Editor:
Sweet syndrome, or acute febrile neutrophilic dermatosis, is
characterized by the acute onset of fever and tender, erythematous skin
nodules and plaques with skin histology demonstrating neutrophilic
infiltration of the dermis. Extracutaneous manifestations such as
pulmonary infiltrates are extremely rare. We present a 15-year-old
female with a new diagnosis of acute myeloid leukemia (AML) who
developed prolonged fever, diffuse painful erythematous maculopapular
rash with multiple nodular and ground-glass opacities in the right lower
lung on chest computed tomography (CT) with the initial concern of
invasive fungal disease. Ultimately, the patient was diagnosed with
Sweet syndrome.
A 15-year-old female was diagnosed with AML and began induction
chemotherapy (daunorubicin, etoposide, and cytarabine). Shortly
thereafter she became febrile and was started on IV Cefepime. On
hospital day 6, the patient developed a painful, pruritic erythematous
maculopapular rash that was first noticed on her face, neck, torso, and
bilateral legs (Figure 1) but quickly spread to her arms and back. Given
prolonged fever with neutropenia, disseminated rash, and chest CT
findings of multiple hazy nodular and ground-glass opacities in the
right lower lung which raised concerns for possible fungal etiology, IV
Amphotericin B was started empirically. Extensive work-up for invasive
fungal infection including serologic testing for Histoplasma,
Aspergillus, and Blastomyces and fungal PCR from both BAL and skin
biopsy were all negative. Skin biopsy did not reveal any bacterial or
fungal elements, but instead demonstrated neutrophils at various stages
of maturation infiltrating the superficial subcutaneous tissues which
was highly consistent with acute febrile neutrophilic dermatosis, or
Sweet syndrome. Her rash evolved again by forming more targetoid areas
with central papule with peripheral clearing (Figure 1) during
neutrophil recovery. Her fever resolved on hospital day 16. Repeat chest
CT demonstrated complete resolution of pulmonary nodules within 3 weeks
from the scan indicating that fungal etiology was less likely. Over the
next several weeks, the patient’s rash became lighter in color, and
within three months, her rash had resolved.
Our case highlights diagnostics and treatment challenges of an unusual
and rare case of sweet syndrome that mimics invasive fungal disease.
Cutaneous manifestations almost always present first, but extracutaneous
manifestations of the syndrome have been reported including pulmonary,
ocular, cardiac, and neurologic. Pulmonary manifestations with only 4
cases reported in literature 5,9,10,11(Table 1). Chest
radiographs can reveal diffuse pulmonary infiltrates or nodules
mimicking pulmonary invasive fungal infection. When BAL is performed,
high neutrophil counts without an identified organism are often found
like in our case. Lung biopsies can also reveal interstitial
inflammation and alveolar infiltration of neutrophils though is not
always feasible.7 Cutaneous manifestation almost
always precede pulmonary involvement.8
The pathogenesis of Sweet syndrome is not well understood. Mechanisms of
neutrophil proliferation are proposed which can be seen in patient who
received G-CSF. Notably, our patient did not receive G-CSF during this
hospitalization, nevertheless, her rash did become more diffuse and
coalesced as her neutrophil recovered. Additionally, there is also
concern that a mutation in a specific gene that encodes a receptor
tyrosine kinase may cause persistent activation of cell proliferation.
This hypothesis of pathogenesis may explain why Sweet syndrome is more
common in AML patients. Diagnostic criteria of Sweet syndrome requires
two major criteria and two of four minor criteria2.
Our patient demonstrated both major criteria as well as two minor
criteria of fever and known hematologic malignancy. Treatment is usually
with corticosteroids; however, symptoms usually self-resolve over weeks
like in our case
Our patient’s clinical presentation was more clinically consistent with
Sweet syndrome than a fungal etiology because of the rash’s rapid,
diffuse, and painful onset. Although pulmonary manifestations certainly
occur in the setting of disseminated fungal infection in
immunocompromised hosts, usually these manifestations are accompanied by
respiratory status changes such as dyspnea or hypoxia. Additionally,
fungal elements would most likely be visualized on histological
evaluation of the skin biopsy, which were not appreciated on our
patient’s specimen.
In cases of patients with cytopenia or severe bone marrow disease, the
degree of neutrophilia within the dermis and the maturation of cells
seen can be variable, making the diagnosis more challenging than in
classic presentations. In cases with more immature myeloid precursors
like the current case, it is important to rule out a diagnosis of
leukemia cutis. In our case, the immunohistochemical profile of the
immature neutrophils did not match that of the patient’s known leukemia
and the cells did not demonstrate blast markers (CD34), helping to
exclude this possibility.
Sweet syndrome can often masquerade as other conditions, such as
disseminated fungal infections in immunocompromised pediatric patients,
it is vital to consider Sweet syndrome in the differential diagnosis and
obtain a skin biopsy in any oncology patient with fever and worsening
rash at the time of recovery. By diagnosing Sweet syndrome early,
unnecessary antimicrobials and procedures can be avoided and, in the
case of leukemia patients, chemotherapy should not be delayed as fungal
etiologies are ruled out. This is the first described case of pulmonary
involvement of Sweet syndrome in a pediatric patient with AML and
increases knowledge of Sweet syndrome as a differential diagnosis in
pediatric oncology with fever and worsening rash.