Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome)

Updated: Aug 14, 2017
  • Author: Yoon-Soo (Cindy) Bae, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Robert Douglas Sweet first described acute febrile neutrophilic dermatosis in 1964, leading to the eponym Sweet syndrome (which, for the most part, is used throughout this article). [1] This condition is a reactive process characterized by the abrupt onset of tender, red-to-purple papules and nodules that coalesce to form plaques. These plaques usually occur on the upper extremities, face, or neck and are typically accompanied by fever and peripheral neutrophilia. [2] Sweet syndrome can be divided into three categories based on the underlying trigger. [3]

First, the most common type is the classic or idiopathic Sweet syndrome, which occurs predominantly in young women after a mild respiratory illness and may be linked to pregnancy [4] or inflammatory bowel disease. [3]

Second, Sweet syndrome can manifest aggressively in concert with an underlying malignancy. In some reports, the lesions of Sweet syndrome are the first clue of underlying malignancy. [5] It is important to note that cutaneous lesions can also occur in the context of an established neoplastic process, as well as a paraneoplastic syndrome. [3] Acute myelogenous leukemia is the most common neoplasm with which malignancy-associated Sweet syndrome occurs. [6, 7]

Finally, an iatrogenic form of Sweet syndrome is recognized based on numerous reports of medications bringing about lesions. The most commonly implicated agents are those that increase granulocyte colony-simulating factor (G-CSF). [8, 9, 10, 11] Other agents that have caused this variant of Sweet syndrome include trimethoprim/sulfamethoxazole (Bactrim), minocycline, levonorgestrel/ethinyl estradiol, and all-trans retinoic acid (ATRA). [12]

In general, Sweet syndrome responds well to oral corticosteroids; however, without treatment, the syndrome may persist for weeks or months and usually improves without scarring. [3] Recurrence has been reported mainly in idiopathic and malignancy-related Sweet syndrome. [3] In rare cases, crops of lesions recur and can persist indefinitely. [2] Cases associated with malignancy can present with bullous or ulcerative lesions, which can resemble atypical pyoderma gangrenosum. These lesions are often recalcitrant to treatment. [2, 8, 13, 14]

The diagnosis of Sweet syndrome is based fulfillment of both clinical and histopathologic criteria. Characteristics that distinguish the lesions of Sweet syndrome from other neutrophilic dermatoses are healing of the lesions without scarring and an absence of vasculitis. However, reports suggest that vasculitis should not exclude the diagnosis since co-occurrence with Sweet syndrome may represent an epiphenomenon instead of a primary immune-mediated process. [15]

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Pathophysiology

Sweet syndrome (acute febrile neutrophilic dermatosis) is a hypersensitivity reaction that occurs in response to systemic factors, such as hematologic disease, infection, inflammation, vaccination, or drug exposure. [2] The condition is neutrophil mediated, as evidenced by its histopathologic appearance, associated neutrophilia, and response to medications that affect neutrophil activity. [2]

The association of exogenous G-CSF with the development of Sweet syndrome also supports the impact of neutrophils and related endogenous cytokines in the underlying process. [8, 10] G-CSF suppresses apoptosis and prolongs the survival of neutrophils in vivo in a CD34+ cell population. G-CSF levels are increased in peripheral blood of patients with active Sweet syndrome, suggesting that high levels of G-CSF may correlate with the activity of disease. [9] The functional properties of neutrophils, rather than the absolute number, is thought to be significant because patients with Sweet syndrome due to G-CSF develop lesions as the neutrophil count rapidly increases, despite a decreased absolute neutrophil count. [14] See the Absolute Neutrophil Count calculator. Other reactive neutrophilic disorders, such as neutrophilic eccrine hidradenitis, are closely related and may represent a spectrum with related pathogenesis. [14]

In addition, some studies have suggested a role for cytokines such as interleukin (IL)–1, IL-2, and interferon-γ (IFN-γ) in concert with type 1 helper T cells, which may contribute to the pathogenesis of Sweet syndrome. [16] This is especially apparent in the malignancy-related form of Sweet syndrome, in which patients who are given G-CSF, IFN-γ, and all-trans retinoic acid develop the characteristic lesions. [17]

A possible genetic link with HLA-B54 has been observed in the Japanese population. [18] A report of two brothers who developed Sweet syndrome in the neonatal period also supports a genetic predisposition. [19] Structural alterations in the long arm of chromosome 3 (3q) have been seen in association with Sweet syndrome; these changes involve genes that affect the regulation of granulopoiesis and neutrophil migration. [19]

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Etiology

Potential causes Sweet syndrome (acute febrile neutrophilic dermatosis) are numerous and depend on the subtype. In one case series of 176 patients, classic or idiopathic Sweet syndrome was the most common presentation and accounted for more than 71% of cases. [20] Sweet syndrome associated with malignancy or an underlying condition (eg, infection or inflammatory disease) accounted for approximately 27% of the cases. [20] Most of the underlying malignancies reported in the literature are hematopoietic (most commonly acute myeloid leukemia), [6, 7, 20] but some are due to solid tumors, mostly involving the genitourinary tract, breast, and gastrointestinal tract. [5] Finally, approximately 2% of cases overall were associated with pregnancy. [4, 20]

Hematologic malignancy–related Sweet syndrome

Several myeloid hematologic malignancies have been associated with Sweet syndrome, including myelodysplasia, [6] chronic myelogenous leukemia, [21] and acute myeloid leukemia, including the promyelocytic (M3) variant of acute myeloid leukemia. [7]

Other nonmyeloid hematologic malignancies reported to co-occur with Sweet syndrome include Hodgkin disease, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, hairy cell leukemia, and multiple myeloma, as patients with immunoglobulin G secretion may be at increased risk for Sweet syndrome. [22, 23]

