Treatment Approaches to Mycobacterium abscessus Pulmonary Disease.

Mycobacterium abscessus pulmonary disease is highly antibiotic-resistant, and the current armamentarium of antibiotics yields poor treatment outcomes with significant drug toxicity. Macrolide susceptibility is a key prognostic factor. Optimal drug combinations, duration of therapy, and management of refractory disease are unknown. Surgical resection, performed at centers with experience in surgical management of nontuberculous mycobacterial pulmonary disease, may produce favorable outcomes in select patients. Multiple emerging therapeutic candidates hold promise for more efficacious and tolerable treatment options.

Characterizing and correcting immune dysfunction in non-tuberculous mycobacterial disease.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic, progressive, and growing worldwide health burden associated with mounting morbidity, mortality, and economic costs. Improvements in NTM-PD management are urgently needed, which requires a better understanding of fundamental immunopathology. Here, we examine temporal dynamics of the immune compartment during NTM-PD caused by Mycobacterium avium complex (MAC) and Mycobactereoides abscessus complex (MABS). We show that active MAC infection is characterized by elevated T cell immunoglobulin and mucin-domain containing-3 expression across multiple T cell subsets. In contrast, active MABS infection was characterized by increased expression of cytotoxic T-lymphocyte-associated protein 4. Patients who failed therapy closely mirrored the healthy individual immune phenotype, with circulating immune network appearing to 'ignore' infection in the lung. Interestingly, immune biosignatures were identified that could inform disease stage and infecting species with high accuracy. Additionally, programmed cell death protein 1 blockade rescued antigen-specific IFN-γ secretion in all disease stages except persistent infection, suggesting the potential to redeploy checkpoint blockade inhibitors for NTM-PD. Collectively, our results provide new insight into species-specific 'immune chatter' occurring during NTM-PD and provide new targets, processes and pathways for diagnostics, prognostics, and treatments needed for this emerging and difficult to treat disease.

CD161 expression defines new human γδ T cell subsets.

γδ T cells are a highly versatile immune lineage involved in host defense and homeostasis, but questions remain around their heterogeneity, precise function and role during health and disease. We used multi-parametric flow cytometry, dimensionality reduction, unsupervised clustering, and self-organizing maps (SOM) to identify novel γδ T cell naïve/memory subsets chiefly defined by CD161 expression levels, a surface membrane receptor that can be activating or suppressive. We used middle-to-old age individuals given immune blockade is commonly used in this population. Whilst most Vδ1+subset cells exhibited a terminal differentiation phenotype, Vδ1- subset cells showed an early memory phenotype. Dimensionality reduction revealed eight γδ T cell clusters chiefly diverging through CD161 expression with CD4 and CD8 expression limited to specific subpopulations. Comparison of matched healthy elderly individuals to bronchiectasis patients revealed elevated Vδ1+ terminally differentiated effector memory cells in patients potentially linking this population with chronic proinflammatory disease.

Value of Pretreatment 18F-fluorodeoxyglucose Positron Emission Tomography in Patients With Localized Pancreatic Cancer Treated With Neoadjuvant Therapy.

Background: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy. Methods: Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUVdx) and 3.5 after neoadjuvant therapy (preoperative; SUVpreop). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal ( ≤ 35 U/mL) or elevated. Results: Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUVdx was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUVpreop was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUVdx and 22 months for the 98 patients with a high SUVdx (p = 0.03). Median OS for patients with low SUVdx/normal preop CA19-9, high SUVdx/normal preop CA19-9, low SUVdx/elevated preop CA19-9, and high SUVdx/elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively (p < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery (p < 0.001). Conclusion: Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC.

Management of Extrapulmonary Nontuberculous Mycobacterial Infections.

Extrapulmonary disease occurs in a minority of nontuberculous mycobacterial (NTM) infections. The pattern of disease tends to be multifocal in immunocompromised individuals and localized in the immunocompetent. There is increasing recognition of disseminated Mycobacterium chimaera infection, as a complication of cardiac surgery, and focal infections due to rapidly growing mycobacteria. Microbiologic diagnosis requires detection of NTM in blood or tissue samples by microscopy, culture, or molecular methods. Management of extrapulmonary NTM infection requires prolonged, targeted multiple-drug therapy and, in some cases, aggressive surgical intervention. The optimal treatment approach is often unknown. Despite combined medical and surgical therapy, outcomes may be poor. A high degree of clinical suspicion and early diagnosis are required to maximize chances of a positive outcome.

