Leukotriene B4-Mediated Neutrophil Recruitment Causes Pulmonary Capillaritis during Lethal Fungal Sepsis.

Candida albicans bloodstream infection causes fungal septicaemia and death in over half of afflicted patients. Polymorphonuclear leukocytes (PMN) mediate defense against invasive candidiasis, but their role in protection versus tissue injury and sepsis is unclear. We observe PMN intravascular swarming and subsequent clustering in response to C. albicans yeast in a lethal septic mouse and human pulmonary circulation model. Live C. albicans sequester to the endothelium and are immediately captured by complement-dependent PMN chemotaxis, which is required for host survival. However, complement activation also leads to Leukotriene B4 (LTB4)-mediated intravascular PMN clustering and occlusion, resulting in capillaritis with pulmonary hemorrhage and hypoxemia. This clustering is unique to fungi and triggered by fungal cell wall components. PMN clustering is absent in mice lacking LTB4-receptor, and capillaritis is attenuated upon pharmacological LTB4 blockade without affecting phagocytosis. Therefore, therapeutically disrupting infection-induced capillaritis may limit organ injury without impairing host defense during fungal sepsis.

New insights on tuberculous aortitis.

OBJECTIVE: Aortitis is an exceedingly rare manifestation of tuberculosis. We describe 11 patients with tuberculous aortitis (TA). METHODS: Multicenter medical charts of patients hospitalized between 2003 and 2015 with TA in Paris, France, were reviewed. Demographic, medical history, laboratory, imaging, pathologic findings, treatment, and follow-up data were extracted from medical records. TA was considered when aortitis was diagnosed in a patient with active tuberculosis. RESULTS: Eleven patients (8 women; median age, 44.6 years) with TA were identified during this 12-year period. No patient had human immunodeficiency virus infection. Tuberculosis was active in all cases, with a median delay of 18 months between the first symptoms and diagnosis. At disease onset, vascular signs were mainly claudication, asymmetric blood pressure, and diminished distal pulses. Constitutional symptoms or extravascular signs were present in all patients at some point. Aortic pseudoaneurysm was the most frequent lesion, but three patients had isolated inflammatory aortic stenosis. TA appeared as extension from a contiguous infection in only three cases. Tuberculosis was considered because of clinical features, tuberculin skin or QuantiFERON-TB Gold (Quest Diagnostics, Madison, NJ) test results, pathologic findings, and improvement on antituberculosis therapy. A definite Mycobacterium tuberculosis identification was made in only three cases. All patients received antituberculosis therapy for 6 to 12 months. Surgery including Bentall procedures, aortic bypass, and open abdominal aneurysm repair was performed at diagnosis in eight patients. Seven patients received steroids as an adjunct therapy. All patients clinically improved under treatment. No patients died for a median follow-up duration of 4 years. CONCLUSIONS: TA may result in aneurysms contiguous to regional adenitis but also in isolated inflammatory aortic stenosis. Steroids may be associated with antituberculosis therapy for inflammatory stenotic lesions. Surgery is indicated for aneurysms and in case of worsening stenotic lesions despite anti-inflammatory drugs. No patient died after such combined treatment strategy.

Mediastinal Fibrosis of the Pulmonary Artery Secondary to Tuberculosis.

Mediastinal fibrosis is an uncommon disease involving the esophagus, respiratory tract, and great vessels. We report a man who presented with dyspnea on exertion. Computed tomography of the chest demonstrated granulomatous disease with dense calcifications leading to severe stenosis of the main pulmonary artery (PA) and narrowing of the superior vena cava. The results of tuberculosis (TB) interferon-γ release assay and TB-polymerase chain reaction were positive for Mycobacterium tuberculosis. The patient received 2 weeks of treatment for latent TB before undergoing resection of fibrotic tissue and replacement of the main and branch PAs using a homograft.

Acute aortic occlusion with sudden paraplegia secondary to Aspergillus niger embolism from Aspergillus niger aortitis.

Acute aortic occlusion caused by a saddle embolus is a rare vascular emergency. Associated sudden paraplegia secondary to spinal cord ischemia is even more uncommon. Aspergillus surgical site infection is typically linked to cardiac surgery but is exceptional. Here we present a case that combines all of these factors. A 67-year-old man presented with sudden paraplegia from acute aortic occlusion with a saddle embolus from Aspergillus niger aortitis 4 months after aortic valve replacement and aortoplasty. We believe this to be the second reported case of Aspergillus niger aortitis and the first presenting as aortic occlusion with paraplegia.