Nonhematologic malignancy–related causes of Sweet syndrome

These rare associations include osteosarcoma, oral cancer/tonsil cancer, ovarian cancer, thyroid cancer, lung cancer, pheochromocytoma, and cervical and rectal carcinoma. [14, 23, 24]

Genitourinary, breast, and gastrointestinal cancers have also been reported in patients with Sweet syndrome. [6]

Infection-related causes of Sweet syndrome

Multiple infections have been associated with Sweet syndrome, often involving the upper respiratory tract. Streptococcal pneumonia is the most commonly implicated infection. [25]

Other bacterial culprits that can lead to Sweet syndrome include Salmonella species, Staphylococcus species, Francisella tularensis, Yersinia enterocolitica, Entamoeba coli, Helicobacter pylori, Borrelia burgdorferi, tuberculous mycobacteria, Mycobacterium chelonae, and Penicillium species. [25, 26, 27]

Notably, Yersinia-associated Sweet syndrome has been noted to improve with antibiotics. [28]

Fungal infections have also been linked in the onset of Sweet syndrome, as it may be a presenting feature of coccidiomycosis and has been associated with sporotrichosis. [29, 30] Viral agents such as HIV, cytomegalovirus (CMV), hepatitis A, hepatitis B, and parvovirus B19 have also been implicated. [31, 32]

Iatrogenic causes of Sweet syndrome

Because the dominant cell in the dermal infiltrate of Sweet syndrome is the neutrophil, drug-induced Sweet syndrome is not considered to a drug hypersensitivity. Granulocyte colony-stimulating factor (G-CSF) is a well-established factor. [2, 33] Established factors include trimethoprim-sulfamethoxazole (Bactrim), all-trans retinoic acid (ATRA), and minocycline, which have all appeared in more than one case report. [12] It is important to note that multiple reports detail drugs to cause Sweet syndrome in patients with underlying malignancy; therefore, the causal link between drugs and Sweet syndrome is still unclear. [2] Anecdotal or limited reports of drug or device associations include the following [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46] :

  • Lithium
  • Furosemide
  • Hydralazine
  • Carbamazepine
  • Oral contraceptives
  • Mirena intrauterine device
  • COX-2 inhibitors
  • Azathioprine
  • Doxycycline
  • Diazepam
  • Diclofenac
  • Nitrofurantoin
  • Propylthiouracil
  • Lenalidomide
  • Bortezomib
  • Abacavir
  • imatinib
  • 5-Azacytidine
  • Decitabine
  • Interleukin (IL)–2
  • Clindamycin
  • Mitoxantrone
  • Vaccinations (eg, for BCG, smallpox, pneumococcal organisms, influenza)
  • Ticagrelor

Systemic disorder–related causes of Sweet syndrome

Associated inflammatory disease can be identified in about 16% of patients with Sweet syndrome. [20] The most common inflammatory conditions are Crohn disease and ulcerative colitis, which some authors consider part of a continuum of neutrophilic dermatosis. [47]

Sjögren syndrome, Behçet disease, lupus erythematosus, rheumatoid arthritis, familial Mediterranean fever, and undifferentiated connective-tissue disease have also been reported in association with Sweet syndrome. [2, 48]

Miscellaneous causes of Sweet syndrome

Rare cases of Sweet syndrome have occurred with spinal surgery, sarcoidosis, erythema nodosum, relapsing polychondritis, thyroiditis, and systemic lupus erythematosus. [2, 49, 50, 51, 52]

A few cases have been observed during pregnancy. [2, 4, 6]

Several cases of Sweet syndrome have occurred with polycythemia vera. [53]

One patient had a mutation in the prothrombin gene (G20210A), but no conclusive association can be made at this time. [54]

A few cases of Sweet syndrome have been reported in the literature in transplantation patients, including those undergoing bone marrow and kidney transplantation. Although these patients are taking immunomodulatory medications, an immune-mediated state has been described to explain the manifestation of Sweet syndrome in this patient population. [55]

Sweet syndrome as a manifestation of HIV-associated immune reconstitution inflammatory syndrome has been suggested. [56]

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Epidemiology

Frequency

Sweet syndrome (acute febrile neutrophilic dermatosis) is uncommon but not rare. In several series, 10-20% of cases have occurred in a setting of malignancy, although most are idiopathic or associated with benign conditions. [12, 13]

Race

Sweet syndrome has no known racial predilection. [2]

Sex

The predilection for sex appears to depend on the type of Sweet syndrome. Classic or idiopathic Sweet syndrome has a female predominance, with a female-to-male ratio of 4:1. [57]

Drug-related Sweet syndrome appears also to have a female predilection. [3]

However, this predilection is not apparent in cases associated with malignancy. [3, 6]

No sex predilection has been observed in children. [58]

Age

Typically, women with Sweet syndrome are aged 30-50 years. [2] However, cases in neonates as young as 5 days have been described. [59] In children, Sweet syndrome is extremely rare and generally associated with infection. [58]

Sweet syndrome occurring in children should prompt a workup for possible infection or immunodeficiency, [58] as well as a thorough workup to rule out malignancy.

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Prognosis

Most cases of Sweet syndrome resolve, although some persist indefinitely and can be difficult to manage because of pain and skin breakdown. Because this condition can be associated with many other diseases, including malignancy, the patient's overall prognosis depends on the underlying cause. [4] The outcome depends on the underlying condition, but recurrence may occur in up to 50% of patients and is most likely in cases associated with hematologic malignancy or drug reactions.

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Patient Education

Patient education should include information about the variable course of this condition, as well as advice on self-monitoring for signs and symptoms of other diseases.

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