Endovascular Treatment of Post Type A Chronic Aortic Arch Dissection With a Branched Endograft: Early Results From a Retrospective International Multicenter Study.
Annals of surgery
Verscheure, D., Haulon, S., Tsilimparis, N., Resch, T., Wanhainen, A., Mani, K., Dias, N., Sobocinski, J., Eagleton, M., Ferreira, M., Schurink, G. W., Modarai, B., Abisi, S., Kasprzak, P., Adam, D., Cheng, S., Maurel, B., Jakimowicz, T., Watkins, A. C., Sonesson, B., Claridge, M., Fabre, D., Kolbel, T.
2019
Abstract
MINI: The objective of this study was to evaluate the outcome of endovascular repair of chronic aortic arch dissecting aneurysms with a custom-made branched endograft during follow-up after acute type A aortic dissection open repair. Unmatched outcomes are reported in a population at high risk for a redo sternotomy.OBJECTIVE: The objective of this study was to evaluate the outcome of endovascular aortic arch repair for chronic dissection with a custom-made branched endograft.BACKGROUND: Acute type A aortic dissections are often treated with prosthetic replacement of the ascending aorta. During follow-up, repair of an aneurysmal evolution of the false lumen distal to the ascending prosthesis can be a challenge both for the surgeon and the patient.METHODS: We conducted a multicenter, retrospective study of consecutive patients from 14 vascular units treated with a custom-made, inner-branched device (Cook Medical, Bloomington, IN) for chronic aortic arch dissection. Rates of in-hospital mortality and stroke, technical success, early and late complications, reinterventions, and mortality during follow-up were evaluated.RESULTS: Seventy consecutive patients were treated between 2011 and 2018. All patients were considered unfit for conventional surgery. In-hospital combined mortality and stroke rate was 4% (n = 3), including 1 minor stroke, 1 major stroke causing death, and 1 death following multiorgan failure. Technical success rate was 94.3%. Twelve (17.1%) patients required early reinterventions: 8 for vascular access complication, 2 for endoleak correction, and 2 for pericardial effusion drainage. Median follow-up was 301 (138-642) days. During follow-up, 20 (29%) patients underwent secondary interventions: 9 endoleak corrections, 1 open repair for prosthetic kink, and 10 distal extensions of the graft to the thoracic or thoracoabdominal aorta. Eight patients (11%) died during follow-up because of nonaortic-related cause in 7 cases.CONCLUSIONS: Endovascular treatment of aortic arch chronic dissections with a branched endograft is associated with low mortality and stroke rates but has a high reintervention rate. Further follow-up is required to confirm the benefits of this novel approach.
View details for PubMedID 30973389
Abstract
Connective Tissue Disease (CTD) represents a group of genetic conditions characterized by disruptive matrix remodeling. When this process involves aortic and vascular wall, patients with CTD have a high risk of developing arterial aneurysms, dissections and ruptures. Open surgical repair is still the gold standard therapy for patients with CTD with reasonable morbidity and mortality risk. The surgical treatment of CTD often requires multiple operations. In the endovascular era, fenestrated and branched stent grafts may play a role in reducing the complications of multiple open operations. Although the long-term results of endovascular treatment in the setting of CTD are unknown, it is generally accepted that endovascular treatment is restricted to selected patients with high surgical risk. In an emergency setting, endovascular intervention can serve as a lifesaving bridge to elective open aortic repair. Aortic centers performing a large volume of complex open and endovascular aortic repairs have started to combine these 2 techniques in a staged fashion. The goal is to reduce the morbidity and mortality associated with extensive aortic repairs in CTD patients. For this reason, recommend endovascular therapy when a "graft to graft" approach is possible. In this scenario, the surgeon who performs the open repair must take into consideration future interventions. Surgical repair in any aortic segment should allow creation of proximal and distal landing zones over 4 cm to secure the sealing of a future stent graft. Connective tissue disease should be treated with a multidisciplinary approach, in high volume centers. Endovascular treatment represents a potential option in patients at high risk for open repair. Staged hybrid procedures have emerged as a way to reduce spinal cord ischemia and avoid multiple open surgeries. The aim of this article is to discuss the management of aortic diseases in CTD, focusing on to the role of standard open surgery and emerging endovascular treatment, and to give an overview of the few series published regarding this topic with a small number of patients.