Acute aortic occlusion from a Candida fungus ball.

Fungal arterial infections are well-described entities resulting in direct invasion of the arterial wall or embolic occlusion of small and medium-sized arteries. However, acute occlusion of large vessels such as the aorta by fungal material is exceedingly rare. A 53-year-old woman presented with acute bilateral lower extremity ischemia. She had a history of fungal endocarditis requiring two prosthetic mitral valve replacements; the last episode was 7 months before the current admission. Imaging studies revealed that she had an acute infrarenal aortic occlusion, with evidence of multiple end-organ emboli. After transfemoral thromboembolectomy, perfusion was restored to her lower extremities with minor neurologic sequelae. She ultimately responded to intravenous antifungal agents.

Proliferation of smooth muscle cells stimulated by Porphyromonas gingivalis is inhibited by apple polyphenol.

BACKGROUND: Porphyromonas gingivalis (Pg) is thought to be involved in the progression of occlusive arterial lesions, whereas vascular smooth muscle cell (SMC) proliferation is considered to be involved in occlusive arterial disease. We previously showed that bacteremia caused by Pg infection induced proliferation of mouse aortic SMCs. Furthermore, human SMCs stimulated with human plasma incubated with Pg showed a marked transformation from the contractile to proliferative phenotype. In the present study, we examine the involvement of Pg gingipains and fimbriae in induction of the SMC transformation and proliferation, and effective inhibitors. METHODS: Pg strains including gingipain- and fimbria-null mutants were incubated in human plasma, after which the bacteria were removed and the supernatants were added to cultured SMCs. To evaluate the effects of inhibitors, Pg organisms were incubated in plasma in the presence of apple polyphenol (AP), epigallocatechin gallate, KYT-1 (Arg-gingipain inhibitor), and KYT-36 (Lys-gingipain inhibitor). RESULTS: Plasma supernatants from wild-type and fimbria-mutant cultures markedly stimulated cellular proliferation, whereas those containing gingipain-null mutants showed negligible effects. SMC proliferation was also induced by plasma treated with trypsin. Furthermore, plasma supernatants cultured in the presence of KYT-1/KYT-36 and AP showed significant inhibitory effects on SMC proliferation, whereas cultures with epigallocatechin gallate did not. CONCLUSION: Our results suggest that Pg gingipains are involved in the induction of SMC transformation and proliferation, whereas this was inhibited by AP.

Basilar artery occlusion after multifactor coagulopathy including Rhizopus oryzae infection in burns.

The authors report a case of a 29-year-old male patient with severe burn injuries (54% TBSA) and inhalation injury. He developed a candidemia and a cutaneous zygomycotic superinfection with Rhizopus oryzae while he received burn intensive care. Despite aggressive surgery, sepsis persisted, and therapy was limited by uncontrollable coagulopathy and catecholamine refractory shock after 15 days. Autopsy revealed a thromboembolic occlusion of the basilar artery that resulted in liquefactive necrosis of the basal brain tissue and the brain stem. Because cerebral vessel occlusions after burn injuries are reported rarely, the current literature was reviewed, and possible pathophysiological aspects are discussed.

Inhalation of Stachybotrys chartarum causes pulmonary arterial hypertension in mice.

Inhalation of Stachybotrys chartarum, a ubiquitous fungus in our living environment, has been suspected as a cause of acute idiopathic pulmonary haemorrhage in infants, but its relation to human diseases is not yet known. The aim of present study was to investigate the effect of repeated intratracheal injection of the fungus into mice, paying special attention to the pulmonary vascular system. Spores of S. chartarum were injected into the trachea of mice from 6 to 18 times over 4-12 weeks, and the lungs were examined by histopathology, morphometrics and haemodynamics. When 1 x 10(4) spores/mouse were injected, histopathological examination showed the development of pulmonary arterial hypertension (PAH). Symmetrical thickening of the intima and media of the pulmonary arterial walls was seen after six injections over 4 weeks. Right ventricular hypertrophy was also evident after 12 injections. PAH was confirmed by the elevation of right ventricular systolic pressure (20.1 +/- 5.7 mmHg in the injected group vs. 12.0 +/- 2.4 mmHg in the control group, P < 0.01). This study showed that the inhalation of S. chartarum caused PAH in mice, suggesting a potential of S. chartarum as a cause of human health problem such as PAH.