Radiology of Chronic Cavitary Infections.

Chronic cavitary lung disease is an uncommon manifestation of pulmonary infection, and is a pattern which worldwide is most commonly caused by reactivation tuberculosis. Other organisms, however, can cause similar radiologic patterns. Endemic fungi have long been recognized as potential causes of this pattern in North and South America, but the frequency with which these diseases present with chronic cavities in North America is relatively small. Nontuberculous mycobacteria and chronic aspergillus infections are recognized with increasing frequency as causes of this pattern. Melioidosis, a bacterial infection that can also cause chronic lung cavities, was previously understood to be relevant primarily in Southeast Asia, but is now understood to have a wider geographic range. While cultures, serologies, and other laboratory methods are key to identifying the infectious causes of chronic lung cavities, radiologic evaluation can contribute to the diagnosis. Differentiating the radiologic patterns of these diseases from reactivation tuberculosis depends on subtle differences in imaging findings and, in some cases, appreciation of underlying lung disease.

Chronic Cavitary Infections Other than Tuberculosis: Clinical Aspects.

Lung cavitation may be due to infectious or noninfectious pathologic processes. The latter category includes nonmalignant conditions, such as granulomatosis with polyangiitis, and malignant conditions, such as squamous cell carcinoma of the lung. Infectious etiologies that produce lung cavitation usually cause chronic illness, although some, particularly pyogenic bacteria, may produce acute cavitary disease. Tuberculosis is the most common cause of chronic pulmonary infection with cavitation. The goal of this review was to highlight a selection of the better-known infectious agents, other than tuberculosis, that can cause chronic lung disease with cavitation. Emphasis is placed on the following organisms: nontuberculous mycobacteria, Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, Aspergillus, Burkholderia pseudomallei, Paragonimus westermani, and Rhodococcus equi. These organisms generally produce clinical features and radiologic findings that overlap or mimic those of tuberculosis. In a companion article, we have further emphasized aspects of the same conditions that are more pertinent to radiologists.

Gender and race as correlates of high risk sex behaviors among injection drug users at risk for HIV enrolled in the HPTN 037 study.

BACKGROUND: Sexual contact has been shown to be a major mode of HIV transmission among people who inject drugs (PWID). This study examined gender and racial differences among PWID' sexual risk behaviors from the perspective of sexual scripts. METHODS: 696 PWID enrolled from Philadelphia on HPTN 037 were classified as engaging in high-risk sex behaviors if they reported having sex in the past 30 days and condomless sex with a non-primary partner, giving/receiving sex for money, or multiple partners. A multivariable logistic regression model was used to assess associations between demographic factors and high risk sex. RESULTS: Findings of the multivariable regression analysis demonstrated that being White (OR = 0.52, p < 0.001) and male (OR = 0.59, p = 0.002) were protective of high risk sex, while homelessness (OR = 1.7, p = 0.005), and being single (OR = 1.83, p = 0.006) were positively associated with high risk sex. African American (AA) women were 1.7 times more likely to report high-risk sex than AA men (p = 0.002), 3.28 times more likely than White men (p < 0.001), and 1.93 times more likely than White women (p < 0.001). CONCLUSIONS: Since AA women report high-risk sex behaviors more than other demographic groups, behavioral interventions for HIV risk reduction among PWID may benefit from focusing on sex-risk reduction among AA women.

TCR Signaling and CD28/CTLA-4 Signaling Cooperatively Modulate T Regulatory Cell Homeostasis.