View details for PubMedID 29943958
Abstract
Only 40% of patients with atrial fibrillation (AF) undergoing cardiac surgery are treated with surgical AF correction. We prospectively studied endocardial cryoablation of the Cox-maze III lesion set following prespecified rhythm assessment with outpatient telemetry.Between 2007 and 2011, 136 patients underwent surgical AF correction using an argon-powered cryoablation device. Patients wore continuous electrocardiogram monitoring prior to and at 6, 12, and 24 months after surgery. The average length of monitoring was 6.5±1 days prior to surgery and 11±4 days at each time point after surgery. Patients were assessed for cardiac rhythm, interval cardioversion or ablation procedures, pacemaker placement, and the use of warfarin or antiarrhythmic medications. The primary endpoint of this study was freedom from AF at 1 year.Mean patient age was 66±12 years, 50% (69 of 138) were male and 41% (55 of 134) had persistent AF. CryoMaze was done in conjunction with mitral valve operation in 95% (131 of 138) and other procedures in 41% (56 of 138). Follow-up was 96% complete at 1 year and 90% at 2 years. Freedom from AF was 76% at 1 year. Perioperative mortality and stroke rates were both 1.5% (2 of 138). Perioperative pacemaker implantation was required in 7% (9 of 136). In univariate analysis, younger age, female gender, decreased height and weight, smaller preoperative and postoperative left atrial diameter, intermittent AF, and freedom from AF at discharge were associated with freedom from AF at 1 year. Actuarial 2- and 4-year (Kaplan-Meier) survival were 93% and 80%, respectively.The CryoMaze procedure is safe and is associated with 76% freedom from AF at 1 year.
View details for DOI 10.1016/j.athoracsur.2013.10.041
View details for Web of Science ID 000333810300022
View details for PubMedID 24582049
Abstract
Any quantitative assessment of blood flow using conventional angiography remains impossible with current technology. Physicians decide the clinical end point of a procedure by subjective interpretation. Color-coded digital subtraction angiography has been invented to meet this demand and is used primarily in neuroradiology. This report presents the endovascular treatment of a rare complex combination of peripheral artery disease and arteriovenous fistula using guidance of blood flow parameters, such as area under the curve.
View details for DOI 10.1016/j.jvscit.2019.03.002
View details for PubMedID 31304438
Abstract
We describe renal stent migration following thoracic endovascular aortic repair (TEVAR) for type B aortic dissection. A 68-year-old male presented with type B aortic dissection. His course was complicated by renal and lower extremity malperfusion. Thoracic endovascular aortic repair was performed and completion angiogram showed no flow in the left renal artery. A renal stent was deployed with the proximal margin of the stent 1 mm into the aortic true lumen, providing improved renal perfusion. One week after TEVAR, contrast-enhanced computed tomography (CT) revealed that the renal stent had embolized to the aortic bifurcation. Additional endovascular therapy successfully crushed the renal stent against the iliac artery wall utilizing a larger bare metal stent. At 3 year follow-up, contrast-enhanced CT demonstrated good patency of the left renal artery and right iliac artery. This complication alerts physicians to consider subsequent aortic remodeling during endovascular intervention for acute aortic dissection with malperfusion.
View details for PubMedID 31010401
Abstract
Endovascular treatment of infrarenal abdominal aortic aneurysm (AAA) with proximal chronic aortic dissection is challenging as a false and true lumen at the level of the infra-renal neck does not allow a sufficient landing zone. We describe staged endovascular neck stabilization prior to standard endovascular aortic repair (EVAR) for AAA with chronic aortic dissection.To create a stable proximal neck (PN) by closing entry tears, thereby resulting in total false lumen thrombosis (FLT) prior to standard EVAR. Case 1 false lumen fenestrations were present at the descending aorta, the right renal artery orifice and PN. After closing the entry tear by thoracic EVAR, an aortic cuff was placed in the true lumen of the PN and renal stenting for the right renal artery was performed. After 2 months, total FLT was achieved, and EVAR was performed. Case 2 false lumen fenestrations were present at the descending, super celiac aorta and PN. After closing the entry by TEVAR, aortic cuffs were placed at infrarenal aorta to close residual entries. After 1 month of achieving total FLT, EVAR was performed. Both cases had no type 1 endoleak during follow-up.The endovascular neck stabilization is a useful treatment option that facilitates standard EVAR for AAA in chronic aortic dissection.
