Modern Pathology (2015) 28, 1428–1434 1428 © 2015 USCAP, Inc All rights reserved 0893-3952/15 $32.00 An elevated IgG4 response in chronic infectious aortitis is associated with aortic atherosclerosis Zakir Siddiquee1, R Neal Smith1 and James R Stone1,2 1Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA and 2Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA Recently, it was shown that infectious bacterial aortitis can stimulate an elevated IgG4+ plasma cell response in the vessel wall, which could mimic IgG4 aortitis/periaortitis. However, the factors that are associated with an elevated IgG4+ plasma cell response in infectious aortitis are unclear. To ascertain these factors, 17 cases of infectious aortitis and 6 cases of non-infectious severe abdominal aortic atherosclerosis were assessed for the magnitude of IgG4+ plasma cell response. The degree of IgG4+ plasma cell infiltration was determined by immunohistochemistry. Infectious cases were subcharacterized as chronic (43 weeks duration) or acute (o3 weeks duration) based on the duration of symptoms, and as involving either the ascending aorta or the distal aorta, ie, the descending thoracic and/or abdominal aorta. There was a 5–16-fold greater degree of IgG4+ plasma cell infiltration in the chronic distal infectious aortitis group compared with the other three infectious aortitis groups (P ≤ 0.0007), and compared with non-infectious severe abdominal aortic atherosclerosis (Po0.0008). This resulted in a greater IgG4/IgG ratio in the chronic distal infectious aortitis group compared with the acute ascending and acute distal infectious aortitis groups (Po0.03). The degree of IgG4+ plasma cell infiltration in chronic distal infectious aortitis overlaps with that seen in the aortitis and periaortitis of IgG4-related disease. In the chronic infectious aortitis cases, the degree of IgG4+ plasma cell infiltration was more intense in patients with moderate to severe aortic atherosclerosis compared with those patients with less aortic atherosclerosis (P = 0.007). These findings indicate that an elevated IgG4+ plasma cell response occurs in the descending thoracic and abdominal aorta in the setting of chronic bacterial infectious aortitis and pre-existing atherosclerosis. This inflammatory response to chronic infection in atherosclerosis-laden aortas may have implications for the development of IgG4-rich inflammatory atherosclerotic aortic aneurysms. Modern Pathology (2015) 28, 1428–1434; doi:10.1038/modpathol.2015.105; published online 4 September 2015 IgG4-related aortitis/periaortitis is a form of non- without evidence of systemic involvement of eleva- infectious aortitis that is distinguished from giant cell tion of serum IgG4 levels. These latter cases typically aortitis and Takayasu aortitis by a lymphoplasmacytic involve aneurysmal segments of the abdominal aorta pattern of inflammation rather than a granulomatous/ that contain severe atherosclerosis and have a giant cell pattern of inflammation, and by increased histologic appearance that in fact overlaps with that – numbers of IgG4-expressing plasma cells.1 6 of severe atherosclerosis. Such cases are also referred IgG4-related aortitis/periaortitis appears to occur in to as IgG4-rich inflammatory atherosclerotic aortic two forms.6 In some cases, there is an outright aortitis aneurysms. Since the presence of an elevated IgG4+ with evidence of systemic IgG4-related disease plasma cell infiltrate is a critical feature for the including elevated serum levels of IgG4. Such cases pathologic diagnosis of this entity, it is important to occur with or without the presence of concurrent understand the factors that can stimulate such an aortic atherosclerosis. In other cases, the disease inflammatory response in the aortic wall. appears to be isolated to a defined aortic segment Recently, some cases of infectious bacterial aortitis were shown to have elevated levels of IgG4+ plasma 7 + Correspondence: Dr JR Stone, MD, PhD, Department of Pathology, cells. In these cases, the degree of IgG4 plasma cell Massachusetts General Hospital, Harvard Medical School, infiltration were such that the cases would satisfy Simches Research Building Room 8236, 185 Cambridge Street international IgG4 staining criteria for IgG4-related CPZN, Boston, MA 02114, USA. aortitis. Patients with IgG4-related disease are E-mail: [email protected] 8 Received 10 June 2015; revised 22 July 2015; accepted 23 July frequently treated with immunosuppression. Thus, 2015; published online 4 September 2015 it is important to be able to distinguish IgG4-related www.modernpathology.org IgG4 in infectious aortitis Z Siddiquee et al 1429 aortitis from infectious forms of aortitis, and to separate control group in a