Neutrophilic dermatosis- acute febrile
Overview
Acute febrile neutrophilic dermatosis, also termed Sweet syndrome, is a reactive process characterized by the abrupt onset of tender, red-to-purple papules, and nodules that coalesce to form plaques. The plaques usually occur on the upper extremities, face, or neck and are typically accompanied by fever and peripheral neutrophilia. Initially described in 1964 by Robert Sweet, the entity currently recognized as Sweet syndrome ranges from classic Sweet disease, which occurs in young women after a mild respiratory illness, to a more aggressive neutrophilic process, which may be associated with other inflammatory diseases or malignancy. In fact, the lesions may be the first evidence of an underlying disorder and should prompt further investigation. A drug-induced variant due to the administration of various medications has been recognized, and a pregnancy-associated form has also been reported. In general, Sweet syndrome responds dramatically to oral corticosteroids and may improve or resolve with treatment of the underlying condition. Without treatment, the syndrome may persist for weeks or months and then improves without leaving scars. Recurrences are common. In rare cases, crops of lesions reappear and the condition persists indefinitely. Cases associated with malignancy can be bullous or ulcerative and resemble atypical pyoderma gangrenosum. These lesions are often recalcitrant to treatment. The diagnosis of Sweet syndrome is based on both clinical and histopathologic findings. Characteristics that distinguish the lesions of Sweet syndrome from other neutrophilic dermatosis are healing of the lesions without scarring and an absence of vasculitis.
Symptoms
History * Fever typically precedes the appearance of each crop of lesions. The fever can precede the skin disease by several days to weeks; however, it may also occur simultaneously. * The crop of plaques or nodules often appears abruptly and may persist for days to weeks. * Many patients report a febrile upper respiratory tract infection, tonsillitis, or flulike syndrome 1-3 weeks prior to onset of skin lesions. Vaccination or a gastrointestinal tract infection may also precede the eruption. * Headache, malaise, and arthralgias are common. * Episodes of disease cluster in the spring and autumn. Physical * Skin manifestations o Typical skin lesions are reddish blue or violet papules, plaques, or nodules. Massive subepidermal edema sometimes produces a deceptively vesicular appearance. Lesions may be studded with pustules. Papules often coalesce into circinate or arcuate plaques 2-10 cm in diameter. o Plaques can cause pain and burning, but they are not pruritic. Lesions spontaneously resolve without scarring, or they resolve after treatment. o The face, neck, and extremities primarily are affected, characteristically in an asymmetric distribution. o Atypical presentations in the external auditory canal and tympanic membrane are reported. Facial cellulitis and soft tissue infections of the extremities have also been described. o Ulcers and bullae are more common in malignancy-associated disease than in other forms. These lesions may be extensive and are generally hard to treat. o Lesions on the dorsum of the hand are not uncommon. They sometimes appear vasculitic, which is not typically seen in Sweet syndrome. + The lesions are predominantly distributed over the dorsal aspects of the fingers and hands in a roughly symmetrical pattern. Other extensor surfaces may also be involved. + Some believe that this is an anatomically limited form of Sweet syndrome, whereas others categorize this as a primary vasculitis. + Atypical pyoderma gangrenosum, bullous Sweet syndrome, and pustular vasculitis of the hands are actually considered by some to be variations of a single disease, neutrophilic dermatosis of the dorsal hands (Walling, 2006). + The vasculitis does not appear to be a primary immune-mediated process, as seen in the primary leukocytoclastic vasculitides, but rather, it is secondary vascular damage caused by toxic metabolites and proteases released from the extensive acute neutrophilic infiltrates in the skin. Prolonged exposure may increase the extent of damage. * Mucosal lesions o Oral lesions can occur on the lips, buccal mucosa, and/or tongue. These lesions most commonly appear as ulcers in Sweet syndrome patients with hematologic disorders. o Conjunctivitis and episcleritis may also occur; these are the most common eye manifestations. Other ocular manifestations reported include uveitis, limbal nodules, glaucoma, subconjunctival hemorrhage, scleritis, and iritis (Levy, 2005). * Extracutaneous manifestations o Sweet syndrome can involve several organ systems. o Pulmonary manifestations can sometimes lead to substantial morbidity. Pulmonary involvement may manifest as dyspnea, chronic cough, or pulmonary infiltrates or effusions on chest radiograph. In rare cases, symptoms may become severe enough to cause respiratory failure or bronchiolitis obliterans organizing pneumonia. Fortunately, most cases of Sweet syndrome with pulmonary involvement tend to be highly responsive to glucocorticoid therapy (Astudillo, 2006). o Other extracutaneous sites that have been reported include the bones, intestines, joints, bone marrow, pancreas, liver, heart, muscles, spleen, and kidneys. o Fewer than 30 cases of CNS involvement are reported in the literature. Encephalitis and meningitis are common neurologic manifestations in these cases. Peripheral neuropathy has also been reported. The most common symptoms are headaches, disturbed consciousness, and seizures (Hisanaga, 2005). + HLA types B54 and CW1 are associated with Sweet syndrome with CNS involvement in Japanese patients. + Unlike Behçet syndrome, in which CNS involvement is progressive and severe, Sweet syndrome usually causes transient CNS involvement, but recurrences may occur. o Proteinuria, hematuria, and decreased creatinine clearance have been reported. o Cerebrospinal fluid pleocytosis also has been described, as has a sterile chronic recurrent multifocal osteomyelitis in children. * Pathergy o Like pyoderma gangrenosum, Sweet syndrome is known to cause pathergy (also referred to as Köebner phenomenon), in which lesions occur in areas of minor trauma, such as sites of scratches, bites, and venipuncture. o The lesions may also be photodistributed or localized to the site of a previous phototoxic reaction (eg, sunburn).