View details for DOI 10.1007/s00270-019-02277-8
View details for PubMedID 31254039
Abstract
To compare the outcome of endovascular aortic aneurysm repair (EVAR) using the Zenith Spiral Z leg (ZSLE) versus the Zenith Flex leg (TFLE).Patients undergoing EVAR using TFLE or ZSLE between October 2009 and December 2017 were retrospectively reviewed. Clinical endpoints were freedom from limb related complications and change of arterial tortuosity indexes. Limb related complication was defined as limb stenosis or occlusion, stent kink, stent disconnection and type1b endoleak. Tortuosity indexes were measured on the preoperative and postoperative CT and compared.A total of 56 patients (11 female, average age was 78.5 ± 5.5 years), 111 limbs were enrolled. One patient was treated using Aorto-uni iliac device. TFLE was deployed in 43 limbs (22 patients), ZSLE in 68 limbs (34 patients). Average follow up was 43.6±27.6 months. In follow-up, eight limb related complications occurred in TFLE group and two in ZSLE group. Freedom from limb related complications at three years was 84.4% in TFLE group and 96.1% in ZSLE group (p=0.039). There was no statistically significant difference between TFLE and ZSLE group in the Aorto-iliac tortuosity change (TFLE vs ZSLE; -6.1 ± 5.8 vs -4.9 ± 6.4, p=0.324). However, there was significant in the Iliac tortuosity change (-7.4 ± 11.7 vs -3.0 ± 7.9, p=0.022).Spiral Z leg showed less occurrence of limb related complications and less iliac artery tortuosity index change compared to Zenith Flex leg. The spiral Z provided better conformability as a stentgraft limb.
View details for PubMedID 31071429
Abstract
A 38-year-old woman, with no comorbidities, presented to an outside institution with a 10-cm aortic arch and descending thoracic aortic aneurysm. After an aborted attempt at hybrid repair, she underwent successful, staged repair with zone 1thoracic endovascular aortic repair and open aneurysmal sac revision. The patient made an uneventful recovery with computed tomographic evidence of complete aneurysmal exclusion. This case demonstrates many of the techniques and issues in the evolving field of aortic arch repair.
View details for PubMedID 30583900
Abstract
Suppressing perioperative inflammation and post-operative atrial fibrillation requires effective drug delivery platforms (DDP). Localized anti-inflammatory and anti-arrhythmic agent release may be more effective than intravenous treatment to improve patient outcomes. This study utilized a dexamethasone (DEX) and amiodarone (AMIO)-loaded Parylene-C (PPX) nano-structured film to inhibit inflammation and atrial fibrillation. The PPX film was tested in an established pericardial adhesion rabbit model. Following sternotomy, the anterior pericardium was resected and the epicardium was abraded. Rabbits were randomly assigned to five treatment groups: control, oxidized PPX (PPX-Oxd), PPX-Oxd infused with DEX (PPX-Oxd[DEX]), native PPX (PPX), and PPX infused with DEX and AMIO (PPX[AMIO, DEX]). 4 weeks post-sternotomy, pericardial adhesions were evaluated for gross adhesions using a 4-point grading system and histological evaluation for epicardial neotissue fibrosis (NTF). Atrial fibrillation duration and time per induction were measured. The PPX[AMIO, DEX] group had a significant reduction in mean adhesion score compared with the control group (control 2.75 ± 0.42 vs. PPX[AMIO, DEX] 0.25 ± 0.42, P < 0.001). The PPX[AMIO, DEX] group was similar to native PPX (PPX 0.38 ± 0.48 vs. PPX[AMIO, DEX] 0.25 ± 0.42, P=NS). PPX-Oxd group adhesions were indistinguishable from controls (PPX-Oxd 2.83 ± 0.41 vs. control 2.75 ± 0.42, P=NS). NTF was reduced in the PPX[AMIO, DEX] group (0.80 ± 0.10 mm) compared to control (1.78 ± 0.13 mm, P < 0.001). Total duration of atrial fibrillation was decreased in rabbits with PPX[AMIO, DEX] films compared to control (9.5 ± 6.8 s vs. 187.6 ± 174.7 s, p = 0.003). Time of atrial fibrillation per successful induction decreased among PPX[AMIO, DEX] films compared to control (2.8 ± 1.2 s vs. 103.2 ± 178 s, p = 0.004). DEX/AMIO-loaded PPX films are associated with reduced perioperative inflammation and a diminished atrial fibrillation duration. Epicardial application of AMIO, DEX films is a promising strategy to prevent post-operative cardiac complications.