Foxp3+ T regulatory cells (Tregs), conventional CD4+Foxp3- T cells, and CD8+ T cells represent heterogeneous populations composed of naive phenotype (NP, CD44low) and memory phenotype (MP, CD44high) subpopulations. NP and MP subsets differ in their activation state, contribution to immune function, and capacity to proliferate in vivo. To further understand the factors that contribute to the differential homeostasis of NP/MP subsets, we examined the differential effects of CD28 and CTLA-4 interaction with CD80/CD86, as well as MHC class II-TCR interaction within mouse Treg pools and CD4+ and CD8+ T cell pools. Blockade of CD80/CD86 with CTLA-4-Ig markedly reduced the cycling and absolute numbers of MP Tregs and MP CD4+ T cells, with minimal effect on the NP T cell subpopulations. Blockade of MHC class II-TCR interaction led to selective expansion of MP Tregs and MP CD4+ and CD8+ T cells that was reversed upon cotreatment with CTLA-4-Ig. Treatment with anti-CTLA-4 mAb altered MP Treg and MP CD4+ and CD8+ T cell homeostasis in a manner similar to that observed with anti-MHC class II. We postulate a complex pathway in which CD28 is the primary driver of Treg proliferation and CTLA-4 functions as the main brake but is likely dependent on TCR signals and CD80/CD86. These findings have important implications for the use of biologic agents targeting such pathways to modulate autoimmune and neoplastic disease.

A Retrospective Study of Survivors of Endovascular Coiling for Posterior and Anterior Aneurysms: Medical and Patient Perspectives.

This article documents the longer-term medical and psychosocial outcomes of patients referred for endovascular coiling.There is limited research investigating outcome following endovascular coiling for posterior compared to anterior circulation aneurysms, and minimal understanding of how medical outcomes relate to patient experiences of treatment and quality of life.We studied a consecutive cohort of 80 patients referred Australia wide for endovascular coiling between 1995 and 2003 (49% posterior; 76% ruptured; 69% women, mean age 51.5 years). We used a mixed methods approach, assessing medical outcome with the Modified Rankin Scale (MRS) in 61 patients (76%), and health-related quality of life and psychosocial functioning using the EuroQol questionnaire and a qualitative semistructured interview in 49 patients (61%).Despite the high proportion of posterior aneurysms, the majority of patients (80%) showed good medical outcomes as indicated by regained independence of activities of daily living (MRS score ≤3). Patients with unruptured aneurysms were significantly more likely to show good outcomes (P < 0.04), whereas aneurysm location (posterior, anterior, or mixed) showed no significant effect. In patients with good medical outcomes, greater functional disability was associated with neurological complications surrounding treatment (P < 0.05). Good outcomes correlated with higher EuroQol ratings (P < 0.001) and the experience of less change after treatment (P < 0.001), although psychosocial adjustment issues were reported by most of the patients, including those with no medical symptoms.These results support the long-term efficacy of endovascular coiling, particularly for posterior circulation aneurysms. They have implications for guiding clinicians and patients in their choice of treatment, as well as the provision of psychological counseling for patient adjustment issues posttreatment.

Effect of flow diversion with silk on aneurysm size: A single center experience.

Alterations in aneurysm size and mass effect can result in alleviation or aggravation of symptoms. We assessed the effects of flow diversion with SILK stents on aneurysm sac size and associated factors. A retrospective evaluation of 14 aneurysms treated with SILK stents alone with MRI follow-up was performed. Aneurysm sac size was measured using the sequence best demonstrating the sac. Aneurysm characteristics and flow-related enhancement on time of flight images were documented. Clinical histories were reviewed for evolution of symptoms. Complete collapse of the aneurysm sac was demonstrated at three and 18 months in 2/14 aneurysms. Increase in size was observed in 2/14 aneurysms with associated persistent flow on time of flight MRA. Blister formation with aggravation of symptoms was observed in one aneurysm, and subsequent decrease in size occurred after treatment with a second SILK. The other aneurysm which increased in size initially continued to enlarge asymptomatically despite retreatment with a second SILK, however at 24 months thrombosis of the sac and decrease in size was observed. The remaining 10/14 aneurysms decreased in size. Nine had corresponding MRA occlusion and the tenth demonstrated decreased but persistent flow on the time of flight MRA. No aneurysm with MRA occlusion increased in size. Decrease in sac size was associated with MRA occlusion in our study. Persistence of flow and blistering were associated with increased sac size. As previously demonstrated flow diversion may be effective in the treatment of large aneurysms presenting with mass effect, however rates of sac obliteration in this small series were not as high as previously reported.

Delayed pan-hypopituitarism as a complication following endovascular treatment of bilateral internal carotid artery aneurysms. A case report and review.