Causes
Potential causes are numerous, but some associations are well documented. Classic Sweet syndrome is the most common presentation and accounts for more than 50% of cases. Sweet syndrome associated with a (malignant) neoplasm accounts for approximately 20-25% of the cases. Most of these are hematopoietic malignancies (most commonly acute myeloid leukemia), but 15% are due to solid tumors, mostly those involving the genitourinary, breast, and gastrointestinal tract. Inflammatory (infectious) conditions are the next most frequently identified causes of Sweet syndrome. * Hematologic malignancy o Myelodysplasia and chronic myelogenous leukemia may be associated with Sweet syndrome. Sweet syndrome can also be seen in association with acute myeloid leukemia (AML), including the promyelocytic (M3) variant of AML. o Other nonmyeloid hematologic malignancies that have occurred in association with acute febrile neutrophilic dermatosis include Hodgkin disease, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, hairy cell leukemia, and multiple myeloma. (Patients with immunoglobulin G [IgG] secretion may be at increased risk for Sweet syndrome). o Nonhematologic malignancy has been associated with Sweet syndrome; rates of genitourinary, breast, and gastrointestinal cancers appear to be slightly increased in this group. * Nonhematologic malignancy: Other rarely reported associations include osteosarcoma, oral cancer/tonsil cancer, ovarian cancer, thyroid cancer, lung cancer, pheochromocytoma, and rectal carcinoma. * Multiple infections are described in association with Sweet syndrome. o These infections often involve the upper respiratory tract. Streptococcal pneumonia is the most commonly described infection. o Other bacterial infections associated with Sweet syndrome also include those due to Salmonella or Staphylococcus species, Yersinia enterocolitica, Entamoeba coli, Helicobacter pylori, Borrelia burgdorferi, nontuberculous organisms, (atypical), and Tuberculous mycobacteria. o Sweet syndrome may be a presenting feature of coccidiomycosis (Dicaudo, 2005). Viral agents such as HIV, cytomegalovirus (CMV), hepatitis A, and hepatitis B have also been implicated. o Yersinia -associated Sweet syndrome has been noted to improve with antibiotics. * Multiple drugs have been reported to cause Sweet syndrome. o Some of these reactions have been noted in patients with underlying malignancy; therefore, the validity of these possible associations is unclear. o Because the dominant cell in the dermal infiltrate is a neutrophil, drug-induced Sweet syndrome is not considered to be a drug hypersensitivity. o G-CSF is a well-established factor. o Established factors include trimethoprim-sulfamethoxazole (Bactrim), all-trans retinoic acid, and minocycline, which have all appeared in more than 1 case report. o Anecdotal or limited reports of drug or device associations include lithium, furosemide, hydralazine, carbamazepine, oral contraceptives, the Mirena intrauterine device, COX-2 inhibitors, doxycycline, diazepam, diclofenac, nitrofurantoin, propylthiouracil, lenalidomide, bortezomib, abacavir, imitinib and vaccinations (eg, for bacille Calmette-Guérin, smallpox, pneumococcal organisms). * Systemic disorders o Associated inflammatory disease can be identified in about 15% of patients with Sweet syndrome. o The most common associated diseases are Crohn disease and ulcerative colitis, which some authors consider part of a continuum of neutrophilic dermatosis. o Sjögren syndrome, Behçet disease, lupus erythematosus, rheumatoid arthritis, and undifferentiated connective tissue disease have been reported in association with acute neutrophilic dermatitis. * Miscellaneous o Rare cases of acute neutrophilic dermatitis have occurred with spinal surgery, sarcoidosis, erythema nodosum, relapsing polychondritis, or thyroiditis. o A few cases have been observed during pregnancy. o Several cases of Sweet syndrome occurred with polycythemia vera. o One patient had a mutation in the prothrombin gene (G20210A), but no conclusive association can be made at this time. * Diagnostic criteria o The presence of 2 major and 2 minor clinical findings have been proposed as criteria for diagnosis, as suggested by Su and Liu and revised by von den Driesch. o Major criteria + Abrupt onset of tender or painful erythematous plaques or nodules, occasionally with vesicles, pustules, or bullae + Predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis o Minor criteria + Preceding nonspecific respiratory or gastrointestinal tract infection or vaccination or associated with inflammatory disease, hemoproliferative disorders, solid malignant tumors, or pregnancy + Periods of general malaise and fever (body temperature >38°C) + Laboratory values during onset showing a erythrocyte sedimentation rate >20 mm, positive C-reactive protein (CRP) result, segmented nuclear neutrophils, bands >70% in peripheral blood smears, and leukocytosis (count >8000/µL) (meeting 3 of 4 of these values is necessary) + Excellent response to treatment with systemic corticosteroids or potassium iodide
Diagnosis
A detailed history is often required for diagnosis, including recent use of OTC drugs. No laboratory tests reliably aid diagnosis, although biopsy of affected skin is often suggestive. Most drug reactions resolve when drugs are stopped and require no further therapy. Whenever possible, chemically unrelated compounds should be substituted for suspect drugs. Sensitivity can be definitively established only by rechallenge with the drug, which may be hazardous and/or unethical. Pruritus can be controlled with antihistamines and topical corticosteroids. When progression from urticaria to anaphylaxis is a concern, treatment is with aqueous epinephrine Some Trade Names ADRENALIN PRIMATENE MIST Click for Drug Monograph (1:1000) 0.2 mL sc or IM and with the slower-acting but more persistent soluble hydrocortisone Some Trade Names CORTEF SOLU-CORTEF Click for Drug Monograph 100 mg IV, which may be followed by an oral corticosteroid for a short period (see also Allergic and Other Hypersensitivity Disorders: Treatment).