View details for DOI 10.1039/c5nr07456h
View details for Web of Science ID 000370761700049
View details for PubMedID 26838117
Abstract
The scarcity of donor organs has led to the development of devices that provide optimal long-term respiratory or cardiopulmonary support to bridge recipients as they wait for lung and/or heart transplantation. This study was designed to evaluate the 30-day in vivo performance of the newly developed pediatric pump-lung (PediPL) for cardiopulmonary support using a juvenile sheep model. The PediPL device was placed surgically between the right atrium and descending aorta in eight sheep (25.4-31.2 kg) and evaluated for 30 days. Anticoagulation was maintained with continuous heparin infusion (activated clotting time 150-200 s). The flow rate was measured continually, and gas transfer was measured daily. Plasma free hemoglobin, platelet activation, hematologic data, and blood biochemistry were assessed twice a week. Sheep were euthanized after 30 days. The explanted devices were examined for gross thrombosis. Six sheep survived for 30-32 days. During the study, the oxygen transfer rate of the devices was 54.9 ± 13.2 mL/min at a mean flow rate of 1.14 ± 0.46 L/min with blood oxygen saturation of 95.4% ± 1.7%. Plasma free hemoglobin was 8.2 ± 3.7 mg/dL. Platelet activation was 5.35 ± 2.65%. The animals had normal organ chemistries except for surgery-related transient alterations in kidney and liver function. Although we found some scattered thrombi on the membrane surfaces of some explanted devices during the necropsy, the device function and performance did not degrade. The PediPL device was capable of providing cardiopulmonary support with long-term reliability and good biocompatibility over the 30-day duration and offers the potential option for bridging pediatric patients with end-stage heart or lung disease to heart and/or lung transplantation.
View details for DOI 10.1111/aor.12487
View details for Web of Science ID 000366398800004
View details for PubMedID 25921361
View details for PubMedCentralID PMC4793917
Abstract
Despite the significant contribution of the Fontan procedure to the therapy of complex congenital heart diseases, many patients progress to failure of their Fontan circulation. The use of ventricular assist devices to provide circulatory support to these patients remains challenging. In the current study, a continuous axial-flow pump was used to support a univentricular Fontan circulation. A modified Fontan circulation (atrio-pulmonary connection) was constructed in six Yorkshire piglets (8-14 kg). A Dacron conduit (12 mm) with two branches was constructed to serve as a complete atrio-pulmonary connection without the use of cardiopulmonary bypass. The Impella pump was inserted into the conduit through an additional Polytetrafluoroethylene (PTFE) graft in five animals. Hemodynamic data were collected for 6 hours under the supported Fontan circulation. The control animal died after initiating the Fontan circulation independent of resuscitation. Four pump supported animals remained hemodynamically stable for 6 hours with pump speeds between 18,000 rpm and 22,000 rpm (P1-P3). Oxygen saturation was maintained between 95% and 100%. Normal organ perfusion was illustrated by blood gas analysis and biochemical assays. A continuous axial-flow pump can be used for temporal circulatory support to the failing Fontan circulation as "bridge" to heart transplantation or recovery.