Arterial thrombosis after intravenous infusion of oral bacterium in a rat model.

Oral bacteria have been detected at atherosclerotic plaque, aneurysms, and thrombosed arteries in Buerger disease. We explored a possible relationship between the oral bacterium Porphyromonas gingivalis and arterial thrombosis at proximal and distal sites in rats. Eighteen rats underwent subcutaneous placement of an infusion pump connected to the jugular vein. The Pg infusion group received a continuous infusion of P. gingivalis for 2 weeks, and the controls received normal saline. At 2 and 4 weeks, specimens were obtained from the iliac, superficial, and below-knee arteries, which were studied pathologically and by polymerase chain reaction (PCR) analysis to detect P. gingivalis-specific DNA. The Pg infusion group had thrombosis in 33.3% at 2 weeks and in 55.6% at 4 weeks, but normal arterial wall structure was preserved without any features of infection. Positive PCR findings were recognized in 73.3% and 22.2% at 2 and 4 weeks, respectively. At 4 weeks, thrombosis was observed in a higher proportion, with the below-knee specimens having an especially high thrombus rate (83.3%). No control specimen had thrombosis or positive PCR results. Bacteremia due to the oral pathogen P. gingivalis may lead to thrombus formation in the peripheral arteries, especially in small-sized arteries.

Periodontitis may increase the risk of peripheral arterial disease.

OBJECTIVES: The aim of this case control study was to evaluate whether periodontitis was associated with peripheral arterial disease (PAD). SUBJECTS AND METHODS: Twenty-five patients diagnosed with aorto-iliac and/or femoro-popliteal occlusive disease and thirty-two generally healthy control subjects were enrolled in this study. Polymerase chain reaction (PCR) was used to identify Porphyromonas gingivalis, Treponema denticola, Actinobacillus actinomycetemcomitans, Prevotella intermedia, Cytomegalovirus (CMV), Chlamydia pneumoniae, and Helicobacter pylori in tissue specimens taken from the anastomotic site of distal bypasses. Periodontal status was evaluated; serum IgG titres against the four listed bacteria were measured. RESULTS: Periodontopathic bacteria were detected in 13/25 (52%) atherosclerotic specimens. CMV or C. pneumoniae was detected in 1/25 (4%) specimens; H. pylori was not detected from any of these specimens. Fontaine grade III or IV patients showed higher detection frequency of P. gingivalis than Fontaine grade II patients (57.1% vs 22.2%, P=0.09). After adjusting for age, gender, diabetes and smoking, periodontitis increased 5-fold the risk of having PAD (OR 5.45). There were preliminary indications that periodontitis was associated with increased serum IL-6 and TNF-alpha concentrations. CONCLUSIONS: This study suggests that periodontitis may be associated with an increased risk of PAD. This association could result from the increased concentration of serum inflammatory cytokines in those with periodontitis.

Subclavian artery occlusion and pseudoaneurysm caused by lung apex mucormycosis: successful treatment with transcatheter embolization.

Subclavian artery pseudoaneurysm and occlusion in young patients are usually post-traumatic. We report the case of a 33-year-old diabetic woman with subclavian artery occlusion and pseudoaneurysm formation caused by pulmonary mucormycosis infection. The patient presented with diabetic ketoacidosis, Horner's syndrome, and absent left arm pulses. A cystic lesion of the left lung apex was found by imaging, was surgically resected, and was histologically diagnosed as mucormycosis infection. Magnetic resonance angiography depicted a left subclavian artery pseudoaneurysm and occlusion adjacent to the mucormycosis lesion. To protect against thromboembolic complications and rupture, the pseudoaneurysm was embolized with coils. The patient is clinically well 1 year after the intervention with no perfusion of the pseudoaneurysm.

Investigation of Chlamydia pneumoniae DNA, chlamydial lipopolisaccharide antigens, and Helicobacter pylori DNA in atherosclerotic plaques of patients with aortoiliac occlusive disease.