Pan-hypopituitarism has been reported in patients who are subsequently found to have a cerebral aneurysm and there have been reports of pituitary dysfunction immediately following both surgical and endovascular treatment. The authors report a rare case of delayed pan-hypopituitarism following endovascular treatment of bilateral internal carotid artery aneurysms with coil embolisation and flow-diverting stents.

Long-term MRI findings of muslin-induced foreign body granulomas after aneurysm wrapping. A report of two cases and literature review.

Muslin-induced foreign body granulomas are rare delayed complications after wrapping of intracranial aneurysms. Few small case series have been reported, with a paucity of documented MRI findings. In addition, there are no reports on long-term radiological appearances or temporal evolution of conservatively managed patients. We thus report on the long-term radiological and clinical follow-up of two patients with asymptomatic muslin-induced foreign body granulomas after wrapping of recurrent middle cerebral arterial aneurysms. Both patients were successfully managed conservatively and remain asymptomatic three and six years after diagnosis of their granulomas. A literature review confirms that MRI features of muslin-induced foreign body granuloma are typical. Features include focal areas of elevated T2 signal with increased diffusion-weighted signal and thin rim enhancement. To the best of our knowledge, this is the first report to confirm that there is a corresponding reduction in apparent diffusion coefficient, as typical in an intracranial abscess. Thus a history of aneurysm wrapping is critical for diagnosis. Accurate clinical recognition of this exuberant inflammatory response will avoid misdiagnosis as pyogenic abscess or tumor and prevent unnecessary or invasive treatment.

A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA).

BACKGROUND AND HYPOTHESIS: Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4·5 h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with 'dual target' vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging 'mismatch' within 4·5 h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. STUDY DESIGN: EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0·9 mg/kg intravenous tissue plasminogen activator within 4·5 h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion : ischemic core mismatch ratio >1·2, absolute mismatch >10 ml, ischemic core volume <70 ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. STUDY OUTCOMES: The coprimary outcome measure will be reperfusion at 24 h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0-1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage.

Endogenous mouse mammary tumor viruses (mtv): new roles for an old virus in cancer, infection, and immunity.

Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV) and endogenous (Mtv) forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted. Historically, Mtv have been appreciated for their role in shaping the T cell repertoire during thymic development via negative selection. In addition, more recent work has demonstrated a larger role for Mtv in modulating host immune responses due to its peripheral expression. The influence of Mtv on host response has been observed during experimental murine models of Polyomavirus- and ESb-induced lymphoma as well as Leishmania major and Plasmodium berghei ANKA infection. Decreased susceptibility to bacterial pathogens and virus-induced tumors has been observed among mice lacking all Mtv. We have also demonstrated a role for Mtv Sag in the expansion of regulatory T cells following chronic viral infection. The aim of this review is to summarize the latest research in the field regarding peripheral expression of Mtv with a particular focus on their role and influence on the immune system, infectious disease outcome, and potential involvement in tumor formation.

Role of hepatic resident and infiltrating macrophages in liver repair after acute injury.

Treatment of liver disease, caused by hepatotoxins, viral infections, alcohol ingestion, or autoimmune conditions, remains challenging and costly. The liver has a powerful capacity to repair and regenerate, thus a thorough understanding of this tightly orchestrated process will undoubtedly improve clinical means of restoring liver function after injury. Using a murine model of acute liver injury caused by overdose of acetaminophen (APAP), our studies demonstrated that the combined absence of liver resident macrophages (Kupffer cells, KCs), and infiltrating macrophages (IMs) resulted in a marked delay in liver repair, even though the initiation and extent of peak liver injury was not impacted. This delay was not due to impaired hepatocyte proliferation but rather prolonged vascular leakage, which is caused by APAP-induced liver sinusoidal endothelial cell (LSEC) injury. We also found that KCs and IMs express an array of angiogenic factors and induce LSEC proliferation and migration. Our mechanistic studies suggest that hypoxia-inducible factor (HIF) may be involved in regulating the angiogenic effect of hepatic macrophages (Macs), as we found that APAP challenge resulted in hypoxia and stabilization of HIF in the liver and hepatic Macs. Together, these data indicate an important role for hepatic Macs in liver blood vessel repair, thereby contributing to tissue recovery from acute injury.