View details for DOI 10.1097/MAT.0000000000000172
View details for Web of Science ID 000352853600014
View details for PubMedID 25396272
Abstract
Device availability of mechanical circulatory or respiratory support to the right heart has been limited. The purpose of this study was to investigate the effect of right heart unloading and respiratory support with a wearable integrated artificial pump-lung (APL).The APL device was placed surgically between the right atrium and pulmonary artery in 7 sheep. Anti-coagulation was performed with heparin infusion. The device's ability to unload the right ventricle (RV) was investigated by echocardiograms and right heart catheterization at different bypass flow rates. Hemodynamics and echocardiographic data were evaluated. APL flow and gas transfer rates were also measured at different device speeds.Hemodynamics remained stable during APL support. There was no significant change in systemic blood pressure and cardiac index. Central venous pressure, RV pressure, RV end-diastolic dimension and RV ejection fraction were significantly decreased when APL device flow rate approached 2 liters/min. Linear regression showed significant correlative trends between the hemodynamic and cardiac indices and device speed. The oxygen transfer rate increased with device speed. The oxygen saturation from the APL outlet was fully saturated (>95%) during support. The impact of APL support on blood elements (plasma free hemoglobin and platelet activation) was minimal.APL device support significantly unloaded the RV with increasing device speed. The device also provided stable hemodynamics and respiratory support in terms of blood flow and oxygen transfer. The right heart unloading performance of this wearable device needs to be evaluated further in an animal model of right heart failure with long-term support.
View details for DOI 10.1016/j.healun.2014.02.026
View details for Web of Science ID 000340013800012
View details for PubMedID 24746636
View details for PubMedCentralID PMC4112015
Abstract
A 64-year-old male with end-stage lung disease underwent right orthotopic lung transplantation. After doing well initially, he developed acute hypoxemic respiratory failure with allograft pneumonia. Donor operative cultures demonstrated mold of the Mucor species, which were corroborated by donor endobronchial cultures obtained near the right mainstem bronchial anastomosis. The patient was treated with reoperative bilateral orthotopic lung transplantation in combination with antifungal agents. The operation was performed successfully, using lungs donated after cardiac death and treated with ex vivo lung perfusion. The patient has recovered well, remaining on room air with good allograft function, without evidence of fungal disease.
View details for DOI 10.1016/j.athoracsur.2013.08.065
View details for Web of Science ID 000338432600084
View details for PubMedID 24996716
Abstract
Large animal models serve as a critical link in the translation of basic science to clinical practice. However, large animal models of myocardial infarction (MI), especially large size MI, have been associated with high mortality because of arrhythmia. The prophylactic effect of amiodarone and lidocaine were retrospectively reviewed in our ovine MI model.A total of 114 Dorset hybrid sheep with 25%-30% MI were included in the present study. The sheep were prophylactically treated with amiodarone plus lidocaine before ligation of the four to six coronary artery branches supplying the apex of the heart (arrhythmia prevention [AP] group, n = 45) and with epinephrine (shock prevention [SP] group, n = 49), respectively. The sheep without prophylactic treatment (no prevention [NP] group, n = 20) were used as the control group. The incidence of arrhythmia requiring treatment, mortality due to arrhythmia, hemodynamics, and arterial blood gas values during surgery were analyzed in these three groups.No significant difference was found in infarct size among the three groups. The incidence of arrhythmia requiring treatment was significantly decreased in the AP group compared with that in the NP or SP groups (4.4% for AP versus 35% for NP and 45% for SP groups; P < 0.05). The mortality due to lethal arrhythmia was 2.2% in the AP group, significantly lower than that in the NP group (15%) or SP group (18.4%). Other than the heart rate, no significant differences were found in the hemodynamic data between the AP and NP groups. Metabolic acidosis was not observed in any group, as indicated by the pH and lactate values.Prophylactic amiodarone plus lidocaine decreased the mortality due to lethal arrhythmia after acute MI in our sheep model without significant negative effects on the hemodynamics. However, epinephrine improved the hemodynamics but also increased the mortality due to lethal arrhythmia. Thus, prophylactic amiodarone plus lidocaine is recommended to improve the stability in a large MI animal model.