secondary analysis. The understand the factors that drive an elevated IgG4 study was approved by the institution’s human response in the setting of infectious aortitis. To subject’s institutional review board. address this issue, we have analyzed the immuno- histochemical staining of IgG and IgG4 in 17 cases of infectious aortitis, the largest series of infectious Immunohistochemistry and Atherosclerosis Grading aortitis analyzed for IgG4 staining that has been Immunohistochemical staining for IgG and IgG4 was reported to date. performed on formalin-fixed paraffin-embedded tissue, as described previously.3,11 The number of cells expressing IgG and IgG4 were counted using Materials and methods a × 400 high-power field (hpf) measuring 0.16 mm2. Immunohistochemical staining for IgG4 and IgG was Case Selection quantified following international consensus guidelines.12 For each case, the cells in three non- Cases were selected from both autopsies and surgical overlapping × 400 hpfs were counted, and the results specimens obtained during the 9-year period from averaged. The hpfs showing the highest number of January 2006 to January 2015. Inclusion criteria were IgG4-expressing plasma cells were selected for the presence of active suppurative infectious aortitis counting. The degree of aortic atherosclerosis was with bacteria identified on Gram, Grocott’s methen- scored as described previously: Grade 0: intimal amine silver, or Steiner stain and the availability of hyperplasia and fatty streaks; Grade 1: intermediate tissue for analysis.1,9 Patients with prior aortic lesions and atheromas without fibrosis (AHA Grade surgery or endovascular graft placement at the site III and IV lesions); Grade 2: fibroatheromas with of infection were excluded. Seventeen cases met the scarring involving o1/3 of the media; Grade 3: study criteria. Three of these cases have been fibroatheromas with scarring involving ≥ 1/3 of the reported previously.7,10 The results of microbial media.1 culture of either peripheral blood or explanted aortic tissue and antibiotic therapy were obtained from the clinical records. Six consecutive patients, without Data Analysis and Statistical Methods infectious aortitis, who underwent resection of the abdominal aorta for complications of atherosclerosis The cases were divided into four patient groups (aneurysm n = 3, luminal thrombosis n = 3) between based on location and duration of symptoms. For January 2010 and May 2013 were included as a location, the patients were classified as having Table 1 Infectious aortitis patient groups based on duration of symptoms and aortic segment involved Ascending Distala Acute Chronic Acute Chronic N4445 Age, yrs (mean ± s.d.) 70 ± 10 57 ± 20 72 ± 6 70 ± 10 Gender (M/F) 3/1 2/2 1/3 4/1 Duration, days (mean ± s.d.) 10 ± 4 68 ± 40 9 ± 4 60 ± 22 Organisms S. aureus ×2 S. aureus ×3 S. aureus ×2 S. aureus Streptococcus mitis GPCb GPC Group B Streptococcus Group B Streptococcus mixedc S. pneumoniae Pasteurella multocida GPC Antibiotics received Cefepime Atovaquone Cefazolin Cefazolin before surgery or death ceftriaxone × 4 daptomycin cefepime × 3 cefepime × 3 clindamycin gentamicin ciprofloxacin ceftriaxone × 3 doxycycline levofloxacin × 2 imipenem × 2 clindamycin gentamicin × 2 linezolid levofloxacin × 2 daptomycin nafcillin metronidazole linezolid imipenem penicillin nafcillin × 2 metronidazole levofloxacin vancomycin × 4 telvancin piperacillin × 2 linezolid vancomycin × 3 tazobactam × 2 metronidazole × 2 vancomycin × 3 piperacillin × 2 sulfmethoxazole tazobactam × 2 telvancin trimethoprim vancomycin × 4 aDistal: descending thoracic and/or abdominal aorta. bGPC: Gram positive cocci not further characterized. cMixed: Enterococcus and Lactobacillus. Modern Pathology (2015) 28, 1428–1434 IgG4 in infectious aortitis 1430 Z Siddiquee et al involvement of either the ascending aorta or the would satisfy either staining criteria for IgG4-related distal aorta, the latter of which encompasses the disease. descending thoracic aorta and/or abdominal aorta. In contrast to the marked association of IgG4+ For duration, the time interval between the onset of plasma cell infiltration with location and chronicity, symptoms and the surgery or autopsy was deter- the IgG4+ plasma cell counts in this cohort were not mined. A duration of o3 weeks was defined as associated with age or gender for all 17 cases, for the acute, and a duration of 43 weeks was defined as 9 chronic infectious aortitis cases, or for the 9 distal chronic. Immunohistochemical staining was infectious aortitis cases. Likewise, there was no compared across the patient groups using ANOVA association of the IgG4+ plasma cell counts with with post-test by Bonferroni. Atherosclerosis scores Staphylococcus