A 34-year-old Hispanic man with a history of alcoholic cirrhosis and type 2 diabetes mellitus presented with 2 weeks of diarrhea, nausea, vomiting, abdominal pain, rash, and syncope. Five days before presentation he developed an erythematous petechial rash on his right hand that spread sequentially to his left hand, forearms, feet, legs, and flanks. The rash was neither pruritic nor painful, and he denied prior history of a rash. He reported no recent infections or antibiotic use. His past medical history was negative for connective tissue disease and was otherwise noncontributory. There were no other significant findings upon review of systems.
Assessment
On admission, the patient was afebrile, hypotensive (82/69 mm Hg), and tachycardic (104 beats per minute), which resolved after normal saline boluses. Physical examination was significant for petechiae on the hard palate and diffuse palpable petechiae in the distribution described above. His examination was otherwise notable for right elbow erythema and purulent drainage. Laboratory serologies were negative for human immunodeficiency virus, hepatitis B and C, and rheumatoid factor. Other laboratory findings included low serum complement component 3 (C3), negative antimyeloperoxidase antibodies, and positive perinuclear antineutrophil cytoplasmic antibodies.
Two of 4 blood cultures and a wound culture from the purulent elbow site were positive for methicillin-sensitive Staphylococcus aureus (MSSA). A transthoracic echocardiogram was negative for vegetations. A punch skin biopsy of the rash showed an infiltrate of lymphocytes, histiocytes, neutrophils, and eosinophils with minimal fibrin deposition in blood vessel walls. Direct immunofluorescence was positive for immunoglobulin G and C3 deposition with trace immunoglobulin A in the walls of papillary dermal vessels. These findings were consistent with early leukocytoclastic vasculitis.
Diagnosis
Palpable purpura on examination raised the suspicion for cutaneous leukocytoclastic vasculitis, which is synonymous with small-vessel vasculitis. However, definitive diagnosis requires histologic confirmation. Two separate punch biopsies, one for hematoxylin and eosin staining and one for direct immunofluorescence, are preferred as this reduces both the possibility of sampling error and the risk of tissue distortion during bisection. Around 80% of small-vessel vasculitis cases show deposition of C3, immunoglobulin (Ig)M, IgA, or IgG in vessel walls on direct immunofluorescence. This patient’s biopsy demonstrated a dense neutrophilic infiltrate and IgG and C3 in papillary dermal vessels on direct immunofluorescence, confirming the diagnosis of a small-vessel vasculitis. C3 deposition in blood vessel walls leads to decreased serum C3, which was seen in this case. This patient was also positive for perinuclear antineutrophil cytoplasmic antibodies and negative for antimyeloperoxidase antibodies, which suggest that in addition to the immune complex-mediated vasculitis, a pauci-immune component may have been active as well. Positive perinuclear antineutrophil cytoplasmic antibodies are diagnostically nonspecific, as they are commonly directed against other neutrophil cytoplasmic enzymes besides myeloperoxidase, including elastase, lactoferrin, lactoperoxidase, lysozyme, azurocidin, and cathepsin G.
Other items in the differential diagnosis include Henoch-Schönlein purpura, microscopic polyangiitis, and Churg-Strauss syndrome. The absence of significant IgA deposition makes the diagnosis of Henoch-Schönlein purpura less likely. The histologic findings of microscopic polyangiitis, including segmental, necrotizing small-vessel vasculitis and a positive antimyeloperoxidase, are absent in this patient. In addition to lacking antimyeloperoxidase, the patient also did not exhibit asthma and eosinophilia, which are key features of Churg-Strauss syndrome.
Small-vessel vasculitis can be either primary or secondary to an underlying process. About half of small-vessel vasculitis is idiopathic, with infection, connective tissue diseases, drugs, and neoplasms as the other major causes. Given the patient’s underlying MSSA bacteremia, he was treated for 2 weeks with a third-generation cephalosporin. The rash improved during this antibiotic course and eventually resolved completely. This presentation represents an unusual case of biopsy-proven leukocytoclastic vasculitis that developed concomitantly with MSSA bacteremia and resolved with cephalosporin treatment. A prior case report described MSSA bacteremia occurring 2 months before leukocytoclastic vasculitis onset. However, the patient received indomethacin for 1 week before the rash, and nonsteroidal antiinflammatory drugs are a widely known cause of leukocytoclastic vasculitis. Other drugs known to cause leukocytoclastic vasculitis include antibiotics such as penicillins, cephalosporins, and macrolides. Our case demonstrated resolution of leukocytoclastic vasculitis during a course of cephalosporin treatment, decreasing the likelihood of a drug-induced vasculitis.
Small-vessel vasculitis is more commonly associated with chronic or subacute species such as Mycoplasma pneumoniae and Mycobacterium tuberculosis, as well as chronic disease such as cystic fibrosis or endocarditis; few reports have associated small-vessel vasculitis with acute pyogenic infections. One previous report identified a patient in which leukocytoclastic vasculitis developed secondary to Klebsiella bacteremia, and treatment of the bacteremia led to resolution of the vasculitis.
The precise mechanism for leukocytoclastic vasculitis initiation remains unclear. Pathologically, the result is a type III hypersensitivity reaction where antigen-antibody immune complexes are deposited in postcapillary venules, leading to complement activation and neutrophil chemotaxis. Local vessel destruction leads to red blood cell leak and an inflammatory infiltrate in the interstitium, making the purpura palpable.
Both infectious and host factors have been proposed in the pathogenesis of bacterial-induced leukocytoclastic vasculitis, including direct toxin effects on vessels, invasion and occlusion of blood vessel walls by microorganisms, distant embolism, and hypersensitivity reaction with immune complex deposition. S. aureus is known to produce many antigenic factors that could stimulate antibody production, resulting in leukocytoclastic vasculitis (lipases, hyaluronidases, hemolysins, thermonucleases, and enterotoxins), including superantigens such as those seen in toxic shock syndrome and possibly microscopic polyangiitis in the setting of S. aureusendocarditis.
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-Christina A. Mosher, BAcorrespondenceemail, Joshua L. Owen, MD, PhD, Blake R. Barker, MD
This article originally appeared in the May 2016 issue of The American Journal of Medicine.