View details for DOI 10.1016/j.jss.2013.05.050
View details for Web of Science ID 000325951100047
View details for PubMedID 23773712
View details for PubMedCentralID PMC3797844
Abstract
Current lung transplantation guidelines stipulate that the ideal donor is aged younger than 55 years, but several institutions have reported that outcomes using donors aged 55 years and older are comparable with those of younger donors.We retrospectively reviewed the United Network for Organ Sharing (UNOS) database to identify all adult lung transplants between 2000 and 2010 in the United States. Patients were stratified by donor age 18 to 34 (reference), 35 to 54, 55 to 64, and ≥ 65 years. Primary outcomes included survival at 30 days and at 1, 3, and 5 years and rates of bronchiolitis obliterans syndrome (BOS). Survival was assessed using the Kaplan-Meier method. Risk factors for mortality were identified by multivariable Cox and logistic regression.We identified 10,666 recipients with median follow-up of 3 years (range, 0-10 years). Older donors were more likely to have died of cardiovascular or cerebrovascular causes, but there were no differences in recipient diagnosis, lung allocation score, or incidence of BOS as a function of donor age. The use of donors aged 55 to 64 years was not a risk factor for mortality at 1 year (odds ratio, 1.1; p = 0.304) or 3 years (odds ratio, 0.923; p = 0.571) compared with the reference group; however, use of donors aged > 65 years was associated with increased mortality at both time points (odds ratio, 2.8 and 2.4, p < 0.02).Outcomes after lung transplantation using donors aged 55 to 64 years were similar to those observed with donors meeting conventional age criteria. Donors aged ≥ 65 years, however, were associated with decreased intermediate-term survival, although there was no increased risk of BOS for this group.
View details for DOI 10.1016/j.healun.2013.04.012
View details for PubMedID 23664760
Abstract
The infant Jarvik 2000 heart is a very small, hermetically sealed, intracorporeal, axial-flow ventricular assist device (VAD) designed for circulatory support in neonates and infants. The anatomic fit, short-term biocompatibility and hemodynamic performance of the device were evaluated in a neonate piglet model.The infant Jarvik 2000 heart with two different blade profiles (low- or high-flow blade design) was tested in 6 piglets (8.8 ± 0.9 kg). Using a median sternotomy, the pump was placed in the left ventricle through the apex without cardiopulmonary bypass. An outflow graft was anastomosed to the ascending aorta. Hemodynamics and biocompatibility were studied for 6 hours.All 6 pumps were implanted without complication. Optimal anatomic positioning was found with the pump body inserted 2.4 cm into the left ventricle. Hemodynamics demonstrated stability throughout the 6-hour duration. The pump flow increased from 0.27 to 0.95 liter/min at increasing speeds from 18 to 31 krpm for the low-flow blade design, whereas the pump flow increased from 0.54 liter/min to 1.12 liters/min at increasing speeds from 16 krpm to 31 krpm for the high-flow blade design. At higher speeds, >80% of flow could be supplied by the device. Blood chemistry and final pathology demonstrated no acute organ injury or thrombosis for either blade design.The infant Jarvik 2000 heart is anatomically and biologically compatible with an short-term neonate piglet model. This in vivo study demonstrates the future feasibility of this device for clinical use.
View details for DOI 10.1016/j.healun.2012.10.011
View details for Web of Science ID 000313223000018
View details for PubMedID 23260711
View details for PubMedCentralID PMC3546489
Abstract
There is a scarcity of source material available in animal models appropriate to test pediatric-size blood pump design for assisting the left ventricle. A juvenile ovine animal model was developed to evaluate two pediatric ventricular assist devices (VADs). The child-size Jarvik 2000 and CircuLite VADs were tested with this model. The 33 in vivo experiments were retrospectively studied to evaluate the reliability of the animal model. Dorset hybrid juvenile sheep (20~36 kg) were used to evaluate the small pediatric VADs. Under general anesthesia, a left lateral thoracotomy was performed through the fifth intercostal space. The devices were implanted between the left ventricle apex and the descending aorta without cardiopulmonary bypass. Heparin was infused continuously for anticoagulation therapy. Support duration averaged 26.7 ± 19.6 days. Completion of 75.7% (25/33) experiments was done as intended. The animals were docile and did not require sitters beyond the immediate operative period. Complication includes leg injury, graft infection, gastrointestinal bleeding, intravenous line disconnection, weight loss, renal failure, red urine, (one for each) and pulmonary failure in two. Activated clotting time was adjusted via continuous intravenous heparin to 150-200 seconds. Reliable hemodynamics and biocompatibility data were collected for evaluate pediatric intracorporeal VADs in the animal model. The juvenile sheep model is reliable, reproducible, and translatable for testing pediatric VADs. These experiments provided vital information for improvement of the devices and for clinical application in the future.