BACKGROUND AND INTRODUCTION: It has been suggested that chronic infections may have a role in both the initiation and progression of atherosclerosis. While the majority of available data are focused on coronary artery disease, our aim was to investigate the presence of Chlamydia pneumoniae and Helicobacter pylori in samples from aortoiliac occlusive disease. METHODS: Aorta-iliac atherectomy specimens were collected under sterile conditions from 21 patients (19 male, 2 female) undergoing surgery for aortoiliac occlusive disease. Seventeen macroscopically healthy vessels (12 internal mammary arteries, 3 radial arteries, prepared for coronary artery bypass graft, and 2 traumatic artery specimens, one of which was a superficial femoral artery and the other was a radial artery) were used as control. Blood samples for serological assays were obtained immediately before surgery. The polymerase chain reaction (PCR) was employed to search for H. pylori and C. pneumoniae DNA in atherosclerotic plaques and healthy vessel samples. Group-specific chlamydial lipopolysaccharide (LPS) antigens in atherosclerotic plaques and in healthy vessel samples and serum IgG antibodies to chlamydial LPS were determined by using a commercially available enzyme-linked immunosorbent assay (ELISA). Antibodies to H. pylori were also tested in all cases by means of an in-house ELISA. RESULTS: Chlamydial LPS and DNA were detected in 6 of 21 (28.57%) atherosclerotic lesions using ELISA or PCR, respectively. There was no evidence of H. pylori DNA in any plaque specimens. All cases in which C. pneumoniae DNA was positive were also seropositive for antichlamydial LPS. Neither C. pneumoniae DNA nor antigen nor H. pylori DNA was found in the macroscopically healthy samples. CONCLUSION: Our results suggest that C. pneumoniae but not, as proposed, H. pylori may be involved in the pathogenesis of aortoiliac atherosclerosis.

Relationship between peripheral arterial occlusive disease (PAOD) and chronic Chlamydophila (Chlamydia) pneumoniae infection. A meta-analysis.

We carried out a meta-analysis of observational case-control studies published before May 2004 to assess the degree of association between Chlamydophila pneumoniae (Cp) infection and PAOD. A search of the Medline database was performed using atherosclerosis and "Chlamyd* pneumoniae" as keywords. Strict criteria were applied for the selection of case studies, which had to be studies of Cp seroprevalence or of Cp detection in patients versus controls. Forty-three published studies that met these criteria were selected. An association between PAOD and Cp was revealed by immunohistochemical analysis (OR=15.4, 95%CI=5.0-46.9) and nested PCR studies of arterial biopsies (OR=4.3, 95%CI=1.8-10), by PCR study of non-arterial samples (OR=2.9, 95%CI=1.2-7.0), by other direct-detection tests (OR=16.7, 95%CI=7.0-39.8), and by ELISA and MIF tests to detect high IgG (OR=2, 95%CI=1.1-3.5 and OR=1.7, 95%CI=1.0-2.9, respectively) and IgA (OR=1.9, 95%CI=1.1-3.4 and OR=1.5, 95%CI=1.1-2.0, respectively) titers. No significant association was found in simple PCR studies of arterial biopsies, MIF tests to detect low IgG titers or IgM, or ELISA studies to detect IgM. According to this review, the association between Cp infection and PAOD depends on the analytical method adopted. Establishing a relationship between Cp and PAOD will require a case-control study with an adequate number of cases and samples that uses a combination of direct and indirect techniques to identify the presence of the bacterium in different types of sample from the same subjects, correlating the results with the activity of the disease.

Determinants of lumbar artery occlusion among patients with sciatica: a three-year follow-up with magnetic resonance angiography.