View details for DOI 10.1097/MAT.0b013e31827986fe
View details for PubMedID 23254234
View details for PubMedCentralID PMC3532522
Abstract
Antibodies to pneumococcus are thought to represent the primary mechanism of naturally acquired resistance to colonization. Here, however, we show that, in patients with chronic obstructive pulmonary disease (COPD), resistance to pneumococcal colonization is not associated with higher concentrations of serum anti-capsular or -noncapsular antibodies. We compared preacquisition serum antibody concentrations to capsular antigens 6B, 7F, 14, 19F, and 23F from patients with COPD who did and did not acquire pneumococcal respiratory tree colonization over the course of 2 years. Colonized patients did not have lower anti-capsular antibody concentrations than control subjects who did not acquire pneumococcus. We found no difference in functional antibody concentrations between colonized patients and control subjects. Furthermore, colonized patients had significantly higher preacquisition concentration of antibody directed against the whole cell and pneumococcal surface protein A than control subjects. We thus conclude that, in adult patients with COPD, resistance to pneumococcal colonization is unlikely to be determined by higher serum antibody concentrations to pneumococcal antigens.
View details for DOI 10.1086/520937
View details for Web of Science ID 000249251800018
View details for PubMedID 17703425
Abstract
Serotype-specific immunity to Streptococcus pneumoniae is conferred by antibodies to the capsular polysaccharides, which define the 90 known serotypes. Whether antibody to the species-common cell wall polysaccharide (C-Ps) is protective has been a matter of controversy. Here we show that C-Ps given intranasally with mucosal adjuvant increased the resistance of mice to experimental nasopharyngeal colonization by capsulated S. pneumoniae of serotype 6B. This immunity could be induced in mice congenitally lacking immunoglobulin but was dependent upon CD4+ T cells. Elimination of the charged amino group on the polymer backbone by N acetylation of C-Ps reduced the immunity, as did treatment of the mice with antibody to the cytokine interleukin-17A at the time of challenge, both consistent with the hypothesis of T-cell activation due to the zwitterionic motif of the polymer. C-Ps also protected in a model of fatal aspiration pneumonia by heavily capsulated serotype 3. These findings suggest a novel immunization strategy against S. pneumoniae.
View details for DOI 10.1128/IAI.74.4.2187-2195.2006
View details for Web of Science ID 000236477000022
View details for PubMedID 16552049
View details for PubMedCentralID PMC1418935
Abstract
Pneumolysin, the cholesterol-dependent cytolysin of Streptococcus pneumoniae, induces inflammatory and apoptotic events in mammalian cells. Toll-like receptor 4 (TLR4) confers resistance to pneumococcal infection via its interaction with pneumolysin, but the underlying mechanisms remain to be identified. In the present study, we found that pneumolysin-induced apoptosis is also mediated by TLR4 and confers protection against invasive disease. The interaction between TLR4 and pneumolysin is direct and specific; ligand-binding studies demonstrated that pneumolysin binds to TLR4 but not to TLR2. Involvement of TLR4 in pneumolysin-induced apoptosis was demonstrated in several complementary experiments. First, macrophages from wild-type mice were significantly more prone to pneumolysin-induced apoptosis than cells from TLR4-defective mice. In gain-of-function experiments, we found that epithelial cells expressing TLR4 and stimulated with pneumolysin were more likely to undergo apoptosis than cells expressing TLR2. A specific TLR4 antagonist, B1287, reduced pneumolysin-mediated apoptosis in wild-type cells. This apoptotic response was also partially caspase dependent as preincubation of cells with the pan-caspase inhibitor zVAD-fmk reduced pneumolysin-induced apoptosis. Finally, in a mouse model of pneumococcal infection, pneumolysin-producing pneumococci elicited significantly more upper respiratory tract cell apoptosis in wild-type mice than in TLR4-defective mice, and blocking apoptosis by administration of zVAD-fmk to wild-type mice resulted in a significant increase in mortality following nasopharyngeal pneumococcal exposure. Overall, our results strongly suggest that protection against pneumococcal disease is dependent on the TLR4-mediated enhancement of pneumolysin-induced apoptosis.
View details for DOI 10.1128/IAI.73.10.6479-6487.2005
View details for Web of Science ID 000232087600030
View details for PubMedID 16177320
View details for PubMedCentralID PMC1230904