We showed previously that chronic Chlamydia pneumoniae infection increases the risk of lumbar artery occlusion. We did not evaluate, however, the effect of other risk factors for cardiovascular diseases in combination with this chronic infection. The purpose of this study was to investigate the combined effect of chronic C. pneumoniae infection and other known determinants of artery occlusion in a population of sciatica patients. Two-dimensional time-of-flight magnetic resonance angiography (MRA) was used to evaluate lumbar arteries at baseline and three years. The arteries on both sides (L1-L4) were evaluated visually and scored as normal, narrowed or occluded. Logistic regression analysis was performed separately for baseline total arterial stenosis and each L1-L4 segmental artery pair, and for incident new stenosis during the follow-up period. The determinants analyzed included age, body mass index (BMI, kg/m(2)), education, gender, and smoking, in addition to presence of chronic C. pneumoniae infection. MRA was obtained at baseline for 147 patients and at 3 years for 134 patients. Sixty-four (47.8%) of 134 patients had new arterial stenosis. Total incidence of new arterial stenosis was distributed quite evenly between the individual segmental levels, varying from 12.7 to 18.6%. BMI was the only predictor of new arterial stenosis (odds ratio (OR) 1.13). A reasonable logistic model could be established only for baseline L4 and total arterial scores. At L4, education was a protective factor (OR 0.07), whereas age (OR for the oldest age group 6.7) and BMI (OR 1.17) were associated with increased risk of occlusion. For total arterial score, chronic C. pneumoniae infection was an independent determinant of arterial occlusion, increasing the risk to almost eightfold. Additionally, BMI (OR 1.16), and age (for the oldest age group OR 11.4) were significant determinants for stenosis. Smoking was not statistically significant. As chronic C. pneumoniae infection was an independent determinant of lumbar artery occlusion, treatments of this chronic infection may have an impact on lumbar diseases. The importance of BMI for new arterial stenosis suggests that weight reduction may also have a beneficial effect in lumbar artery disease.

Progression of peripheral arterial occlusive disease is associated with Chlamydia pneumoniae seropositivity and can be inhibited by antibiotic treatment.

A possible influence of Chlamydia pneumoniae seropositivity on the clinical course of peripheral arterial occlusive disease (PAOD) has not been investigated previously. Though roxithromycin therapy was found to inhibit progression of PAOD, the nature of this effect (antibiotic or anti-inflammatory) has remained elusive. The course of PAOD was prospectively assessed in elderly men during 4 years, comparing 51 C. pneumoniae seropositive (IgG>/=1:128) with 46 seronegative patients (IgG<1:64 and IgA<1:32). Twenty of the seropositive patients were treated with roxithromycin (400 mg daily) for 4 weeks. Limitation of the walking distance to 200 m or less was observed in 55% of the seropositive untreated patients as compared to 30% of both, seronegative and macrolide-treated patients. The number of invasive revascularizations per patient was 1.7 in the seropositive untreated group as compared to 0.5 in the seronegative and the macrolide-treated group. Considering possible confounding variables, such as classical vascular risk factors, ordinal regression analyses showed a significant association of C. pneumoniae seropositivity with limitation of the walking distance (p=0.027) and need for invasive revascularization (p=0.037). The effect of macrolide treatment on these outcome measures was marked (p<0.001 and p=0.040, respectively) during 2.7 years but decreased in the second part of the observation period. This study provides good evidence that C. pneumoniae are involved in the progression of PAOD and that antibiotic treatment directed against C. pneumoniae is effective in inhibiting this process.

Detection and localization of periodontopathic bacteria in abdominal aortic aneurysms.

OBJECTIVES: We examined a possible link between periodontal disease and abdominal aortic aneurysm (AAA) by studying resected aneurysmal specimens from AAA patients for the presence of periodontopathic bacteria. DESIGN: Prospective case control study. MATERIAL AND METHODS: Thirty-two AAA patients were enrolled in the study. Periodontitis was classified according to the probing depth of periodontal pocket. Thirty-two aneurysmal walls, 16 mural thrombi, 5 atherosclerotic occlusive aorta and 5 control arterial tissue, were examined for 7 periodontal bacteria using polymerase chain reaction (PCR) method. The localization of the bacteria in the aneurysmal/atherosclerotic wall was determined by thromboendarterectomy. RESULTS: All patients had periodontal disease, and most cases were severe. PCR examination of the aneurysmal specimens showed that 86% were positive for periodontal bacterial DNA. No bacteria were detected in the control specimens. The bacteria were found in both the intimal/medial layer and the adventitial layer of the aneurysmal wall but only in intimal/medial layer of the atherosclerotic occlusive aorta. CONCLUSION: Periodontopathic bacteria were present in a high percentage of specimens of diseased arteries from AAA patients and were found throughout the whole aneurysmal wall. These bacteria may play a role in the development of AAAs and/or contribute to weakening the aneurysmal wall.